type 2 diabetes mellitus richard sachson md. 0 4 8 12 198019902000 (estimated) from centers for...
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TYPE 2 DIABETES MELLITUSTYPE 2 DIABETES MELLITUS
Richard Sachson MD
0
4
8
12
1980 1990 2000 (Estimated)From Centers for Disease Control and Prevention, 2000.
Dia
gnos
ed C
ases
(M
illi
ons)
+17%
+60%
Diabetes: 16 Million and Climbing• Estimated 10.3 million diagnosed + 5.4 million
undiagnosed cases• Type 2 diabetes accounts for 90-95% of cases
Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286(10).
Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990, 1995 and 2000
1990 1995
2000
Diabetes in the U.S. Diabetes in the U.S.
< 4% 4-6% > 6% % incidence of diabetes among adults 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)
MI = myocardial infarction.* These patients had no prior MI at baseline.Haffner SM, et al. N Engl J Med. 1998;339:229–234.
05
101520253035404550
7-y
ea
r in
cid
enc
e ra
te o
f M
I
No prior MI* MI No prior MI* MI
Nondiabetic Diabeticn = 1373 n = 1059
P < 0.001 P < 0.001
4%
19% 20%
45%
Diabetes and Obesity: The Continuing Epidemic
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.
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
1990 1992 1994 1996 1998 2000
• Prevalence of obesityincreased by 61%since 1991
• More than 50% of US adults are overweight
• Only 43% of obesepersons advised to loseweight during checkups
• BMI and weight gain majorrisk factors for diabetes
Pre
vale
nce
(%
)
kgYear
72
73
74
75
76
77
78
Diabetes
Mean Body Weight
ExcessGlucoseProduction
ReducedGlucoseUptake
Pancreas
MuscleLiver
FFAs = free fatty acids.Adapted from UK Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.DeFronzo RA. Diabetes. 1988;37:667-687.
0
25
50
75
100
–10 –6 –2 2 6-C
ell
Fu
nctio
n (
%)
Years After Diagnosis
N = 376
Insulin Resistance:
Defective -Cell Secretion:
Pathophysiology of Type 2 Diabetes
REASN14-6/2000
Pathogenesis of Type 2 Diabetes: InsulinResistance and -Cell Dysfunction
-Cell Dysfunction
Pancreas Liver Muscle Fat
Insulin Resistance
Fat
FFAs
Fasting Hyperglycemia Postprandial Hyperglycemia
Progression of Type 2 Diabetes
Glucose
Relative Function
0
100
200
300
-10 -5 0 5 10 15 20 25 30
50
150
250
350
Years of Diabetes
Insulin Resistance
Insulin Level
Fasting Glucose
Beta cell failure
Post Meal Glucose
At risk for Diabetes
Adapted from D Kendall, R Bergenstal, © International Diabetes Center
Insulin Resistance
FFA production Glucose production
Hyperinsulinemia
Dyslipidemia
T2D
SNS activityAbnormal Na+
handling
HTN
Atherosclerosis
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.
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
Visceral Fat Distribution:Normal vs Type 2 Diabetes
Normal Type 2 Diabetes
2-11
13
Complication Prevalence (%)*Any complication 50Retinopathy 21Abnormal ECG 18Absent foot pulses ( 2) and/or ischemic feet 14 Impaired reflexes and/or decreased vibration sense 7Myocardial 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.
Prevalence of Complicationsat Time of Diagnosis: UKPDS
Adult Treatment Panel III (ATP III) Guidelines
National Cholesterol Education Program
Diabetes
In ATP III, diabetes is regarded as a CHD risk equivalent.
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.
Target Lipid Levels forAdult Patients with Diabetes
< 150 mg/dLTriglycerides:
Men: > 45 mg/dL
Women: > 55 mg/dLHDL Cholesterol:
< 100 mg/dLLDL Cholesterol:
Target BP Patients aged 18 years <130/80 mm Hg
Isolated systolic hypertension180 mm Hg <160 mm Hg160–179 mm Hg of 20 mm Hg
American Diabetes Association. Diabetes Care. 2001;24(suppl 1):S33-S43.
Recommended Treatment Goals for Hypertension for Adults With Diabetes
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
IGT = impaired glucose tolerance; BMI = body mass index.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.
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
The Finnish Diabetes Prevention Study: Lifestyle Modifications
FPG = fasting plasma glucose; PPG = postprandial glucose.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.
0
20
40
60
80
100
Inci
denc
e of
Dia
bete
s(C
ases
/100
0 P
erso
n-Y
ears
)
58%P < .001
-20
-10
0
102-Hour PPGFPG
P < .001
P < .003
Cha
nge
from
Bas
elin
e (m
g/dL
)ControlIntervention (Diet and Exercise)
Quintile Weight Change (%) Risk Reduction (%)
1 11 832 5 613 2 134 No change No change5 3 218
Finnish DPP: Results
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.
Intensive Lifestyle Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)
Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg*
Diabetes: 29%† Diabetes: 14%† Diabetes: 22%†
United States Diabetes Prevention Program: Results
*Average; †Cumulative incidence at 3 years.Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
Intensive Lifestyle Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)
Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg*
Diabetes: 29%† Diabetes: 14%† Diabetes: 22%†
Risk reduction: Risk reduction: 58% 31%
United States Diabetes Prevention Program: Results
*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
Rosiglitazone
Pioglitazone
Glucose Uptake
Insulin Resistance
=
MuscleHyperglycemia
GutCarbohydrate Metabolism
Miglitol
Acarbose
Hyperglycemia
Metformin
Hepatic GlucoseProduction Hyperglycemia
Liver
Exogenous Insulin Rx
Sulfonylurea
Repaglinide
Nateglinide
Impaired Insulin Secretion
Insulin Deficiency
=
PancreasHyperglycemia
Sulfonylureas
Sulfonylurea Effects on the -cell
SulfonylureaMetabolism
FreeCa++
Glucose
K+
K+ATP Channel
[ATP]
[ADP]
Ca++
VDCC(+)
-Cell
Insulin Release
SUR
Depolarization
Hu S et al. J Pharmacol Exp Ther 2000;293:444–52
Inzucchi SE. JAMA. 2002;287:360-372.
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
Second-Generation Sulfonylureas
24 hours5-20Glucotrol XL®
16-24 hours
12-24 hours
16-24 hours
Duration of Action
1-8Amaryl®Glimepiride
5-40*Glucotrol®Glipizide
2.5-20Micronase®, DiaBeta®, Glynase®
Glyburide
Daily Dosage (mg)Trade NamesDrug
*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 pancreaticinsulin 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
180-360Starlix®Nateglinide
1.5-16Prandin®Repaglinide
Daily Dosage (mg)Trade NamesDrug
DeFronzo RA. Ann Intern Med. 1999;131:281-303.Starlix® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.
Biguanides
Inzucchi SE. JAMA. 2002;287:360-372.
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
*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.
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
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
15-45Actos®Pioglitazone
2-8Avandia®Rosiglitazone
Daily Dosage (mg)
Trade NamesDrug
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
25 t.i.d. to 100 t.i.d.
Glyset®Miglitol
25 q.d. to 50-75 t.i.d.
Precose®Acarbose
Daily Dosage
(mg)Trade NamesDrug
DeFronzo RA. Ann Intern Med. 1999;131:281-303.
Combination Therapy
Synergistic Mechanisms of Action of Glyburide and Metformin
ImprovesGlycemicControl
MetforminGlyburide/
Decreases Insulin Resistance• Increases peripheral glucose uptake• Decreases hepatic glucose production• Decreases intestinal absorption of
glucose
Enhances Insulin
Secretion
Complementary Mechanisms of Action
ImprovesImprovesGlycemicGlycemicControlControl
ImprovesImprovesGlycemicGlycemicControlControl
Metaglip™
(glipizide and metformin HCl) tablets
Metformin• Improves insulin sensitivity by
increasing peripheral glucose uptake • Decreases hepatic glucose production• Decreases intestinal absorption of
glucose
Glipizide•Enhances insulin secretionEnhances insulin secretion
Please see full prescribing information, including boxed WARNING regarding Lactic Acidosis.
Avandamet
Avandia + Metformin
Basic Steps in the Management of Type 2 Diabetes
+ +
diet &exercise
Oral monotherapy
insulin
+
Oralcombination
Oral plusInsulin
DeFronzo. Ann Intern Med. 1999;131:281–
303.
InsulinAdvantages• 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
Insulins for Type 2 Diabetes
6868
Pre-Mixed Insulin Analogs
Humalog Mix75/25
75% NPL / 25% Lispro
6969
R
LRL
R
NPH
+
+
Why NPL Was DevelopedWhy NPL Was Developed
L
NPL
L
L
7070
NPL Component Compared to Human NPH
Hours After Injection
00
11
22
33
44
55
66
77
88
00 22 44 66 88 1010 1212 1414 1616
Human NPH (0.4 U/kg)
NPL Component (0.4 U/kg)
n=8 n=8 Non-diabetic Subjects
Glu
cose
Infu
sio
n R
ate
mg
/min
/kg
7171
00 44 88 1212 1616 2020 2424
00
22
44
66
88
1010
1212
Glu
cose
Infu
sio
n R
ate
Glu
cose
Infu
sio
n R
ate
mg
/kg
/min
mg
/kg
/min
HoursHours
LisproLispro
Lispro Mix75/25Lispro Mix75/25
NPLNPL
Lispro Mix75/25: PharmacodynamicsLispro Mix75/25: Pharmacodynamics
Heise T, et al. Diabetes Care. 1998;21:800-803.
NOVOLOG 70/30
Premix Insulin Profiles
Insulin aspart protamine suspension
Insulin aspart30%
70% NeutralProtamine Hagedorn
(NPH)
Human regular30%
70%
NovoLog®
Mix 70/30
Human
Premixed 70/30
Recommended Dosing
Weight (kg*) x units/kg = total daily dose
2/3 or 1/2 AM2/3 or 1/2 AM
1/3 or 1/2 PM1/3 or 1/2 PM
1 kg = 2.2 lbs
Dosing Guidelines
0.2—0.5 for nonobese individuals
0.4 – 0.8 for obese individuals
Obese= BMI over 30Kgm
DIETDIET
Silverware for dietingSilverware for dieting
Questions: