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

The “Deadly Quintet” for CHD p  LDL cholesterol  HDL cholesterol  Haemoglobin A 1c  Systolic blood pressure Smoking(0.056) Stepwise selection of major risk factors for 280 coronary artery disease events in 2,693 UKPDS 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

Microvascular disease Updated mean HbA 1c (%) Incidence per 1000 patient-years Myocardial infarction Relationship of Complications to HbA 1c UKPDS 35. BMJ 2000; 321:

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

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

UKPDS Monotherapy Approach UKPDS 57. Diabetes Care 2002; 25: Add metformin Years from randomisation mg/dl Add SU Fasting plasma glucose mmol/L

Progressive Decline in Beta Cell Function UKPDS 16. Diabetes 1995; 44: ConventionalSulphonylureaMetformin Non overweightOverweight Beta cell loss ~4% per year HOMA %B Years from randomisation

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 endpoint %myocardial infarction(0.052) 25%microvascular disease %retinopathy at twelve years %albuminuria at twelve years UKPDS Glucose Study Results UKPDS 33. Lancet 1998; 352:

p= % 10% 20% 30% % 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:

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

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

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

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: Enrolled n=5102 Intensive glucose control policy with SU or Insulin n= in total

32% % % % % 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:

Cumulative Myocardial Infarction Incidence UKPDS 34. Lancet 1998; 352:

Sulphonylurea/Metformin Substudy Sulphonylurea (main study) Sulphonylurea plus Metformin Sulphonylurea alone Number of events over 6.6 yrs p=0.039n.s.

UKPDS Blood Pressure Study Results UKPDS 38. BMJ 1998; 317: 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 endpoint %Fatal and non-fatal stroke % Microvascular disease % Retinopathy progression % Deterioration of vision0.0036

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

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

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

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

Can We Predict the Future?

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

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:

UKPDS Outcomes Model Equations UKPDS 68. Diabetologia 2004; 47:

UKPDS Outcomes Model Algorithm UKPDS 68. Diabetologia 2004; 47:

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

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: *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) HbA 1c (%) 7.9 Within-trial changes HbA 1c -0.5 % SBP-3 mmHg HDL-C+0.1 mmol/l Weight+4.0 kg

UKPDS Outcomes Model Simulation Results Secondary EndpointRRR95% CI PROactive study result16%2 to 28% UKPDS Outcomes Model13% Holman et al, Lancet 2006; 367: 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

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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