TYPE 2 DIABETES MELLITUS
Richard Sachson MD
Diabetes: 16 Million and Climbing
• Estimated 10.3 million diagnosed + 5.4 million
undiagnosed cases
• Type 2 diabetes accounts for 90-95% of cases
Diagnosed Cases (Millions)
12
+60%
+17%
8
4
0
1980
1990
From Centers for Disease Control and Prevention, 2000.
2000 (Estimated)
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%
Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286(10).
> 6%
N/A
DIABETES AND GESTATIONAL
DIABETES AMONG ADULTS IN THE
U.S. -2001
Type 2 diabetes and CHD: 7-year incidence
of fatal/nonfatal MI (East West Study)
7-year incidence
rate of MI
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
19%
No prior MI*
MI
MI = myocardial infarction.
* These patients had no prior MI at baseline.
Haffner SM, et al. N Engl J Med. 1998;339:229–234.
20%
No prior MI* MI
Diabetes and Obesity:
The Continuing Epidemic
7.5
78
Diabetes
Mean Body Weight
77
6.5
76
6.0
kg
Prevalence (%)
7.0
75
5.5
74
5.0
73
4.5
72
4.0
1990
1992
1994
Year
1996
1998
2000
• Prevalence of obesity
increased by 61%
since 1991
• More than 50% of US
adults are overweight
• Only 43% of obese
persons advised to lose
weight during checkups
• BMI and weight gain
major
risk factors for diabetes
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.
Defective
b-Cell Secretion:
Pancreas
sfunction
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:
eas
Liver
Excess
Glucose
Production
Liver
Fasting Hyperglycemia
Muscle
Reduced
Glucose
Uptake
Muscle
Postprandial
Hyperglycemia
Fat
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
Post Meal Glucose
350
250
Glucose
Fasting Glucose
150
50
300
Insulin Resistance
Relative 200
Function
100
Insulin Level
At risk for
Diabetes
Beta cell failure
0
-10
-5
0
5
10
15
20
25
30
Years of Diabetes
Adapted from D Kendall, R Bergenstal, © International Diabetes Center
Insulin Resistance
 FFA production
 Glucose production
Hyperinsulinemia
Dyslipidemia
 SNS activity
T2D
Abnormal Na+
handling
HTN
Atherosclerosis
Metabolic Syndrome
• 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
• 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.
13
National Cholesterol Education
Program
Adult Treatment Panel III
(ATP III) Guidelines
Diabetes
In ATP III, diabetes is regarded
as a CHD risk equivalent.
Target Lipid Levels for
Adult Patients with Diabetes
LDL Cholesterol:
< 100 mg/dL
HDL Cholesterol:
Men: > 45 mg/dL
Women: > 55 mg/dL
< 150 mg/dL
Triglycerides:
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
160–179 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.
100
80
60
40
20
0
58%
P < .001
Change from Baseline (mg/dL)
Incidence of Diabetes
(Cases/1000 Person-Years)
The Finnish Diabetes Prevention Study:
Lifestyle Modifications
10
FPG
2-Hour PPG
0
P < .001
-10
-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.
P < .003
Finnish DPP: Results
Quintile Weight Change (%) Risk Reduction (%)
1
2
3
4
5
11
5
2
No change
3
Each 3-kg weight loss doubles the benefit.
DPP = diabetes prevention program.
Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.
83
61
13
No change
218
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)
Intensive Lifestyle
Intervention
(n = 1079)
Metformin
(n = 1073)
Wt loss: 0.1 kg*
Wt loss: 5.6 kg*
Wt loss: 2.1 kg*
Diabetes: 29%†
Diabetes: 14%†
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)
Intensive Lifestyle
Intervention
(n = 1079)
Metformin
(n = 1073)
Wt loss: 0.1 kg*
Wt loss: 5.6 kg*
Wt loss: 2.1 kg*
Diabetes: 29%†
Diabetes: 14%†
Risk reduction:
58%
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
Liver
Muscle
Glucose = Insulin
Hyperglycemia
Uptake
Resistance
Hepatic Glucose
Production
Hyperglycemia
Rosiglitazone
Metformin
Pioglitazone
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
K+ATP Channel
K+
Sulfonylurea
[ATP]
[ADP]
Free
Ca++
Metabolism
Insulin
Release
Glucose
Hu S et al. J Pharmacol Exp Ther 2000;293:444–52
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
Glyburide
Glipizide
Glimepiride
Daily Dosage
Trade Names
(mg)
Duration of
Action
Micronase®,
DiaBeta®,
Glynase®
Glucotrol®
2.5-20
16-24 hours
5-40*
12-24 hours
Glucotrol XL®
5-20
24 hours
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
Daily Dosage
Trade Names
(mg)
Repaglinide
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
Biguanides (Metformin)
• 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.
Metformin
•
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
•
•
•
•
•
®
(Glucophage )
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 (pioglitazone only), sulfonylurea, metformin
Inzucchi SE. JAMA. 2002;287:360-372.
Thiazolidinediones
Drug
Trade
Names
Daily Dosage
(mg)
Rosiglitazone
Avandia®
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
Daily
Dosage
(mg)
Drug
Trade Names
Acarbose
Precose®
25 q.d. to
50-75 t.i.d.
Miglitol
Glyset®
25 t.i.d. to
100 t.i.d.
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
DeFronzo. Ann Intern Med. 1999;131:281–303.
Disadvantages
• Hypoglycemia
• Weight gain
• Parenteral administration
Insulins for Type 2
Diabetes
68
Pre-Mixed Insulin Analogs
Humalog Mix75/25
75% NPL / 25% Lispro
69
Why NPL Was Developed
R
L
L
L
R
+
R
NPH
L
L
+
NPL
70
Glucose Infusion Rate
mg/min/kg
NPL Component Compared to Human NPH
8
7
6
5
4
3
2
1
0
Human NPH (0.4 U/kg)
NPL Component (0.4
U/kg)
n=8 Non-diabetic Subjects
0
2
4
6
8
10
12
Hours After Injection
14
16
71
Lispro Mix75/25: Pharmacodynamics
Glucose Infusion Rate
mg/kg/min
12
Lispro
Lispro Mix75/25
NPL
10
8
6
4
2
0
0
4
8
Heise T, et al. Diabetes Care. 1998;21:800-803.
12
Hours
16
20
24
NOVOLOG 70/30
Premix Insulin Profiles
Insulin aspart
30%
70%
30%
Insulin aspart
protamine suspension
NovoLog®
Mix 70/30
70%
Human regular
Neutral
Protamine
Hagedorn
(NPH)
Human
Premixed 70/30
Recommended Dosing
2/3 or
1/2 AM
Weight (kg*) x units/kg = total daily dose
Dosing Guidelines
0.2—0.5 for nonobese individuals
0.4 – 0.8 for obese individuals
1 kg = 2.2 lbs
Obese= BMI over 30Kgm
1/3 or
1/2 PM
DIET
Silverware for dieting
Questions: