Diabetes .

Diabetes . . .

Common and underdiagnosed

Causes macro- and microvascular events

Reduces duration and quality of life

Estimated Prevalence of Diabetes in the USAdult Men and Women

Harris, et al. Diabetes Care. 1998;21:518-24.

0

10

20

30

75+60-7450-5940-4920-39Age (y)

1.6 1.7

6.8 6.1

12.9 12.4

20.217.8

21.1

17.5

MenWomen

Perc

ent o

f Pop

ulat

ion

Diagnosed and Undiagnosed Diabetes in the USEstimated Cases Among Adults, 1997

Harris, et al. Diabetes Care. 1998;21:518-24.

0

2

4

6

8

10

12

UndiagnosedDiagnosed

10.2

5.4

Mill

ions

of C

ases

Retinopathy in Adults not Known to Have Diabetes Rationale for Diagnostic Criteria for DiabetesGlycemic Values in Deciles of Populations

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19.

FPG2hPGHbA1c

Ret

inop

athy

(%)

15

10

5

0

US (NHANES III)

42- 87- 90- 93- 96- 98- 101- 104- 109- 120-34- 75- 86- 94- 102- 112- 120- 133- 154- 195-3.3- 4.9- 5.1- 5.2- 5.4- 5.5- 5.6- 5.7- 5.9- 6.2-

FPG (mg/dL)2hPG (mg/dL)

HbA1c (%)

Retinopathy in Adults not Known to Have Diabetes Rationale for Diagnostic Criteria for DiabetesGlycemic Values in Deciles of Populations

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19.

50

30

10

0

40

20

Ret

inop

athy

(%) FPG

2hPGHbA1c

Egypt

57- 79- 84- 89- 93- 99- 108- 130- 178- 258-39- 80- 90- 99- 110- 125- 155- 218- 304- 386-2.2- 4.7- 4.9- 5.1- 5.4- 5.6- 6.0- 6.9- 8.5- 10.3-

FPG (mg/dL)2hPG (mg/dL)

HbA1c (%)

Glucose Tolerance Categories

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97.

FPG

126 mg/dL

110 mg/dL

7.0 mmol/L

6.1 mmol/L

Impaired FastingGlucose

Normal

2-Hour PG on OGTT

200 mg/dL

140 mg/dL

11.1 mmol/L

7.8 mmol/L

Diabetes Mellitus

Impaired GlucoseTolerance

Normal

Diabetes Mellitus

Diagnosis of DiabetesThree Methods

1. Random plasma glucose >200 mg/dL on 2 separate occasions + symptoms (polyuria, polydipsia,unexplained weight loss)

2. FPG >126 mg/dL on 2 separate occasions

3. 2-hour plasma glucose >200 mg/dL during OGTTon 2 separate occasions

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97.

THE FUNAGATA DIABETES STUDY Impaired Glucose Tolerance is a CV Risk Factor

Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. Diabetes Care 1999;22:920-4.

NormalIGT (2 hr PG 140-200)DM (2 hr PG >200)

1.00

Cumulative Cardiovascular Survival

0.99

0.98

0.97

0.96

0.95

0.94

0

1.00

0.98

0.96

0.94

0.92

0

NormalIFG (FPG 110-126)DM (FPG >126)

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7Year Year

FRAMINGHAM STUDY AND JOSLIN PATIENTS

Diabetes is a CV Risk Factor

Krolewski AS, et al. Evolving natural history of coronary disease in diabetes mellitus. Am J Med 1991;90(Supp 2A):56S-61S.

DiabetesNo Diabetes

60Men

0-3Duration of Follow-up (Years)

50

40

30

20

10

0

Women

4-7 8-11 12-15 16-19 20-23

60

0-3Duration of Follow-up (Years)

50

40

30

20

10

04-7 8-11 12-15 16-19 20-23

Mor

talit

y R

ate

Per

1000

Mor

talit

y R

ate

Per

1000

2x

4-5x

MRFIT Type 2 Diabetes is a CV Risk FactorAdditive Effects of Hypertension, Hypercholesterolemia, and Smoking

Stamler J, et al. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44.

0

20

40

60

Number of Risk FactorsNone One Two All Three

No DiabetesDiabetes

Age

Adj

uste

d C

V D

eath

Rat

ePe

r 10

,000

Per

son

Yea

rs

80

100

120

140

Type 2 Diabetes is a CV Risk FactorDiabetes and Prior MI Predict Mortality Equally

Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.

100

Year3

Surv

ival

(%)

80

60

40

20

00 1 2 4 5 6 7 8

No Diabetes or MIDiabetes without MIMI without Diabetes

Diabetes + MI

Reduced Life-expectance with DiabetesUS Adults Aged 55 to 64 in 1971 to 1975

Gu K, et al. Mortality in adults with and without diabetes in a national cohort of the US population, 1971-1993.Diabetes Care 1998;21:1138-45.

0

10

20

30Median Life Expectance

Women Men

No Diabetes

DiabetesY

ears25

1718

10

Lifetime Microvascular Events in Type 2 Diabetes Predictions from a Statistical Model

Eastman RC, et al. Model of complications of non-insulin dependent diabetes mellitus. II analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997;20:735-44.

Standard Care Comprehensive Care PercentageHbA1c 10% HbA1c 7.2% Change

Blindness 19% 5% -72

Renal failure 17% 2% -87

Symptomaticneuropathy 31% 10% -68

Amputation 15% 5% -67

Treatment Improves Outcomes

KUMAMOTO STUDY

Effect of Treatment on HbA1c

Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus. A randomized prospective 6-year study. Diab Res Clin Pract 1995;28:103-17.

ConventionalIntensive

Years

9

0

HbA

1c (%

)12

11

10

8

6

5

7

1 2 3 4 5 6

2.3%HbA1c

KUMAMOTO STUDY

Risk Reduction of Microvascular Complications

Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus. A randomized prospective 6-year study. Diab Res Clin Pract 1995;28:103-17.

Cum

ulat

ive

Perc

ent P

rogr

essi

ng

5040302010

0

5040302010

0

40302010

0

403020100

Years0 1 2 3 4 5 6

Years0 1 2 3 4 5 6

RetinopathyPrimary Prevention

NephropathyPrimary Prevention

RetinopathySecondary Intervention

NephropathySecondary Intervention

-62%P=0.032

-70%P=0.039

-52%P=0.049

-52%P=0.044

ConventionalIntensive

UKPDS MAIN STUDY


Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.

Conventional(10-y cohort)

9

8

7

6

00 3 6

6.2% upper limit of normal range

ADA goal

ADA action

9 12 15Time From Randomization (y)

Intensive(all patients)

Conventional(all patients)

Intensive(10-y cohort)

Med

ian

HbA

1c (%

)

UKPDS MAIN STUDY

Risk Reduction of Microvascular Complications

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.

% o

f Pat

ient

s With

an

Eve

nt

Risk Reduction 25%P=0.0099

Conventional Intensive

0 3 6

0

10

20

30

9 12 15

Time From Randomization (y)

UKPDS MAIN STUDY

Risk Reduction of Various Endpoints

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

Risk Reduction (%)

P=0.000054

P=0.015

P=0.052

P=0.0099

P=0.029

0 5 10 15 20 25 30 35

Diabetes-relatedend points

Myocardialinfarction

Albuminuria

Retinopathy

Microvascular 25%

21%

16%

33%

12%

UKPDS METFORMIN SUBSTUDY



Med

ian

HbA

1c (%

)

Conventional (200)Insulin (199)Chlorpropamide (129)Glyburide (148)Metformin (181)

0 2 406

7

8

9


Upper limit of normal range (6.2%)

ADA goal

ADA action


Gain of Weight During Treatment


Mea

n C

hang

e (k

g)

Conventional (200)Insulin (199)Chlorpropamide (129)Glyburide (148)Metformin (181)

0 2 4-5

0

5

10


Baseline = 85 kg


Risk-Reduction of Microvascular Complications


% o

f Pat

ient

s With

Eve

ntConventional (411)Intensive (951)Metformin (342)

0 3 60

10

20

30


P=0.19 M vs. C

P=0.39M vs. I


Diabetes-Related Deaths


Patients at RiskConventionalMetforminIntensive

404339930

378321870

304267701

132123319

232861

Conventional (411)

Metformin (342)Intensive (951)

Prop

ortio

n W

ith E

vent

(%)

30

20

10

00 3 6 9 12 16

Time From Randomization (y)

M vs. CP=.017

M vs. IP=.11

UKPDS HYPERTENSION SUBSTUDY

Effect of Atenolol or Captopril on Blood Pressure

UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13.

Less Tight ControlTight Control withAtenolol or Captopril

Years from Randomization0

Mea

n B

lood

Pre

ssur

e (m

m H

g)160

1 2 3 4 5 6 7 8 9

140

120

100

80

0

Systolic

Diastolic


Risk-Reduction of Microvascular Endpoints



Patie

nts W

ith E

vent

s (%

)20

1 2 3 4 5 6 7 8 9

10

0

Less Tight ControlTight Control

Risk-Reduction 37%P=0.0092


Risk-Reduction of Stroke


0

Patie

nts W

ith E

vent

s (%

)20

1 2 3 4 5 6 7 8 9

10

0

Years from Randomization




Diabetes-Related Deaths



Mor

talit

y (%

)40

1 2 3 4 5 6 7 8 9

20

0

30

10




Diabetes-Related Deaths: Atenolol vs. Captopril

UK Prospective Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascualr complications in type 2 diabetes.: UKPDS 39. BMJ 1998;317:713-720.


Mor

talit

y (%

)20

1 2 3 4 5 6 7 8 9

10

0

15

5

Less Tight ControlCaptoprilAtenolol

P=0.28

SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP)

Diabetes Subgroup AnalysisEffect of Thiazide-Based Treatment on Blood Pressure

Curb JD, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-92.

PlaceboTreatment

Years

Blo

od P

ress

ure

(mm

Hg)

180160140120100

80604020

0

180160140120100

80604020

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

YearsB

lood

Pre

ssur

e (m

m H

g)

Diastolic

Systolic Systolic

Diastolic

No Diabetes Diabetes

SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP)

Diabetes Subgroup AnalysisEffect of Thiazide-Based Treatment on CV Events

Curb JD et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-92.

0

10

20

40 Risk Reduction 34%

No Diabetes(n=4736)

Diabetes(n=583)

PlaceboTreatment

Perc

ent W

ith E

vent

s at 5

Yea

rs

18.4

13.3

31.5

21.4

30

Risk Reduction 34%

SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (4S)

Diabetes Subgroup AnalysisReduction of LDL-Cholesterol

Pyorala K et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614-20.


n 4242 202

Baseline mmol/L 4.88 4.80 mg/dL 189 186

Reduction 34% 36%

SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (4S)

Diabetes Subgroup AnalysisReduction of Major Recurrent CV Events

Pyorala K et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614-20.

Years Since Randomization

Prop

ortio

n W

ith M

ajor

CH

D E

vent 0.60

0

0.50

0.40

0.30

0.20

0.10

0.001 2 3 4 5 6

Placebo Simvastatin

Diabetes

Years Since Randomization

Prop

ortio

n W

ith M

ajor

CH

D E

vent 0.60

0

0.50

0.40

0.30

0.20

0.10

0.001 2 3 4 5 6

No DiabetesPlacebo Simvastatin

Risk Reduction 32% P=0.0001

Risk Reduction 55% P=0.002

CARE TRIAL

Diabetes Subgroup AnalysisReduction of LDL-Cholesterol by Pravastatin

Goldberg RB, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol And Recurrent Events (CARE) Trial. Circulation 1998;98:2513-19.


n 3573 586

Baseline mmol/L 3.59 3.52 mg/dL 139 136

On Pravastatin 40 mg mmol/L 2.56 2.48 mg/dL 99 96

Reduction 29% 29%

CARE TRIAL

Diabetes Subgroup AnalysisReduction of Recurrent CV Events

Goldberg RB et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol And Recurrent Events (CARE) Trial. Circulation 1998;98:2513-19.

Years of Follow-up0

Perc

ent W

ith E

vent

45

PlaceboPravastatin

1 2 3 4 5

4035302520151050

0

Perc

ent W

ith E

vent

45

1 2 3 4 5

4035302520151050

PlaceboPravastatin

No Diabetes DiabetesRisk Reduction 23%P<0.001

Risk Reduction 25%P<0.05

CV Risk-Reduction With Antiplatelet TherapyHigh-Risk PatientsDiabetes Subgroup Meta-analysis

Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patient. BMJ 1994;308:71-2.


n 21,197 21,136

Vascular events Control 16.4% 22.3%

Antiplatelet Rx (usually ASA) 12.8% 18.5%

Risk Reduction 28% 21%

Targets and Tacticsfor

Typical Patients

UKPDS

Metabolic Profile at Diagnosis of Type 2 Diabetes

UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683-7.

Women Men

N 1574 2139

Age years 53 52

BMI kg/m2 30.8 28.3

FPG mmol/L 12.4 11.6 mg/dL 223 209

HbA1c % 9.3 9.0

BP mm/Hg 140/84 134/82

LDL-cholesterol mmol/L 3.90 3.35 mg/dL 151 139

ADA Glycemic Targets

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.

Normal Goal ActionLevel

HbA1c (%) <6 <7 >8

Fasting and preprandialblood glucose mmol/L <6.1 4.4 to 6.7 >7.8 mg/dL <110 80 to 120 >140

ADA Blood Pressure Targets

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.

Goal mm Hg

Usual patient <130/85

Isolated systolic hypertension If ≥180 <160 If 160 to 179 Reduce by 20

ADA LDL-Cholesterol Targets

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41 & S56-S59.

Medical Nutrition Therapy Drug TherapyBegin Rx Goal Begin Rx Goal

With CV disease >100 ≤100 >100 ≤100

No CV disease >100 ≤100 >130 ≤100

Tactics for Reaching Glycemic Targets

Medical Management of Type 2 Diabetes, Fourth Edition, Zimmerman BR ed, American Diabetes Association, Alexandria, VA, 1998.

Lifestyle intervention Oral monotherapy Oral combination Oral-insulin combinations Multiple insulin injections

Tactics for Reaching Blood Pressure Targets

Kaplan NM. Hypertension in patients with diabetes. In Current Management of Diabetes Mellitus, ed. De Fronzo RA, Mosby, 1998.American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 1999;22(Suppl):S56-S59.

Lifestyle Intervention Control weightLimit sodium and alcoholOptimize activity

Initial Drug Choices ACE-inhibitor or-blocker or Low-dose diuretic

Combinations Two or three of the aboveOther options• -blockers • Calcium antagonists• Hydralazine

Calcium Antagonists vs. Other AntihypertensivesControversy Over Use in Diabetes

Pahor M et al. Treatment of hypertensive patients with diabetes. Lancet 1998;351:690-1.

Trial Comparison Calcium RiskDrug Antagonist Ratio

ABCD Enalapril Nisoldipine 1/5.5

FACET Fosinopril Amilodipine 1/2.4

MIDAS Hydrochlorothiazide Isradipine 1/2.7

Tactics for Reaching Lipid Targets

American Diabetes Association. Management of Dyslipidemia in Adults with Diabetes. Diabetes Care 1999;22(Suppl):S56-S59.

Lifestyle Intervention Control weightLimit fatOptimize activity

Initial Drug Choices Usual patient• StatinTriglyceride >400 mg/dL• Fibric acid derivative

Combinations Statin + fibric acid derivativeOther options• Bile acid binding resins• Nicotinic acid

THE CURVES STUDY

LDL Reduction With Various Statins

Jones P et al. Comparative dose efficacy of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia. Am J Cardiol 1998;81:582-7.

Total Daily Dose (mg)

Mea

n %

Cha

nge

in L

DL

-C-10

10 mg 20 mg 40 mg 80 mg

-30

-60

-20

-50

-40

FluvastatinPravastatinLovastatinSimvastatinAtorvastatin

Summary

Epidemiologic and interventional evidence defines these targets HbA1c 7% Blood Pressure 130/85 mm Hg LDL-cholesterol 100 mg/dL

Basic treatment tactics include For glycemic control

– Oral and oral-insulin combinations For blood pressure control

– ACE-inhibitor, -blocker, and diuretic combinations For LDL-cholesterol control

– Statins For vascular protection

– ASA 81-325 mg daily

Documents

Diabetes .