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The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications. David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008. Diabetes, Hyperglycemia and Cardiovascular Disease: One and the Same?. David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008. Nosology.

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the role of cardiovascular assessment in the approval process of diabetic medications

The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications

David M. Nathan, M.D.

FDA Advisory Meeting

July 1, 2008

diabetes hyperglycemia and cardiovascular disease one and the same

Diabetes, Hyperglycemia and Cardiovascular Disease:One and the Same?

David M. Nathan, M.D.

FDA Advisory Meeting

July 1, 2008

slide3

Nosology

  • Diabetes mellitus is a chronic disease characterized by abnormal metabolism of glucose (blood sugar) as well as other nutrients such as protein and fat, and accompanied by the risk of long-term complications specific to diabetes that affect the eye, kidney and nervous system.
  • World Book Encyclopedia, 2000
slide4

Retinopathy and Glucose Control

Type 2 diabetes (n-185)

Retinopathy

Prevalence

%

Hemoglobin A1c (%)

Nathan et al.

Diabetes 1986;35:797

P=.002 for trend

slide5

Association of Glycemia with Complications

Pima

Retinopathy

PimaEgyptNHANES

FPG 116 108 110

2h 180 155 154

A1c 6.0 6.0 6.0

Egyptian

NHANES

1997 ADA

Expert Committee

slide6

Risk

of

Retinopathy

[Glycemia]

Diagnostic Criteria for Diabetes Mellitus

  • Predicated on glucose levels associated with risk for complications
  • Although risk increases with rising glycemia, there is a threshold below which complications do not occur
slide7

Retinopathy in Recent Onset Diabetes and Non-diabetic Persons at High Risk of Diabetes in the Diabetes Prevention Program

Diabetes Prevention Program

Outcomes Study Research Group

Writing Group: D. Nathan (Chair), E. Chew, C. Christophi, M. Davis, S. Fowler, B. Goldstein, R. Hamman, L. Hubbard, W. Knowler, M. Molitch

slide9

Tight Control and Type 1 Diabetes

2%

Primary Prevention Secondary Intervention

54%

76%

DCCT Research Group

NEJM 1993;342:381

intensive therapy of type 1 diabetes
Intensive Therapy of Type 1 Diabetes

Hypoglycemia

Weight gain

Effort

Expense

DCCT

SDIS

Reduced

development and

progression of

all complications

slide11

UKPDS Results

DCCT

2%

1%

Obese and non-obese treated with conventional vs insulin/sulphonylureas

UKPDS

Lancet 1998;352; 837.

slide12

Intensive Therapy of Type 2 Diabetes

Minimal hypoglycemia

Weight gain

No excess CVD

Effort

Expense

UKPDS

Kumamoto

Reduced

development and

progression of

complications

slide13

Relationship between Glycemia and Complications

DCCT and UKPDS

43% reduction in risk

for every 10%

decrease in HbA1c

Event

Rate

per

1000 Pt-Y

DCCT

37% reduction in risk

for every 1%

decrease in HbA1c

UKPDS

Current Mean HbA1c (%)

©2005 David M. Nathan

slide14

D

I

A

G

N

O

S

I

S

Retinopathy

Categories and Continua: Hyperglycemia and its Consequences

R

I

S

K

IGT IFG Diabetes

[Glycemia]

© 2005 David M. Nathan

glycemia and complications
Glycemia and Complications
  • Apparent glycemic thresholds for the development of complications define the diagnostic cut-points for diabetes
  • Glycemia in the “diabetic” range is associated with risk for developing complications
  • Treatment that lowers glycemia reduces the risk for development and progression of microvascular diabetic complications
glycemia and diabetes
Glycemia and Diabetes
  • On the basis of the intimate association between glycemia, and in particular measures of chronic glycemia, and diabetes complications (epidemiology, clinical trials), the effectiveness of medications to lower HbA1c has been used as a metric in considering new diabetes medications
  • However, recent experience has suggested that some anti-diabetic medications may worsen CVD risk
glycemia and diabetes17
Glycemia and Diabetes
  • Some have questioned whether the FDA posture of approving diabetes medications on the basis of their effects on glycemia (a “surrogate”) is adequate
  • Should the effect(s) of diabetes medications on CVD be required during approval process
    • Toxicity
    • Benefits
slide18

Circulation

1999; 100:1132-46

slide19

Thus, diabetes must take its place alongside the other major risk factors as important causes of CVD. In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.”

Circulation 1999; 100:1134

effect of type 2 dm on cvd outcome
Effect of Type 2 DM on CVD Outcome

Population-based Finnish Study

1373 Non-diabetic

1059 diabetic

Aged 45-64

7 year

incidence

(%)

MI CVA Mort MI CVA Mort

No Prior MI Prior MI

Haffner et al.

NEJM 1998;339:229

© 2005 David M. Nathan

framingham heart study
Framingham Heart Study

Relative Risk

MenWomen

CHF 2.8 7.7

CAD 1.9 3.6

CAD Death 2.6 7.2

Stroke 3.3 5.6

Claudication 4.7 8.9

Kannel, McGee JAMA 1979;241:2035

© 2005 David M. Nathan

pathophysiology of cvd in diabetes mellitus

LDL

HDL

Hypertension

Smoking

Hyperglycemia

Renal disease

Auto. Neuropathy

Glycated lipoproteins

Hemorheologic

PAI-1

Platelet activ.

Endothel. Dysf.

Obesity

Insulin resistance

Hyperinsulinemia

Type 2

Pathophysiology of CVD in Diabetes Mellitus

Attained Age

Dyslipidemia

Triglycerides/VLDL

Small, dense LDL

Oxidized lipoproteins

FFA

Inflammation

CVD

© 2008 David M. Nathan

association of glycemia with cvd
Association of Glycemia with CVD
  • 1045 survivors of original Framingham cohort
  • (44% of survivors)
  • HbA1c measured in 1986-89
  • Prevalence of CVD (CAD,CHF, PVD, stroke/TIA)
  • correlated with A1c (more strongly in women than men)
  • A1c remained significant factor in models where other
  • known risk factors included
  • 39% increase in risk for CVD for each 1% increase in A1c
  • D. Singer, D. Nathan
  • Diabetes 1992;41:202
  • Early studies could not establish relationship, owing in part to poor measures of chronic glycemia
  • In 1992, we established a significant relationship between glycemia, measured with A1c, and prevalent CVD in the predominantly non-diabetic Framingham population
  • Subsequently, numerous studies confirmed association

© 2008 David M. Nathan

association of hba1c with cvd
Association of HbA1c with CVD

Framingham Heart Study

P=.001

Relative

Risk

P=.04

Results

unchanged if

diagnosed

diabetics

removed

HbA1c: < 5.1 5.1-5.46 5.47-5.92 > 5.92

N- women 145 164 165 155

men 112 104 93 107

Diagnosed

diabetes (%) 3.4 4.3 4.2 25

© 2005 David M. Nathan

slide26

Hemoglobin A1c as a CVD Risk Factor

EPIC Study

Men, n=4662

Followup ~ 6 years

RR*

Diagnosed

diabetes

Hemoglobin A1c

*Age adjusted. No significant change when adjusted

for other CVD risk factors.

Khaw

Ann Int Med 2004;141:413

© 2005 David M. Nathan

framingham offspring study
Framingham Offspring Study

Population-based Cohort- children of original

Framingham Heart Study population: OGTT

at 4th four year cycle exam

FPGHbA1cNumber

(mg/dL) (%)

NGT 1 60-85 5.1 418

NGT 2 86-90 5.2 541

NGT 3 91-95 5.2 635

NGT 4 96-100 5.3 502

NGT 5 101-139 5.4 559

IGT 76-140 5.5 329

DM 89-298 6.8 125

Meigs, Nathan et al.

Ann Int Med 1998; 128:524

Framingham Offspring Study

cvd risk associated with glycemia

P< .001, for trend

CVD Risk Associated with Glycemia

Prevalence of Hypertension: Diastolic > 95,

Systolic > 160, or Treatment

60

50

%

40

Men

30

Women

20

10

0

NGT 1

NGT 2

NGT 3

NGT 4

NGT 5

IGT

Type 2

Meigs, Nathan et al.

Ann Int Med 1998; 128:524

Framingham Offspring Study

cvd risk associated with glycemia29
CVD Risk Associated with Glycemia

Prevalence of Dyslipidemia: HDL < 35 men, women < 45 mg/dL

P< .001, for trend

%

Meigs, Nathan et al.

Ann Int Med 1998; 128:524

Framingham Offspring Study

distribution of hemostatic factors
Distribution of Hemostatic Factors

Q1 Q2 Q3 Q4 Q5 IGT NIDDM P

Fibrinogen 285 289 292 298 302 302 315 *

Factor VII 95 95 97 97 98 101 101 *

PAI-1 17 18 20 22 24 30 35 *

t-PA 7.6 7.7 8.5 8.7 9.7 10.9 11.8 *

vW factor 125 124 126 127 128 133 140 +

* <.0001 for trend; + < .05

Framingham Offspring Study

slide31

D

I

A

G

N

O

S

I

S

CVD

Retinopathy

Categories and Continua: Hyperglycemia and its Consequences

R

I

S

K

IGT IFG Diabetes

[Glycemia]

© 2005 David M. Nathan

slide32

The Effect of Intensive Diabetes Management

on Cardiovascular Events in Type 1 Diabetes

DCCT/EDIC Research Group

June 12, 2005

slide33

Cardiovascular Events in Type 1 Diabetes

Non-Fatal MI, Stroke or CVD Death

0.12

0.10

Risk reduction 57%

95% CI: 12, 79

Log-rank P = 0.018

0.08

Cumulative Incidence

0.06

Conventional

0.04

0.02

Intensive

0.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years from Study Entry

Number at Risk

Intensive: 705 686 640 118

Conventional: 721 694 637 96

DCCT/EDIC

pathophysiology of cvd in diabetes mellitus34

Type 1

LDL

LDL

HDL

HDL

Hypertension

Hypertension

Smoking

Hyperglycemia

Renal disease

Auto. Neuropathy

Glycated lipoproteins

Hemorheologic

PAI-1

Platelet activ.

Endothel. Dysf.

Hemorheologic

PAI-1

Platelet activ.

Endothel. Dysf.

Obesity

Obesity

Insulin resistance

Hyperinsulinemia

Insulin resistance

Hyperinsulinemia

Type 2

Pathophysiology of CVD in Diabetes Mellitus

A t t a I n e d A g e

Dyslipidemia

Triglycerides/VLDL

Small, dense LDL

Oxidized lipoproteins

FFA

Inflammation

CVD

slide35

Cardiovascular Events in Type 2 Diabetes

  • No CCTs have demonstrated a benefit of
  • intensive therapy aimed at lowering glycemia
  • on CVD events
  • UGDP ADVANCE RECORD
  • UKPDS PROACTIVE
  • ACCORD VADT
  • Some trials have suggested harm with specific
  • drugs or regimens
  • UGDP- tolbutamide ACCORD regimen
  • UKPDS- SU + metformin
  • Some trials have suggested benefit
  • UKPDS-metformin
  • PROACTIVE- pioglitazone
are diabetes and cvd the same
Are Diabetes and CVD the Same?

Common Soil

  • Are there common antecedent risk factors that underlie CVD and diabetes?
    • Demographic
    • Clinical
    • Biochemical
    • Genetic
  • If common soil is present, are there treatments that modify such factors that might ameliorate both diabetes and CVD?
are diabetes and cvd the same37

FFA Resistin

Leptin TNF

Adiponectin

Hypertension

IGT

Inflammation

Dyslipidemia

Endothelial

dysfunction

IL-6

CRP

VLDL

HDL

Thrombosis

+

VCAM

ICAM

MCP

E-selectin

NO

Fat Mass

t-PA

PAI-1

vWF

Insulin deficiency

Diabetes

CVD

Are Diabetes and CVD the Same?

Common Soil: Obesity

Insulin resistance

are diabetes and cvd the same38
Are Diabetes and CVD the Same?

Common Soil

Insulin resistance

Diabetes

CVD

are diabetes and cvd the same39
Are Diabetes and CVD the Same?

Common Soil

Inflammation

Diabetes

CVD

diabetes and cvd common soil

Reykjavik Heart Study

  • Population-based study
  • Mean followup- 18 years
  • 2459 fatal or non-fatal Mis
  • 3969 controls
  • Age 59
  • 70% males
  • Cases were heavier, higher
  • BP, BMI, T-chol, triglycerides
  • CRP 1.8 vs 1.3 mg/L, P< .001

*

*

*

CRP

CRP

ESR

ESR

vWF

vWF

Adjusted for Adjusted for other

other risk factors risk & inflam. factors

OR for MI, top 1/3 vs bottom

significant

Diabetes and CVD: Common Soil

Inflammation: CRP

Danesh et al.

NEJM 2004;350:1387

*

diabetes and cvd common soil41
Diabetes and CVD: Common Soil

Inflammation: CRP

  • MONICA Study
  • Population-based study
  • N= 3993
  • Mean followup- 7 years
  • 101 incident cases of diabetes

Arch Int Med, 2003

Adjusted for Adjusted for age,

Age and BMI BMI,smoking, BP

OR for Incident Diabetes

by CRP quartile

diabetes and cvd common soil42
Diabetes and CVD: Common Soil

Inflammation: CRP

  • Rotterdam Study
  • Population-based study
  • N= 6,935
  • Mean followup- 9.8 years
  • 544 incident cases of diabetes

Dehgan et al.

Diabetes 2007;56:872

Adjusted for Adjusted for age, sex

Age and sex BMI, BPsys, BP diast, HDL

OR for Incident Diabetes

by CRP quartile

cultivating the common soil

No good examples of CVD interventions

  • that improve glycemia
  • DREAM study failed to demonstrate the
  • putative benefit of ACE-inhibitors
  • Several CVD medications (beta-adrenergic
  • blockers) worsen glycemia
  • The TINSAL study is studying the effects of
  • an anti-inflammatory on diabetes

Cultivating the Common Soil

Effects of CVD Treatments on Diabetes

cultivating the common soil44

Life-style interventions

  • Glycemic medication therapy
  • Chronic
  • Acute
  • Toxic drugs?
  • Beneficial interventions?

Cultivating the Common Soil

Effects of Diabetes Treatments on CVD

slide45

Effects of Life-style on CVD Risk Factors

Look:AHEAD Study- 1 year results

47

89%

45

7.25

6.61 7.15

165

15

69

127

67

153

13

x101

107

107

121

79%

Diabetes Care

2007;30:1374

cultivating the common soil46

Life-style interventions

  • Glycemic medication therapy
  • Chronic- ACCORD,ADVANCE, etc
  • Acute
  • Toxic drugs?
  • Beneficial interventions?

Cultivating the Common Soil

Effects of Diabetes Treatments on CVD

cultivating the common soil47

Life-style interventions

  • Glycemic therapy
  • Chronic
  • Acute
  • Toxic drugs?
  • Beneficial interventions?

Cultivating the Common Soil

Effects of Diabetes Treatments on CVD

role of specific anti diabetic agents in cvd
Role of Specific Anti-diabetic Agents in CVD
  • Are specific therapies cardiotoxic?
    • Sulfonylureas-UGDP 1%/yr excess CVD mortality
    • Biguanides- UKPDS (with sulfonylureas)
    • Rosiglitazone
    • ACCORD intensive regimen
  • Are specific therapies cardioprotective?
    • Insulin- DIGAMI
    • Metformin- UKPDS monotherapy
    • Acarbose
    • Pioglitazone
cultivating the common soil49

Life-style interventions

  • Glycemic therapy
  • Chronic
  • Acute
  • Toxic drugs?
  • Beneficial interventions?

Cultivating the Common Soil

Effects of Diabetes Treatments on CVD

role of specific anti diabetic agents in cvd50
Role of Specific Anti-diabetic Agents in CVD
  • Are specific therapies cardiotoxic?
    • Sulfonylureas-UGDP 1%/yr excess CVD mortality
    • Biguanides- UKPDS (with sulfonylureas)
    • Rosiglitazone
  • Are specific therapies cardioprotective?
    • Insulin- DIGAMI, Leuven
    • Metformin- UKPDS monotherapy
    • Acarbose- STOPNIDDM
    • Pioglitazone- PROACTIVE
conclusions
Conclusions

The Basics

  • Diabetes, its long-term specific complications and hyperglycemia are tightly linked
  • The rationale for decreasing glycemia is primarily based on its demonstrated effect on diabetes-specific complications
  • Although hyperglycemia is associated with CVD, no studies of type 2 diabetes have demonstrated a benefit of lowering glycemia on CVD
conclusions52
Conclusions

The Basics

  • Approval of diabetes medications on the basis of lowering glycemia seems merited, assuming they are safe
  • The potential adverse (or beneficial) effects, especially on CVD, of such medications, should obviously be taken into account, but should not be the primary basis of approving- or not approving- glucose lowering drugs