Diabetes Update:

Recent Research and Impact on Diabetes Management

• • •

Type 1 Diabetes

–

Post DCCT findings--improving glycemic control and preventing complications Type 2 Diabetes

–

Impact of the United Kingdom Prospective Diabetes Study on Current Practice

–

Relationship between blood glucose, blood pressure dyslipidemia and complications Diabetes in Pregnancy

–

New screening, diagnostic and treatment criteria (use of Glyburide) for GDM IDC

Epidemiology of Diabetes Interventions and Complications Trial

6-Year Follow-up

710 Intensively Treated Patients HbA1c=7.2% 1375 Subjects Recruited Both original groups are now treated with the goal of HbA1c <7% 710 Conventionally Treated Patients HbA1c=9.2% Annual measurements at 28 sites IDC

EDIC:

Comparison of Baseline and Year 6 HbA1c

9.5

9 8.5

8 7.5

7 6.5

6 7.2

9.2

Diabetes 48:383–390, 1999 Baseline 7.5

8.5

Year 6 Intensive Conventional IDC

Risk of Complications

Benefits of Lowering Hemoglobin A1c

16 12 8 4 Hemoglobin A1c Average Glucose 0 6 120 7 150 UKPDS 33: Lancet 1998; 352, 837-853.

DCCT Study Group. N Engl J Med 329:977, 1993 8 180 9 210 10 240 11 270 12 300 IDC

DCCT and EDIC: Conclusions for Type 1 Diabetes

• • •

HbA1c <7% because near normal blood glucose control prevents the development and progress of microvascular disease Intensive insulin therapies can be utilized as they do not increase the risk of macrovascular disease Any lowering of blood glucose is important since there is a continuous relationship between glucose lowering and reduction in the risk of complications IDC

Type 2 Diabetes: Controversies

•

Does intensive glycemic control in Type 2 diabetes reduce micro and macrovascular complications?

•

Are there advantages or disadvantages to sulfonylureas, insulin or metformin?

– –

? Increased cardiovascular risk with insulin or SU Is metformin advantageous in those with obesity?

•

Does aggressive lowering of blood pressure reduce the risk of secondary complications?

IDC

UKPDS: Study Overview

• •

Designed in 1976 A 20-year, multicenter (23), prospective, randomized, interventional trial

•

Recruited 5102 newly diagnosed type 2 diabetes patients

–

FPG >108 mg/dL (6 mmol/L) on two occasions

•

Mean duration of follow-up: 11 years UKPDS Group: Lancet 1998; 352, 837-853.

IDC

UKPDS: Glucose Control Study 5102 patients treated with diet (3 months) 4209 patients randomized (82%) Conventional therapy (n=1138) Initial therapy - medical nutrition Target FPG < 270 mg/dL (13.5 mmol/L) Intensive therapy=3071 * Initial drug monotherapy Target FPG < 108mg/dL (6 mmol/L) * These therapies were combined or changed to maintain target Metformin

Overweight only

n=342 Sulfonylureas

Initial therapy

n=1573 Insulin

Single-multi injection

n=1156 IDC

UKPDS: Conclusions From Intensive Glucose Control Study

•

Intensive glucose control achieved HbA1c lowering of ~ 1.0% at 10 years

–

Mean Hb A1c 7.9%



7.0%

•

Intensive glucose control significantly reduced clinical complications

–

Reduced microvascular complications by 25%

•

Glycemic control deteriorated over time regardless of therapy IDC

Intensive Treatment versus Conventional Therapy for Type 2 Diabetes:

UK Prospective Diabetes Study

9 Conventional Mean 7.9% 8 7 6 0 Insulin, Sulfonylurea Metformin Intensive Mean 7.0%

6.2% upper limit of normal range

3 6 9 12 Years from randomization 15 IDC

UKPDS:

Effect of Treatment on Microvascular Endpoints

25% 20% Cumulative risk reduction of 25% when intensive treatment is compared to conventional

P=0.0099

15% 10% 5% Conventional Intensive 0% 0 3 6 9 Years from randomization UKPDS Group. Lancet. 1998;352:837-853.

12 15 IDC

UKPDS: Outcomes Intensive Glucose Control Study Outcome Measure Any diabetes endpoint Myocardial infarction Microvascular disease Retinopathy progression Cataract extraction Microalbuminuria

*Compared with conventional therapy.

Relative Risk*

   

% 12

 

16 25 21 24 33 P Value 0.029

0.052

0.0099

0.015

0.046

<0.001

UKPDS Group. Lancet. 1998;352:837-853.

IDC

UKPDS: Clinical Observations

Intensive Glucose Control Study

• • •

Intensive therapy for Type 2 diabetes

– –

Lowered risk of microvascular complications Sulfonylureas and insulin DO NOT increase cardiovascular mortality Intensive therapy results in:

– –

Increased risk of mild hypoglycemia (Severe episodes rare) Associated with significant increase in weight (~6.8 lbs) No evidence of glycemic threshold

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Benefits of intensive glycemic control outweigh the risk of hypoglycemia IDC UKPDS Group. Lancet. 1998;352:837-853.

UKPDS: Myocardial Infarction in Metformin Study 35% 30% Conventional (n=411) Intensive (n=951) Metformin (n=342) 20% 10% 0% 0 UKPDS Group. Lancet. 1998;352:854-865.

3 6 Metformin vs Conventional P=0.010

9 Years from randomization 12 15 IDC

UKPDS: Conclusions Metformin Therapy in Overweight Patients

• •

Metformin therapy may be preferable in overweight individuals

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Comparable glycemic control

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Achieved with limited weight gain and less hypoglycemia Potential benefit of metformin on CVD risk

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Lower risk of myocardial infarction in those treated with metformin monotherapy

–

Benefit related to treatment of insulin resistance?

IDC

Achieving Sustained Glycemic Control in Type 2 Diabetes

Treatment Priorities After UKPDS

• •

Type 2 Diabetes - A Progressive Disease

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Glucose control deteriorated over time

–

Insulin resistance and insulin deficiency Selection of Therapy

– –

Numerous treatment options available Therapy must be selected to “fit” individual patient needs and should change to adapt to disease progression IDC

Pathogenesis of Type 2 Diabetes

Insulin Resistance and Insulin Deficiency

Insulin Deficiency Insulin Resistance Type 2 Diabetes DeFronzo RA.

Diabetes

. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996 . Robertson RP. Diabetes. 43:1085, 1994.

Tokuyama Y.

Diabetes

44:1447, 1995. Polonsky KS.

N Engl J Med

1996;334:777.

IDC

Natural History of Type 2 Diabetes

350 300 250 200 150 100 50 250 200 150 100 50 0

normal

At risk for Diabetes

-15 -10 -5 0

Post Meal Glucose Beta cell failure Insulin Resistance

5 10 15 Years of Diabetes 20

Fasting Glucose Insulin Level

25 30 Adapted from: DeFronzo RA.

Diabetes

. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996 . Robertson RP. Diabetes. 43:1085, 1994.

Tokuyama Y.

Diabetes

44:1447, 1995. Polonsky KS.

N Engl J Med

1996;334:777.

IDC © International Diabetes Center

Confirmation of the Natural History of Type 2 Diabetes:

UKPDS

9 8 7 6 0 Conventional 3 6 Intensive 9 12 15

• •

Increasingly intensive therapies were required to maintain glucose control over time Multi-drug therapy or multi-dose insulin was required in a majority of patients to maintain glucose control IDC

Lifestyle SU Repaglinide Metformin Thiazolidinediones Insulin 350 300 250 200 150 100 50 250 200 150 100 50 0

normal

At risk for Diabetes

-15 -10 -5 0

Post Meal Glucose Beta cell failure Insulin Resistance

5 10 15 Years of Diabetes 20

Fasting Glucose Insulin Level

25 30 Adapted from: DeFronzo RA.

Diabetes

. 37:667, 1988. Saltiel J. Diabetes. 45:1661-1669, 1996 . Robertson RP. Diabetes. 43:1085, 1994.

Tokuyama Y.

Diabetes

44:1447, 1995. Polonsky KS.

N Engl J Med

1996;334:777.

IDC © International Diabetes Center

UKPDS:

Risk Factors for Coronary Artery Disease in Type 2 Diabetes

Identified 5 major risk factors for CAD:

Dyslipidemia

(High LDL, Low HDL)

Hyperglycemia Hypertension Smoking Turner, RC et al.

BMJ 316:823-8, 1998 IDC

UKPDS: Intensive Blood Pressure Control in Type 2 Diabetes

Goals: to determine whether:

1. Tight blood pressure control policy can reduce morbidity and mortality in Type 2 diabetic patients 2. ACE inhibitor (captopril) or Beta-blocker (atenolol) is advantageous in reducing the risk of development of clinical complications IDC

UKPDS:

Intensive Blood Pressure Control Study

Treatment Outcomes Start Finish Less tight control: 160/94 mm Hg 154/87 mm Hg Tight control: 161/94 mm Hg 144/82 mm Hg Average difference: ----



10/5 mm Hg UKPDS Group. BMJ. 1998;317:703-713.

IDC

UKPDS:

Intensive Blood Pressure Control Study

Any diabetes-related endpoint Diabetes-related deaths Myocardial infarction Heart failure Stroke Microvascular disease Risk reduction* 24% 32% P value 0.0046

0.019

21% 56% 44% 37% NS 0.0043

0.013

0.0092

*Tight vs less tight control.

UKPDS Group. BMJ. 1998;317:703-713.

IDC

UKPDS: Treatment of Hypertension

•

ACE inhibitor

(captopril)

and beta-blocker

(atenolol)

were equally effective in reducing the risk of secondary complications

•

Continuous relationship between systolic BP and diabetes related complications above 130 mm Hg IDC

Type 2 Diabetes:

Potential Benefit of Combined Blood Pressure and Glucose Control (UKPDS)

Micro and Macrovascular Complications Risk 12 10 8 6 4 2 0 Adapted from UKPDS 35: Lancet. 1998;352:837-853 UKPDS 38: BMJ 317, 703-713, 1998 UKPDS 32: BMJ 316:823-8, 1998 HbA1c 1 2 3 BP 4 IDC

Implications of UKPDS

Priorities of Care

• •

Intensive glycemic control in Type 2 diabetes

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ESSENTIAL to reduce risk of microvascular disease

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DOES NOT increase risk of macrovascular disease

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Continuous relationship of glucose with complications Macrovascular disease prevention

–

Requires treatment of cardiovascular risk factors including hypertension and dyslipidemia IDC

Systematic Approach to Management of Type 2 Diabetes Hyperglycemia Type 2 Diabetes Fasting BG

>

126 mg/dL Casual BG

>

200 mg/dL Diabetes Self Management Skills Medical Nutrition Therapy & Activity Plan Patient Education Glucose Monitoring Lipid Disorders Hypertension Complications Other Components of Care IDC

Understanding GDM

The Role of Insulin Resistance

250 200 150 100 50 300 200 100 0

Post Meal Glucose Fasting Glucose Insulin Resistance Insulin Level

20 22 24 26 28 30 Weeks of Pregnancy 32 34 36 IDC © International Diabetes Center

Screening For GDM

• • • •

Guidelines All women by the 26th gestational week At risk women at first pre-natal visit: age, multi-parity, previous GDM, genetic, obesity 1 hour post-50 gm challenge >140 mg/dl (7.8 mmol/l) If suspected use SMBG IDC

Diagnosis

• • • •

75 gm or 100 gm glucose challenge (OGTT) 75 gm: 2hr > 140 mg/dl 100 gm: fasting 105 mg/dl 1 hr 2 hr 3 hr > 2 abnormal value 190 mg/dl 165 mg/dl 145 mg/dl IDC

Comparison of Intensive and Conventional Diagnostic Approaches 1000 Pregnancies 500 Conventional 250 not screened 0 Positive 250 Screened 62 Positive 15 Undiagnosed GDM 5 Adverse Outcomes 15 GDM 2 Adverse outcomes 500 Intensive 500 Screened 125 Positive 31 GDM 3 Adverse outcomes SDM reduces adverse perinatal outcome by 58% Mazze RS. Mayo Clin Proc 1992 Oct;67(10):995-1002 IDC

Treatment

Guidelines

• • •

FPG target 70-90mg/dl (<5mmol/L) CPG target <120mg/dl (<6.7mmol/L) SMBG all patients

IDC

Overview of GDM

Master DecisionPath Fasting < 95 mg/dl (5.2 mmol/l) Food Plan & Exercise Stage* Fasting > 95 mg/dl

*Reported not to pass the placental barrier Langer, ADA, 1999

Insulin Stage 2* R/N – 0 – R/N – 0 Insulin Stage 3A* R/N – 0 – R – N Insulin Stage 4A* R – R – R – N IDC

Summary: Gestational Diabetes

• •

All pregnant women should be screened Tight glycemic control IDC

Diabetes Update: Recent Research and Impact on Care

• • •

Type 1:

–

Blood glucose control directly related to development of both micro and macrovascular complications Type 2:

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Blood glucose control directly related to development of both micro and macrovascular complications Gestational Diabetes:

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Adverse perinatal outcome associated with blood glucose control; target prevention of development of type 2 diabetes IDC