TYPE 2 DIABETES MELLITUS

Richard Sachson MD

Diabetes in the U.S.

Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990, 1995 and 2000

1990

1995

2000

% incidence of diabetes among adults

< 4%

4-6%

> 6%

N/A

Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286(10).

DIABETES AND GESTATIONAL DIABETES AMONG ADULTS IN THE U.S. -2001

Global Projections for Diabetes 19952010

26.5 32.9 24% 84.5 132.3 57% 9.4 14.1 50% 15.6 22.5 44% 1.0 1.3 33%

14.2 17.5 23%

Reprinted with permission from Zimmet P et al. Nature. 2001;414:782787.

World 2000 = 151 million 2010 = 221 million Increase: 46%

Diabetes and Obesity: The Continuing Epidemic

7.5 78

7.0

Prevalence (%)

Diabetes Mean Body Weight

77 76

6.5
6.0

Prevalence of obesity increased by 61% since 1991 More than 50% of US adults are overweight

kg
5.5

75 74

5.0 4.5 73 72 1992 1994 1996 1998 2000

Only 43% of obese persons advised to lose weight during checkups

BMI and weight gain major risk factors for diabetes

4.0
1990

Year

BMI = body mass index. Mokdad AH et al. Diabetes Care. 2000;23:1278-1283; Mokdad AH et al. JAMA. 1999;282: 1519-1522; Mokdad AH et al. JAMA. 2001;286:1195-1200.

sfunction

Defective b-Cell Secretion:

Pancreas

b-Cell Function (%)

Pathophysiology of Type 2 Diabetes ogenesis of Type 2 Diabetes: Insulin 100 Resistance and b-Cell Dysfunction 75
50 25 N = 376 Insulin Resistance 0 10 6 2 2 6

Years After Diagnosis

FFAs

Insulin Resistance:

Liver

Excess Glucose Production

Muscle

Reduced Glucose Uptake

Fat

eas

Liver Fasting Hyperglycemia

Muscle Postprandial Hyperglycemia

Fat

FFAs = free fatty acids. Adapted from UK Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258. DeFronzo RA. Diabetes. 1988;37:667-687.

Progression of Type 2 Diabetes

350 250

Post Meal Glucose

Glucose
150 50 300

Fasting Glucose

Insulin Resistance

Relative 200 Function

100 0
-10 -5 0 At risk for Diabetes

Insulin Level
Beta cell failure
5 10 15 20 25 30

Years of Diabetes
Adapted from D Kendall, R Bergenstal, International Diabetes Center

Diabetes: 16 Million and Climbing

Estimated 10.3 million diagnosed + 5.4 million undiagnosed cases Type 2 diabetes accounts for 90-95% of cases
12 Diagnosed Cases (Millions)

+60% +17%

1980

1990

2000 (Estimated)

From Centers for Disease Control and Prevention, 2000.

Insulin Resistance FFA production Glucose production

Hyperinsulinemia

Dyslipidemia T2D

SNS activity

Abnormal Na+ handling

HTN Atherosclerosis

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

 Also known as dysmetabolic syndrome, insulin resistance syndrome, syndrome X, the deadly quartet Prevalence in the United States: approximately 47 million Defined by having 3 of the following:
Abdominal obesity: waist > 40" (men); > 35" (women) TG 150 mg/dL HDL < 40 mg/dL (men); < 50 mg/dL (women) Blood pressure 130/85 mm Hg FPG 110 mg/dL

Metabolic Syndrome

New ICD-9-CM code for dysmetabolic syndrome X is 277.7

TG = triglycerides; FPG = fasting plasma glucose. Ford ES et al. JAMA. 2002;287:356-359. JAMA. 2001;285:2486-2497. American Association of Clinical Endocrinologists. New ICD-9-CM code for dysmetabolic syndrome X. Available at: http://www.aace.com/members/socio/syndromex.php. Accessed January 10, 2002.

Visceral Fat Distribution:

Normal vs Type 2 Diabetes

Normal

Type 2 Diabetes

2-11

Prevalence of Complications at Time of Diagnosis: UKPDS

Complication Prevalence (%)* Any complication 50 Retinopathy 21 Abnormal ECG 18 Absent foot pulses ( 2) and/or ischemic feet 14 Impaired reflexes and/or decreased vibration sense 7 Myocardial infarction/angina/claudication 2-3 Stroke/transient ischemic attack 1
*Some patients had more than 1 complication at diagnosis. Prevalence of each individual condition. UKPDS = United Kingdom Prospective Diabetes Study. UKPDS Group. Diabetologia. 1991;34:877-890. 16

National Cholesterol Education Program

Adult Treatment Panel III (ATP III) Guidelines

Diabetes
In ATP III, diabetes is regarded as a CHD risk equivalent.

Type 2 diabetes and CHD: 7-year incidence of fatal/nonfatal MI (East West Study)
Nondiabetic n = 1373
50 45 P < 0.001 40 35 30 25 20 15 10 4% 5 0

Diabetic n = 1059 45% P < 0.001

7-year incidence rate of MI

19%

20%

No prior MI*
MI = myocardial infarction. * These patients had no prior MI at baseline.

MI

No prior MI* MI

Haffner SM, et al. N Engl J Med. 1998;339:229234.

Target Lipid Levels for Adult Patients with Diabetes

LDL Cholesterol:
HDL Cholesterol:

< 100 mg/dL (high risk < 70 mg/dl)

Triglycerides:

Men: > 45 mg/dL Women: > 55 mg/dL < 150 mg/dL

Note: The recent NCEP/ATP III guidelines suggest that in patients with triglycerides 200 mg/dL, the non-HDL cholesterol be calculated with a goal being < 130. American Diabetes Association. Diabetes Care. 2002;25:S33.

Recommended Treatment Goals for Hypertension for Adults With Diabetes

Target BP Patients aged 18 years <130/80 mm Hg

Isolated systolic hypertension 180 mm Hg <160 mm Hg 160179 mm Hg of 20 mm Hg

American Diabetes Association. Diabetes Care. 2001;24(suppl 1):S33-S43.

Aspirin
Use aspirin therapy ( 75-325 mg/day ) in all adult patients with diabetes and macrovascular disease. Consider aspirin therapy for primary prevention in patients over age 40 with diabetes and one or more other CV risk factors ( including obesity ). Also consider patients between age 30-40.

Type 2 Diabetes Prevention

Finnish Diabetes Prevention Program

522 patients with IGT Age: 40-65 years Mean BMI: 31 kg/m2 Intervention: diet and exercise Mean duration of follow up: 3.2 years

IGT = impaired glucose tolerance; BMI = body mass index. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

The Finnish Diabetes Prevention Study: Lifestyle Modifications

Incidence of Diabetes (Cases/1000 Person-Years)

100 80 60 40 20 0
58% P < .001

Change from Baseline (mg/dL)

10

FPG

2-Hour PPG

0
P < .001

-10
P < .003

-20

Control Intervention (Diet and Exercise)

FPG = fasting plasma glucose; PPG = postprandial glucose. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

Finnish DPP: Results

Quintile Weight Change (%) Risk Reduction (%)

1 2 3 4 5

11 5 2 No change 3

83 61 13 No change 218

Each 3-kg weight loss doubles the benefit. DPP = diabetes prevention program. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

United States Diabetes Prevention Program

3234 patients with IGT
32.3% male; 67.7% female Mean age: 50.6 years 10.7 years

55% Caucasian, 20% African American, 16% Hispanic, 9% Asian and American Indian Interventions: diet (reduced calorie, 25% fat) and exercise ( 150 minutes/week physical activity) or metformin (850 mg b.i.d.) Average follow-up: 2.8 years (range: 1.8-4.6 years)
IGT = impaired glucose tolerance. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

United States Diabetes Prevention Program: Results

Placebo (n = 1082) Wt loss: 0.1 kg* Diabetes: 29% Intensive Lifestyle Intervention (n = 1079) Wt loss: 5.6 kg* Diabetes: 14% Metformin (n = 1073) Wt loss: 2.1 kg* Diabetes: 22%

*Average; Cumulative incidence at 3 years. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

United States Diabetes Prevention Program: Results

Placebo (n = 1082) Wt loss: 0.1 kg* Diabetes: 29% Intensive Lifestyle Intervention (n = 1079) Wt loss: 5.6 kg* Diabetes: 14% Risk reduction: 58% Metformin (n = 1073) Wt loss: 2.1 kg* Diabetes: 22% Risk reduction: 31%

*Average; Cumulative incidence at 3 years. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

TREATMENT OF TYPE 2 DIABETES

Therapy for Type 2 Diabetes: Sites of Action

Muscle
Glucose = Insulin Hyperglycemia Uptake Resistance

Liver
Hepatic Glucose Production Hyperglycemia

Rosiglitazone Pioglitazone Metformin

Gut
Carbohydrate Metabolism Acarbose Miglitol

Pancreas
Hyperglycemia Hyperglycemia Impaired = Insulin Deficiency Insulin Secretion
Sulfonylurea Repaglinide Nateglinide Exogenous Insulin Rx

Sulfonylureas

Sulfonylurea Effects on the b-cell

Ca++ VDCC (+)
Depolarization

b-Cell
[ATP] [ADP] Metabolism Free Ca++

K+ATP Channel K+

Sulfonylurea

Insulin Release

Glucose
Hu S et al. J Pharmacol Exp Ther 2000;293:44452

Sulfonylureas
Mechanism of action: increases pancreatic insulin secretion Reported A1C reduction: 0.9%-2.5% Advantages: well-established, decreases microvascular risk, convenient daily dosing Disadvantages: hypoglycemia, weight gain, hyperinsulinemia (role uncertain) FDA approval status: monotherapy; combination with insulin, metformin, thiazolidinedione, -glucosidase inhibitors
Inzucchi SE. JAMA. 2002;287:360-372.

Second-Generation Sulfonylureas
Drug Daily Dosage Trade Names (mg) Duration of Action

Glyburide

Glipizide

Micronase, DiaBeta, Glynase Glucotrol

Glucotrol XL

2.5-20

16-24 hours

5-40* 5-20

12-24 hours 24 hours

Glimepiride

Amaryl

1-8

16-24 hours

*The maximally effective dosage is 20 mg/d, although it is approved for dosages 40 mg/d. DeFronzo RA. Ann Intern Med. 1999;131:281-303.

Nonsulfonylurea Secretagogues

Nonsulfonylurea Secretagogues (Repaglinide or Nateglinide)

Mechanism of action: increases pancreatic insulin secretion Reported A1C reduction: 0.6%-1.9% Advantages: targets postprandial glycemia, possibly less hypoglycemia and weight gain than with sulfonylureas Disadvantages: 3-times daily dosing, hypoglycemia, weight gain, no long-term data, hyperinsulinemia (role uncertain) FDA approval status: monotherapy; combination with metformin
Inzucchi SE. JAMA. 2002;287:360-372.

Nonsulfonylurea Secretagogues
Drug Repaglinide Daily Dosage Trade Names (mg) Prandin 1.5-16

Nateglinide

Starlix

180-360

DeFronzo RA. Ann Intern Med. 1999;131:281-303. Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.

Biguanides

 Mechanism of action: decreased hepatic glucose production Reported A1C reduction: 0.8%-3.0% Advantages: well established, weight loss, no hypoglycemia, decreases microvascular risk, decreases macrovascular risk, nonglycemic benefits (decreased lipid levels, increased fibrinolysis, decreased hyperinsulinemia), convenient daily dosing Disadvantages: adverse gastrointestinal effects, many contraindications, lactic acidosis (rare) FDA approval status: monotherapy; combination with insulin, sulfonylurea, nonsulfonylurea secretagogue, thiazolidinedione
Inzucchi SE. JAMA. 2002;287:360-372.

Biguanides (Metformin)

Metformin

(Glucophage )

Usual starting dose is 500 mg b.i.d. or 850 mg q.d. given with meals

Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks up to 2000 mg q.d. Maximum daily dose of 2550 mg per day
doses > 2000 mg may be better tolerated given t.i.d. with meals

Contraindications: renal disease or renal dysfunction*, congestive heart failure requiring pharmacologic treatment, known hypersensitivity to the drug, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, temporarily discontinue in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials Warning: if lactic acidosis is suspected, the drug should be discontinued immediately and general supportive measures promptly instituted Precautions: monitoring of renal function, hypoxic states, surgical procedures, alcohol intake, impaired hepatic function, vitamin B12 levels, change in clinical status, hypoglycemia, loss of control of blood glucose Pregnancy category B

*Serum creatine levels 1.5 mg/dL in males, 1.4 mg/dL in females. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2000.

Thiazolidinediones

Thiazolidinediones
Mechanism of action: increased peripheral glucose disposal Reported A1C reduction: 1.5%-1.6% Advantages: reverses one of the primary defects of type 2 diabetes, no hypoglycemia, nonglycemic benefits (decreased lipid levels, increased fibrinolysis, decreased hyperinsulinemia, improved endothelial function), possible beta-cell preservation, convenient daily dosing Disadvantages: liver function test monitoring, weight gain, edema, slow onset of action, no long-term data FDA approval status: monotherapy; combination with insulin , sulfonylurea, metformin
Inzucchi SE. JAMA. 2002;287:360-372.

