Blood glucose: is lower better for diabetic patients? Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes

Miracle of insulin Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset 4

Chronic complications of hyperglycemia Hyperglycaemia ??

Glycemic Control on Diabetic Microvascular Complications Type 2 UKPDS 8  7% 17-21% 24-33% - HbA1c Retinopathy Nephropathy Neuropathy Type 1 DCCT 9  7% 76% 54% 60% Kumamoto 69% 70% DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998

UKPDS:Intensive glycemic control reduces microvascular complications All microvascular endpoints Cataract extraction Retinopathy Microalbuminuria 25% 24% 21% 33% Reference: UK Prospective Diabetes Study (UKPDS) 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; 352:837–853. P = 0.0099 P = 0.046 P = 0.015 P = 0.000054

Rationale for near-normoglycemia Lessons from UKPDS: Better control means fewer complications EVERY 1% reduction in HBA1C REDUCED RISK* 1% -21% Deaths from diabetes -14% Heartattacks Microvascular complications Lessons from UKPDS: better control means fewer complications The UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes. In an epidemiological analysis of the UKPDS cohort every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of diabetes-related death ( 21%) myocardial infarction ( 14%) microvascular complications ( 37%) peripheral vascular disease ( 43%) There is no lower limit beyond which reductions in HbA1C cease to be of benefit. Taking diabetes-related death as an example, this means that:  HbA1C of 2% delivers a 42% reduction in risk  HbA1C of 3% delivers a 63% reduction in risk, and so on. Therefore, the greater the reduction in HbA1C, the greater the protection against complications. Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12. -37% Peripheral vascular disorders -43% *p<0.0001 UKPDS 35. BMJ 2000; 321: 405-12

chronic complications of hyperglycemia Hyperglycaemia ??

Risk of myocardial infarction is increased in type 2 diabetes * † 60% No prior myocardial infarction Prior myocardial infarction 40% Risk of fatal or non-fatal myocardial infarction * † 20% In this Finnish-based, population study involving 2,432 individuals, patients with type 2 diabetes without any previous history of myocardial infarction (MI) were found to have as high a risk of an MI as non-diabetic patients with a history of MI. These results suggest that cardiovascular risk factors should be treated as aggressively in diabetic patients as they are in non-diabetic patients with a history of cardiovascular disease. Haffner SM. New Engl J Med 1998; 339:229–234. 0% Non diabetic subjects Type 2 diabetic subjects n = 1,304 69 890 169 Seven-year incidence in a Finnish-based cohort *P < 0.001 vs no prior MI †P < 0.001 vs no diabetes Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.

Recent Studies Evaluating Effect of Glycemic Control on CVD ACCORD ADVANCE VADT

ACCORD: Action to Control Cardiovascular Risk in Diabetes 10,251 Enrollees 60% male 40% female Mean age 62.2 Baseline HgA1c 8.1% BMI - 32 30% macrovascular dx Duration DM: 10 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group

ACCORD: Treatment effects on glucose control Time (years) Standard therapy Intensive therapy 6 9.0 8.5 8.0 7.5 7.0 6.5 6.0 1 2 3 4 5 ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

ACCORD: Treatment effect on primary outcome 25 20 Standard therapy HR 0.90 (0.78-1.04) P = 0.16 Patients with events (%) 15 10 Intensive therapy 5 1 2 3 4 5 6 Time (years) Primary Outcome: NFMI, NF Stroke or CVD Death ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

February 7, 2008 Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for)

ADVANCE Treatment effect on primary macrovascular outcome CV death, MI stroke Follow-up (months) 25 20 15 10 5 6 12 18 24 30 36 42 48 54 60 66 HR 0.94 (0.84-1.06) P = 0.32 Standard control Intensive control Cumulative incidence (%) ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

VADT - Veterans Administration Diabetes Trial Primary Endpoint: no difference in CVD outcomes Standard: 29.3% (predicted – 40%) Intensive: 27.4% (predicted – 31.6%)

The intensive approach led to confusion over the best approach It does not result in a significantly lower number of major CVA after 5 y It led to more death Reasons for the higher mortality in the intensive-therapy group are unknowns Many factors could be implicated :

The intensive approach led to confusion over the best approach Many factors could be implicated : The severe hypoglycemia ? The degree of reduction in A1c ? The relatively short intervention period (3.7 years) ? The observed The role of various drugs, drug combinations or drug interactions; weight gain ? interaction between the blood-pressure and hyperlipidemia and glycemia trials with respect to mortality ? It led to more death

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus Lipid Values Figure 1. Lipid Values. Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

Mean Systolic Blood-Pressure Levels at Each Study Visit Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus Mean Systolic Blood-Pressure Levels at Each Study Visit Figure 1. Mean Systolic Blood-Pressure Levels at Each Study Visit. I bars indicate 95% confidence intervals. The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

Survival as a function of HbA1c in people with type 2 diabetes Currie CJ, Peters JR, Tynan A et al.:Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–89

Cardiovascular safety of diabetes drugs The Truth Is Not So Sweet The goal of marely lowering blood glucose levels in diabetes is too simplistic With respect to CVD it appears important how you lower blood sugar as well as how much Diabetes drugs, even within the same “class” may yield dramatically different CV outcomes

Conclusion: is lower better for diabetic patients? The optimal mechanism, speed, and extent of glycated hemoglobin reduction are different for differing populations Yes For patients with recently diagnosed diabetes, aggressive treatment will lower cardiovascular risk No : For patients who have diabetes of more than 15 years’ duration and are older and have other comorbidities, less aggressive treatment is indicated And For all patients, treatment of the dyslipidemia and hypertension that are associated with diabetes further reduces CVD risk

The Promise Land of diabetes therapy Thank you Merci شكراً

Number of Participants With One or More Severe Hypoglycemia Events Requiring Medical Assistance (n and %) Intensive Group Standard Group # Events ** n % 1 400 7.8 130 2.5 2 82 1.6 34 0.7 3 to 5 43 0.8 10 0.2 >5 6 0.1 **Cumulative number of events The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559. 26

No! Can we blame it all on hypoglycemia? Intensive Strategy Higher Rates of Hypoglycemia Higher Mortality Intensive Strategy Higher Rates of Hypoglycemia Higher Mortality No! The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559. 27

ACCORD: Study design N = 10,251 with T2DM and existing CVD or additional CV risk factors BP trial (n) Lipid trial* (n) SBP <120 mg Hg SBP <140 mg Hg Group A Group B A1C <6% 1178 1193 1383 1374 5128 Glycemia trial A1C 7.0%-7.9% 1184 1178 1370 1391 5123 2362 2371 2753 2765 4733 5518 *Statin + fibrate vs statin, treatment group assignment blinded until end of trial Primary outcome: CV death, MI, stroke ACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i. www.accordtrial.org

A1c Levels at Baseline, at the Intensive-Therapy Group's Transition to Standard Therapy, and After the Transition in the ACCORD Trial Time of A1c assessment Intensive therapy, n=5128 (%) Standard therapy, n=5123 (%) Baseline 8.3 At transition 6.6 7.7 After transition 7.4 7.8

Tight glycemic control Any benefits mortality Tight glycemic control

Any Diabetes-related Endpoint: legacy effect Intervention Trial Median follow-up 10.0 years Intervention Trial + Post-trial monitoring Median follow-up 16.8 years RR=0.88 (0.79-0.99) P=0.029 Conventional Sulfonylurea/ Insulin

DCCT/EDIC; Memory effect Metabolic Results DCCT Intervention S t u d y Y e a r DCCT 1 2 3 4 5 6 7 8 9 EDIC Observation Training EDIC Conventional EDIC mean 8.2% Intensive EDIC mean 8.0% DCCT/EDIC Study Research Group, NEJM 2005

Outcomes Primary Secondary First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease. Secondary Death from any cause. Also measured the effect of the intervention on microvascular disease, hypoglycemia, cognition, and quality of life. cardiovascular causes included death from myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, cardiovascular causes after noncardiovascular surgery, stroke, unexpected death presumed to be from ischemic cardiovascular disease occurring within 24 hours after the onset of symptoms, and death from other vascular diseases The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

Observations Targeting HbAIC levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years Magnitude of reduction Speed of reduction Rate of hypoglycaemia Adverse drug interactions at high doses compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors. The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559. 35

The intensive approach led to confusion over the best approach Many factors could be implicated : The patients selection ?

The intensive approach led to confusion over the best approach Many factors could be implicated : The patients selection ? The severe hypoglycemia ?

The intensive approach led to confusion over the best approach Many factors could be implicated : The patients selection ? The severe hypoglycemia ? The degree of reduction in A1c ?

ACCORD: Treatment effects on glucose control Time (years) Standard therapy Intensive therapy 6 9.0 8.5 8.0 7.5 7.0 6.5 6.0 1 2 3 4 5 ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

The intensive approach led to confusion over the best approach Many factors could be implicated : The patients selection ? The severe hypoglycemia ? The degree of reduction in A1c ? The relatively short intervention period (3.7 years) ?

The intensive approach led to confusion over the best approach Many factors could be implicated : The patients selection ? The severe hypoglycemia ? The degree of reduction in A1c ? The relatively short intervention period (3.7 years) ? The observed The role of various drugs, drug combinations, or drug interactions; weight gain ? to

ACCORD: Treatment effect on all-cause mortality Time (years) 25 20 15 10 5 1 2 3 4 6 Standard therapy Intensive therapy HR 1.22 (1.01-1.46) P = 0.04 CVD Death: HR 1.35 (1.04–1.76) P=0.02 Patients with events (%) ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

ADVANCE: Action in Diabetes and Vascular Disease Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM 11,140 Enrollees 60% male 40% female Mean age 66 50% macrovascular dx 10% microvascular Baseline HgA1c: 7.51% “standard” : 7.30% Intensive: 6.53%

ADVANCE Treatment effect on glucose control Follow-up (months) Standard control Intensive control 10.0 9.0 8.0 7.0 6.0 5.0 0.0 6 12 18 24 30 36 42 48 54 60 66 P < 0.001 Mean A1C (%) ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

ADVANCE 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk Intensive (A1c 6.4%) vs Conventional (A1c 7.3%) Benefit with regard to microvascular complications No Excess Mortality In Intensive Group

VADT - Veterans Administration Diabetes Trial BMI 31.3 Majority had multiple CV risk factors 72% HTN 40% macrovascular dx 62% retinopathy 43% neuropathy 1742 Enrollees 97% male Mean age 60.4

confusion over the best approach to cardiovascular risk reduction

Patients selection in ACCORD & UKPDS Duration DM: 10 years 30% macrovascular dx Majority of intensive group on 3-5 oral agents plus insulin UKPDS Newly diagnosed Less CVD Less therapeutic combinations

What HbA1c goal should we try to achieve? In newly diagnosed diabetes, the goal is clear: treat to a target HbA1c =6.5-7% (Take advantage of the legacy effect and metabolic memory) In older patients with multiple comorbidities and diabetes of long duration; The HbA1c =7.5% and 8% may be more appropriate To reduce the CVD, treat the dyslipidemia and hypertension In some patients who have had diabetes for more than 10 years: may not be able to sense hypoglycemiaglucose monitoring In patients whose hyperglycemia is not coming down despite our best efforts (multiple antihyperglycemic agents): it may be appropriate to try to determine the cause of the inadequate response