FDA Endocrinologic and MetabolicDrugs Advisory Committee

1st June 2008

Rury Holman

Clinical outcomes with anti-diabetic drugs: Clinical outcomes with anti-diabetic drugs: What we already knowWhat we already know

Clinical outcomes with anti-diabetic drugs: Clinical outcomes with anti-diabetic drugs: What we already knowWhat we already know

The “Deadly Quintet” for CHDThe “Deadly Quintet” for CHD

p

LDL cholesterol 0.000014

HDL cholesterol 0.00014

Haemoglobin A1c 0.0022

Systolic blood pressure 0.0065

+ Smoking (0.056)

Stepwise selection of major risk factors for 280 coronaryartery 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

0

20

40

60

80

0 5 6 7 8 9 10 11

Microvasculardisease

Updated mean HbA1c (%)

Inci

denc

e pe

r 10

00 p

atie

nt-y

ears

Myocardialinfarction

Relationship of Complications to HbARelationship of Complications to HbA1c1c

UKPDS 35. BMJ 2000; 321: 405-12

Impact of Nephropathy on Risk of DeathImpact of Nephropathy on Risk of Death

UKPDS 64. Kidney International 2003; 63: 225-232

No nephropathyNo nephropathy

MicroalbuminuriaMicroalbuminuria

2.0%

MacroalbuminuriaMacroalbuminuria

2.8%

ESRDESRD

2.3%

1%1%

3%3%

5%5%

19%19%

DEATHDEATH

Annual Risk

UKPDS Head to Head Therapy ComparisonUKPDS Head to Head Therapy Comparison

Overweight patient cohortBody mass index 31.4 kg/m2

0%6%

7%

8%

9%

10%

0 2 4 6 8 10Years from randomisation

Hb

A1

c

ConventionalConventional

ChlorpropamideChlorpropamideGlibenclamideGlibenclamide

InsulinInsulinMetforminMetformin

UKPDS 34. Lancet 1998; 352: 837-853

UKPDS Monotherapy ApproachUKPDS Monotherapy Approach

UKPDS 57. Diabetes Care 2002; 25: 330-336

Addmetformin

0

108

190

270

0 2 4 6 8 10Years from randomisation

mg/

dl

AddSU

0

6.0

10.5

15.0

Fasting plasma glucose

mm

ol/L

Progressive Decline in Beta Cell FunctionProgressive Decline in Beta Cell Function

UKPDS 16. Diabetes 1995; 44: 1249-58

20

40

60

80

100

ConventionalConventional SulphonylureaSulphonylurea MetforminMetformin

Non overweight Overweight

Beta cell loss ~4% per year

HO

MA

%B

00 1 2 3 4 5 6 0 1 2 3 4 5 6

Years from randomisation

A monotherapy approach, which achieved a median HbA1c difference of 0.9% (7.0% vs. 7.9%) over10 years, reduced risk by:

p12% any diabetes related endpoint 0.029

16% myocardial infarction (0.052)

25% microvascular disease 0.0099

21% retinopathy at twelve years 0.015

33% albuminuria at twelve years 0.000054

UKPDS Glucose Study ResultsUKPDS Glucose Study Results

UKPDS 33. Lancet 1998; 352: 837-853

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pat

ient

s w

ith a

n ev

ent

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 IncidenceCumulative Microvascular Disease Incidence

UKPDS 33. Lancet 1998; 352: 837-853

Cumulative Myocardial Infarction IncidenceCumulative Myocardial Infarction Incidence

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pat

ient

s w

ith a

n ev

ent

Years from randomisation

Intensive

Conventional

p=0.052

Risk reduction 16%(95% CI: 0% to 29%)

fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)

UKPDS 33. Lancet 1998; 352: 837-853

Meta-analysis of HbAMeta-analysis of HbA1c1c Reduction and CHD Reduction and CHD

Stettler et al. Am Heart J 2006; 152: 27-38

Meta-analysis of HbAMeta-analysis of HbA1c1c Reduction and CHD Reduction and CHD

Stettler et al. Am Heart J 2006; 152: 27-38

Primary Metformin Randomisation

Conventionalglucose control

policy n=411

Intensive glucosecontrol policy with

metforminn=342

Main Randomisation >120% ideal body weight

n=1704

UKPDS 34. Lancet 1998; 352: 837-853

Enrolledn=5102

Intensive glucosecontrol policy with

SU or Insulinn=911

753 in total

32% 0.0023

39% 0.010

36% 0.011

29% 0.19

0.6% HbA1c difference achieved in overweight patients allocated metformin compared with conventional Rx

Median follow up 10.7 years (range 6 to 20)

ARR RRR p“Any diabetes-related endpoint” 13.5%

Myocardial infarction 7.0%

All cause mortality 7.1%

Microvascular disease 2.5%

UKPDS Metformin Study ResultsUKPDS Metformin Study Results

UKPDS 34. Lancet 1998; 352: 837-853

Cumulative Myocardial Infarction IncidenceCumulative Myocardial Infarction Incidence

UKPDS 34. Lancet 1998; 352: 837-853

Sulphonylurea/Metformin SubstudySulphonylurea/Metformin Substudy

Sulphonylurea (main study)

Sulphonylurea plus Metformin

Sulphonylureaalone

0

10

20

30

40

35 1426Nu

mb

er o

f ev

ents

ove

r 6.

6 yr

s p=0.039n.s.

UKPDS Blood Pressure Study ResultsUKPDS 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 endpoint 0.0046

44% Fatal and non-fatal stroke 0.013

37% Microvascular disease 0.0092

34% Retinopathy progression 0.0038

47% Deterioration of vision 0.0036

UKPDS 2x2 Glucose & Blood Pressure OutcomeUKPDS 2x2 Glucose & Blood Pressure Outcome

UKPDS 75. Diabetologia 2006: 49: 1761-769

p for trend= 0.024

ITT rate per1,000 patient years

n=887

CHD Relative Risk & HbACHD Relative Risk & HbA1c1c

0.5

1

5

0 5 6 7 8 9 10 11Updated mean HbA1c

Haz

ard

ratio

14% decrease per 1%HbA1c decrement, p<0.0001

UKPDS 35. BMJ 2000; 321: 405-12

UKPDS Glucose Study showed:16% decrease for a 0.9% HbA1c difference

p=0.052

Observational analysis

14% decrease per 10 mmHgSBP decrement, p<0.0001

0.5

1

5

110 120 130 140 150 160 170

Relative Risk for CHD & Blood PressureRelative Risk for CHD & Blood Pressure

Updated mean systolic blood pressure

Haz

ard

ratio

UKPDS 36. BMJ 2000; 321: 412-19

UKPDS Blood Pressure Study showed:21% decrease for a 10 mmHg SBP difference

Observational analysis

Relative Risk for CHD & LDL CholesterolRelative Risk for CHD & LDL Cholesterol

1 2 3 4 5 6

Updated mean LDL-cholesterol (mmol/l)

29% decreased riskper 1 mmol/l decrementp<0.001

1.0

5.0

0.2

Haz

ard

rat

io

Unpublished data

Heart Protection Study showed:27% decrease for a 1 mmol/lLDL-C difference

Observational analysis

Can We Predict the Future?Can We Predict the Future?

Problems with Therapies for Type 2 DiabetesProblems with Therapies for Type 2 Diabetes

UGDP 1969 Tolbutamide MI<0.05

UGDP 1971 Phenformin MI<0.05

Lilly 1988 Proinsulin MIn.s.

VA Study 1994 Intensive insulin MIn.s.

DPP 2000 Troglitazone Livern.s.

Meta analysis 2005 Muriglitazar CVD<0.03

Meta analysis 2007 Rosiglitazone CVD<0.043

ACCORD 2008 Intensive control Death<0.04

The UKPDS Outcomes ModelThe 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

UKPDS Outcomes Model EquationsUKPDS Outcomes Model Equations

UKPDS 68. Diabetologia 2004; 47: 1747-59

Start: define the following patient characteristics:Age at diagnosis, ethnicity, sex, BMI, HbA1c, total:HDL(Lipids), blood pressure, smoking status, atrial fibrillation at diagnosis, peripheral vascular disease (PVD) at diagnosisHistory of diabetes-related events:

Ischaemic heart disease (IHD), congestive heart failure (CHF), blindness,amputation, renal failure, myocardial infarction (MI), stroke

Randomly order and run event equations:

Ischaemic Heart Disease (IHD) Eq. 1

Myocardial infarction (MI) Eq. 2

Congestive Heart Failure (CHF) Eq. 3

Stroke Eq. 4

Amputation Eq. 5

Blindness Eq. 6

Renal failure Eq. 7

Diabetes-related mortality Eq. 8 & (conditional on CHF, amputation, Eq. 9renal failure, MI or stroke having occurred)

Other mortality Eq. 10

Update patient risk factors using risk factor equations:

HbA1c Eq. 11

Blood pressure Eq. 12

Total:HDL Eq. 13

Smoking Eq. 14

Update history of diabetes-related events

Calculate lifeyears & QALYs

Commence model cycle

Dead?

yes no

UKPDS Outcomes Model AlgorithmUKPDS Outcomes Model Algorithm

UKPDS 68. Diabetologia 2004; 47: 1747-59

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, HbA1c, lipids, blood pressure,

smoking status and peripheral vascular disease

PROactive Study Simulation*PROactive Study Simulation*

Holman et al, Lancet 2006; 367: 25-26

*Outcomes estimated for subgroup withoutprevious myocardial infarction or stroke

Baseline CharacteristicsCaucasian 98.7%Males 65.6%Age (y) 61.6Diabetes duration (y) 8.0Weight (kg) 88.5SBP (mmHg) 143.3HbA1c (%) 7.9

Within-trial changes

HbA1c -0.5 %

SBP -3 mmHg

HDL-C +0.1 mmol/l

Weight +4.0 kg

UKPDS Outcomes Model Simulation ResultsUKPDS Outcomes Model Simulation Results

Secondary Endpoint RRR 95% CI

PROactive study result 16% 2 to 28%

UKPDS Outcomes Model 13%

Holman et al, Lancet 2006; 367: 25-26

PROactive study result 39% increase

Congestive Heart Failure RRR

UKPDS Outcomes Model 11% decrease

Conclusions• Secondary endpoint risk reduction is consistent

with the risk factor changes observed• CHF risk is the converse of that expected

ConclusionsConclusions

• 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

Thank you

www.dtu.ox.ac.uk

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