Diabetes type 2 Landmark Outcomes Trials

Diabetes type 2 Landmark Outcomes Trials
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United Kingdom Prospective Diabetes Study
UKPDS United Kingdom Prospective Diabetes Study BACKGROUND The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised, prospective, 20-year, interventional trial ( ) that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes were recruited between 1977 and 1991 and were followed up for a median of 10.0 years. REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 2

UKPDS Objective and Study Design UKPDS
Investigated the advantages of intensive glucose control with metformin1 20-year prospective interventional trial from 1977 to 19971 Intensive treatment with sulfonylurea or insulin Intensive treatment with metformin Conventional treatment with diet 5102 patients with newly diagnosed type 2 diabetes recruited between 1977 and 19911 Median follow-up: 10 years, range: 6-20 years2 Results presented at the 1998 EASD meeting in Barcelona2 UKPDS 10-year posttrial monitoring from 1997 to 20072 Annual follow-up of survivor cohort (n=3227) Clinic-based for first 5 years Questionnaire-based for last 5 years Median overall follow-up: 17 years, range: years2 BACKGROUND The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised, prospective, 20-year, interventional trial ( ) that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes were recruited between 1977 and 1991 and were followed up for a median of 10.0 years.1 All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored2: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCES UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131): Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): UKPDS=United Kingdom Prospective Diabetes Study. 1. UKPDS Group. Lancet 1998;352(9131): 2. Holman et al. N Engl J Med 2008;359(15): 3

UKPDS Posttrial Monitoring
Conventional (n=880) Sulfonylurea/insulin (n=2118) Metformin (n=279) 1997 Survivor cohort 2002 Clinic Questionnaire 2007 Posttrial monitoring Conventional (n=379) Sulfonylurea/insulin (n=1010) Metformin (n=136) Mortality 44% Lost to follow-up 3.5% Mean age 628 years BACKGROUND The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised, prospective, 20-year, interventional trial ( ) that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes were recruited between 1977 and 1991 and were followed up for a median of 10.0 years. All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): UKPDS=United Kingdom Prospective Diabetes Study. Holman et al. N Engl J Med 2008;359(15): 4

Sulfonylurea/Insulin vs Conventional
Posttrial Changes in HbA1c Sulfonylurea/Insulin vs Conventional 10 Sulfonylurea/insulin Conventional 9 HbA1c (%) 8 KEY POINT At the beginning of the posttrial monitoring period, patients who had been originally randomised to intensive therapy with a sulfonylurea and insulin had a significantly lower HbA1c than patients who received conventional therapy; however, this difference was lost by year one, with similar improvements observed in these two groups until 2002. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 7 p=.008 p=.14 p=.82 p=.84 p=.99 p=.71 1997 1998 1999 2000 2001 2002 Vertical bars represent 95% CI. Holman et al. N Engl J Med 2008;359(15): 5

Metformin vs Conventional
Posttrial Changes in HbA1c Metformin vs Conventional 10 Metformin ‡ Conventional † * 9 ║ HbA1c (%) 8 KEY POINTS The vertical bars represent 95% confidence intervals. Baseline differences in mean HbA1c levels between metformin (intensive therapy) and the conventional therapy group were lost by 1 year, with similar HbA1c improvements thereafter in both groups. Note that the difference in HbA1c levels between the metformin group and the conventional therapy group was smaller than the difference between the sulfonylurea/insulin group and the conventional therapy group (refer to reference or sulfonylurea/insulin group and the conventional therapy group slide). BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 7 p=.59 p=.99 p=.18 p=.89 p=.37 p=.86 1997 1998 1999 2000 2001 2002 Vertical bars represent 95% CI. Holman et al. N Engl J Med 2008;359(15): 6

Intensive (Sulfonylurea/Insulin) vs Conventional Glucose Control
Microvascular Disease* Hazard Ratio Intensive (Sulfonylurea/Insulin) vs Conventional Glucose Control 1.4 Microvascular disease Sulfonylurea/insulin Conventional 1.2 *p=.01 1.0 †p=.001 * † Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for sulfonylurea/insulin therapy; the vertical bars represent 95% confidence intervals. The significant reduction in relative risk of microvascular disease that was observed in the sulfonylurea/insulin group vs conventional therapy group was maintained over the 10-year posttrial monitoring period. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 Number of events Con: Int: 121 225 155 277 187 338 205 378 212 406 222 429 1997 1999 2001 2003 2005 2007 *Photocoagulation, vitreous haemorrhage, renal failure; Vertical bars represent 95% CI ;Con=conventional therapy; Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 7

Intensive (Metformin) vs Conventional Glucose Control
Microvascular Disease* Hazard Ratio Intensive (Metformin) vs Conventional Glucose Control 1.4 Microvascular disease Metformin * Conventional † 1.2 *p=.19 †p=.30 1.0 Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for metformin therapy; the vertical bars represent 95% confidence intervals. After 10 years post-trial, a statistically significant risk reduction in myocardial infarction emerged. Among patients in the metformin group, as compared with overweight patients in the conventional therapy group, no significant reductions were observed during or after the trial for microvascular disease. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 Number of events Con: Int: 38 24 58 37 70 44 73 52 74 58 78 66 1997 1999 2001 2003 2005 2007 *Photocoagulation, vitreous haemorrhage, renal failure; Vertical bars represent 95% CI ;Con=conventional therapy; Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 8

Myocardial Infarction* Hazard Ratio Intensive (Sulfonylurea/Insulin) vs Conventional Glucose Control 1.4 Myocardial infarction Sulfonylurea/insulin Conventional 1.2 *p=.052 * † 1.0 †p=.01 Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for sulfonylurea/insulin therapy; the vertical bars represent 95% confidence intervals. After 10 years posttrial, a statistically significant risk reduction in myocardial infarction emerged. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 Number of events Con: Int: 186 387 212 450 239 513 271 573 296 636 319 678 1997 1999 2001 2003 2005 2007 Fatal or nonfatal myocardial infarction or sudden death ; Vertical bars represent 95% CI ;Con=conventional therapy; Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 9

Death from Any Cause Hazard Ratio Intensive (Sulfonylurea/Insulin) vs Conventional Glucose Control 1.4 Death from any cause Sulfonylurea/insulin Conventional 1.2 * *p=.44 †p=.006 † 1.0 Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for sulfonylurea/insulin therapy; the vertical bars represent 95% confidence intervals. In the posttrial period, death from any cause was reduced in the sulfonylurea/insulin vs conventional therapy group. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 Number of events Con: Int: 213 489 267 610 330 737 400 868 460 1028 537 1163 1997 1999 2001 2003 2005 2007 Vertical bars represent 95% CI; Con=conventional therapy. Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 10

Myocardial Infarction* Hazard Ratio Intensive (Metformin) vs Conventional Glucose Control 1.4 Myocardial infarction Metformin Conventional 1.2 *p=.01 1.0 †p=.005 * † Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for metformin therapy; the vertical bars represent 95% confidence intervals. In the posttrial period, myocardial infarction was reduced in the intensive (metformin) vs conventional therapy group. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 Number of events Con: Int: 73 39 83 45 92 55 106 64 118 68 126 81 1997 1999 2001 2003 2005 2007 Fatal or nonfatal myocardial infarction or sudden death ; Vertical bars represent 95% CI ;Con=conventional therapy; Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 11

Death from Any Cause Hazard Ratio Intensive (Metformin) vs Conventional Glucose Control 1.4 Number of events Death from any cause Con: Int: 89 50 113 70 136 86 160 110 183 123 217 152 * † Metformin Conventional 1.2 *p=.01 1.0 †p=.002 Hazard Ratio 0.8 0.6 KEY POINT The overall values at the end of the study in 1997 are shown in red; hazard ratios below 1 indicate a favourable outcome for metformin therapy; the vertical bars represent 95% confidence intervals. In the posttrial period, death from any cause was reduced in the metformin vs conventional therapy group. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 0.4 1997 1999 2001 2003 2005 2007 Vertical bars represent 95% CI; Con=conventional therapy. Int=intensive therapy. Holman et al. N Engl J Med 2008;359(15): 12

After Median 8.5 Years of Posttrial Follow-Up
Legacy Effect of Earlier Glucose Control: Sulfonylurea and Insulin Therapy After Median 8.5 Years of Posttrial Follow-Up Aggregate Endpoint 19971 20072 Any diabetes-related endpoint RRR: P: 12% .029 9% .04 Microvascular disease RRR: P: 25% .0099 24% .001 Myocardial infarction 16% .052 15% .01 All-cause mortality 6% .44 13% .007 KEY POINT In the sulfonylurea/insulin group as compared with the conventional therapy group, significant reductions in relative risk that had been observed during the interventional trial for any diabetes-related endpoint and microvascular disease were maintained. Benefits persisted despite the early loss of within-trial differences in HbA1c levels between the intensive therapy group and the conventional therapy group—a so-called legacy effect. The pathophysiological mechanisms responsible for such a legacy effect of intensive glycaemic control are unclear. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCES Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258): Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): RRR=relative risk reduction. P=log rank. 1. Stratton et al. BMJ 2000;321(7258): 2. Holman et al. N Engl J Med 2008;359(15): 13

Legacy Effect of Earlier Glucose Control: Metformin Therapy
After Median 8.8 Years of Posttrial Follow-Up Aggregate Endpoint 19971 20072 Any diabetes-related endpoint RRR: P: 32% .002 21% .01 Microvascular disease RRR: P: ― 16% .31 Myocardial infarction 39% .010 33% .005 All-cause mortality 36% .011 27% KEY POINT In the metformin group as compared with the conventional therapy group, significant reductions in relative risk that had been observed during the interventional trial for any diabetes-related endpoint and microvascular disease were maintained. Benefits persisted despite the early loss of within-trial differences in HbA1c levels between the intensive therapy group and the conventional therapy group—a so-called legacy effect. The pathophysiological mechanisms responsible for such a legacy effect of intensive glycaemic control are unclear. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCES UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. UK Prospective Diabetes Study (UKPDS 34) Group. Lancet ;352(9131): Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): RRR=relative risk reduction. P=log rank. 1. UKPDS Group. Lancet 1998;352(9131): 2. Holman et al. N Engl J Med 2008;359(15): 14

UKPDS Conclusions1-3 Observations from these studies indicate intensive glucose control starting at the time of diagnosis is associated with a significantly decreased risk of myocardial infarction and death from any cause These data are in addition to the well-established risk reduction of microvascular disease Glucose lowering is essential in reducing risk of coronary events and death from any cause These findings strengthen the rationale for attaining optimal glycaemic levels and indicate emergent long-term benefits on cardiovascular risk Despite an early loss of glycaemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of posttrial follow-up A continued benefit after metformin therapy was evident among overweight patients KEY POINT In the metformin group as compared with the conventional therapy group, significant reductions in relative risk that had been observed during the interventional trial for any diabetes-related endpoint and microvascular disease were maintained. Benefits persisted despite the early loss of within-trial differences in HbA1c levels between the intensive therapy group and the conventional therapy group—a so-called legacy effect. The pathophysiological mechanisms responsible for such a legacy effect of intensive glycaemic control are unclear. BACKGROUND The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised, prospective, 20-year, interventional trial ( ) that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes were recruited between 1977 and 1991 and were followed up for a median of 10.0 years.1 All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital-based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored2,3: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCES UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. UK Prospective Diabetes Study (UKPDS 34) Group. Lancet ;352(9131): Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258): 3. Stratton et al. BMJ 2000;321(7258): UKPDS=United Kingdom Prospective Diabetes Study. 1. UKPDS Group. Lancet 1998;352(9131): 2. Holman et al. N Engl J Med 2008;359(15): 15

DCCT/EDIC Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications KEY POINT In the metformin group as compared with the conventional therapy group, significant reductions in relative risk that had been observed during the interventional trial for any diabetes-related endpoint and microvascular disease were maintained. Benefits persisted despite the early loss of within-trial differences in HbA1c levels between the intensive therapy group and the conventional therapy group—a so-called legacy effect. The pathophysiological mechanisms responsible for such a legacy effect of intensive glycaemic control are unclear. BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.1,3 REFERENCES The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): 16

DCCT/EDIC Objectives and Study Design
Compared intensive and conventional diabetes therapy and their effects on the development and progression of early vascular and neurologic complications of insulin-dependent diabetes mellitus (IDDM)1 10-year prospective interventional trial from 1983 to 1993; patients divided into two cohorts (N=1441) No retinopathy at baseline Mild retinopathy at baseline Cohorts randomised to: Intensive insulin therapy: given via an external insulin pump or by ≥3 daily insulin injections/day guided by frequent glucose monitoring Conventional therapy: one or two insulin injections/day Mean follow-up: 6.5 years DCCT/EDIC2 (1994 to 1998) Designed to assess if risk of microvascular complications persists for 4 years after the DCCT2 Enrolled both cohorts who completed DCCT (N=1375) and randomised to: Intensive insulin therapy or conventional insulin therapy as described in DCCT Care of all patients transferred to their own physicians KEY POINT In the metformin group as compared with the conventional therapy group, significant reductions in relative risk that had been observed during the interventional trial for any diabetes-related endpoint and microvascular disease were maintained. Benefits persisted despite the early loss of within-trial differences in HbA1c levels between the intensive therapy group and the conventional therapy group—a so-called legacy effect. The pathophysiological mechanisms responsible for such a legacy effect of intensive glycaemic control are unclear. BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.1,3 REFERENCES The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. 1. DCCT Research Group. N Engl J Med 1993;329(14): 2. DCCT/EDIC Research Group. N Engl J Med 2000;342(6): 17

DCCT/EDIC Study Design
1993 Completers of DCCT who enrolled in EDIC (N=1375) Conventional insulin therapy cohort (n=688) Intensive insulin therapy cohort (n=687) 1994 Initiation of EDIC follow-up study Randomisation KEY POINT All surviving patients in the Diabetes Control and Complications Trial (DCCT) were evaluated at the close of the trial, between January and April In 1994, 1375 of the patients in the original cohort, including 688 patients in the former conventional therapy group and 687 patients in the former intensive therapy group, volunteered to participate in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which included annual follow-up examinations. During the EDIC study, all therapy was provided by the patients’ own physicians. BACKGROUND All of the surviving patients from the UKPDS (n=3277) entered the 10-year posttrial monitoring programme after the intervention trial closed on 30 September, Patients returned to their community or hospital- based diabetes care with no attempt to maintain previously randomised therapies. Patients were seen annually from in UKPDS clinics with standardised collection of outcome data (blood pressure, fasting glucose, HbA1c, creatinine, albumin:creatinine ratio, and results of the European Quality of Life-5 Dimensions and a health resources questionnaire) and from , questionnaires were sent to physicians and patients. Seven prespecified clinical outcomes were monitored: Any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) Diabetes-related death (sudden death or death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia, or hypoglycaemia) Death from any cause Myocardial infarction (sudden death or fatal or nonfatal myocardial infarction) Stroke (fatal or nonfatal stroke) Peripheral vascular disease (amputation of at least one digit or death from peripheral vascular disease) Microvascular disease (vitreous haemorrhage, retinal photocoagulation, or renal failure) REFERENCE The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): Conventional insulin therapy cohort Intensive insulin therapy cohort Primary outcome of EDIC: to assess if the reduced risk of microvascular complications associated with intensive insulin therapy persists for 4 years after the end of the DCCT 1998 EDIC completers n=603 n=605 DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. DCCT/EDIC Research Group. N Engl J Med 2000;342(6): 18

HbA1c Following DCCT/EDIC
Distribution of HbA1c Values: Intensive vs Conventional Therapy 11 Conventional therapy Intensive therapy 10 9 + + HbA1c (%) + + + 8 + + + + + + + 7 KEY POINT This is the distribution of HbA1c values in the conventional therapy and intensive therapy groups at the end of DCCT, in each of the four years of the EDIC study, and averaged over the four years of the EDIC study. Data are for the 1208 patients who had an eye evaluation in year 4 of the EDIC study.1 The boxes represent the second and third quartiles of the distribution, the centre lines represent the medians, and the plus signs represent the means. BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.1,3 REFERENCES The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): 6 p.001 p.001 p.001 p=.005 p=.07 p.001 1 2 3 4 Years 1-4 (Average) End of DCCT EDIC Year DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. DCCT/EDIC Research Group. N Engl J Med 2000;342(6): 19

Progression of Diabetic Retinopathy Following DCCT/EDIC
Cumulative Incidence of Further Progression of Retinopathy: Intensive vs Conventional Therapy 24 22 Conventional therapy Intensive therapy 20 18 16 14 Cumulative Incidence (%) 12 10 8 KEY POINT This analysis included assessments of the level of retinopathy in approximately 25% of the cohort at years 1, 2, and 3 and indicates that the difference in cumulative incidence of progressive retinopathy between groups steadily increased each year. By the fourth year, the intensive therapy group was significantly (70%) lower than that in the conventional therapy group (95% confidence interval, 58%-78%; P.001).1 BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.1,3 These data are based on regression analysis adjusted for the level of retinopathy at the end of DCCT, whether patients received therapy as primary prevention or secondary intervention, and both the duration of diabetes and the HbA1c value on enrollment in DCCT. Patients who underwent scatter photocoagulation during DCCT were excluded from the analysis (22 in the conventional therapy group and nine in the intensive therapy group). Bars denote 95% confidence intervals.1 REFERENCES The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): 6 4 2 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 EDIC Year DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. DCCT/EDIC Research Group. N Engl J Med 2000;342(6): 20

Glycaemia and Cardiovascular Disease Evidence from DCCT/EDIC
Cumulative Incidence of the First of Any Predefined Cardiovascular Disease Outcome .12 Conventional treatment Intensive treatment .10 .08 Cumulative Incidence of Any Predefined Cardiovascular Outcome .06 .04 .02 KEY POINT Intensive treatment reduced the risk of any predefined cardiovascular disease outcome by 42% as compared with conventional treatment (95% confidence interval, 9%-63%; P=.02).1 BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.2,3 REFERENCES The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): .00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years since Entry Number at Risk Intensive treatment 705 683 629 113 Conventional treatment 714 688 618 92 DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. Nathan et al. N Engl J Med 2005;353(25): 21

Average Risk Reduction
Impact of Glycaemic Control on Diabetic Microvascular Complications Average Risk Reduction Study (Disease Type) HbA1c (Conventional vs Intensive) Diabetic Retinopathy Diabetic Nephropathy Diabetic Neuropathy DCCT1 (Type 1 diabetes) 9% vs 7% 76% 54% 60% Ohkubo2 (Type 2 diabetes) 69% 70% ↑NCV* UKPDS3 8% vs 7% 21% 34% NS KEY POINT Improvement of glycaemic control reduced microvascular complications independent of the type of diabetes and hypoglycaemic agent used. It should be noted that the impact of intensive control was similar across all diabetic microvascular complications, including diabetic retinopathy, suggesting a common underlying pathogenic mechanism. BACKGROUND The Diabetes Control and Complications Trial (DCCT)1 Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from 1983 through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial. The Ohkubo study2 examined whether intensive glycaemic control could decrease the frequency or severity of diabetic microvascular complications in Japanese patients with type 2 diabetes. A total of 110 patients were randomly assigned to multiple insulin injection treatment or conventional insulin injection treatment. The United Kingdom Prospective Diabetes Study (UKPDS)3 was a randomised interventional trial that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes (median age 53), who after 3 months of diet treatment had a mean fasting plasma glucose concentration of 6.1 to 15.0 mmol/L, were recruited. REFERENCES Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomised prospective 6-year study. Diabetes Res Clin Pract. 1995;28(2): UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131): *Nerve conduction velocity (NCV) measured at entry and after 6 years of intensive insulin therapy. Increase in measure indicates improved nerve signalling/function. DCCT=Diabetes Control and Complications Trial; NS=nonsignificant; UKPDS=United Kingdom Prospective Diabetes Study. 3. UKPDS Group. Lancet 1998;352(9131): 1. DCCT Research Group. N Engl J Med 1993;329(14): 2. Ohkubo et al. Diabetes Res Clin Pract 1995;28(2): 22

DCCT/EDIC Conclusions
In patients with type 1 diabetes: Intensive insulin therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, neuropathy, and diabetic microvascular disease1-3 The risk reduction of these diabetes complications resulting from intensive insulin therapy persists for at least 4 years despite increasing hyperglycaemia1-3 Intensive insulin therapy has long-term beneficial effects on the risk of cardiovascular disease3 DCCT/EDIC data are consistent with the findings of other long-term intensive insulin therapy studies4,5 KEY POINT In patients with type 1 diabetes intensive insulin therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, neuropathy, and diabetic microvascular disease.1-3 The risk reduction of these diabetes complications resulting from intensive insulin therapy persists for at least 4 years despite increasing hyperglycaemia.1-3 Intensive insulin therapy has long-term beneficial effects on the risk of cardiovascular disease.3 DCCT/EDIC data are consistent with the findings of other long-term intensive insulin therapy studies.4,5 BACKGROUND The Diabetes Control and Complications Trial (DCCT) Research Group examined whether intensive treatment, with the goal of maintaining blood glucose concentrations close to the normal range, could decrease the frequency and severity of microvascular and neurologic complications patients with type 1 diabetes were recruited at 29 centres from through In June 1993, after an average follow-up of 6.5 years (range, 3-9 years), the independent data monitoring committee determined that the study results warranted terminating the trial.2 93% of the patients were subsequently followed until February 2005, during the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.1,3 The Kumamoto study examined whether intensive glycaemic control could decrease the frequency or severity of diabetic microvascular complications in Japanese patients with type 2 diabetes. A total of 110 patients were randomly assigned to multiple insulin injection treatment or conventional insulin injection treatment.4 The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised interventional trial that compared intensive glucose therapy (either sulfonylurea or insulin or, in overweight patients, metformin) to conventional dietary therapy in patients with type 2 diabetes patients with newly diagnosed type 2 diabetes (median age 53), who after 3 months of diet treatment had a mean fasting plasma glucose concentration of 6.1 to 15.0 mmol/L, were recruited.5 REFERENCES Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med ;329(14): The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med ;342(6): Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25): Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomised prospective 6-year study. Diabetes Res Clin Pract. 1995;28(2): UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet ;352(9131): DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications. 1. DCCT Research Group. N Engl J Med 1993;329(14): 2. DCCT/EDIC Research Group. N Engl J Med 2000;342(6): 3. Nathan et al. N Engl J Med 2005;353(25): 4. Ohkubo et al. Diabetes Res Clin Pract 1995;28(2): 5. UKPDS Group. Lancet 1998;352(9131): 23

The Treat-to-Target Trial
BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): 24

Treat-to-Target Objectives and Study Design
Assessed the abilities and associated hypoglycaemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA1c Open-label, parallel, 24-week study (N=756) 756 overweight men and women with type 2 diabetes and inadequate glycaemic control (HbA1c >7.5%) Allowed to continue their current diabetes medications (one or two oral agents) Bedtime glargine or NPH once daily added to oral regimen Insulin titrated to achieve a fasting glucose <5.5 mmol/L Outcome measures Fasting glucose HbA1c Incidence of nocturnal hypoglycaemia Percentage of patients reaching HbA1c ≤7% without nocturnal hypoglycaemia BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): Riddle et al. Diabetes Care 2003;26(11): 25

Comprised ITT population
Treat-to-Target Trial Study Design Completed study (n=334) Allocation Enrollment Withdrew from treatment with glargine (n=33) Treatment criteria: No nocturnal hypoglycaemia Target FPG ≤5.6 mmol/L (≤100 mg/dL) Started insulin dose 10 IU and titrated weekly NPH insulin (n=389) Glargine insulin (n=367) Withdrew from treatment with NPH (n=32) Completed study (n=357) Eligible patients N=756 Enrollment criteria: Insulin-naïve Age years Type 2 diabetes ≥2 years On stable dose(s) of 1-2 oral agents ≥3 months Comprised ITT population BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): FPG=fasting plasma glucose; ITT=intent to treat. Riddle et al. Diabetes Care 2003;26(11): 26

Addition of Insulin to Oral Therapy Lowers FPG in Type 2 Diabetes
FPG in the Treat-to-Target Trial 11.0 Glargine NPH FPG (mmol/L) 8.25 KEY POINT Fasting glucose levels gradually declined in both groups, with a plateau being reached by 12 weeks. Mean FPG at endpoint was 6.5 mmol/L (117 mg/dL) for glargine and 6.7 mmol/L (120 mg/dL) for NPH (P=NS; between-group differences: -0.2 mmol/L [-3.6 mg/dL]; 95% confidence interval, to 0.09). BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): 5.5 4 8 12 16 20 24 Weeks of Treatment FPG=fasting plasma glucose; NPH=Neutral Protamine Hagedorn. Riddle et al. Diabetes Care 2003;26(11): Reprinted with permission from the American Diabetes Association. 27

Addition of Insulin to Oral Therapy Lowers HbA1c in Type 2 Diabetes
HbA1c in the Treat-to-Target Trial 4 8 12 16 20 24 6.0 7.5 9.0 8.0 8.5 7.0 6.5 Weeks of Treatment Glargine NPH HbA1c (%) KEY POINT HbA1c declined predictably at a slower rate than FPG and stabilised after 18 weeks. Mean HbA1c at endpoint was 6.96% with glargine vs 6.97% with NPH (P=NS; between-treatment difference: %, 95% confidence interval, -0.13% to 0.08%). BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): Riddle et al. Diabetes Care 2003;26(11): Reprinted with permission from the American Diabetes Association. 28

Cumulative Number of Events Documented PG 4 mmol/L (72 mg/dL)
Cumulative Incidence of Hypoglycaemia 2500 Glargine NPH 2000 Cumulative Number of Events Documented PG 4 mmol/L (72 mg/dL) 1500 1000 KEY POINT Although glargine and NPH achieved similar FPG and HbA1c levels, fewer incidents of hypoglycaemia occurred with glargine than NPH. Presumably, this was due to less variability in FPG levels with glargine than NPH. BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): 500 24 48 72 96 120 144 168 Time (Days) PG=plasma glucose. Riddle et al. Diabetes Care 2003;26(11): Reprinted with permission from the American Diabetes Association. 29

Treat-to-Target Trial Conclusions
Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1c in a majority of overweight men and women with type 2 diabetes and inadequate glycaemic control (HbA1c >7.5%) Glargine causes significantly less nocturnal hypoglycaemia than NPH This may reduce a leading barrier to initiating insulin A simple insulin regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standard of diabetes care KEY POINT This trial showed that systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1c in a majority of overweight men and women with type 2 diabetes with HbA1c between 7.5 and 10.0% on oral agents alone. Due to this glargine causes significantly less nocturnal hypoglycaemia than NPH, and reduces a leading barrier to initiating insulin. This regimen can aid in effective insulin use and improve standard diabetes care. BACKGROUND This was a randomised, open-label, parallel, 24-week, multicentre (80) trial, which was performed between 7 January, 2000, and 22 October, overweight patients with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily. A simple algorithm targeting fasting plasma glucose (FPG) 5.5 mmol/L (100 mg/dL) was used. Outcome measures were FPG, HbA1c, hypoglycaemia, and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. REFERENCE Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): Riddle et al. Diabetes Care 2003;26(11): 30

Diabetes Prevention Program
DPP Diabetes Prevention Program BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): 31

DPP Objectives and Study Design
Designed to determine if lifestyle intervention and treatment with metformin prevents or delays the onset of diabetes Randomised trial conducted at 27 centres in the United States Persons at risk for developing type 2 diabetes (N=3234) were randomised to three treatment arms: Intensive lifestyle intervention programme Written recommendation for healthy diet and increased exercise and annual 20- to 30-minute individual sessions provided to this cohort Goal of lifestyle intervention: Achieve weight reduction of ≥7% of initial body weight through a healthy diet Engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes/week Metformin 850 mg twice daily Placebo Primary outcome Diabetes Diagnosed by annual oral glucose tolerance test or semiannual fasting glucose BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): DPP=Diabetes Prevention Program. Knowler WC et al. N Engl J Med 2002;346(6): 32

DPP Study Design 1996-1999 2001 Allocation Enrollment
Eligible patients (N=3234) Enrollment criteria: Age ≥25 years No history of diabetes Elevated fasting and postload plasma glucose BMI ≥24 (BMI ≥22 in Asians) Not taking medications known to alter glucose tolerance Allocation Enrollment Outcome measure: new diagnosis of diabetes Diagnosed on the basis of an oral glucose-tolerance test or a semiannual fasting plasma glucose Standard lifestyle recommendations Metformin 850 mg twice daily (n=1073) Standard lifestyle recommendations + placebo twice daily (n=1082) Intensive lifestyle modification (n=1079) 2001 BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. The number of participants decreased over time due to attrition (ie, weight data: n=3085 at 0.5 year; 3064 at 1 year; 2887 at 2 years; and 1510 at 3 years). The primary outcome was new diagnosis of diabetes. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): DPP=Diabetes Prevention Program; BMI=body mass index. Knowler WC et al. N Engl J Med 2002;346(6): 33

Changes in Leisure Physical Activity Adherence to Medication Regimen
Changes Over Time in Weight, Activity, and Medication Adherence by Study Group Changes in Body Weight Change in Weight (kg) 4 -8 -6 -4 -2 2 Changes in Leisure Physical Activity Change in Physical Activity (MET-hr/wk) 2 4 6 8 Placebo Metformin Lifestyle KEY POINT Changes in weight and leisure activity differed significantly over time among the treatment groups (P.001 for each comparison). The proportion of participants who took at least 80% of the prescribed dose of the study drug was slightly higher in the placebo group than in the metformin group (77% vs 72%; P.001). 97% of the participants taking placebo and 84% of those taking metformin were given the full dose of one tablet (850 mg in the case of metformin) twice a day; the remainder were given one tablet a day to limit side effects. BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. The number of participants decreased over time due to attrition (ie, weight data: n=3085 at 0.5 year; 3064 at 1 year; 2887 at 2 years; and 1510 at 3 years). The primary outcome was new diagnosis of diabetes. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): Adherence to Medication Regimen Medication Adherence (%) 85 0.5 1.0 1.5 2.5 3.0 3.5 4.0 65 70 75 80 60 2.0 Year Knowler WC et al. N Engl J Med 2002;346(6): 34

HbA1c Values in the DPP Study
HbA1c by Study Group HbA1c Values in the DPP Study 6.2 Placebo Metformin Lifestyle 6.1 6.0 HbA1c (%) 5.9 KEY POINT HbA1c values in the three groups differed significantly from 0.5 to 3 years (P.001). BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. This analysis included all participants, whether or not diabetes had been diagnosed. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): 5.8 5.7 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Year DPP=Diabetes Prevention Program. Knowler WC et al. N Engl J Med 2002;346(6): 35

FPG Concentrations in the DPP Study Fasting Plasma Glucose (mmol/L)
Fasting Plasma Glucose by Study Group FPG Concentrations in the DPP Study 6.3 Placebo Metformin Lifestyle 6.1 Fasting Plasma Glucose (mmol/L) 5.8 KEY POINT Changes in fasting glucose values over time in the three groups differed significantly (P.001). BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. This analysis included all participants, whether or not diabetes had been diagnosed. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): 5.5 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Year DPP=Diabetes Prevention Program; FPG=fasting plasma glucose. Knowler WC et al. N Engl J Med 2002;346(6): 36

Cumulative Incidence of Diabetes
Cumulative Incidence of Diabetes in the DPP Study 40 Placebo Metformin Lifestyle 30 Cumulative Incidence of Diabetes (%) 20 KEY POINTS The cumulative incidence of diabetes (diagnosis based on the American Diabetes Association criteria) was lower in the metformin and lifestyle intervention groups than in the placebo group throughout the follow-up period. The incidence of diabetes was 58% lower (95% confidence interval, 48%-66%) in the lifestyle intervention group and 31% lower (95% confidence interval, 17%-43%) in the metformin group than in the placebo group. The incidence of diabetes was 39% lower (95% confidence interval, 24%-51%) in the lifestyle intervention group than in the metformin group. The estimated cumulative incidence of diabetes at 3 years was 28.9%, 21.7%, and 14.4% in the placebo, metformin, and lifestyle intervention groups, respectively. On the basis of these rates, the estimated numbers of persons who would need to be treated for 3 years to prevent one case of diabetes during this period is 6.9 (95% confidence interval, ) for the lifestyle intervention and 13.9 (95% confidence interval, ) for metformin. BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): 10 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Year DPP=Diabetes Prevention Program. Knowler WC et al. N Engl J Med 2002;346(6): 37