Thiazolidinediones
Drug
Rosiglitazone Trade Names Avandia Daily Dosage (mg) 2-8

Pioglitazone

Actos

15-45

DeFronzo RA. Ann Intern Med. 1999;131:281-303.

-Glucosidase Inhibitors

-Glucosidase Inhibitors
Mechanism of action: decreased gut carbohydrate absorption Reported A1C reduction: 0.4%-1.3% Advantages: targets postprandial glycemia, no hypoglycemia, nonsystemic Disadvantages: t.i.d. dosing, adverse gastrointestinal effects, no long-term data Miglitol FDA approval status: monotherapy; combination with sulfonylurea Acarbose FDA approval status: monotherapy; combination with sulfonylurea, insulin, and metformin
Inzucchi SE. JAMA. 2002;287:360-372.

-Glucosidase Inhibitors
Drug Trade Names Daily Dosage (mg)

Acarbose

Precose

25 q.d. to 50-75 t.i.d.

25 t.i.d. to 100 t.i.d.

Miglitol

Glyset

DeFronzo RA. Ann Intern Med. 1999;131:281-303.

Combination Therapy

Synergistic Mechanisms of Action of Glyburide and Metformin

Glyburide/ Metformin
Enhances Insulin Secretion

Decreases Insulin Resistance

Increases peripheral glucose uptake Decreases hepatic glucose production Decreases intestinal absorption of glucose

Improves Glycemic Control

Complementary Mechanisms of Action

Metaglip
(glipizide and metformin HCl) tablets

Glipizide
Enhances insulin secretion

Metformin
Improves insulin sensitivity by increasing peripheral glucose uptake Decreases hepatic glucose production Decreases intestinal absorption of glucose
Improves Glycemic Control

Please see full prescribing information, including boxed WARNING regarding Lactic Acidosis.

Avandamet

Avandia + Metformin

Basic Steps in the Management of Type 2 Diabetes

+ + +

Insulin
Advantages Can control all patients Used to overcome glucose toxicity Flexibility in dosing Multiple insulin preparations available Use during pregnancy
Disadvantages Hypoglycemia Weight gain Parenteral administration

DeFronzo. Ann Intern Med. 1999;131:281303.

Insulins for Type 2 Diabetes

72

Pre-Mixed Insulin Analogs

Humalog Mix75/25 Novolog mix 70/30

73

Why NPL Was Developed

R L

+
R

NPH

L
L

+
NPL
74

Premix Insulin Profiles

30% Insulin aspart 30% Human regular

70%

Insulin aspart protamine suspension

70%

Neutral Protamine Hagedorn (NPH)

NovoLog Mix 70/30

Human Premixed 70/30

NPL Component Compared to Human NPH

8 7 6 5 4 3 2 1 0

Glucose Infusion Rate mg/min/kg

Human NPH (0.4 U/kg) NPL Component (0.4 U/kg) n=8 Non-diabetic Subjects

6 8 10 12 Hours After Injection

14

16

76

Lispro Mix75/25: Pharmacodynamics

12 Glucose Infusion Rate mg/kg/min 10 8 Lispro Lispro Mix75/25 NPL

6
4

2
0

12 Hours

16

20

24

Heise T, et al. Diabetes Care. 1998;21:800-803.

Recommended Dosing

2/3 or 1/2 AM

Weight (kg*) x units/kg = total daily dose

Dosing Guidelines 0.20.5 for nonobese individuals 0.4 0.8 for obese individuals

1/3 or 1/2 PM

1 kg = 2.2 lbs

Obese= BMI over 30Kgm

GLP-1

GLP-1 Modes of Action in Humans

Upon ingestion of food

Stimulates glucose-dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying

GLP-1 is secreted from the L-cells in the intestine

Reduces food intake Improves insulin sensitivity Long term effects demonstrated in animals

This in turn

Increases beta-cell mass and maintains beta-cell efficiency

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171

Exendin-4 in the Gila Monster

Exendin-4 was originally isolated from the salivary secretions of the Gila monster Exendin-4 was subsequently found to circulate as a meal-related peptide in this animal Exendin-4 has possible endocrine function in the lizard Heloderma suspectum (Gila monster)
Plasma Exendin-4 Concentration (pg/mL)

400000

4 mice 1 rat

300000

200000

100000

0 0 3 6 9 12

Time After Meal (h)

Data from: Young AA. Glucagon-like peptide-1, exendin and insulin sensitivity. In Hansen B, Shafrir E, Editors. Insulin Resistance and Insulin Resistance Syndrome. 1st ed. Harwood Academic Press; 2002,

Questions:

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS