1. Drug Treatments in Type 2 Diabetes
Dr Richard Brice MB BCh MA MRCGP
GPSI in Diabetes
Chairman, Whitstable Medical Practice

2. Prevalence ( % of population)
UK Trends for Diabetes
Equivalent to 3.9% of the population
Prevalence ( % of population)
UK Prevalence Trends for Diabetes
The number of people being diagnosed with diabetes has been increasing dramatically over recent years. Currently there are around 2.5 million people in the UK with diabetes and an estimated further 0.5 million who remain undiagnosed. Projections estimates that by 2025 over 4 million people will be diagnosed with diabetes. The trend is influenced by several factors:
Increasing incidence of obesity (especially central obesity)
Decreased physical activity
Patients are being diagnosed younger
Diabetes is slightly more prevalent in men than women and is more common in middle aged and older people.
Ethnicity also affects the incidence of diabetes. Prevalence is as high as 10% in Indian and Black Caribbean men (5.9% and 8.4% for women respectively). Other races that show high prevalence are Bangladeshi (8.2%), Pakistani (7.3%) and Black Africans (5%).
However, recently type 2 diabetes is being seen in younger people. In 2000 the first diagnosis of type 2 diabetes in children was made in overweight girls of Pakistani, Indian or Arabic origin age Type 2 diabetes was first reported in white adolescents in 2002.
Diabetes UK Report “Diabetes in the UK” 2009
National diabetes prevalence
Forecast
Diabetes UK Report “Diabetes in the UK” (2009)

3. 3

4. ©2005. American College of Physicians. All Rights Reserved.

5. ©2005. American College of Physicians. All Rights Reserved.

6. Diabetes: An NHS priority
Diabetes is an NHS priority. The National Service Framework of 2001 set 12 standards for care. This was followed by the Delivery Strategy published in January 2003 to support implementation. Since then there have been subsequent annual reviews of progress – the most recent, The Way Ahead: The Local Challenge of Improving Diabetes Services, Four Years On, was published in March 2007.
There have been a number of significant reports since the publication of the NSF including:
Working Together for Better Diabetes Care: the clinical case for change’ published May 2007
‘Making Every Young Person with Diabetes Matter’ working group set up in 2005, report published April 2007
Healthcare Commission Service Review of Diabetes ‘Managing Diabetes: Improving services for people with diabetes’ published by the Healthcare Commission July 2007
Diabetes, Heart Disease and Stroke Prevention project launched March 2008
Diabetes Commissioning Toolkit launched November 2006
‘Care Planning in Diabetes: Report from the joint Department of Health and Diabetes UK Care Planning Working Group’ published jointly by the joint Department of Health and Diabetes UK Care Planning Working Group on 4th December 2006
In May 2008 Clinical Guideline 66 – Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (Update) was published replacing previous guidance.
In primary care the priority accorded to diabetes is highlighted by the fact that there are 18 indicators for reward.
UK/LR/0809/0366

7. The Cost of Diabetes to the NHS Budget
10% = £1m per hour
The Cost of Diabetes to the NHS Budget
It is currently estimated that 10% of the NHS budget is spent on diabetes1. Based on the 2007/2008 budget for the NHS of approximately £90.7billion2, this works out about £9billion/year -so that is £173 million/week or £1million/hour.
One in 10 people admitted to hospital has diabetes and in some age groups this can be as high as 1 in 5. Diabetes prescribing now accounts for 7% of all prescribing costs.
1.Department of Health (2006). Turning the corner improving diabetes care
_ pdf
2. NHS Confederation. Key statistics on the NHS
Costs are increasing as a result of the obesity epidemic, sedentary lifestyles and an ageing population
Diabetes UK Report “Diabetes in the UK” (2009)

8. The Burden for People with T2D
60-70% will die of cardiovascular disease1
Almost 1 in 3 will develop overt kidney disease2
Commonest cause of blindness in the working population3
Up to 50% will develop neuropathy4
Commonest cause of lower limb amputation5
Depression twice as common compared with the general population6
Sexual dysfunction is a problem7,8
(prevalence not known)
The Burden for People with T2D
Having T2D not only impinges on people’s lifestyle but carries the risk of developing a plethora of other disease conditions. As well as health consequences T2D can affect mental well-being and sexual function.
1.Duckworth et al. NEJM, 2009;
2. Department of Health (2006). Turning the corner: improving diabetes care
h_ pdf
3.Hamilton AMP, Ulbig MW, Polkinghorne P (1996). Management of diabetic retinopathy, London: BMJ Publishing
4. Boulton AJM (2005). Management of diabetic peripheral neuropathy. Clinical Diabetes 23; 9–1 5. This figure is based on four different studies in which estimates of neuropathy range from 66 per cent in people with Type 1 diabetes over 60 years of age to per cent in people who been diagnosed for over seven years.
5. National Diabetes Support Team (2006). Diabetic foot guide
6. Katon W, von Korff M, Ciechanowski P et al (2004). Behavioral and clinical factors associated with depression among individuals with diabetes. Diabetes Care 27; 914–920.
7. Al-Hunayan J, Al-Mutar M, Kehinde EO et al (2007). The prevalence and predictions of erectile dysfunction in men newly diagnosed with Type 2 diabetes mellitus. BJU International 99 (1); 130–134
8.Diabetes in the UK 2009:Key Statistics in Diabetes. Diabetes UK
1 Duckworth et al NEJM, 2009;360:129-39;2 DoH (2006); 3Hamilton et al. Management of diabetic retinopathy, London 1996: BMJ Publishing; 4Boulton, Clin Diabetes 2005; 23: 9–15; 5National Diabetes Support Team (2006). Diabetic foot guide; 6Katon et al Diabetes Care 2004;27: 914–920. 7Al-Hunayan et al. Br J Urol Int 2007;99 (1): 130–134; 8Diabetes in the UK 2009:Key Statistics in Diabetes. Diabetes UK

9. Life Expectancy and Diabetes
Life expectancy is decreased by 5–10 yrs in type 2 diabetes
Life Expectancy and Diabetes
Adults with diabetes have an annual mortality of about 5.4% - double the rate for non-diabetic adults. Average age at diagnosis is 53 years. A person diagnosed in their 50s can potentially lose 10 years in life expectancy.
Although the increased death rate is mainly due to cardiovascular disease, death from non-cardiovascular causes are also increased. A diagnosis of diabetes increases the risk of developing various complications that are largely irreversible and are due to vascular disease at both the microvascular and macrovascular level.
Goodkin, J Occup Med 1975; 17: 716–721
Donnelly et al. BMJ 2000; 320:1062–1066
Goodkin, J Occup Med 1975; 17: 716–721; Donnelly et al. BMJ 2000; 320:1062–1066

10. T2D: the Challenge Insulin Resistance Hyperinsulinaemia
Obesity
Atherosclerosis
Hypertension
Insulin Resistance
Diabetes & Vascular
Disease
Hyperinsulinaemia
Dyslipidaemia
Thrombosis
People who have T2D are affected by the interrelated conditions of hyperinsulinaemia and insulin resistance.
The condition is frequently accompanied by a well defined cluster of other conditions such as obesity, hypertension, and dyslipdaemia that pre-dispose to micro- and macro-vascular disease.
In T2D the primary need is to prevent long-term complications but it is important to note that, hyperinsulinaemia is an independent cardiovascular risk factor in its own right. The “core” issues of insulin resistance and hyperinsulinaemia both need to be adddresed.
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 22 (7): 1183–1203
Hyperglycaemia

11. Targets Amenable to Pharmacotherapy
HbA1c < 7.0% (53 mmol/ml)
BP <130/80
Total cholesterol <4.0, LDL <2.0

12. NICE BP Algorithm 2008
NICE Clinical Guideline 66 Type 2 Diabetes (update) 2008 12

13. Lipid Management Get them on a statin, usually simvastatin 40mg
Aim for total cholesterol <4.0 and LDL <2.0
In statin intolerance, encourage several different statins
Even a low dose of a statin is better than any other lipid lowering Rx
Plant sterols etc should be an adjunct to statin treatment, not a substitute

14. Relation between the proportional reduction in MAJOR VASCULAR EVENTS and mean absolute LDL reduction in 14 statin trials
Cholesterol Treatment Trialists Collaboration (Lancet 2008: 371: )

15. Alsheikh-Ali et al J Am Coll Cardiol 2007;50:409-1815

16. STELLAR - Efficacy Change in LDL-C at 6 weeks
Change in LDL-C from baseline (%) –5
–10
–15
–20
–25
–30
–35
–40
–45
–50
–55
–60 10 mg * 20 mg † 40 mg ‡
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg 80 mg
Supplementary slide
This slide contains the same data as the previous slide but with a different graphical representation.
Rosuvastatin 10–40 mg reduced LDL-C by 45.8–55.0% compared with 36.8–51.1% with atorvastatin 10–80 mg, 28.3–45.8% with simvastatin 10–80 mg and 20.1–29.7% with pravastatin 10–40 mg.
Rosuvastatin 10 mg produced statistically significantly greater reductions in LDL-C compared with atorvastatin 10 mg, simvastatin 10, 20 and 40 mg, and pravastatin 10, 20 and 40 mg.
Rosuvastatin 20 mg produced statistically significantly greater reductions in LDL-C compared with atorvastatin 20 and 40mg, simvastatin 20, 40 and 80 mg, and pravastatin 20 and 40 mg.
Rosuvastatin 40 mg produced statistically significantly greater reductions in LDL-C compared with atorvastatin 40 mg, simvastatin 40 and 80 mg, and pravastatin 40 mg.
Reference
Jones PH et al for the STELLAR Study Group. Comparison of efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003; 92: 152–160. 10 mg 20 mg 40 mg
Rosuvastatin 10 mg (–46%)
*p<0.002 vs ATV 10mg; SIM 10, 20, 40mg; PRA 10, 20, 40mg
†p<0.002 vs ATV 20, 40mg; SIM 20, 40, 80mg; PRA 20, 40mg
‡p<0.002 vs ATV 40mg; SIM 40, 80mg; PRA 40mg 16
Jones PH et al. Am J Cardiol 2003; 92: 152–160

17. Normal Islet Function: Glucose Regulation17

18. Natural History of Type 2 Diabetes
Years from
diagnosis
-10 -5 5 10 15
Onset
Diagnosis
Insulin resistance
Insulin secretion
Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Pre-diabetes
Type 2 diabetes
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ;
Nathan DM. N Engl J Med ;347:

19. Major Metabolic Defects in T2D
Insulin resistance
-cell dysfunction
glucose output
VLDL production
 glucose uptake and metabolism
glucose uptake
(↑lipolysis )
Major Metabolic Defects in T2D
T2D is underpinned by two core defects – insulin resistance and worsening -cell function. As T2D progresses over time, developing insulin resistance precedes the decline in insulin production.
As resistance develops in the liver, it increases its glucose output and VLDL production. Peripherally both muscle and fat tissue show impaired responses to insulin by a decrease in the amount of glucose taken up from the blood and metabolised. This contributes to the hyperglycaemia in the blood. Fat tissue also shows decreased lipolysis.
Impaired feedback on insulin release results in hyperinsulinaemia and ultimately “exhaustion” of the  cells.
With deteriorating control of blood sugar, the risk of atherosclerotic disease and consequent ischaemic cardiovascular events increases. This can give important clues to choice of hypoglycaemic agents.
Hyperglycaemia (and dyslipidaemia)
Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol. 1999;58:

20. Postprandial Glucagon Is Inappropriately Elevated in Type 2 Diabetes
Nondiabetic Subjects†
Meal
360
Hyperglycaemia
Deficient Insulin
Release
Glucagon
Not Suppressed
(Postprandially)
Defects in Diabetes
Glucose (mg/%)
300
240
110 80
DISCUSSION
In patients with diabetes, postprandial glucagon does not fall, in spite of hyperglycaemia.
Additionally, there is a paradoxical increase in glucagon secretion during the first hour postprandially in patients with diabetes.
BACKGROUND
The effect of large carbohydrate or protein meals on plasma glucagon was compared in 14 control patients and 24 patients with diabetes. Insulin and plasma glucose levels were also measured.
Control patients consumed an average of 107  11 (SEM) grams (g) carbohydrate; mean plasma glucagon levels fell from the fasting value of 126  15 to 90  11 µµg/mL.
12 patients with diabetes consumed meals containing an average of 120  16 (SEM) g carbohydrate; mean plasma glucagon levels rose slightly above the fasting value of 124  15 to 142  18 µµg/mL.
120
Insulin‡ (µU/mL) 60
140
Glucagon (µg/mL)
120
100
-60 60
120
180
240
Time (min)
Mean ± SEM;*N = 14; †N = 12; ‡mean insulin values N = 5.
Adapted from Muller WA, et al. N Engl J Med. 1970;283:
Copyright © 1970 Massachusetts Medical Society. All rights reserved. Translated with permission 2005.

21. The Incretin Effect Demonstrates the Response to Oral vs IV Glucose
Oral Glucose IV Glucose 11
2.0 *
1.5
DISCUSSION
Despite the same plasma glucose profiles, there are significant differences in the -cell response to oral versus (vs) intravenous glucose, as measured by C-peptide.
BACKGROUND
This was a crossover study involving healthy subjects.
Six young healthy subjects were given a 25, 50, or 100 g oral glucose load or isoglycaemic intravenous glucose infusions. The 50-g data is shown above.
C-peptide may be a better measure of insulin secretion than plasma insulin, because C-peptide levels are not affected by hepatic insulin extraction.
This difference in C-peptide levels in response to oral vs intravenous glucose suggests that other factors (incretins), and not merely the direct actions of plasma glucose, affect the insulin secretory response.
Incretin Effect
5.5
C-peptide (nmol/L)
1.0
Venous Plasma Glucose (mmol/L)
0.5
0.0 02 01 02 60
120
180 01 60
120
180
Time (min)
Time (min)
Mean ± SE; N = 6; *P .05; = glucose infusion time.
Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: Copyright The Endocrine Society. 21

22. GLP-1 Effects in Humans Promotes satiety and reduces appetite
DISCUSSION
By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis.
Upon food ingestion, GLP-1 is secreted into the circulation.
GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion.
BACKGROUND
GLP-1 is secreted from L cells of the small intestine.
GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:
Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:
Alpha cells:
↓ Postprandial glucagon secretion
Liver: ↓ Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes.1998;47:

23. The Incretin Effect Is Reduced in Patients With Type 2 Diabetes
Intravenous Glucose
Oral Glucose
Control Subjects
Patients With Type 2 Diabetes 80 80
DISCUSSION
The -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with diabetes.
Patients with diabetes exhibited a greater -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion.
BACKGROUND
Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. measured insulin and C-peptide responses to a 50-g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses.
Insulin measurements are shown here.
Plasma insulin responses were studied for 14 patients
This study with type 2 diabetes and 8 metabolically healthy control subjects. 60 60
Insulin (mU/L) 40 40 * * 20 20 30 60 90
120
150
180 30 60 90
120
150
180
Time (min)
Time (min)
*P ≤.05 compared with respective value after oral load.
Nauck MA, et al. Diabetologia. 1986;29: Reprinted with permission from Springer-Verlag © 1986. 23

24. Postprandial GLP-1 Levels Are Decreased in Patients With Type 2 Diabetes
Normal Glucose Tolerance Impaired Glucose Tolerance
Type 2 Diabetes
Meal 20 * * * * *
DISCUSSION
Over the time period from 60 to 150 minutes, postprandial GLP-1 concentrations were statistically significantly reduced in patients with type 2 diabetes compared with subjects with normal glucose tolerance (P<.05 between the type 2 diabetes and normal glucose tolerance groups).
BACKGROUND
The primary objective of this study was to investigate potential reasons for the diminished incretin effect observed in type 2 diabetes mellitus.
The sample consisted of 54 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 33 control subjects.
This study measured the secretion of GLP-1 and GIP, fatty acids, and plasma concentrations of insulin, C-peptide, pancreatic polypeptide, and glucose.
Plasma concentration of GLP-1, shown here, was measured using an antibody code specific for the C-terminus of GLP-1, which measures the sum of GLP-1 (7-36) amide and its metabolite GLP-1 (9-36) amide.
The study concluded that decreased meal-related GLP-1 response in type 2 diabetes may contribute to the decreased incretin effect in type 2 diabetes. * 15 *
GLP-1 (pmol/L) 10 5 60
120
180
240
Time (min)
Mean ± SE; N = 102; *P <.05 between T2DM and NGT groups.
Toft-Nielsen M, et al. Determinants of the impaired secretion of glucagon-like peptide 1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86: Copyright The Endocrine Society.

25. GLP-1 Effects in Humans Promotes satiety and reduces appetite
DISCUSSION
By decreasing β-cell workload and improving β-cell response, GLP-1 is an important regulator of glucose homeostasis.
Upon food ingestion, GLP-1 is secreted into the circulation.
GLP-1 increases β-cell response by enhancing glucose-dependent insulin secretion.
BACKGROUND
GLP-1 is secreted from L cells of the small intestine.
GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:
Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:
Alpha cells:
↓ Postprandial glucagon secretion
Liver: ↓ Glucagon reduces hepatic glucose output
Beta cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes.1998;47:

26. Continuously infused GLP-1 nearly normalizes BG in patients with T2D.
Main Point:
Continuously infused GLP-1 nearly normalizes BG in patients with T2D.
Discussion:
• Continuously infused GLP-1 nearly normalized both basal and postprandial blood glucose in patients with T2D
• Plasma glucose levels were measured overnight and during the day (22:00 to 17:00) in healthy subjects and in patients with T2D
• In healthy subjects, mean glucose levels were 5.6 mmol/L (101 mg/dL) during the overnight period; they rose modestly after meals and then returned to baseline
• In patients with T2D, mean fasting glucose concentrations were 7.8 mmol/L (141mg/dL) and rose markedly during the meal periods
• When these patients were infused intravenously with GLP-1 at a rate of 1.2pmol/kg/minute, their glucose levels were nearly normalised, including the responses to meals
SLIDE BACKGROUND
• The effect of continuous IV infusion of GLP-1(7-36) amide on glucose concentrations during the overnight period and after three standard meals was studied in patients with T2D (n=7) and compared with responses to 0.9% saline infusion in T2D patients and in healthy subjects (n=6)
• Glucose control was assessed overnight in each individual by time-averaged mean of values from 2400 to 0800 hours, and during the day by time-averaged mean of values from 0800 to 1700 hours
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27. DPP-4 Inhibitors: Rationale
Mixed Meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
Both GLP-1 and glucose-dependent insulinotropic peptide (GIP) are incretins; i.e., gut peptides that are released from the GI tract in response to a meal to potentiate glucose-dependent insulin release.1 The physiologic role of incretin hormones in maintaining glycemic control suggests that the incretin axis is a potential target for therapeutic intervention in type 2 diabetes.1 After their release into the circulation, both GLP and GIP are degraded by the enzyme dipeptidyl peptidase IV (DPP-IV).2
Prevention of the degradation of GLP-1 and GIP to their inactive metabolites via DPP-IV inhibition therefore may represent a rational approach to the treatment of type 2 diabetes.1
DPP-4
GLP-1 (9-36)
inactive
DPP-4 inhibitor
DPP-IV=dipeptidyl peptidase IV
Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372.
References
Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Invest Drugs 2003;12(1):87–100.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. 27

28. Treating T2D – the Challenge
Address insulin resistance
Concordance with multiple therapies
Preserve -cell function
To address core defects as well as their sequelae
Therapy limitations
Prevent/delay vascular complications
Management of dyslipidaemia
Durable glycaemic control
T2D – the Challenge
Treating T2D presents many challenges. The core defects of insulin resistance and diminishing -cell function must be addressed, but at the same time the patients’ cardiovascular health must be protected as much as possible. Hence it is important to not only strive to achieve glycaemic control, but to also measure blood pressure and blood lipids and treat appropriately.
Such an approach inevitably leads to polypharmacy and patients may need to take several tablets per day. This introduces problems of concordance with therapy that may compromise outcome.
In the DARTS study (Diabetes Audit and Research in Tayside Scotland) Donnan et al. tested the hypothesis that taking one tablet per day was associated with better adherence than taking multiple tablets, in a retrospective cohort of 2920 patients with Type 2 diabetes receiving at least 12 months prescriptions with a single oral antidiabetic agent.
Adequate adherence (>90%) was found in 31% or 34% of those prescribed sulphonylurea or metformin alone, respectively. Additionally, there were significant trends of poorer adherence with each increase in co-medication for sulphonylureas alone after adjustment for other factors (p=0.0001) and the number of sulphonylurea tablets taken per day (p=0.001).
Donnan et al Diabetic Medicine, 2002;19:
Management of hypertension 28

29. UKPDS: a 1% Reduction in HbA1c Significantly Reduced the Risk of Diabetes-related Complications
Any diabetes-related endpoint†
Diabetes- related deaths
Amputation or death from PVD
Microvascular complications
Myocardial infarction
Stroke
** -12%
* -14%
Reduction in risk (%)
* -21%
* -21%
UKPDS: a 1% Reduction in HbA1c Significantly Reduced the Risk of Diabetes-related Complications
This slide shows results from the UKPDS study, demonstrating that a 1% reduction in HbA1c can reduce the risk of diabetes related complications
This study and other supporting evidence has led to the current glycaemic targets set out in various guidelines for the management of Type 2 diabetes. For example:
NICE <6.5% and <7.5%
QOF Target HbA1c < 7.0, 8.0 and 9.0%
ADA/EASD <7% (aiming for normal glycaemia)
IDF <6.5%
* -37%
* -43%
Median follow up = 10 years, n = 3642 for relative risk analysis †Primary endpoint; *p<0.0001; **p=0.035
UKPDS = United Kingdom Prospective Diabetes Study; PVD = peripheral vascular disease
Stratton et al. BMJ 2000;321:405–412

30. Currently Available Treatments for Glycaemic Control in T2D
Sulphonylureas and Meglitinides
Increase insulin secretion from pancreatic -cells
Biguanides (metformin)
Decrease hepatic glucose production and increase glucose uptake
Glitazones
Increase insulin sensitivity and glucose uptake in skeletal muscle. Decrease lipolysis in adipose tissue and decrease hepatic glucose output.
DPP-4 inhibitors
Prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release
GLP-1 agonists
Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying
Pharmacologic Targets of Current Drugs Used in the Treatment of T2D
The number of antihyperglycemic drugs for use either alone, in combination, or with insulin has grown in recent years, and includes agents with widely differing mechanisms of action.1
The major mechanism of action of biguanides (eg, metformin) is to decrease hepatic glucose output primarily by decreasing gluconeogenesis and, to a lesser degree, increasing glucose uptake by skeletal muscle.1
Sulphonylureas (SUs; eg, glimepiride, glyburide) and meglitinides (eg, nateglinide, repaglinide) stimulate insulin secretion from the β-cell. SUs bind to a specific cell-surface receptor causing metabolic changes that promote exocytosis of insulin-containing vesicles.
Meglitinides also bind to the SU receptor with similar effects, although with a relatively prompt and brief stimulatory effect.1
α-glucosidase inhibitors (eg, acarbose) do not target any specific pathophysiological defect in Type 2 diabetes mellitus. Rather, they act by inhibiting α-glucosidase and other intestinal brush-border enzymes responsible for the breakdown of oligosaccharides and disaccharides to monosaccharides suitable for absorption.1
Glitazones (eg, rosiglitazone, pioglitazone) act as insulin sensitizers, particularly in peripheral tissues. They bind to a specific nuclear receptor active in adipocytes and muscle cells, promoting the expression of various genes involved in carbohydrate and lipid metabolism.1
Glucagon-like peptide (GLP-1) is an incretin hormone released by gut cells in response to food intake, promoting pancreatic islet activity. Unlike the other agents described here, GLP-1 agonists (eg exenatide, liraglutide) are not orally available and must be injected.2
By inhibiting dipeptidyl peptidase-4 (DPP-4), DPP-4 inhibitors such as sitagliptin or vildagliptin prolong the action of GLP-1 to stimulate insulin secretion and suppress glucagon release in response to glucose.2
Insulin is normally the final addition to the regimen for those with inadequate glucose control with optimised oral drugs. It is the most effective hypoglycaemic agent, being capable, when used in adequate doses, of lowering any elevated HbA1c level to, or close to, the therapeutic goal.
Cheng AY, Fantus IG. Oral antihyperglycemic therapy for Type 2 diabetes mellitus. CMAJ 2005; 172:
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase- 4 inhibitors in Type 2 diabetes. Lancet 2006; 368:
-glucosidase inhibitors
Delay intestinal carbohydrate digestion and absorption
Insulins
Increase glucose uptake in skeletal muscle and reduce hepatic glucose production
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=Type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ 2005; 172: 213–226. 30

31. HbA1c cross-sectional, median values
UKPDS 33 Lancet 1998; 352:

32. Aggregate Clinical Endpoints
UKPDS 33 Lancet 1998; 352:

33. HbA1c overweight patients cohort, median values
UKPDS Group. Lancet 1998;352:854-65

34. Change in Weight overweight patients cohort, mean values
UKPDS Group. Lancet 1998;352:854-65

35. Hypoglycaemic episodes per annum
Actual Therapy analysis
overweight patients
Conventiona l Metformin Chlorpropramide Glibenclamide Insulin
UKPDS Group. Lancet 1998;352:854-65

36. Myocardial Infarction
overweight patients
M v C p=0.010
M v I p=0.12
UKPDS Group. Lancet 1998;352:854-65

37. UKPDS: benefit of metformin in overweight Type 2 diabetes patients*45
p = 0.017
p = 0.01 40
p = 0.011 35
p = 30 25
Risk reduction (%) 20 15 10
In the UKPDS, treatment with metformin was associated with a reduction in any diabetes-related endpoints, diabetes-related deaths, all-cause mortality and myocardial infarction.
It was the only therapy studied that reduced deaths.
References
United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865. 5
Diabetes-related endpoints
Diabetes-related deaths
All-cause mortality
Myocardial infarction
*Compared to conventional treatment group
United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865. 37

38. What is hypoglycaemia?
Hypoglycaemia (or a ‘hypo’) occurs when the level of glucose in the blood falls too low
Clinical definition of hypoglycaemia1:
Mild – when a person can self-treat the episode
Severe – an episode that requires external medical assistance or assistance from another person to recover
1. Barnett et al. Int J Clin Pract. 2010

39. Causes of hypoglycaemia
Anti-diabetes treatment (for example insulin and sulphonylureas)1
Irregular eating habits or delayed eating2
Exercise, either when an individual is more physically active than usual or regular exercise without sufficient food intake2
Alcohol consumption, particularly in those on anti-diabetes treatments or where there is also insufficient food intake2
1. Zammit and Frier, Diabetes Care, Vol 28, No 12, 2005
2. Barnett et al. Int J Clin Pract. 2010 39

40. Specific risk factors for severe hypoglycaemia in type 2 diabetes
Diabetes medication, particularly insulin and sulphonylureas 1
Intensive glycaemic control 2,3
Extremes of age- older people due to of cognitive decline, younger people because of impaired awareness and ability to self-treat 1,4,5
Long duration of diabetes 1
History of previous severe hypoglycaemia 5
Impaired awareness of hypoglycaemia 6,7
Sleep (via impaired awareness/autonomic response to hypoglycaemia)8
Renal impairment 1
Periods of fasting e.g. Ramadan, clinical investigations
1. Amiel SA et al. Diabet Med. 2008;25(3):245–254
2. Wright et al. J Diabetes Complications. 2006;20:395–40
3. California Healthcare Foundation. J Am Ger Soc. 2003;51(5, suppl):S265–S280,
4. Matyka K et al. Diabetes Care. 1997;20(2):135–141,
5. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S62–S64,
6. Chico A et al. Diabetes Care. 2003;26(4):1153–1157
7. Henderson JN et al. Diabet Med. 2003;20:1016–1021,
8. Cryer, P. E. Diabetes , 40

41. Risk factor: Age Hypoglycaemia in the elderly
Advanced age is a risk factor for hypoglycaemia and many individuals will have had diabetes for several years 1
Symptoms of hypoglycaemia in elderly patients can include neuroglycopenic symptoms, such as weakness, drowsiness, poor concentration, dizziness and confusion and neurological symptoms such as blurred vision, lack of co-ordination and slurred speech 2
Many of the prominent symptoms of hypoglycaemia in elderly people may be misinterpreted as other neurological conditions such as transient cerebral ischaemia, vertebrobasilar insufficiency or vasovagal attacks 2
Elderly people may, in general, have reduced awareness of hypoglycaemia symptoms 3
1. Amiel SA et al. Diabet Med. 2008;25(3):245–254
2. McAulay et al. Diabetic Medicine. 2001; 18:
3. Matyka K et al. Diabetes Care. 1997; vol 20;2:

42. What are the Symptoms of Hypoglycaemia?
Autonomic symptoms (these act as a warning signal): palpitations, pallor, sweating, nausea, tremor, anxiety, dilated pupils.
Generally occur at glucose levels <4
Neuroglycopaenic symptoms (where glucose levels are too low for the brain to function optimally: confusion, slurred speech, personality change, double vision, seizures, coma
Generally occur at glucose levels <3
Hunger may occur at a wide variety level of blood glucose levels, and is a very non-specific symptom

43. Endocrine, symptomatic and neurological responses to acute hypoglycaemia in non- diabetic subjects
5.0
4.0
3.0
2.0
1.0
4.6 mmol/L
Inhibition of endogenous insulin secretion
3.8 mmol/L
Counterregulatory hormone release
Glucagon
Adrenaline
mmol/L
mmol/L
Onset of symptoms
3.0 mmol/L
Neurophysiological
dysfunction
Evoked responses
Onset of EEG changes
Arterialised venous blood glucose concentration (mmol/l)
2.8 mmol/L
Cognitive
dysfunction
Inability to perform complex tasks
Severe neuroglycopenia
Reduced conscious level
Convulsions
Coma
<1.5 mmol/L
Adapted from: Hypoglycaemia and Clinical Diabetes”, 2nd edition, Eds. Frier BM and Fisher M, 2007, John Wiley and Sons, Chichester

44. The glycaemic threshold for hypoglycaemia symptom response alters with age2
2.5 3
3.5 4
Blood
glucose
(mmol/L)
symptoms
reaction time
(defined as 4-choice reaction time test)
younger men n=7
(22-26 years)
older men n=7
(60-70 years)
younger men
Glycaemic thresholds for subjective symptomatic awareness of hypoglycaemia and for the onset of cognitive dysfunction in young and elderly non-diabetic males
In young adult males awareness of symptoms occurred when blood glucose was 3.6 mmol/L, but impairment in cognitive function occurred at 2.6 mmol/L
In older males these thresholds are much closer together - awareness of symptoms occurred almost simultaneously with cognitive decline
Hypoglycaemia and Clinical Diabetes”, 2nd edition, Eds. Frier BM and Fisher M, 2007, John Wiley and Sons, Chichester
(Adapted from: Matyka et al (1997) Diabetes Care 20: 135)

45. Frequency of severe hypoglycaemia increases over time50 40 30 20 10
Annual prevalence of severe hypoglycaemia (%)
Severe: requiring external assistance
T2DM SU
T2DM
< 2 yrs
T2DM
> 5 yrs
T1DM
< 5 yrs
T1DM
> 15 yrs
Type 2 DM sulphonylureas n =103
Type 2 DM <2 years insulin n = 85
Type 2 DM >5 years insulin n = 75
Type 1 DM <5 years n = 46
Type 1 DM >15 years n = 54
Error bars = 95% confidence intervals
Adapted from: UK Hypoglycaemia Study Group (2007) Diabetologia 50: 1140

46. Morbidity of hypoglycaemia in diabetes
Brain
Blackouts, seizures, coma
Cognitive dysfunction
Psychological effects
Cardiovascular
Myocardial ischaemia (angina and infarction)
Cardiac arrhythmia
Musculoskeletal
Falls, accidents (driving)
Fractures, dislocations

47. Driving and diabetes
The DVLA issue ‘Medical Rules’ on a number of conditions, including diabetes
For up-to-date guidance please visit the DVLA or direct.gov.uk websites:
‘Information for drivers with insulin diabetes’
‘Information for drivers of cars or motorcycles with diabetes treated by tablets, diet, or both’
Physicians should ensure that patients with diabetes are aware of the DVLA regulations and guidance in relation to hypoglycaemia and driving 1. 47

48. Increasing HCP awareness around hypoglycaemia in type 2 diabetes
GPs, practice nurses and pharmacists need to:
Be aware of the prevalence of hypoglycaemia in patients with type 2 diabetes
Recognise the causes and risk factors for hypoglycaemia in type 2 diabetes
Inform patients of the risks
Be aware that patients may use different language
‘I feel a bit hungry late mornings especially if I’ve been out shopping’ or ‘I have dizzy dos’ 48

49. Glycaemic Levels During the DCCT/EDIC
DCCT/EDIC Study Research Group.N Engl J Med. 2005;353:

50. CV death, nonfatal MI, stroke*
DCCT/EDIC: Intensive glucose control associated with reduced long-term CV risk
N = 1441 with type 1 diabetes, mean baseline age 27
0.12
52 events
0.12
42% Risk
(9%–63%)
P = 0.02
57% Risk
(12%–79%)
P = 0.02
0.10
0.10
0.08
0.08
CV death, nonfatal MI, stroke*
Any initial CV event*
25 events
0.06
0.06
0.04
0.04
31 events
11 events
0.02
0.02
DCCT/EDIC: Intensive glucose control associated with reduced long-term CV risk
The Diabetes Control and Complications Trial (DCCT) compared the effects of intensive vs conventional diabetes treatment on the long-term incidence of CV disease in patients with type 1 diabetes who were treated for 6.5 years.
At the end of DCCT, participants on intensive therapy had a mean A1C level of 7.4% vs 9.1% in the conventional-treatment group.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study followed 97% of the DCCT subjects for an additional 11 years after treatment ended in a post-trial observational study.
At the end of the follow-up, the intensive-therapy group had a 42% relative reduction in the risk of CV events and a 57% relative reduction in the risk of severe clinical events, including nonfatal MI, stroke, and CV death, compared with the group that had received conventional treatment. 5 10 15 20 5 10 15 20
Time (years)
DCCT ends
DCCT ends
A1C 7.4% vs 9.1%
Conventional
Intensive
DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:
*Cumulative incidence

51. HbA1c cross-sectional, median values
UKPDS 33 Lancet 1998; 352:

52. Post-Trial Changes in HbA1c
UKPDS results presented
Mean (95%CI)
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

53. Microvascular Disease Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
(photocoagulation, vitreous haemorrhage, renal failure)
HR (95%CI)
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

54. Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

55. All-cause Mortality Hazard Ratio
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

56. Blood-glucose lowering therapy – Therapeutic Choices Standard approach
Consider
First
Metformin SU
HbA1c ≤ 6.5%
Monitor for deterioration
Alternative approach
As per CG66
As per CG66
HbA1c ≤ 6.5%
Monitor for deterioration
Consider
Second SU
TZD
DPP-4 inhibitor
As per CG66
Add to Met
Add to SU
Add to Met
Add to SU
Consider
Third
NPH Insulin
Other Insulin
TZD
Sitagliptin
Exenatide
Acarbose
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66
Added to Met + SU
Added to Met + SU if poor response to DPP-4 inhib or not tolerated.
Added to Met + SU
Added to Met + SU if poor response to TZD or not tolerated.
1. Added to Met + SU
As per CG66
NICE CG87 – a sequential treatment-oriented view of the whole algorithm for glycaemic management
Consider
Fourth
NPH Insulin
Other Insulin
HbA1c < 7.5%
Monitor for deterioration
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66

57. Blood-glucose lowering therapy – Therapeutic Choices
Standard approach
Consider
First
Metformin SU
Alternative approach
As per CG66
As per CG66
Consider sulfonylurea here if:
patient is not overweight (tailor the assessment of body-weight-associated risk according to ethnic group), or
metformin is not tolerated or is contraindicated, or
a rapid therapeutic response is required because of hyperglycaemic symptoms
Consider
Second SU
TZD
DPP-4 inhibitor
As per CG66
Add to Met
Add to SU
Add to Met
Add to SU
Consider
Third
NPH Insulin
Other Insulin
TZD
DPP-4 inhibitor
Exenatide
Acarbose
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66
Added to Met + SU
Added to Met + SU if poor response to DPP-4 inhib or not tolerated.
Added to Met + SU
Added to Met + SU if poor response to TZD or not tolerated.
1. Added to Met + SU
As per CG66
NICE CG87 – SU notes
Consider
Fourth
NPH Insulin
Other Insulin
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66

58. HbA1c ≤ 6.5% Blood-glucose lowering therapy – Therapeutic Choices
Standard approach
Consider
First
Metformin SU
Alternative approach
As per CG66
As per CG66
Consider substituting a DPP4-inhibitor or a TZD for an SU if there is significant risk of hypos or an SU is not tolerated or is contraindicated
Consider
Second SU
TZD
DPP-4 inhibitor
As per CG66
Add to Met
Add to SU
Add to Met
Add to SU
HbA1c ≤ 6.5%
Monitor for deterioration
Consider
Third
NPH Insulin
Other Insulin
TZD
DPP-4 inhibitor
Exenatide
Acarbose
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66
Added to Met + SU
Added to Met + SU if poor response to DPP-4 inhib or not tolerated.
Added to Met + SU
Added to Met + SU if poor response to TZD or not tolerated.
1. Added to Met + SU
As per CG66
NICE CG87 – recommended action if SU not possible
Consider
Fourth
NPH Insulin
Other Insulin
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66

59. HbA1c < 7.5% Blood-glucose lowering therapy – Therapeutic Choices
Standard approach
Consider
First
Metformin SU
Alternative approach
As per CG66
As per CG66
Consider
Second SU
TZD
DPP-4 inhibitor
As per CG66
Add to Met
Add to SU
Add to Met
Add to SU
Consider
Third
NPH Insulin
Other Insulin
TZD
Sitagliptin
Exenatide
Acarbose
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66
Added to Met + SU
Added to Met + SU if poor response to DPP-4 inhib or not tolerated.
Added to Met + SU
Added to Met + SU if poor response to TZD or not tolerated.
1. Added to Met + SU
As per CG66
HbA1c < 7.5%
Monitor for deterioration
NICE CG87 – recommended place in therapy of exenatide
Consider
Fourth
NPH Insulin
Other Insulin
Consider adding exenatide to metformin and SU if:
BMI ≥ 35 in patients of European descent, or
BMI < 35 and insulin is unacceptable or weight-loss would benefit other comorbidities
As per CG66
Long-acting analogue – as an alternative to starting NPH
Premix insulin as per CG66

60. Liraglutide STA recommendation (triple therapy)2
Slide No 60
Date of preparation: September UK/LR/0910/0213
Liraglutide STA recommendation (triple therapy)2
“Liraglutide 1.2 mg daily in triple therapy regimens is recommended as an option for the treatment of people with T2DM…when:
control of blood glucose remains or becomes inadequate (HbA1c ≥ 7.5%, or other higher level agreed with the individual), and the person has :
a body mass index (BMI) ≥ 35 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, or
a BMI < 35 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related co morbidities.”
When liraglutide 1.2mg is used in a triple therapy regimen, NICE has recommended that it can be used when certain conditions are met:
Firstly, the patient’s blood glucose level will be inadequately controlled - defined as an HbA1c level equal or greater to 7.5%, or even higher in certain individual cases.
Secondly, the person must either have a BMI in excess of 35kg/m2 and specific medical or psychological problems associated with their high body weight, or
Alternatively, the person might have a lower BMI, but could benefit from losing weight for reasons associated with other comorbidities, or
Where treatment with insulin could have significant occupational implications, such as causing a person to lose their driving licence.
The BMIs given refer to people of European descent; NICE acknowledges that BMI levels will need to be adjusted for other ethnic populations.
(All from National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1.1 Guidance Pages 1.)
NB. Note that the wording of this recommendation and the limitations are identical to the recommendations made for exenatide in the 2009 NICE clinical guideline, no. 87. (National Institute for Health and Clinical Excellence. CG87 Type 2 Diabetes - newer agents (partial update of CG66). Clinical Guideline 87. May 2009.)
2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1 Guidance. Section 1.1. 60

61. Liraglutide STA recommendation (dual therapy)2
Date of preparation: September UK/LR/0910/0213
Liraglutide STA recommendation (dual therapy)2
“Liraglutide 1.2 mg daily in dual therapy regimens (in combination with metformin or a sulphonylurea) is recommended as an option for the treatment of people with T2DM, only if:
the person is intolerant of either metformin or a sulphonylurea, or treatment with metformin or a sulphonylurea is contraindicated; and
the person is intolerant of thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors, or treatment with thiazolidinediones and DPP-4 inhibitors is contraindicated.”
These are the recommendations from the FAD for liraglutide in dual therapy regimens.
Essentially, liraglutide 1.2mg is recommended as an option or those people who are intolerant of other first or second line therapies – metformin, SU, the DPP-4 inhibitors or the ‘glitazones – or where treatment with those agents is contraindicated. (National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1.3 Page 2.)
2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1 Guidance. Section 1.3. 61

62. Liraglutide FAD recommendation (stopping rules)2
Slide No 62
Date of preparation: September UK/LR/0910/0213
Liraglutide FAD recommendation (stopping rules)2
Treatment with liraglutide 1.2mg daily should only be continued…if a beneficial metabolic response has been shown.
In triple therapy regimens, “beneficial metabolic response” is defined as:
a reduction of at least 1 percentage point in HbA1c; and
a weight loss of at least 3% of initial body weight at 6 months
In dual therapy regimens, “beneficial metabolic response’’ is defined as:
a reduction of at least 1 percentage point in HbA1c only
People with T2DM currently receiving liraglutide 1.2mg who do not meet the criteria specified, or who are receiving liraglutide 1.8 mg, have the option to continue their current treatment until they and their clinicians consider it appropriate to stop.
It is usual for NICE to make recommendations about when a particular treatment should be stopped.
In the case of liraglutide 1.2mg, NICE recommends that treatment should only continue if a “beneficial metabolic response” has been demonstrated.
The definition of “beneficial metabolic response” is different , depending upon whether liraglutide is used in a triple therapy regimen or a dual therapy regimen. (National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1. Guidance. Sections 1.2 and 1.4).
In a triple therapy regimen, liraglutide will be used in patients with a very high BMI. In such a case, a “beneficial metabolic response” is defined as comprising both weight loss and blood glucose lowering .(National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1.Guidance. Section 1.2)
In a dual therapy regimen, however, it is sufficient to show a reduction in HbA1c only. (National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1.Guidance. Section 1.4)
People who are already receiving liraglutide treatment, but who do not meet the FAD eligibility criteria, have the option to continue to receive treatment until such time as they and their clinicians think it appropriate to stop. (National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1.Guidance. Section 1.6)
2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. Last accessed 17 September Section 1 Guidance. Section 1.2 and 1.4 62

