1. FDA Endocrinologic and Metabolic Drugs Advisory Committee 1st June 2008 Rury Holman Clinical outcomes with anti-diabetic drugs: What we already know

2. The “Deadly Quintet” for CHD p  LDL cholesterol0.000014  HDL cholesterol0.00014  Haemoglobin A 1c 0.0022  Systolic blood pressure0.0065 +Smoking(0.056) Stepwise selection of major risk factors for 280 coronary artery disease events in 2,693 UKPDS patients @ 10 years Age and gender also major risk factors but HDL displaced triglyceride as a significant risk factor UKPDS 23. BMJ 1998; 316: 823-8

3. 0 20 40 60 80 0567891011 Microvascular disease Updated mean HbA 1c (%) Incidence per 1000 patient-years Myocardial infarction Relationship of Complications to HbA 1c UKPDS 35. BMJ 2000; 321: 405-12

4. Impact of Nephropathy on Risk of Death UKPDS 64. Kidney International 2003; 63: 225-232 No nephropathy Microalbuminuria  2.0% Macroalbuminuria  2.8% ESRD  2.3% 1% 3% 5% 19% DEATH Annual Risk

5. UKPDS Head to Head Therapy Comparison Overweight patient cohort Body mass index 31.4 kg/m 2 0% 6% 7% 8% 9% 10% 0246810 Years from randomisation HbA 1c Conventional ChlorpropamideGlibenclamideInsulin Metformin UKPDS 34. Lancet 1998; 352: 837-853

6. UKPDS Monotherapy Approach UKPDS 57. Diabetes Care 2002; 25: 330-336 Add metformin 0 108 190 270 0246810 Years from randomisation mg/dl Add SU 0 6.0 10.5 15.0 Fasting plasma glucose mmol/L

7. Progressive Decline in Beta Cell Function UKPDS 16. Diabetes 1995; 44: 1249-58 20 40 60 80 100ConventionalSulphonylureaMetformin Non overweightOverweight Beta cell loss ~4% per year HOMA %B 0 01234560123456 Years from randomisation

8. A monotherapy approach, which achieved a median HbA 1c difference of 0.9% (7.0% vs. 7.9%) over 10 years, reduced risk by: p 12%any diabetes related endpoint0.029 16%myocardial infarction(0.052) 25%microvascular disease0.0099 21%retinopathy at twelve years0.015 33%albuminuria at twelve years0.000054 UKPDS Glucose Study Results UKPDS 33. Lancet 1998; 352: 837-853

9. p=0.0099 0% 10% 20% 30% 03691215 % of patients with an event Years from randomisation Intensive Conventional Risk reduction 25% (95% CI: 7% to 40%) photocoagulation, vitreous haemorrhage, renal failure or renal death 346 of 3867 patients (9%) Cumulative Microvascular Disease Incidence UKPDS 33. Lancet 1998; 352: 837-853

10. Cumulative Myocardial Infarction Incidence fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%) UKPDS 33. Lancet 1998; 352 : 837-853

11. Meta-analysis of HbA 1c Reduction and CHD Stettler et al. Am Heart J 2006; 152: 27-38

12. Meta-analysis of HbA 1c Reduction and CHD Stettler et al. Am Heart J 2006; 152: 27-38

13. Primary Metformin Randomisation Conventional glucose control policy n=411 Intensive glucose control policy with metformin n=342 Main Randomisation >120% ideal body weight n=1704 UKPDS 34. Lancet 1998; 352: 837-853 Enrolled n=5102 Intensive glucose control policy with SU or Insulin n=911 753 in total

14. 32%0.0023 39%0.010 36%0.011 29%0.19 0.6% HbA 1c difference achieved in overweight patients allocated metformin compared with conventional R x Median follow up 10.7 years (range 6 to 20) ARR RRR p “Any diabetes-related endpoint”13.5% Myocardial infarction7.0% All cause mortality7.1% Microvascular disease2.5% UKPDS Metformin Study Results UKPDS 34. Lancet 1998; 352: 837-853

15. Cumulative Myocardial Infarction Incidence UKPDS 34. Lancet 1998; 352: 837-853

16. Sulphonylurea/Metformin Substudy Sulphonylurea (main study) Sulphonylurea plus Metformin Sulphonylurea alone 0 10 20 30 40 351426 Number of events over 6.6 yrs p=0.039n.s.

17. UKPDS Blood Pressure Study Results UKPDS 38. BMJ 1998; 317: 703-713 A step-wise, treat-to-target approach, which achieved a mean blood pressure difference of 10/5 mmHg over 8 years (144/82 vs. 154/87), reduced risk by: p 24% Any diabetes-related endpoint0.0046 44%Fatal and non-fatal stroke0.013 37% Microvascular disease0.0092 34% Retinopathy progression0.0038 47% Deterioration of vision0.0036

18. UKPDS 2x2 Glucose & Blood Pressure Outcome UKPDS 75. Diabetologia 2006: 49: 1761-769 p for trend = 0.024 ITT rate per 1,000 patient years n=887

19. CHD Relative Risk & HbA 1c 0.5 1 5 0567891011 Updated mean HbA 1c Hazard ratio 14% decrease per 1% HbA 1c decrement, p<0.0001 UKPDS 35. BMJ 2000; 321: 405-12 UKPDS Glucose Study showed: 16% decrease for a 0.9% HbA 1c difference p=0.052 Observational analysis

20. 14% decrease per 10 mmHg SBP decrement, p<0.0001 0.5 1 5 110120130140150160170 Relative Risk for CHD & Blood Pressure Updated mean systolic blood pressure Hazard ratio UKPDS 36. BMJ 2000; 321: 412-19 UKPDS Blood Pressure Study showed: 21% decrease for a 10 mmHg SBP difference Observational analysis

21. Relative Risk for CHD & LDL Cholesterol 123456 Updated mean LDL-cholesterol (mmol/l) 29% decreased risk per 1 mmol/l decrement p<0.001 1.0 5.0 0.2 Hazard ratio Unpublished data Heart Protection Study showed: 27% decrease for a 1 mmol/l LDL-C difference Observational analysis

22. Can We Predict the Future?

23. Problems with Therapies for Type 2 Diabetes UGDP1969TolbutamideMI<0.05 UGDP1971PhenforminMI<0.05 Lilly1988ProinsulinMIn.s. VA Study1994Intensive insulinMIn.s. DPP2000TroglitazoneLivern.s. Meta analysis2005MuriglitazarCVD<0.03 Meta analysis2007RosiglitazoneCVD<0.043 ACCORD2008Intensive controlDeath<0.04

24. The UKPDS Outcomes Model Captures UKPDS risk factor and outcomes data in a format that can be easily interrogated Evaluates likely rates of different complications e.g. myocardial infarction, stroke, heart failure, renal failure Predicts likely sequences of complications over a patient’s simulated lifetime Summarises individual life courses as QALE Estimates overall differences between treatment strategies that may have different impacts on quality of life and costs UKPDS 68 Diabetologia 2004; 47: 1747-59

25. UKPDS Outcomes Model Equations UKPDS 68. Diabetologia 2004; 47: 1747-59

26. UKPDS Outcomes Model Algorithm UKPDS 68. Diabetologia 2004; 47: 1747-59

27. 5,283 patients Could the PROactive Result be Predicted? Lancet 2005; 366: 1279–89

28. Computer-generated patient-cohort, matched for age, ethnic origin, sex, body mass index, HbA 1c, lipids, blood pressure, smoking status and peripheral vascular disease PROactive Study Simulation* Holman et al, Lancet 2006; 367: 25-26 *Outcomes estimated for subgroup without previous myocardial infarction or stroke Baseline Characteristics Caucasian98.7% Males65.6% Age (y) 61.6 Diabetes duration (y) 8.0 Weight (kg) 88.5 SBP (mmHg) 143.3 HbA 1c (%) 7.9 Within-trial changes HbA 1c -0.5 % SBP-3 mmHg HDL-C+0.1 mmol/l Weight+4.0 kg

29. UKPDS Outcomes Model Simulation Results Secondary EndpointRRR95% CI PROactive study result16%2 to 28% UKPDS Outcomes Model13% Holman et al, Lancet 2006; 367: 25-26 PROactive study result39% increase Congestive Heart FailureRRR UKPDS Outcomes Model11% decrease Conclusions Secondary endpoint risk reduction is consistent with the risk factor changes observed CHF risk is the converse of that expected

30. Conclusions Diabetes is a chronic, complex, metabolic condition that requires long-term trials to fully assess outcomes Improved therapies are needed urgently to: –Arrest disease progression –Reduce/prevent microvascular complications –Reduce/prevent macrovascular complications Innovative and adaptive study designs are required, given the progressive nature of the condition Monitor off-target outcomes - “Do no harm” Life time models can help optimise trial designs Large-scale, pragmatic trials in a usual care setting should be commenced with all new agents as early as possible

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