DPP Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk The lifestyle intervention was more effective than metformin Lifestyle intervention was particularly effective, with one case of diabetes prevented per seven persons treated for three years Based on this study, it should be possible to delay or prevent the development of complications, substantially reducing the individual and public health burden of diabetes KEY POINT The clinical trial showed that lifestyle intervention reduced the incidence by 58% and metformin by 31%, as compared with placebo; the lifestyle intervention was significantly more effective than metformin. Lifestyle changes and treatment with metformin can reduce the incidence of diabetes in persons at high risk and can be more effective than metformin. BACKGROUND The Diabetes Prevention Program (DPP) was a randomised clinical trial initiated in 1996, which was designed to determine whether lifestyle intervention or pharmacological therapy with metformin would prevent or delay the onset of diabetes in individuals who had impaired glucose tolerance and thus were at risk of developing type 2 diabetes participants were randomised to one of three arms: lifestyle intervention, metformin (850 mg twice daily), or placebo. The lifestyle modification programme was developed with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of participants was 51 years, and the mean body mass index was 34.0; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. REFERENCE Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): DPP=Diabetes Prevention Program. Knowler WC et al. N Engl J Med 2002;346(6): 38

ADVANCE and ACCORD Action in Diabetes and Vascular Disease and Action to Control Cardiovascular Risk in Diabetes 39

ADVANCE & ACCORD Objectives
To evaluate whether lowering of blood pressure with an ACE inhibitor-diuretic combination and intensively controlling glycaemia with a sulfonylurea-based regimen in high-risk patients with type 2 diabetes (hypertensive and nonhypertensive) reduces the incidence of macrovascular and microvascular disease ACCORD2 To determine whether cardiovascular disease (CVD) event rates can be reduced in patients with type 2 diabetes who are at high risk for CVD events by intensively targeting three important risk factors: Hyperglycaemia Dyslipidaemia Hypertension BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified-release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator initiated trial (IIT) study sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT study sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): ACCORD=Action to Control Cardiovascular Risk in Diabetes; ACE=angiotensin-converting enzyme; ADVANCE=Action in Diabetes and Vascular Disease. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 40

ADVANCE & ACCORD Study Designs
Patients (N=11,140) with T2DM, 55 years, and either a history of CVD or at least 1 other CV risk factor; no history of insulin treatment Glycaemic control target Intensive control (HbA1c 6.5%) vs standard control (HbA1c= %) ACCORD2 Patients (N=10,251) with T2DM and either confirmed CVD or combined risk factors and/or conditions suggesting a high likelihood of CVD Intensive control (HbA1c 6.0%) vs standard control (HbA1c= %) BP target Intensive control (systolic BP 120 mm Hg) vs standard control (systolic BP 140 mm Hg) Lipid target Fibrates to ⁭ HDL-C and TG + statins to LDL-C vs statins to LDL-C alone BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified-release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator initiated trial (IIT) study sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT study sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 41

ADVANCE & ACCORD Study Designs (Cont’d) ADVANCE1 2x2 factorial design
Median duration of follow-up of 5 years ACCORD2 Double 2x2 factorial design with targeted sample sizes Mean duration of follow-up of 5.6 years Blood Pressure Glycaemic Control Intensive Standard  Lipid Blood Pressure Glycaemic Control Fibrate + Statin Placebo + Intensive Standard 1450 1050 BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator-initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2,3 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99(12A):21i-33i. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. Buse JB et al. Am J Cardiol 2007;99(12A):21i-33i. 42

ADVANCE & ACCORD Treatments ADVANCE1 Need for Treatment ACCORD2
Gliclazide modified release ( mg) QD vs nonsulfonylurea therapy Diet/exercise Add-on of other oral agents, then to insulin in both groups Glycaemic control Open-label treat-to-target with available glucose-lowering medications (algorithms) Combo perindopril (2-4 mg)/ indapamide ( mg; ACE/diuretic - Preterax™) vs placebo Other BP therapies added in both groups to achieve BP target BP Open-label treat-to-target with available antihypertensives — Lipids Simvastatin + fenofibrate 160 mg/day vs placebo Diet, exercise, smoking cessation Lifestyle Diabetes education, diet, exercise, smoking cessation, aspirin daily BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator-initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2,3 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99(12A):21i-33i. ACE=angiotensin-converting enzyme. BP=blood pressure. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. Buse JB et al. Am J Cardiol 2007;99(12A):21i-33i. 43

ADVANCE & ACCORD Primary and Secondary Outcomes
Primary outcomes Composites of major macrovascular events (death from all causes, nonfatal myocardial infarction, nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy) Secondary outcomes Cerebrovascular disease Coronary heart disease Heart failure Peripheral vascular disease Microalbuminuria Visual deterioration Neuropathy Dementia All-cause mortality ACCORD2 Primary outcome Time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator-initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 44

Results: Disposition ADVANCE
Patients Registered N=12,877 Patients Randomised N=11,140 Lost to Follow-Up n=7 Intensive Glucose Control n=5571 Standard Glucose Control n=5569 Lost to Follow-Up n=10 Unknown Vital Status n=7 (0.1%) Died n=498 (8.9%) Lived n=5066 (90.9%) Assessed at Final Visit n=4828 (86.7%) Adherence to Gliclazide n=4209 (75.6%) Unknown Vital Status n=10 (0.2%) Died n=533 (9.6%) Lived n=5026 (90.2%) Assessed at Final Visit n=4741 (85.1%) KEY POINT This figure highlights the enrollment, randomisation, and follow-up of the study participants. BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised, controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified-release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator-initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR). REFERENCE ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 45

Did Not Meet Inclusion Criteria n=1915
Results: Disposition ACCORD Patients Screened N=19,716 Did Not Meet Inclusion Criteria n=1915 Not Randomised n=776 Screen Incomplete n=6774 Patients Randomised N=10,251 Enrollment Intensive Group n=5128 Refused Intensive Approach n=11 Too Busy n=3 Family or Physician Advice n=3 Other n=5 Standard Group n=5123 Refused Standard Approach n=26 Too Busy n=2 Family or Physician Advice n=2 Problem With Study Drugs n=4 Other n=18 Allocation Lost to Follow-Up n=26 Discontinued Intervention n=336 Problem With Study Drugs n=11 Intervening Illness n=8 Medical Advice n=7 Other n=310 KEY POINT This figure depicts the disposition of patients in the ACCORD study. BACKGROUND ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of 62.2 years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an investigator-initiated trial sponsored by the National Heart, Lung and Blood Institute (NHLBI). REFERENCE The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): Lost to Follow-Up n=24 Discontinued Intervention n=322 Problem With Study Drugs n=10 Intervening Illness n=5 Medical Advice n=5 Other n=302 Follow-Up Analysed n=5128 Analysis Analysed n=5123 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 46

ADVANCE & ACCORD Results: Treatments at Study Completion ADVANCE1
Type of Treatment Intensive Standard Insulin 41% 24% 77% 55% Metformin 74% 67% 95% 87% Secretagogue 94% 84% TZDs 17% 11% 92% 58% Incretin N/A 18% 5% Statin 46% 48% 88% Antihypertensive 89% 91% ACE inhibitor All, by design 70% 72% Aspirin 57% 76% KEY POINT In ADVANCE, during the follow-up period, the use of most classes of oral hypoglycaemic drugs and insulin had increased to a greater degree in the intensive control group than in the standard control group. 17% of patients in the intensive therapy group were receiving a thiazolidinedione vs 11% in the standard glucose control group. The use of blood pressure-lowering, lipid-modifying, and antiplatelet treatment was similar between the two groups.1 In ACCORD, subjects in the intensive treatment group had a greater exposure to glucose-lowering agents from every class than did subjects in the standard group. Subjects in both groups had similar exposure to cardiovascular protective interventions; however, significantly fewer patients in the intensive therapy group received an angiotensin-converting enzyme (ACE) inhibitor than in the standard therapy group (70% vs 72%; P=.02).2 BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): ACE=angiotensin-converting enzyme; TZDs=thiazolidinediones. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group N Engl J Med 2008;358(24): 47

ADVANCE & ACCORD Results: Measures of Interest ADVANCE1 ACCORD2
Intensive Standard HbA1c (%) 6.4 7.0 7.5 FPG (mmol/L) 6.2 7.3 N/A BP (systolic; mm Hg) 9.5 7.1 126 127 BP (diastolic; mm Hg) 7.3 6.2 66.9 67.7 LDL (mmol/L) 90.8 90.6 HDL (mmol/L) No change Weight (kg) 0.1 1.0 Hypoglycaemia incidence (%) 2.7 1.5 3.1 1.0 Smoking ~6% points KEY POINT In ADVANCE, the intensive glucose control yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy.1 In ACCORD, the use of intensive therapy to target normal HbA1c levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identified a previously unrecognised harm of intensive glucose lowering in high-risk patients with type 2 diabetes.2 BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): BP=blood pressure; FPG=fasting plasma glucose. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 48

ADVANCE & ACCORD Primary Outcomes ADVANCE1 ACCORD2 — Outcome Intensive
Standard HR (95% CI) P-Value Combined 18.1% 20.0% 0.90 ( ) .01 — Macrovascular 10.0% 10.6% 0.94 ( ) .32 Microvascular Nephropathy 9.4% 4.1% 10.9% 5.2% 0.86 ( ) 0.79 ( ) .006 Time to first occurrence of CV death, nonfatal MI, or stroke 6.9% 7.2% ( ) .16 KEY POINT In ADVANCE, intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1% vs 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval, ; P=.01) as well as that of major microvascular events (9.4% vs 10.9%; hazard ratio, 0.86; 95% confidence interval, ; P=.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs 5.2%; hazard ratio, 0.79; 95% confidence interval, ; P=.006) with no significant effect on retinopathy (P=.50).1 In ACCORD, there were fewer occurrences of the composite primary outcome in the intensive therapy group, with rates of the primary outcome beginning to separate in the two study groups after 3 years. This rate was not significant, with rates of 6.9% in the intensive therapy group and 7.2% in the standard therapy group (hazard ratio, 0.90; 95% confidence interval, ; P=.16).2 BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 49

ADVANCE & ACCORD Secondary Outcomes ADVANCE1 ACCORD2 Outcome Intensive
Standard HR (95% CI) P-Value All-cause death 8.9% 9.6% 0.93 ( ) 5.0% 4.0% 1.22 ( ) .04* CV death 4.5% 5.2% 0.88 ( ) 2.6% 1.8% 1.35 ( ) .02 Nonfatal MI 2.7% 2.8% — 3.6% 4.6% 0.76 ( ) .004 Nonfatal stroke 3.8% 1.3% 1.2% 1.06 ( ) .74 Heart failure 3.9% 4.1% 3.0% 2.4% 1.18 ( ) .17 KEY POINT In ADVANCE, there was no significant effect of intensive glucose control on the risk of macrovascular events or increased mortality.1 In ACCORD, the rate of death from any cause was higher in the intensive therapy group than in the standard therapy group (5.0% vs 4.0%; hazard ratio, 1.22; 95% confidence interval, ; P=.04) and more deaths from cardiovascular disease also occurred in the intensive treatment group. The rate of nonfatal myocardial infarction was lower than in the standard therapy group. There was no significant difference in nonfatal strokes and congestive heart failure between both groups.2 BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction. *Study stopped early. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 50

Cumulative Incidence (%) Patients With Events (%)
ADVANCE & ACCORD Results: Macrovascular Outcomes ADVANCE1 CV Death, MI, Stroke ACCORD2 Primary Outcome 25 25 Intensive Control Standard Control Intensive Control Standard Control 20 20 15 HR=0.94 (95% CI, ) P=.32 15 HR=0.90 (95% CI, ) P=.16 Cumulative Incidence (%) Patients With Events (%) 10 10 KEY POINT In ADVANCE, as compared with standard control, intensive control did not significantly reduce the incidence of major macrovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) (hazard ratio, 0.94; 95% confidence interval, ; P=.32). There was no evidence of an interaction between the blood pressure intervention and the blood glucose intervention for the primary outcomes (P.50 for all comparisons).1 In ACCORD, the rate of death from cardiovascular causes was higher in the intensive therapy group than in the standard group; however, the rate of nonfatal myocardial infarction was lower (3.6% vs 4.6%; hazard ratio 0.76, 95% confidence interval, ; P=.004). There was no significant difference in the rate of nonfatal stroke (1.3% vs 1.2%; hazard ratio, 1.06; 95% confidence interval, ; P=.74). Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 5 5 6 12 18 24 30 36 42 48 54 60 66 1 2 3 4 5 6 Follow-Up (Months) Time (Years) CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 51

Cumulative Incidence (%) Patients With Events (%)
ADVANCE & ACCORD Results: Macrovascular Outcomes ADVANCE1 All-Cause Mortality ACCORD2 All-Cause Mortality 25 25 Intensive Control Standard Control Intensive Control Standard Control 20 20 15 15 Cumulative Incidence (%) Patients With Events (%) 10 10 HR=0.93 (95% CI, ) P=.28 HR=1.22 (95% CI, ) P=.04 KEY POINTS In ADVANCE, there was no significant differences between the two study groups in the rate of death from any cause. These findings contrast with the reported excess mortality that led to the premature termination in the ACCORD trial (see below).1 In ACCORD, the rate of death from any cause was higher in the intensive therapy group than in the standard therapy group (5.0% vs 4.0%; hazard ratio, 1.22; 95% confidence interval, , P=.04). Rates of death in the two study groups began to separate after 1 year and the differences persisted throughout the follow-up period. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February BACKGROUND ADVANCE (Action in Diabetes and Vascular Disease) was a 2x2 factorial randomised controlled trial conducted with 11,140 participants with type 2 diabetes, age 55 years, at high risk of vascular disease. Participants, who were recruited from approximately 215 clinical sites globally, initiated a 6-week, open-label, run-in treatment of perindopril-indapamide combination and were subsequently randomised to continue perindopril-indapamide or matching placebo, and to an intensive gliclazide modified release (MR)-based glucose control regimen or usual guidelines-based therapy. Primary outcomes were a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death and a composite of new or worsening nephropathy or diabetic eye disease. Median follow-up was 5 years. ADVANCE was an investigator- initiated trial (IIT) sponsored by Servier (maker of perindopril-indapamide and gliclazide MR).1 ACCORD (Action to Control Cardiovascular Risk in Diabetes) was a multicentre, randomised, double 2x2 factorial study conducted in 77 sites in the US and Canada, which enrolled 10,251 participants with type 2 diabetes (mean age of years, and median HbA1c of 8.1%), who received intensive therapy (targeting an HbA1c 6.0%) or standard therapy (HbA1c= %) patients were also randomised to lower their blood pressure (BP) by receiving intensive therapy (systolic BP 120 mm Hg) or standard therapy (systolic BP 140 mm Hg). In addition, 5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of LDL cholesterol with simvastatin. Primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Due to higher mortality in the intensive therapy group, and after a mean duration of follow-up of 3.5 years, the data and safety monitoring committee recommended the discontinuation of the intensive regimen in February ACCORD was an IIT sponsored by the National Heart, Lung and Blood Institute (NHLBI).2 REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 5 5 6 12 18 24 30 36 42 48 54 60 66 1 2 3 4 5 6 Follow-Up (Months) Time (Years) HR=hazard ratio. 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 52

ADVANCE & ACCORD Conclusions ADVANCE1
Intensive glucose control involving gliclazide and other drugs (as required) that lowered HbA1c to 6.5% yielded a 10% reduction in combined macro- and microvascular events, primarily due to a 21% relative reduction in nephropathy ACCORD2 Intensive therapy to target normal HbA1c for 3.5 years increased mortality and did not significantly reduce major cardiovascular events “These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes” KEY POINT Review the conclusions from the ADVANCE (Action in Diabetes and Vascular Disease)1and ACCORD (Action to Control Cardiovascular Risk in Diabetes)2 trials. REFERENCES ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 1. ADVANCE Collaborative Group. N Engl J Med 2008;358(24): 2. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358(24): 53

What Does It Mean? ADA/EASD Guidelines1,2 AACE Guidelines3
Treat to target HbA1c 7.0% Antihypertensive (ACE, ARB) Statin Aspirin AACE Guidelines3 Treat to target HbA1c 6.5% Antihypertensive (ACE, ARB) Statin Aspirin IDF Guidelines4 Treat to target HbA1c 6.5% Antihypertensive (ACE, A2RB); not a-adrenergic blockers In addition to statin, fenofibrate where serum triglycerides are 2.3 mmol/L Aspirin KEY POINT Based upon recent studies, standards of care have been developed by the ADA/EASD, AACE, and IDF organisations. Although slightly different HbA1c guidelines have been developed, all of the recommendations are believed to favourably affect health outcomes of patients with diabetes. These include active management of blood pressure with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, lipid management with a statin, and the use of low-dose aspirin as an antiplatelet agent. REFERENCES American Diabetes Association. Executive summary: standards of medical care in diabetes Diabetes Care. 2009;32 (suppl 1):S6-12. Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1): Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract ;13(suppl 1):1-68. International Diabetes Federation. Global guideline for type 2 diabetes. Available at: Accessed March 14, 2009. 1. ADA. Diabetes Care 2009;32 (suppl 1):S6-12 2. Ryden et al. Eur Heart J 2007;28(1): 3. Rodbard HW, et al. Endocr Pract 2007;13(suppl 1):1-68. 4. International Diabetes Federation. Available at: Accessed March 14, 2009. 54

Steno-2 Multifactorial Intervention and Cardiovascular Disease in Patients With Type 2 Diabetes BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. The two primary endpoints were a microvascular analysis as measured by the development of diabetic nephropathy after 4 years of intervention, and a macrovascular analysis in which a composite endpoint for macrovascular disease after 8 years of intervention was the primary endpoint. The 80 patients randomly assigned to the conventional treatment group received treatment from their general practitioners according to the 1988 recommendations of the Danish Medical Association with the possibility of being referred to a specialist. Interventions in the intensive therapy group were: dietary intervention (total daily intake of fat and saturated fatty acids 30% and 10%, respectively, of the daily energy intake), light to moderate exercise for at least 30 minutes three to five times weekly recommended, and all smoking patients and their spouses were invited to participate in smoking cessation courses. All patients were prescribed an angiotensin-converting enzyme (ACE) inhibitor in a dose equivalent to 50 mg of captopril twice daily or, if such a drug was contraindicated, an angiotensin II-receptor antagonist in a dose equivalent to 50 mg losartan twice daily, irrespective of the blood pressure level. Patients also received a daily vitamin-mineral supplement. Initially, 150 mg aspirin per day was given as a secondary prevention to patients with a history of ischaemic cardiovascular disease, and after October 1999, all patients received aspirin (unless there were contraindications). If patients were unable to maintain an HbA1c 6.5% with diet and increased physical activity, an oral hypoglycaemic agent was started. REFERENCE Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5): 55

Steno-2 Background Information
Open-parallel study of patients with type 2 diabetes and microalbuminuria (N=160) randomised to: Conventional treatment (n=80) Addressing multiple risk factors in accordance with national guidelines overseen by patients’ general practitioners Intensive treatment (n=80) Undergoing intensive multifactorial intervention involving strict treatment goals overseen by a multidisciplinary project team Primary endpoints Development of diabetic nephropathy after 4 years of intervention Macrovascular disease after 8 years of intervention Mean follow-up period: 7.8 years Mean age: 55.1 years BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. The two primary endpoints were a microvascular analysis as measured by the development of diabetic nephropathy after 4 years of intervention, and a macrovascular analysis in which a composite endpoint for macrovascular disease after 8 years of intervention was the primary endpoint. The 80 patients randomly assigned to the conventional treatment group received treatment from their general practitioners according to the 1988 recommendations of the Danish Medical Association with the possibility of being referred to a specialist. Interventions in the intensive therapy group were: dietary intervention (total daily intake of fat and saturated fatty acids 30% and 10%, respectively, of the daily energy intake), light to moderate exercise for at least 30 minutes three to five times weekly recommended, and all smoking patients and their spouses were invited to participate in smoking cessation courses. All patients were prescribed an angiotensin-converting enzyme (ACE) inhibitor in a dose equivalent to 50 mg of captopril twice daily or, if such a drug was contraindicated, an angiotensin II-receptor antagonist in a dose equivalent to 50 mg losartan twice daily, irrespective of the blood pressure level. Patients also received a daily vitamin-mineral supplement. Initially, 150 mg aspirin per day was given as a secondary prevention to patients with a history of ischaemic cardiovascular disease, and after October 1999, all patients received aspirin (unless there were contraindications). If patients were unable to maintain an HbA1c 6.5% with diet and increased physical activity, an oral hypoglycaemic agent was started. REFERENCE Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5): Gaede et al. N Engl J Med 2003;348(5): 56

Steno-2 Study Design Enrollment Allocation Analysis
Excluded (n=146) Declined to enroll (n=37) Normoalbuminuria (n=97) Macroalbuminuria (n=7) Other exclusion criteria (n=5) Patients screened (N=315) Enrollment Positive microalbuminuria n=169 Excluded because of stimulated C-peptide of <600 pmol/L (n=9) Stratified according to urinary albumin excretion then randomised (n=160) KEY POINTS The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. REFERENCE Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5): Allocation Intensive treatment (n=80) Conventional treatment (n=80) Completed interventional study (n=67) Completed interventional study (n=63) Completed follow-up study (n=55) Completed follow-up study (n=38) Analysis Gaede et al. N Engl J Med 2008;358(6): 57

Steno-2: Cardiovascular Events
Cardiovascular Events in the Steno-2 Study 40 Intensive therapy Conventional therapy 35 30 25 Number of Cardiovascular Events 20 15 10 KEY POINT This figure shows the number of cardiovascular events for each component of the composite macrovascular disease endpoint. A total of 209 cardiovascular events occurred during the years of observation (51 events in 25 patients in the intensive therapy group and 158 events in 48 patients in the conventional therapy group). The mean number of major cardiovascular events was 0.6 in the intensive therapy group and 2.0 in the conventional therapy group. BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. 24 patients in the intensive therapy group died, as compared with 40 in the conventional therapy group (hazard ratio, 0.54; 95% confidence interval, ; P=.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% confidence interval, ; P=.04) and of cardiovascular events (hazard ratio, 0.41; 95% confidence interval, ; P.001). REFERENCE Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): 5 Death from Cardiovascular Cause Stroke Myocardial Infarction CABG PCI Revascularisation Amputation CABG=coronary artery bypass graft; PCI=percutaneous coronary intervention. Gaede et al. N Engl J Med 2008;358(6): 58

Cumulative Incidence of Any Cardiovascular Event (%)
Steno-2: Incidence of Cardiovascular Events Cumulative Incidence of Cardiovascular Events in the Steno-2 Study 80 Intensive therapy Conventional therapy 70 60 p<.001 50 40 Cumulative Incidence of Any Cardiovascular Event (%) 30 20 KEY POINT This figure shows the cumulative incidence of a secondary composite endpoint of cardiovascular events, including death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, revascularisation for peripheral atherosclerotic artery disease, and amputation. The absolute risk of death from cardiovascular causes was reduced by 13% among those receiving intensive therapy. BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. 24 patients in the intensive therapy group died, as compared with 40 in the conventional therapy group (hazard ratio, 0.54; 95% confidence interval, ; P=.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% confidence interval, ; P=.04) and of cardiovascular events (hazard ratio, 0.41; 95% confidence interval, ; P.001). REFERENCE Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): 10 1 2 3 4 5 6 7 8 9 10 11 12 13 Number at Risk Years of Follow-Up Intensive therapy 80 72 65 61 56 50 47 31 Conventional therapy 80 70 60 46 38 29 25 14 Gaede et al. N Engl J Med 2008;358(6): 59

Metabolic Goals Are Difficult to Achieve: Steno-2 Results
Percentage of Patients Reaching Intensive-Therapy Treatment Goals at the end of the Steno-2 Study 100 Intensive therapy Conventional therapy 90 p=.14 p=.35 p=.005 80 70 60 Patients (%) 50 40 p=.27 30 p=.31 KEY POINT This figure shows the percentage of patients in each group who reached the treatment goals for the intensive therapy group at the end of the study. Only one patient (in the intensive therapy group) reached all five treatment goals at the end of the follow-up. BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. 24 patients in the intensive therapy group died, as compared with 40 in the conventional therapy group (hazard ratio, 0.54; 95% confidence interval, ; P=.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% confidence interval, ; P=.04) and of cardiovascular events (hazard ratio, 0.41; 95% confidence interval, ; P.001). REFERENCE Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): 20 10 HbA1c 6.5% Cholesterol 175 mg/dL Triglycerides 150 mg/dL Systolic Blood Pressure 130 mm Hg Diastolic Blood Pressure 80 mm Hg Gaede et al. N Engl J Med 2008;358(6): 60

Steno-2: Incidence of Death
Cumulative Incidence of the Risk of Death from any cause during the Steno-2 Study 80 Intensive therapy Conventional therapy 70 60 50 p=.02 40 Cumulative Incidence of Death (%) 30 20 KEY POINT This figure shows the study’s primary endpoint, which was the cumulative incidence of the risk of death from any cause during the 13.3-year study period. There was an absolute risk reduction for death from any cause of 20% among patients who received intensive therapy as compared to those who received conventional therapy. The absolute risk of death from cardiovascular causes was reduced by 13% among those receiving intensive therapy. During the entire follow-up period, the rate of death among patients in the conventional therapy group was 50%. BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. 24 patients in the intensive therapy group died, as compared with 40 in the conventional therapy group (hazard ratio, 0.54; 95% confidence interval, ; P=.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% confidence interval, ; P=.04) and of cardiovascular events (hazard ratio, 0.41; 95% confidence interval, ; P.001). REFERENCE Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): 10 1 2 3 4 5 6 7 8 9 10 11 12 13 Number at Risk Years of Follow-Up Intensive therapy 80 78 75 72 65 62 57 39 Conventional therapy 80 80 77 69 63 51 43 30 Gaede et al. N Engl J Med 2008;358(6): 61

Steno-2 Conclusions During the 13.3-year study period, the rate of death among patients was: 50% in the conventional therapy group 30% in the intensive therapy group In at-risk patients with type 2 diabetes, intensive therapy sustained beneficial effects with respect to: Vascular complications Rates of death from any cause Rates of death from cardiovascular causes In patients with type 2 diabetes, metabolic goals were difficult to achieve Only one patient (in the intensive therapy group) reached all five treatment goals at the end of the follow-up KEY POINT At-risk patients with type 2 diabetes, intensive therapy with multiple drug combinations and behavior modifications had sustained benefits on vascular complications and rates of death from all cause and cardiovascular causes. BACKGROUND The Steno-2 study evaluated the effect of behavioural modification and polypharmacologic therapy, which targeted several modifiable risk factors (hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria) on cardiovascular disease in patients with type 2 diabetes and microalbuminuria as compared to conventional intervention. 160 patients with type 2 diabetes were enrolled; 80 patients were randomised to receive conventional treatment and 80 were randomised to intensive treatment. Mean age was 55.1 years and the mean follow-up time was 7.8 years. Patients were then followed observationally for a mean of 5.5 years until 31 December, The primary endpoint at 13.3 years of follow-up was the time to death from any cause. 24 patients in the intensive therapy group died, as compared with 40 in the conventional therapy group (hazard ratio, 0.54; 95% confidence interval, ; P=.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% confidence interval, ; P=.04) and of cardiovascular events (hazard ratio, 0.41; 95% confidence interval, ; P.001). REFERENCE Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): Gaede et al. N Engl J Med 2008;358(6): 62

Diabetes Insulin-Glucose in Acute Myocardial Infarction
DIGAMI Studies Diabetes Insulin-Glucose in Acute Myocardial Infarction BACKGROUND The Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) study was a multicentre, randomised study on the effect of an insulin-glucose infusion on mortality and morbidity when given to patients with a suspected acute myocardial infarction and diabetes.1 The infusion was initiated as soon as possible and continued until stable normoglycaemia was attained and at least for 24 hours. It was followed by a 3-month minimum of four-dose subcutaneous insulin therapy daily. All patients were followed prospectively with scheduled visits at the outpatient clinic 3 and 12 months after randomisation. 306 patients were randomised to treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for 3 months and 314 to conventional therapy (N=620). After 1 year, 57 patients (18.6%) in the infusion group and 82 (26.1%) in the control group had died (relative mortality reduction, 29%; P=.027), and at 3.4 years1 of follow-up, the intensive approach reduced the long-term relative mortality by 30% in the insulin-treated group, thus concluding that an insulin-glucose infusion followed by a multidose insulin regimen improved long-term prognosis in patients with diabetes who had a myocardial infarction.2 DIGAMI 2 was a multicentre, prospective, randomised, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. The management protocols were 1.) a 24-hour insulin-glucose infusion followed by subcutaneous insulin-based long-term glucose control (n=474); 2.) a 24-hour insulin-glucose infusion followed by standard glucose control (n=473); and 3.) routine metabolic management according to local practice (n=306). The primary objective was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective was to compare morbidity, such as nonfatal reinfarction, congestive heart failure, and stroke, among the three groups. The median study duration was 2.1 years. In this study, none of the oral glucose-lowering treatments were associated with improved survival during the study period.3 REFERENCES Malmberg K. Role of insulin-glucose infusion in outcomes after acute myocardial infarction: the diabetes and insulin-glucose infusion in acute myocardial infarction (DIGAMI) study. Endocr Pract. 2004;10(suppl 2):13-16. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26(1):57-65. Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008;29(2): 63

DIGAMI Background DIGAMI
Prospective, randomised, open-label, parallel study of patients with diabetes (insulin and noninsulin-dependent) and hospitalised with acute myocardial infarction (N=620) Hypothesis Rapid improvement of metabolic control in patients with diabetes and acute myocardial infarction by means of insulin-glucose infusion will decrease the high initial mortality rate and that continued good metabolic control during early postinfarction period will improve subsequent prognosis Two treatment cohorts Treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for ≥3 months (n=306) Conventional therapy (n=314) Mean follow-up time 344 days Conclusions At 1 year: insulin-glucose infusion followed by a multidose insulin regimen improved long-term prognosis in patients with diabetes and acute myocardial infarction BACKGROUND The Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) study was a prospective, randomised, open-label, parallel study of patients with diabetes (insulin and noninsulin-dependent) who were hospitalised with an acute myocardial infarction who were admitted to the coronary care units of 19 Swedish hospitals. Patients were randomised in a blinded manner to receive either an insulin-glucose infusion according to a predefined protocol for ≥24 hours, then subcutaneous insulin four times daily for ≥3 months (n=306) or conventional (control) treatment, which was according to standard coronary care unit practice; patients in this group did not receive insulin unless it was deemed clinically indicated (n=314). Mean follow-up of each group was 344 days. The overall mortality rate was considerably lower than expected at each checkpoint during the study in the infusion group vs the control group. The overall mortality rate at 1 year was 18.6% in the infusion group vs 26.1% in the control group (P=.0273). The authors concluded that an insulin- glucose infusion followed by a multidose insulin regimen improved long-term prognosis in patients with diabetes with an acute myocardial infarction. REFERENCE Malmberg K, Rydén L, Efendic S, Herlitz J, Nicol P, Waldenström A, Wedel H, Welin L. Randomized Trial of Insulin-Glucose Infusion Followed by Subcutaneuos Insulin Treatment in Diabetic Patients with Acute Myocardial Infarction (DIGAMI Study): Effects on Mortality at 1 Year. J Am Coll Cardiol ;26:57-65. DIGAMI=Diabetes Insulin-Glucose in Acute Myocardial Infarction. Malmberg et al. J Am Coll Cardiol 1995;26(1):57-65. 64

