Can we further reduce CV risk in patients with Type2 DM or Prediabetes

1
Can we further reduce CV risk in patients with
Type2 DM or Prediabetes?

• Dr.A.Ramachandran
• India

2
Reducing Global risk of CVD in Diabetes
Prediabetes

• 1.CV Risk in Diabetes
• 2.Reducing CV Risk in Diabetes
• 3.CV Risk in Prediabetes
• 4.Reducing CV Risk in Prediabetes

3
Framingham Heart study 30 year follow up
CVD events in patients with diabetes (aged 35
64 yr)
Relative risk ratio
4
Prevalence of MI in Finnish subjects aged 35-70yrs
Prevalence of MI
Type 2 diabetic subjects reported the highest
prevalence of MI than normoglyceamic subjects.
Isomaa et al , Diab. Care, 2001
5
Hazard ratio (1.4, 95 CI 0.7-2.6) for death from
CHD for groups 1 4 were similar suggesting
similar risks of infarction in the two groups.
p lt 0.001
6

• Conclusions
• Diabetic patients without previous MI have as
  high a risk of MI as nondiabetic patients with
  previous MI.
• Data provided a rationale for treating
  cardiovascular risk factors in diabetic patients
  as aggressively as in nondiabetic patients with
  prior MI.
• Haffner et al 1998

7

• Comparison of cardiovascular risk between
  patients with type 2 diabetes and those who had
  had a myocardial infarction Cross sectional and
  cohort studies.
• Evans et al, BMJ,2002.
• Objective
• To compare risks of cardiovascular outcomes
  between patients with type 2 diabetes and
  patients with established CHD.
• Main outcome measures
• Risk ratios for death from all causes,
  cardiovascular death, and hospital admission for
  MI were calculated
• Cox proportional hazards analysis , adjusted
  for age and gender was done.

8

• Two arms of the study
• 1. Cross sectional study 2. Cohort study
• 1155 type 2 diabetics 3477 patients of all
  ages
• aged 45 - 64yrs compared with
  newly diagnosed
• with 1347 who had MI in the type 2
  diabetes were
• preceding 8 years. Compared with
  7414
• (Jan 1982 Dec 1987 )
  patients who had an MI
• 
  (Jan 1988 Dec 1995 - 8 yrs) .

9
Cross sectional study - Risk of death from all
causes and hospital admissions for MI.
RR 1.33

RR 2.27
Risk of death is higher in the MI group
compared with DM group.
Evans et al, BMJ,2002
10
Cohort Study - Risk of death from all causes,
death from cardiovascular causes, and hospital
admission for MI.
RR 1.35

RR 2.93
RR 3.1

• Patients in the MI cohort had a three fold
  higher risk of death from a cardiovascular cause
  than patients in the diabetic cohort.

Evans et al, BMJ,2002
11

• Conclusion
• Patients with type 2 diabetes were at lower risk
  of cardiovascular outcomes than patients with
  established coronary heart disease.

Evans et al, BMJ,2002
12
Prevalence of Diabetes IGT in Acute Coronary
Syndrome
Hyperglycemia a mediator of Risk of
Coronary Heart Disease?
13
Dysglycemia is Common with MI
OGTT at discharge n 164
OGTT at 3 months n 145
66 Abnormal Glucose Tolerance
(Norhammar et al Lancet 2002 359 2140)
14
High Incidence of Glucose Intolerance in
Asian-Indian Subjects With Acute Coronary
Syndrome

• Ambady Ramachandran, Snehalatha Chamukuttan,
  Sathyamurthy Immaneni, Ravi Marimuthu Shanmugam,,
  Nalini Vishnu,, Vijay Viswanathan, and
  Tuomilehto Jaakko,
• Diabetes Research Centre, M.V. Hospital for
  Diabetes, WHO Collaborating Centre for Research,
  Education Training in Diabetes, Royapuram,
  Chennai, India

All subjects admitted with Acute Coronary
Syndrome into two centres in Chennai were
recruited to look for hyperglycemia. We excluded
known diabetics.
15
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16
Prevalence of Glucose Intolerance in Indian
subjects admitted with ACS in non-diabetic
subjects at entry (3 months followp-up results)
Ramachandran et al Diabetes Care 2005
17
Prevalence of abnormal glucose metabolism in non
diabetic subjects with myocardial
infarction/acute coronary syndrome
Ramachandran et al Int Jl of Met Fax Diabetes
care 2005
18
Reducing Global risk of CVD in Diabetes
Prediabetes

