fda endocrinologic and metabolic drugs advisory committee 1st june 2008 rury holman clinical...
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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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