DIGAMI 2 Background Information
Prospective, randomised, open-label trial with blinded evaluation comparing 3 different treatment strategies in patients with type 2 diabetes and hospitalised with acute myocardial infarction (N=1253) Primary objective Compare total mortality between two cohorts (groups 1 and 2) receiving different treatment strategies for type 2 diabetes during time of follow-up (n=474 and n=473, respectively) Secondary objective Compare total mortality between two cohorts (groups 2 and 3) receiving different treatment strategies for type 2 diabetes during time of follow-up (n=473 and n=306, respectively) Tertiary objective Compare morbidity such as nonfatal infarction, congestive heart failure, and stroke among all cohorts (groups 1, 2, and 3) Conclusions Results of DIGAMI 2 did not verify the findings of DIGAMI BACKGROUND Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI 2) was a prospective, randomised, open-label trial with blinded evaluation comparing three different treatment strategies in patients with type 2 diabetes and hospitalised with an acute myocardial infarction. The three treatment strategies were: group 1—a 24-hour insulin-glucose infusion followed by subcutaneous insulin-based long-term glucose control (n=474); group 2—24-hour insulin-glucose infusion followed by standard glucose control (n=473); group 3—routine metabolic management according to local practice (n=306). The primary objective was to compare total mortality between two cohorts (groups 1 and 2) receiving different treatment strategies for type 2 diabetes during time of follow-up (n=474 and n=473, respectively). The secondary objective was to compare total mortality between two cohorts (groups 2 and 3) receiving different treatment strategies for type 2 diabetes during time of follow-up (n=473 and n=306, respectively) and the tertiary objective was to compare morbidity such as nonfatal infarction, congestive heart failure, and stroke among all cohorts (groups 1, 2, and 3). The results of DIGAMI 2 did not support the findings in DIGAMI. REFERENCE Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26(7): DIGAMI=Diabetes Insulin-Glucose in Acute Myocardial Infarction. Malmberg et al. Eur Heart J 2005;26(7): 65

DIGAMI 2 Study Design Enrollment Allocation Analysis
Patients with type 2 diabetes or admission glucose >11.0 mmol/L admitted to a coronary care unit with myocardial infarction and/or ECG changes (N=1253) Randomisation Allocation Group 1 24-hour insulin-glucose infusion followed by subcutaneous insulin- based long-term glucose control (n=474) Group 2 24-hour insulin-glucose infusion followed by standard glucose control (n=473) Group 3 Routine metabolic management according to local practice (n=306) Analysis Primary objective Groups 1 and 2: compare total mortality Secondary objective Groups 2 and 3: BACKGROUND Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) 2 was a multicentre, prospective, randomised, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. The management protocols were 1.) a 24-hour insulin-glucose infusion followed by subcutaneous insulin-based long- term glucose control (n=474); 2.) a 24-hour insulin-glucose infusion followed by standard glucose control (n=473); and 3.) routine metabolic management according to local practice (n=306). The primary objective was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective was to compare morbidity, such as nonfatal reinfarction, congestive heart failure, and stroke, among the three groups.1 Median study duration was 2.1 years.2 REFERENCES Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26(7): Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008;29(2): Tertiary objective Groups 1, 2, and 3: compare morbidity DIGAMI=Diabetes Insulin-Glucose in Acute Myocardial Infarction; ECG=electrocardiogram. 1. Malmberg et al. Eur Heart J 2005;26(7): 2. Mellbin et al. Eur Heart J 2008;29(2): 66

DIGAMI 2 Effect of different updated glucose-lowering treatments on mortality and morbidity Metformin (200/981)* Hazard Ratio (95% CI) Death (33/173)** 0.91 ( ) CV death (24/139)** 0.93 ( ) Death/reinfarction/stroke (56/304)** 0.78 ( ) Reinfarction/stroke (28/176)** 0.63 ( ) Sulfonylurea (268/913)* Death (51/155)** 1.08 ( ) CV death (41/122)** 1.15 ( ) Death/reinfarction/stroke (80/280)** 0.93 ( ) Reinfarction/stroke (40/164)** 0.81 ( ) Insulin (690/491)* Death (134/72)** 1.12 ( ) CV death (105/58)** 1.05 ( ) Death/reinfarction/stroke (243/117)** 1.42 ( ) Reinfarction/stroke (145/59)** 1.73 ( ) Any glucose-lowering drug (1005/176)* Death (176/30)** 0.89 ( ) CV death (139/24)** 0.84 ( ) Death/reinfarction/stroke (311/49)** 1.04 ( ) Reinfarction/stroke (179/25)** 1.19 ( ) KEY POINT This figure illustrates the effect of different glucose-lowering treatments on mortality and morbidity. Following adjustment, none of the oral glucose-lowering treatments were associated with improved survival during the study period.1 The outcome of DIGAMI 2 contrasted with the findings of DIGAMI, which concluded that an insulin-glucose infusion therapeutic regimen reduced mortality in patients with diabetes who had an acute myocardial infarction. The authors of this DIGAMI 2 publication cited differences in eligibility criteria, glucose goals, overall long-term glucose control, and other factors in the two studies, which may have contributed to the differences in results. BACKGROUND Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) 2 was a multicentre, prospective, randomised, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. The management protocols were 1.) a 24-hour insulin-glucose infusion followed by subcutaneous insulin-based long- term glucose control (n=474); 2.) a 24-hour insulin-glucose infusion followed by standard glucose control (n=473); and 3.) routine metabolic management according to local practice (n=306). The primary objective was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective was to compare morbidity, such as nonfatal reinfarction, congestive heart failure, and stroke, among the three groups.2 Median study duration was 2.1 years.1 REFERENCES Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008;29(2): Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26(7): *Number of patients using drug/number of patients not using drug at discharge. **Number of endpoints for patients using drug/number of endpoints for patients not using drug. CV=cardiovascular. 0.50 0.70 1.00 1.45 2.00 4.00 Drug Better Drug Worse Mellbin et al. Eur Heart J 2008;29(2): 67

DIGAMI 2 Conclusions The outcomes of DIGAMI 2 contrasted with the findings of DIGAMI Researchers cited differences in eligibility criteria, glucose goals, overall long-term glucose control, and other factors, which may have contributed to the differences in results An acutely introduced long-term insulin treatment did not improve survival in patients with type 2 diabetes following myocardial infarction when compared to conventional treatment at similar levels of glucose control Insulin-based treatment did not lower the number of nonfatal myocardial reinfarctions and strokes KEY POINT The outcome of DIGAMI 2 contrasted with the findings of DIGAMI, which concluded that an insulin-glucose infusion therapeutic regimen reduced mortality in patients with diabetes who had an acute myocardial infarction. The authors of this DIGAMI 2 publication cited differences in eligibility criteria, glucose goals, overall long-term glucose control, and other factors in the two studies, which may have contributed to the differences in results. BACKGROUND Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) 2 was a multicentre, prospective, randomised, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. The management protocols were 1.) a 24-hour insulin-glucose infusion followed by subcutaneous insulin-based long- term glucose control (n=474); 2.) a 24-hour insulin-glucose infusion followed by standard glucose control (n=473); and 3.) routine metabolic management according to local practice (n=306). The primary objective was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective was to compare morbidity, such as nonfatal reinfarction, congestive heart failure, and stroke, among the three groups.1 Median study duration was 2.1 years.2 REFERENCES Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26(7): Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008;29(2): DIGAMI=Diabetes Insulin-Glucose in Acute Myocardial Infarction. 1. Malmberg et al. Eur Heart J 2005;26(7): 2. Mellbin et al. Eur Heart J 2008;29(2): 68

Treatment Options for Type 2 Diabetes in Adolescents and Youth
TODAY Treatment Options for Type 2 Diabetes in Adolescents and Youth KEY POINT The outcome of DIGAMI 2 contrasted with the findings of DIGAMI, which concluded that an insulin-glucose infusion therapeutic regimen reduced mortality in patients with diabetes who had an acute myocardial infarction. The authors of this DIGAMI 2 publication cited differences in eligibility criteria, glucose goals, overall long-term glucose control, and other factors in the two studies, which may have contributed to the differences in results. BACKGROUND Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) is a randomised, parallel-group trial funded by the National Institutes of Health. The study consists of a screening visit, a 2- to 6-month single-blind run-in period, and a treatment period of up to 5 years. Participants who meet eligibility criteria at the end of run-in are randomised 1:1:1 to a.) metformin alone; b.) metformin plus rosiglitazone; or c.) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program. TODAY intends to recruit 800 patients over a 4-year period and follow patients for a minimum of 2 years and a maximum of 6 years. The primary outcome is the time to treatment failure, defined in one of two ways: a.) all regularly scheduled HbA1c values 8% over a 6-month period, or b.) the inability to wean from temporary insulin therapy within 3 months following acute metabolic decompensation. TODAY will enroll children, ages 10-17, at 13 sites in the United States. Enrollment began in May 2004 and goes through TODAY intends to recruit and randomise patients within 2 years of their diagnosis1 and follow them for 2-5 years, depending on the date of enrollment.2 REFERENCES The TODAY Study Group. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74-87. Today.org. Treatment options for type 2 diabetes in adolescents and youth. Available at: Accessed July 17, 2009. 69

TODAY Background Information
Prospective, randomised, parallel study being conducted at 13 sites around the United States1 Initiated due to the increase in type 2 diabetes in the paediatric population Funded by the National Institutes of Health1 First large-scale systematic study of treatment effectiveness for type 2 diabetes in youth2 Enrolling paediatric participants to achieve N=800 over 4 years2 Age years Follow-up period was 2-6 years Designed to test hypothesis: aggressive reduction in insulin resistance early in course of type 2 diabetes is beneficial for prolongation of glycaemic control and will improve associated abnormalities and risk factors2 BACKGROUND Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) is a randomised, parallel-group trial funded by the National Institutes of Health. The study design consists of a screening visit, a 2- to 6-month single-blind run-in period, and a treatment period of up to 6 years.1 This study will attempt to enroll 800 children, ages 10-17, over 4 years at 13 sites in the United States. TODAY intends to recruit and randomise patients within 2 years of their diagnosis and follow them for 2-6 years, depending on the date of enrollment.1,2 REFERENCES Today.org. Treatment options for type 2 diabetes in adolescents and youth. Available at: Accessed July 17, 2009. The TODAY Study Group. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74-87. TODAY=Treatment Options for type 2 Diabetes in Adolescents and Youth. 1.Today.org. Available at: Accessed July 17, 2009. 2.The TODAY Study Group. Pediatr Diabetes 2007;8(2):74-87. 70

TODAY Study Objectives
Primary objective To compare the treatment efficacy of three treatment arms on time to treatment failure based on glycaemic control Secondary objectives Compare and evaluate the safety and cost-effectiveness of the three treatment groups Compare the treatments’ effects on the pathophysiology of type 2 diabetes Evaluate the influence of individual and family behaviours on treatment response KEY POINTS2 The primary objective is the time to treatment failure, defined in one of two ways: a.) all regularly scheduled HbA1c values 8% over a 6- month period, or b.) the inability to wean from temporary insulin therapy within 3 months following acute metabolic decompensation. Secondary objectives include the effect of the alternative treatments on insulin secretion and resistance, body composition, nutrition, physical activity and fitness, cardiovascular risk monitoring, microvascular complications, quality of life, depression, eating pathology, and resource utilisation. BACKGROUND Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) is a randomised, parallel-group trial funded by the National Institutes of Health. The study design consists of a screening visit, a 2- to 6-month single-blind run-in period, and a treatment period of up to 5 years. Participants who meet eligibility criteria at the end of run-in are randomised 1:1:1 to a.) metformin alone; b.) metformin plus rosiglitazone; or c.) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program. This study will enroll children, ages 10-17, at 13 sites in the United States. Enrollment began in May 2004 and goes through TODAY intends to recruit and randomise patients within 2 years of their diagnosis and follow them for 2-6 years, depending on the date of enrollment.1 Inclusion criteria:2 Age 10-17 Type 2 diabetes by American Diabetes Association (ADA) criteria Body mass index 85th percentile Fasting C-peptide 0.6 mg/mL GAD and ICA125 negative Exclusion criteria:2 Medications Known to affect insulin sensitivity or secretion Known to cause weight gain or weight loss Known to affect metabolism of study drug Inhaled or oral steroids Participation in a formal weight loss programme Physical limitations preventing participation in lifestyle interventions REFERENCES Today.org. Treatment options for type 2 diabetes in adolescents and youth. Available at: Accessed July 17, 2009. The TODAY Study Group. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74-87. TODAY=Treatment Options for type 2 Diabetes in Adolescents and Youth. Today.org. Available at: Accessed July 17, 2009. 71