• 1.CV Risk in Diabetes
• 2.Reducing CV Risk in Diabetes
• 3.CV Risk in Prediabetes
• 4.Reducing CV Risk in Prediabetes

19
Good Glycaemic Control Reduces Incidence of
Complications
Risk reduction by decrease in A1c ()
Complications DCCT1,2 Ohkubo3 UKPDS4 of
diabetes mellitus (9 7) (9 7)
(8 7) Retinopathy -63 -69
-21 Nephropathy -54 -70 -34 Neuropathy
-60 Macrovascular disease -41 -16
Not statistically significant. DCCT, Diabetes
Control and Complications Trial UKPDS, United
Kingdom Prospective Diabetes Study. 1. DCCT
Research Group. N Engl J Med. 1993329977-986.
2. DCCT Research Group. Diabetes.
199544968-983. 3. Ohkubo Y et al. Diabetes Res
Clin Pract. 199528103-117. 4. UKPDS Group.
Lancet. 1998352837-853.
20
Glucose Control Study Summary
The intensive glucose control policy maintained a
lower HbA1c by mean 0.9 over a median follow
up of 10 years from diagnosis of type 2 diabetes
with reduction in risk of 12 for any diabetes
related endpoint p0.029 25 for microvascular
endpoints p0.0099 16 for myocardial
infarction p0.052 24 for cataract
extraction p0.046 21 for retinopathy at twelve
years p0.015 33 for albuminuria at twelve
years p0.000054
21
Diabetes Related Deaths
22
Fatal and Non-Fatal Myocardial Infarction
23
Is Glycemia the only targetin reducing CVD risk?
24
The UKPDS Showed.
Blood Pressure control in 1148 Type 2 diabetic
patients a tight blood pressure control policy
which achieved blood pressure of 144 / 82 mmHg
gave reduced risk for.. any diabetes-related
endpoint 24 p0.0046 diabetes-related
deaths 32 p0.019 stroke
44 p0.013 microvascular disease 37 p0.0092 he
art failure 56 p0.0043 retinopa
thy progression 34 p0.0038 deterioration of
vision 47 p0.0036
Glucose control The intensive glucose
control policy maintained a lower HbA1c by mean
0.9 over a median follow up of 10 years from
diagnosis of type 2 diabetes with reduction in
risk of.. 12 for any diabetes related
endpoint p0.029 25 for microvascular
endpoints p0.0099 16 for myocardial
infarction p0.052 24 for cataract extraction
p0.046 21 for retinopathy at twelve years
p0.015 33 for albuminuria at twelve years
p0.000054
Glycemic control reduced microvascular
complications in DM,but did not significantly
reduce CVD while along with BP control both
reduced significantly
25
Relationship between endpoints and HbA1c or BP in
the UKPDS
-1
Incidence (1000-pt-yr
)
Rate 95 CI
80
Microvascular endpoints
Myocardial infarction
60
HbA
1c
40
HbA
1c
BP
20
BP
0
5.0
7.0
9.0
11.0
5.0
7.0
9.0
11.0
110
130
150
170
110
130
150
170
HbA
() or systolic BP (mmHg)
HbA
() or systolic BP (mmHg)
1c
1c
Stratton et al, BMJ 200032140512.
26
21 ? per 1 ? in HbA1C in Diabetes related end
points 12 ? per 10mm ? in SBP in Diabetes
related end points 17 ? per 10mm ? in SBP in
deaths.
27
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28
Dyslipidemia as CV risk factor in Diabetes
29
Target Dyslipidemia-use of statins The
large-scale intervention studies of statins have
focused attention on Dyslipidemia and
specifically elevated LDL-chol levels as a
significant modifiable risk factor for CHD in the
general population and in people with diabetes in
particular.
30
The Collaborative Atorvastatin Diabetes Study
(CARDS)

• Atorvastatin 10mg daily for primary prevention of
  CAD in type 2 diabetic patients without high LDL
  cholesterol levels was used for a median period
  of 3.9 years
• ACS reduced by 36 - coronary revascularization
  by 31, stroke by 48, death by 27
• Atorvastatin 10mg daily is safe and efficacious
  in patients with type 2 diabetes even in the
  absence of high LDL cholesterol

Colhoun HM et al , Lancet 2004
31

• Collaborative Atorvastatin Diabetes Study (CARDS)
  
• To assess the effectiveness of 10 mg of
  atorvastatin in the primary prevention of
  cardiovascular disease in patients with type 2
  diabetes.
• The trial was stopped 2 years earlier than
  planned because of significant benefit at the
  second interim analysis.
• Helen C et al. Lancet, 2004.

32

• Collaborative Atorvastatin Diabetes Study (CARDS)
  Contd.
• Atorvastatin 10 mg daily leads to
• A Reduction of
• Major cardiovascular events by 37
• Risk of stroke by 48
• All-cause mortality by 27
• The effect was independent of pretreatment
  cholesterol level.

33
Veterans Affairs High Density Lipoprotein
Cholesterol Intervention Trial (VA-HIT)

• Effect of fibrate therapy on mortality and risk
  of major coronary event was assessed
• 25 of the participants had diabetes
• By increasing HDL Cholesterol by just under 8
  and decreasing triglycerides by 25, the risk of
  a major cardiovascular event was cut by 22 in
  people with diabetes.
• First trial to demonstrate a diminished risk of
  cardiac events from an intervention that raised
  HDL levels but did not reduce LDL levels.

34

• Clinical trials of Lipid lowering in Diabetic
  subjects
• Scandinavian Simvastatin Survival Study (4S)
  trial
• Simvastatin significantly reduced CHD
  incidence and total mortality in patients with
  high HDL cholesterol and with previous clinical
  CHD.
• Cholesterol and Recurrent Events (CARE) Study
• Pravastatin reduced CHD incidence
  significantly in patients with average LDL levels
  and with previous clinical CHD.
• Helsinki Heart Study
• Gemfibrozil (fibric acid derivative)
  was associated with a reduction in CHD in
  diabetic patients without prior CHD.

35
Benefits of Lipid LoweringThe Scandinavian
Simvastatin Survival Study (4S)4444 subjects
with cardiovascular disease

• Cholesterol - lowering was associated with 42
  reduction in total mortality compared with an
  equal number of patients treated with placebo.
  About 5 had diabetes and in them 55 reduction
  in major coronary events was observed.
• Similar Observations in Diabetes
• Helsinki Heart Study - Gemfibrosil.
• CARE Study(Chol Recurrent Event Study)
  -Provastatin.

36
Scandinavian Simvastatin Survival Study (4S)

• Major coronary events were halved in people
  with diabetes being treated with statin therapy
• Total cholesterol was reduced by 27, LDL
  cholesterol by 36, triglycerides by 11 and HDL
  cholesterol increased by 7

37
Cholesterol and Recurrent Events Trial (Care)

• Assessed the effect of a statin on the risk of a
  fatal or non-fatal heart attack in people with
  CHD and high cholesterol levels.
• 14 of the participants had diabetes and
  demonstrated a 25 reduction of major coronary
  events in people being treated with the statin
• Total cholesterol levels reduced by 19, LDL
  cholesterol by 27, triglycerides by 13 and HDL
  cholesterol was increased by 4

38
Dylipidemia Treatment

• Statins - Studies showing risk reduction of
  cardio artery disease
• Scandinavian Simvastatin Survival Study (4s) and
• The Heart Protection Study (HPS) - Simvastatin
• Cholesterol and Recurrent Events (CARE) trial
  and
• The Long-Term Intervention with Pravastatin in
  Ischaemic Disease (LIPID) trial Pravastatin
• Post Coronary Artery Bypass Graft Trial -
  Lovastatin

39

• Fibrates
• Veterans Affairs Cooperative Studies Program
  High-Density Lipoprotein Cholesterol Intervention
  Trial (VA-HIT) Gemfibrozil.
• Diabetes Atherosclerosis Intervention Study
  (DAIS) - Fenofibrate.

40
How low we should reduce the cholesterol?
41
Evidence for a Curvilinear (Log-Linear)
Relationship between LDL-C and CHD Risk (2001)
Epidemiology
CHDRiskCurvilinearorLog-Linear
Clinical Trials
?
100
LDL-C (mg/dL)
42
NCEP July 2004 , New goals ATP3 Panel

• Overall goal for high risk patients is
  LDLlt100mg/dl
• Option to set goal 70mg/dl
• For
• very high risk patients

43
Treatment

• Statins should be prescribed for patients over 40
  years
• Statins should be prescribed for patients under
  40 who have micro or macrovascular complications,
  hypertension, metabolic syndrome, or a strong
  family history of CVD
• Total cholesterol should be lt4.5 mmol/l
• LDL cholesterol should be lt2.5 mmol/l
• Fibrates should be prescribed if triglycerides
  are gt2.3mmol/l and LDL-cholesterol values are
  lt2.5 mmol/l

44

• Lifestyle
• Patients should be encouraged to lose weight if
  necessary, exercise and eat healthily
• Aspirin
• Although no studies have been performed on
  primary prevention of CVD in diabetes, low dose
  aspirin is usually recommended, even in the
  absence of overt CVD.
• Smoking
• It is essential that patients stop smoking to
  reduce the risk of CVD and probably the risk of
  microvascular complications

Treatment
45
Treatment

• Treatment with statins reduces the risk of a
  major cardiovascular event by 37 in patients
  with type 2 diabetes. The reduction in relative
  risk is as great in the diabetic as in the
  non-diabetic so that the absolute benefit is
  greater.
• Glycated haemoglobin should be as low as possible
  but avoid hypoglycemia - Aim for lt7 if on
  insulin or lt 6.5 if not on insulin
• Blood pressure should be as low as possible - Aim
  for lt 130/80mmHg or lt125/75mm Hg if proteinuria
  is present or has cardiovascular disease.

46
Order of priorities for treatment of diabetic
dyslipidaemia

• LDL cholesterol lowering
• HMG CoA reductase inhibitor (statin)
• Bile acid binding resin (resin) or
  fenofibrate
• HDL cholesterol raising
• Weight loss,increased physical activity and
  smoking cessation
• Glycaemic Control
• Triglyceride lowering
• Glycaemic Control
• Fibric acid derivative (gemfibrozil,fenofibrat
  e)
• Statins
• Combined hyperlipidaemia
• Glycaemic control plus high dose statin.
• Glycaemic control plus Statin plus fibric
  acid derivative.
• Glycaemic control plus resin plus fibric
  acid derivative.

47
Multiple risk factor intervention is more
effective in Diabetes
Steno 2 Study Multifactorial Intervention
and Cardiovascular Disease in Patients with Type
2 Diabetes, Peter Gaede et al, NEJM 2003 Aim
To compare the effect of intensified ,
multifactorial intervention with that of
conventional treatment on modifiable
cardiovascular risk factors in patients with type
2 diabetes with microalbuminuria.
48
Steno 2 study The Mean
follow-up period was 7.8 years. Conclusion
The intensified intervention aimed at multiple
risk factors reduces the risk of
cardiovascular and microvascular events
by about 50 percent.
49
Importance of Multifactorial Care

• The importance of a structured, protocol driven,
  multifactorial approach to managing the
  complications of diabetes is shown in Steno 2
  study.
• Intensively managed group received lifestyle
  advice, aspirin and angiotensin converting enzyme
  inhibitors, with tight targets for glucose, blood
  pressure and lipids. The conventionally managed
  group received usual structured care in a primary
  care setting.
• Over eight years, the risks of progression of
  microvascular and macrovascular disease were
  reduced by 40-60 in the intensively managed
  group.

50
Reducing Global risk of CVD in Diabetes
Prediabetes

• 1.CV Risk in Diabetes
• 2.Reducing CV Risk in Diabetes
• 3.CV Risk in Prediabetes
• 4.Reducing CV Risk in Prediabetes

51
Is there a risk threshold for Glycemia below
the Hyperglycemic levels of Diabetes?
52
Dysglycemic IcebergsMetabolic Status of the
Population
Eye, Nerve, Kidney Risk
Diabetes
IGT
CV Risk
High
Dysglycemia is a progressive risk factor for CV
events - higher glucose levels ? higher risk -
no clear glucose threshold for risk
53

• Blood glucose a continuous CHD risk factor
• People with IGT have a higher risk for CHD. Even
  in the presence of normoglycemia, an increase in
  cardiovascular risk is observed as the glucose
  increases
• Glucose is a continuous cardiovascular risk
  factor, similar to hypercholesterolemia and
  hypertension.
• In the Whitehall study, there was an increase of
  1.5 to 2- fold in CHD mortality with 2h post
  glucose value of 5.4 mmol/l independent of age,
  smoking, blood pressure, cholesterol and
  occupation.
• The Rancho Bernado Study n 3458 followed for
  an average of 14 years showed a linear increase
  in ischemic heart disease mortality rates with
  increasing fasting blood glucose.

54
All-cause mortality has a linear relationship
with 2-hour plasma glucose
55
Relative risk of CVD mortality by 2-hr
post-load glucose - DECODE Multivariate adjusted
6 5 4 3 2 1 0
Relative risk
gt14.5
lt3.0
Normal
Diabetes
IGT
0 2 4 6 8 10 12 14 16
2-hour plasma glucose (mmol/l)

56
SURVIVAL IN THE FUNAGATA COHORT IN JAPAN
ACCORDING TO THE 2-HR GLUCOSE CRITERIA
NGT (n2,016)
IGT (n382)
Diabetes (n136)
P lt 0.05.
A all causes
B cardiovascular death
57

• In a large cohort of 24,160 non-diabetic
  patients elevated FPG after adjusting for other
  risk variables showed a hazard ratio of 1.13 for
  CAD on long term follow up.

Nielson C et al, Diabetes Care 2006
58

• Role of HbA1c
• In elderly men with type 2 diabetes in Kuopio,
  Finland, the most important single risk factor
  associated with CHD death or event was HbA1c,
  after adjusting for gender, history of previous
  MI current smoking, waist hip ratio, SBP, HDL
  cholesterol and duration of diabetes.
• Patients in the highest HbA1c had a threefold
  higher risk of CHD compared with those in the
  lowest tertile.

59
HbA1c predicts all cause and CVD mortality
4.0
3.5
3.0
2.5
Relative risk(age/sex adjusted)
All cause
2.0
CVD
1.5
1.0
0.5
0
?6.5
5.2
5.25.5
5.66.4
HbA1c () ranges

de Vegt et al, Diabetologia 19994292631.
60
Age Specific prevalence of IGT and Diabetes in
Urban Indian Population.
IF IGT CARRY HIGH CV RISK , THEN CV RISK
STARTS EARLY IN INDIANS
IGT higher in younger age

Age groups (years)
Prevalence of IGT was significantly higher than
diabetes in the age group below 40 yrs.
IGT was 13, diabetes 5. ?2 206.9, P lt 0.0001
61
CVD Risk factors - Population data (age gt 20
years)
NGT IGT
DM Number
1666 225
294 Age(yrs)(mean,SD) 38,12
45,12 49,9 Values in BMI gt25kg/m2
20.5 31.6 34.7
?WHR (Mgt.9,Fgt.85) 41.5
59.1 74.8 Chol gt 209mg/dl
26.4 44.6
47.0 TG gt165mg/dl 26.7
35.7 53.8 , Plasma Insulin (uU/ml)
Fasting (gt16) 34.6
51.5 54.1 2h (gt 41)
39.3 80.6 62
, p lt 0.05 vs NGT , p lt 0.05 vs
IGT Subjects with IGT have higher prevalence of
all the CV risk factors. Prevalence of many of
the risk factors are similar to that in diabetes.
62
Prevalence of CAD risk variables in categories
of glucose tolerance

NGT IFG IGT IFGIGT

n129 n44 n68
n29 percentages ? Obesity
43 54.5 48.5
37.9 ? WHR
49.6 61.4 59.7
44.8 Hypertension 14
25 30.9 20.7
Dyslipidaemia 54.3
61.4 80.9 , 69
p lt 0.04 Vs NGT , Vs IFG
63
Global and regional mortality from Ischaemic
Heart Disease and Stroke Attributable to higher
than Optimum Blood Glucose Concentration
Comparative Risk Assessment
Goodarz D et al, The Lancet 368 1651 59, 2006

• Population level effects of higher then optimum
  blood glucose on mortality from cardiovascular
  diseases was studied.
• Data from population health survey from 52
  countries were used for a meta analysis of over
  than 2,00,000 participants in the Asia Pacific
  region

64
- Cond-

• 9,59,000 death directly assigned to diabetes
• In addition to 959,000 deaths directly assigned
  to diabetes, 1 490,000 deaths from ischaemic
  heart disease and 709,000 from stroke were
  attributable to high blood glucose, accounting
  for 21 and 13 of all deaths from these
  conditions.
• 84 of these deaths were in low and middle
  income countries,
• especially of south Asia,
  Europe and Central Asia

65
- Cond

• Higher than optimum blood glucose is a leading
  cause of cardiovascular mortality

66
Reducing Global risk of CVD in Diabetes
Prediabetes

• 1.CV Risk in Diabetes
• 2.Reducing CV Risk in Diabetes
• 3.CV Risk in Prediabetes
• 4.Reducing CV Risk in Prediabetes

67
Does reducing blood glucose(targeting
normoglycemia) help in subjects with
non-diabetic levels of hyperglycemia ?
68
Is Targeting normoglycemia beneficial in
subjects with non-diabetic levels of
hyperglycemia ?

• 1.Digami study
• 2.Stop NIDDM Trial
• 3.Diabetes Prevention Programme (DPP)
• 4.Indian Diabetes Prevention Programme (IDPP)
• 5.Other Recent trials

69

• DIGAMI (Diabetes Mellitus, Insulin Glucose
  Infusion in Acute Myocardial Infarction ) Study
• Diab Ob Metab, 2002
• A Multi centre, randomized prospective study in
  19 Coronary Care Units in Sweden.
• 620 patients with diabetes and or stress
  hyperglycaemia.
• Randomized
• To insulin treatment n 306,
• Received insulin glucose infusion
  followed by a multi dose subcutaneous insulin
  regime for at least 3 months.
• Control group n 314,
• Given insulin if clinically indicated.

70

• Important results from the DIGAMI study
• 30 reduction in mortality was demonstrated at
  1 year in the insulin group (18.6 Vs. 26.1 , p
  lt 0.027)
• The reduced mortality was maintained at a mean
  follow up of 3.4 years (44 Vs. 33 , p lt
  0.011).

71
Acute Insulin Rx in ICU DM Non-DMVan den
Berghe et al. NEJM 2001 345 1359

• 1548 patients (87 no DM) in a surgical ICU
• Insulin infused to maintain PG of 79 110 mg/dl
• Death rate on insulin 8.0 ? 4.6 (Plt0.04)

72
Acarbose Progression / Regression of Disease
Incidence of type 2 diabetes
24.8
Reduction
p 0.0015
Return to normal glucose tolerance
29.5
Increase
p lt0.0001
Intent-to-treat population Cox proportional
hazards model time to single OGTT gt 11.1 or lt
7.8 mmol/L acarbose vs placebo
73
Number of CV - events
Acarbose
Placebo
Cardiovascular Death 1 2 Myocardial
infarction 1 14 Angina 5 13 Cong. Heart
Failure 0 2 Stroke/Cerebrovasc. Acc. 2
4 Peripheral Vascular Dis. 1
1 Revascularization Proc. 14 24 Any
prespecified CV -event 24 60
prospectively defined events in STOP-NIDDM
study protocol post-hoc adjudicated via a
study independent, blinded experts committee
74
Number of subjects with CV - events
Acarbose
Placebo
Cardiovascular Death 1 2 Myocardial
infarction 1 12 Angina 5 12 Cong. Heart
Failure 0 2 Stroke/Cerebrovasc. Acc. 2
4 Peripheral Vascular Dis. 1
1 Revascularization Proc. 11 20 Total 15 32
subjects with prospectively defined events in
STOP-NIDDM study protocol post-hoc
adjudicated via a study independent, blinded
experts committee
75
Risk Reduction on Acarbose
34 p 0.0059
New Hypertension
91 p 0.0226
Myocardial Infarction
Any CV- Event
49 p0.0326

76
Impact of Intensive Lifestyle and Metformin
Therapy on Cardiovascular Disease Risk Factors in
the Diabetes Prevention Program

• Intensive lifestyle intervention reduced known
  risk factors for CVD, hypertension, high
  triglyceride levels, low HDL levels, and small
  dense LDL.

Diabetes Care 28 888 894, 2005
77
Effect of Treatment on Incidence of Diabetes

• Placebo Metformin Lifestyle
• Incidence of diabetes 11.0
  7.8 4.8
• (percent per year)
• Reduction in incidence ---- 31
  58
• compared with placebo
• Number needed to treat ---- 13.9
  6.9
• to prevent 1 case in 3 years

The DPP Research Group, NEJM 346393-403, 2002
78
CV disease risk in DPP

• LSM group
• 1.Increased HDL sig reduced athero LDL
• 2.The use of drugs to treat HTN was 27-28 less.
• 3.25 less for hyper lipidemia compare to both
  placebo Metformin.
• 4.No difference in CVD event rates.

79
DREAM

• Diabetes REduction Assessment with ramipril and
  rosiglitazone Medication

80
Rosiglitazone Primary Outcome
81
Effect on Glucose Category Rosiglitazone
HR 1.71 P lt 0.0001
HR 1.83 P lt 0.0001
HR 0.38 P lt 0.0001
82
Rosiglitazone Median Glucose
Fasting PG (mM)
2 Hour PG (mM)
2 HOUR PG mM
Placebo
Placebo
Rosiglitazone
Rosiglitazone
83
Cardiovascular Outcomes Rosiglitazone
HR 1.37 (0.97-1.94) P0.08
14 (0.5) vs. 2 (0.1) P0.01
LOG HR (95 CI)
84
Summary Conclusions Rosiglitazone

• A dose of 8 mg/day reduces new DM by gt 60 in
  people with IGT or IFG
• Promotes regression to normal FPG 2 hr PG by
  gt70
• Effective in all regions of the world
• Eliminates the gradient of DM risk with
  increasing weight
• 3 increase in body weight, but a favourable
  effect on waist/hip ratio
• Reduces ALT

85
Summary Conclusions Rosiglitazone

• Modestly lowers systolic BP diastolic BP
• Increases the risk of CHF
• Too few events to draw any conclusions re the
  effect on other CV events or death
• For every 1000 people treated with rosiglitazone
  for 3 years, 144 cases of DM will be prevented
  with an excess of 4 cases of CHF

86
Conclusions of the DREAM Trial

• Rosiglitazone has a substantial benefit on
  prevention of diabetes regression to
  normoglycaemia
• Ramipril has a modest benefit on regression to
  normoglycaemia
• The durability of the glycaemic effect of these
  drugs is being assessed in a washout phase

DREAM Slides www.phri.ca/dream 2 DREAM Papers
NEJM Lancet - online
87
Should we then consider targeting normoglycemia
in IGT IFG with Insulin ?
ORIGIN Trial
88
Outcome Reduction with an Initial Glargine
Intervention(ORIGIN )Study

• In high risk people with IFG, IGT
• or early diabetes,
• does insulin replacement with Glargine reduce
  the risk of cardiovascular events ?
• Aim FPG lt95mg/dl

89

• Justification for glycemic optimization in
  IGT IFG and Early Insulin use.
• In the natural history of diabetes, the plasma
  glucose levels at which the insulin secretion
  declines could be an indicator of early insulin
  intervention.
• With FPG gt 140 mg/dl, 75 of ? cell function is
  lost and acute insulin response is totally lost
  with FPG gt 180 mg/dl.
• Similarly insulin secretion starts to become
  impaired with 2h PG gt 200 mg/dl.
• At this point insulin should be
  replaced!!!

90
ORIGIN StudyHypothesis

• 1.Diabetes, IFG IGT are common CV risk factors
• 2. Insulin is either absolutely or relatively
  deficient in people with diabetes IFG/IGT
• 3.Supplying enough insulin to restore physiologic
  glucose levels may reduce CV events

91
Nateglinide and Valsartan in ImpairedGlucose
Tolerance Outcomes Research
Sponsor Novartis
92
Inclusion Criteria

• Either
• Established cardiovascular disease
• One or more manifestations of CVD
• 50 years or older
• Or
• Risk factors for cardiovascular disease
• One or more risk factor for CVD
• 55 years or older
• AND
• shown to have IGT on an OGTT

93
Two by Two Factorial Design
Started 2001 Follow-up 5 to 7 yrs Results
expected 2008 with 1374 or more CVD events Three
month washout period
94
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95
Prevalence of hyperlipidemia DPP
Participants with dyslipidemia ()