63. Liraglutide FAD recommendations (1.8mg dose)2
Slide No 63
Date of preparation: September UK/LR/0910/0213
Liraglutide FAD recommendations (1.8mg dose)2
Liraglutide 1.8 mg daily is not recommended for the treatment of people with type 2 diabetes.
As previously noted, NICE does not recommend the 1.8 mg dose of liraglutide as a treatment option. (National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1 Guidance. Section 1.5)
2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September Section 1 Guidance. Section 1.5 63

64. 1. Data on file: Composite endpoint
A clinical composite endpoint: Reaching HbA1c<7.0% combined with weight loss1
HbA1c
Indirect comparison of intention-to-treat data from 5 phase III trials with liraglutide and active comparators1
Rosiglitazone 4 mg
LEAD 1, Marre Diab Med. 2009
15%
Weight
25%
Glargine 24 IU
LEAD 5, Russell-Jones Diabetologia 2009
32%
Glimepiride 4 mg
LEAD 2, Nauck Diabetes Care 2008
56%
Sitagliptin 100mg
LIRA-DPP4 Study, Pratley Lancet 2010
72%
Exenatide 10 μg BID
LEAD 6, Buse Lancet 2009
72%
Liraglutide 1.2 mg
LEAD 2, Nauck Diabetes Care 2008
78%
Liraglutide 1.8 mg
LEAD 6, Buse Lancet 2009
1. Data on file: Composite endpoint

65. UKPDS 2x2 Glucose & Blood Pressure Outcome
ITT rate per 1,000 patient years n=887
p for trend = 0.024
UKPDS 75. Diabetologia 2006: 49:

66. Steno-2: treatment conditions
Conventional group
Aim: to modify CV risk factors to conventional targets:
Systolic BP < 160
Diastolic BP < 95
HbA1c < 7.5%
Fasting serum total cholesterol: 6.4
Fasting serum triglycerides: 2.2
Aspirin for those with known ischaemia
Intensive group
Aim: to modify CV risk factors to strict targets:
Systolic BP < 130
Diastolic BP < 80
HbA1c < 6.5%
Fasting serum total cholesterol 4.8
Fasting serum triglycerides 1.7
Aspirin for those with known ischaemia or peripheral vascular disease
Automatic treatment with ACE inhibitor
Targets presented are those in place at the start of the trial. During the final 2 years of the trial ( ), several of the targets were lowered following the revision of standard treatment guidelines including:
Systolic blood pressure (135 and 130 for conventional and intensive, respectively)
Diastolic blood pressure (85 and 80 for conventional and intensive, respectively)
HbA1c (6.5 for conventional, unchanged for intensive)
Fasting serum cholesterol (180 for conventional, unchanged for intensive)
Automatic treatment with ACE inhibitor in conventional group
Aspirin treatment for paitents without coronary heart disease or peripheral heart disease in intensive group only
Treatment goals in both groups were achieved using any of the following alone or in combination: dietary modification, smoking cessation programmes, exercise regimens, antihypertensive agents, statins, oral glucose lowering agents and insulin in the intensive group.
Steno-2: N Engl J Med 2003;348:383–93
Steno-2: Lancet 1999;353:617–22

67. Steno-2: relative risk reduction with intensive treatment
Autonomic neuropathy
Nephropathy
Retinopathy
CVD
Relative risk reduction for intensive vs conventional treatment (%)
* p < ** p < 0.01
During the average follow-up period of 7.8 years, intensive treatment significantly reduced the risk of the development of both CVD and microangiopathy relative to conventional treatment. * * ** **
Adapted from: N Engl J Med 2003;348:383–93

68. Intensive Multiple Risk Factor Management in Patients with Type 2 Diabetes: STENO-2
N=160; follow-up = 7.8 years
Conventional Therapy
20% Absolute
Risk Reduction
Primary Composite Endpoint* (%)
Aggressive treatment of†:
Microalbuminuria with
ACEIs, ARBs, or
combination
Hypertension
Hyperglycemia
Dyslipidemia
Secondary prevention of CVD
Intensive Therapy†
Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2
The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01).
Reference:
Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: 12 24 36 48 72 96 60 84
Months of Follow-up
Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).
*Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease. †Behavior modification and pharmacologic therapy.
Adapted from Gaede P et al. N Eng J Med 2003;348:383–393.

69. STENO-2: Lipid-Lowering Therapy Accounted for More Than 70% of Cardiovascular Risk Reduction
Analysis of STENO-2 data based on the risk engine from the United Kingdom Prospective Diabetes Study (UKPDS)
Percent of Total Calculated Risk Reduction in Cardiovascular Disease-Related Events
STENO-2: Lipid-Lowering Therapy Accounted for More Than 70% of Cardiovascular Risk Reduction
A subsequent analysis of those factors that could be responsible for the dramatic reduction in cardiovascular events in the STENO-2 study showed that reduction in total cholesterol accounted for approximately 70% of the overall benefit, with less of the overall benefit attributable to either improvement in glycemic control or reduction of systolic blood pressure.
Reference:
Gaede P, Pedersen O. Intensive integrated therapy of type 2 diabetes: implications for long-term prognosis. Diabetes. 2004;53(Suppl 3):S39-S47.
Lipids
Hemoglobin
A1c
Systolic Blood
Pressure
Slide Source
Lipids Online Slide Library
Reprinted with permission from Gaede P, Pederson O. Diabetes. 2004;
53(Suppl 3):S39−S47. Copyright © 2004 American Diabetes Association.

70. Steno-2 Study Results
Intensive therapy resulted in an absolute risk reduction of:
20% for all cause mortality
29% for cardiovascular events
13% for CV mortality
Relative risk reduction in microvascular disease of 50%

71. Summary
The goal is to achieve good glucose, blood pressure and lipid control with minimal side effects
In practice, this means achieving the lowest possible glucose levels, without paying the price of hypoglycaemia, weight gain and other side effects
HbA1c <7.0% (lower for newly diagnosed, higher for the elderly and those with CVD)
BP <130/80
Cholesterol <4.0, LDL<2.0