TODAY Treatment Groups
Screening and Run-in Year 1 Year 2 and Thereafter Titrate to maximum tolerated dose of metformin Wean from other diabetes medications Provide comprehensive diabetes education Assess ability to keep records, monitor glucose, and other study-related tasks Metformin ( mg BID) Metformin ( mg BID) + rosiglitazone 4 mg BID KEY POINT Participants who meet eligibility criteria at the end of run-in are randomised 1:1:1 to a.) metformin alone; b.) metformin plus rosiglitazone; or c.) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program. This study will enroll children, ages 10-17, at 13 sites in the United States. Enrollment began in May 2004 and goes through TODAY intends to recruit and randomise patients within 2 years of their diagnosis and follow them for 2-6 years, depending on the date of enrollment. BACKGROUND Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) is a randomised, parallel-group trial funded by the National Institutes of Health. The study design consists of a screening visit, a 2- to 6-month single-blind run-in period, and a treatment period of up to 5 years. Participants who meet eligibility criteria at the end of run-in are randomised 1:1:1 to a.) metformin alone; b.) metformin plus rosiglitazone; or c.) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program. This study will enroll children, ages 10-17, at 13 sites in the United States. Enrollment began in May 2004 and goes through TODAY intends to recruit and randomise patients within 2 years of their diagnosis and follow them for 2-6 years, depending on the date of enrollment.1 Inclusion criteria:2 Age 10-17 Type 2 diabetes by American Diabetes Association (ADA) criteria Body mass index 85th percentile Fasting C-peptide 0.6 mg/mL GAD and ICA125 negative Exclusion criteria:2 Medications Known to affect insulin sensitivity or secretion Known to cause weight gain or weight loss Known to affect metabolism of study drug Inhaled or oral steroids Participation in a formal weight loss programme Physical limitations preventing participation in lifestyle interventions The primary objective is the time to treatment failure, defined in one of two ways: a.) all regularly scheduled HbA1c values 8% over a 6- month period, or b.) the inability to wean from temporary insulin therapy within 3 months following acute metabolic decompensation. Secondary objectives include the effect of the alternative treatments on insulin secretion and resistance, body composition, nutrition, physical activity and fitness, cardiovascular risk monitoring, microvascular complications, quality of life, depression, eating pathology, and resource utilisation. REFERENCE The TODAY Study Group. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74-87. Metformin ( mg BID) + intensive lifestyle intervention Visits every 2 months 4 visits every year V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 BID=Twice Daily; TODAY=Treatment Options for type 2 Diabetes in Adolescents and Youth. The TODAY Study Group. Pediatr Diabetes 2007;8(2):74-87 72

TODAY Expectations The TODAY study will:
Provide critical new information regarding the natural history of type 2 diabetes in youth Identify the benefits of initiating early aggressive treatment in this population Support the efficacy of delivering an intensive and sustained lifestyle intervention to children with type 2 diabetes KEY POINT Participants who meet eligibility criteria at the end of run-in are randomised 1:1:1 to a.) metformin alone; b.) metformin plus rosiglitazone; or c.) When successfully completed, the TODAY study will provide critical new information regarding the natural history of type 2 diabetes in youth, the benefits of initiating early aggressive treatment in these patients, and the efficacy of delivering an intensive and sustained lifestyle intervention to children with type 2 diabetes. REFERENCE The TODAY Study Group. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007;8(2):74-87. TODAY=Treatment Options for type 2 Diabetes in Adolescents and Youth. The TODAY Study Group. Pediatr Diabetes 2007;8(2):74-87. 73

Collaborative AtoRvastatin Diabetes Study
CARDS Collaborative AtoRvastatin Diabetes Study BACKGROUND The Collaborative AtoRvastatin Diabetes Study (CARDS) was a multicentre, randomised, placebo- controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with type 2 diabetes. The primary objective was to determine whether atorvastatin 10 mg daily reduced the incidence of major cardiovascular events. At entry, patients had a least one other risk factor for coronary heart disease in addition to diabetes such as current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. The study included 2838 men and women ages years.1 CARDS was terminated almost 2 years earlier than planned because at the second prescheduled interim analysis the data safety monitoring board found a highly significant benefit with treatment beyond that stipulated in the early stopping rule.2 REFERENCES Colhoun HM, Thomason MJ, Mackness MI, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabet Med. 2002;19(3): Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435): 74

CARDS Background Information
Randomised, placebo-controlled, double-blind study of primary prevention of cardiovascular disease in patients with type 2 diabetes (N=2838) Ages years Patients had no history of established clinical cardiovascular disease Primary objective To determine if atorvastatin 10 mg daily reduced the incidence of major cardiovascular events In addition to diabetes, subjects had at least one other risk factor for coronary heart disease Current smoking Hypertension Retinopathy Micro- or macroalbuminuria Study comprised three periods Screening visit to determine eligibility 6-week placebo baseline to establish baseline values of study parameters Minimum 4-year double-blind treatment BACKGROUND The Collaborative AtoRvastatin Diabetes Study (CARDS) was a multicentre, randomised, placebo- controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with type 2 diabetes. The study included 2838 men and women ages years. The patients had no history of established clinical cardiovascular disease. The primary objective was to determine if atorvastatin 10 mg daily reduced the incidence of major cardiovascular events. At entry, patients had a least one other risk factor for coronary heart disease in addition to diabetes such as current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. The study was comprised of three study periods: a screening visit to establish eligibility; a 6-week baseline to establish baseline values of study parameters; and a minimum 4-year double-blind treatment period. REFERENCE Colhoun HM, Thomason MJ, Mackness MI, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabet Med. 2002;19(3): CARDS=Collaborative AtoRvastatin Diabetes Study. Colhoun et al. Diabet Med 2002;19(3): 75

CARDS: Collaborative AtoRvastatin Diabetes Study
Atorvastatin 10 mg High-risk patients with type 2 diabetes (N=2838) Placebo KEY POINTS Patients with a serum LDL cholesterol 4.14 mmol/L (160 mg/dL) and triglycerides 6.78 mmol/L (600 mg/dL) but without established coronary or cerebrovascular disease were enrolled.1 Placebo once daily was prescribed for 6 weeks to establish baseline values of various study entry parameters. In the treatment period, 10 mg atorvastatin or placebo were prescribed once daily. Randomisation was started in September and was completed in June The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat.1 CARDS was terminated almost 2 years earlier than planned because at the second prescheduled interim analysis the data safety monitoring board found a highly significant benefit with treatment beyond that stipulated in the early stopping rule.3 BACKGROUND The Collaborative AtoRvastatin Diabetes Study (CARDS) was a multicentre, randomised, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with type 2 diabetes. The primary objective was to determine whether atorvastatin 10 mg daily reduced the incidence of major cardiovascular events. At entry, patients had a least one other risk factor for coronary heart disease in addition to diabetes such as current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. The study included 2838 men and women ages years.1 Patients were seen monthly for the first 3 months, then at 6 months, and thereafter every 6 months. Patients were deemed compliant if they had taken 80% of the study drug.2 REFERENCES Colhoun HM, Thomason MJ, Mackness MI, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabet Med. 2002;19(3): Colhoun H.M Betteridge DJ, Durrington PN, et al. Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia. 2005;48(12): Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435): Randomisation complete June 2001 Early termination June 2003 Results announced June 2004 Planned completion 2005 Primary outcome: reduction in composite of major coronary events, revascularisations, unstable angina, resuscitated cardiac arrest, and stroke. Colhoun et al. Diabet Med 2002;19(3): 76

Cumulative Hazard of Major Cardiovascular Events
CARDS: Statin Reduces Primary Outcome Cumulative Hazard of Major Cardiovascular Events 16 Placebo (127 events) Years Placebo 127 events Atorvastatin 83 events 37% risk reduction P=.001 Atorvastatin (83 events) 12 Cumulative Hazard (%) 4 KEY POINTS This figure represents the cumulative hazard of the primary endpoint: major cardiovascular events. Major cardiovascular events were defined as deaths from acute myocardial infarction, other acute coronary heart disease deaths, and nonfatal myocardial infarction including silent infarction.1 Incidence of major cardiovascular disease events was 24.6 per 1000 person-years at risk in the placebo group and 15.4 per person-years at risk in the atorvastatin group.3 The results of CARDS showed that atorvastatin 10 mg resulted in a substantial reduction (37%) in major cardiovascular events in patients with type 2 diabetes and without high LDL cholesterol concentrations. A 27% reduction in all-cause mortality was noted in subjects allocated to atorvastatin.3 BACKGROUND The Collaborative AtoRvastatin Diabetes Study (CARDS) was a multicentre, randomised, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with type 2 diabetes. The primary objective was to determine whether atorvastatin 10 mg daily reduced the incidence of major cardiovascular events. At entry, patients had a least one other risk factor for coronary heart disease in addition to diabetes such as current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. The study included 2838 men and women ages years.1 Patients were seen monthly for the first 3 months, then at 6 months, and thereafter every 6 months. Patients were deemed compliant if they had taken 80% of the study drug.2 Adverse event rates were similar in the treated and placebo groups, and no cases of rhabdomyolysis were noted.3 REFERENCES Colhoun HM, Thomason MJ, Mackness MI, et al. Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes. Diabet Med. 2002;19(3): Colhoun H.M Betteridge DJ, Durrington PN, et al. Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia. 2005;48(12): Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435): 1 2 3 4 4.75 Number at Risk 1410 1351 1306 1022 651 305 Placebo 1428 1392 1361 1074 694 328 Atorvastatin CARDS=Collaborative AtoRvastatin Diabetes Study. Colhoun et al. Lancet 2004;364(9435): 77

CARDS Clinical Summary
In patients with type 2 diabetes, atorvastatin 10 mg daily was safe and highly effective in reducing the risk of first cardiovascular events, including stroke Consistent effect regardless of baseline lipid level, age, or sex Number needed to treat over 4 years for benefit was 27 CARDS suggests that in patients with type 2 diabetes, overall cardiovascular risk—and not baseline LDL cholesterol level—should be the key determinant for initiating statin therapy REFERENCE Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo- controlled trial. Lancet. 2004;364(9435): CARDS=Collaborative AtoRvastatin Diabetes Study. Colhoun et al. Lancet 2004;364(9435): 78

Diabetes type 2 Landmark Outcomes Trials

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