UPDATE ON MANAGEMENT OF TYPE 2 DIABETES – NEW AND OLD TREATMENT OPTIONS • Mayer B. Davidson, MD • Professor of Medicine • Charles Drew University & David Geffen School of Medicine at UCLA

CURRENT AMERICAN DIABETES ASSOCIATION GUIDELINES Frequency

Goal

1.

Hb A1c

every 6 months if goal attained; every 3 months if greater

80yo Potential for lactic acidosis? BID/TID dosing

Characteristics of Oral Antidiabetes Agents Sulfonylureas

Advantages Rapid onset of action Few adverse effects Dosing often qd Generic formulations avail

Disadvantages Hypoglycemia Weight gain

IDENTIFICATION OF TYPE 2 DIABETES • • •

All three components must be present: Minority status Obesity At least one first degree relative, i.e., parent, sibling or child, must have type 2 diabetes* *Very important criterion

2

3

Characteristics of Oral Antidiabetes Agents Glinides (repaglinide, nateglinide) Advantages Rapid onset of action Short time to peak Short half life Enhances insulin response to meals

Disadvantages ?Hypoglycemia ?Weight gain Freq admin

Characteristics of Oral Antidiabetes Agents

Characteristics of Oral Antidiabetes Agents

α-Glucosidase Inhibitors (acarbose, miglitol)

Thiazolidinediones (TZD’s) (Glitazones) (Rosiglitazone, Pioglitazone)

Advantages No hypoglycemia* No weight gain

Disadvantages Flatulence common Very slow dose titration Dosing three times a day Contraindications (creatinine >2 mg/dl; intestinal disorders)

*If hypoglycemia occurs due to SU’s, glinides or insulin, it must be treated with glucose tablets or milk (drugs do not block enzyme that breaks down lactose to glucose)

Effect of Glitazones as Triple Oral Therapy

Advantages No hypoglycemia Dosing once daily Renal insufficiency not a contra-indication

Disadvantages Slow onset of action Weight gain (increased fat) Edema (fluid retention) Heart failure Decreased bone mineral density Increased fractures Expensive

Characteristics of Oral Antidiabetes Agents Colesvelam (WelChol®)* Advantages Lowers LDL cholesterol Less GI side effects than other bile acid resins

Disadvantages Raises triglycerides Some GI side effects

*Other bile acid resins do not claim to lower glycemia

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Deficient Insulin: Hypersecreted Glucagon TYPE 2 DIABETES

• Defects in diabetes:

Without Diabetes (n=14) Type 2 Diabetes (n=12) 120

Insulin (µU/mL)

THE INCRETIN AXIS

60

• Deficient insulin release

0 140

Glucagon 120 (pg/mL) 100

Glucose (mg/dL)

• Glucagon not suppressed (postprandially)

Meal

360 300 240 110 80 -60

0

60

120

Time (min)

180

240

• Hyperglycemia

Data from Muller WA, et al. N Engl J Med 1970; 283:109-115

Postprandial Glucagon is Excessive and Not Corrected by Exogenous Insulin IMBALANCED GLUCOSE APPEARANCE AND DISAPPEARANCE CHO Meal

Values After Insulin Infusion Values Before Insulin Infusion

Insulin

*

300

“One wonders if the development of a pharmacological means of suppressing glucagon to appropriate levels would not increase the effectiveness of available insulin, markedly reduce insulin requirements, and perhaps improve control of the diabetic state.” — R.H. Unger

*

μU/mL 100 60

Insulin

*

20 120 100

Glucagon

*

Incretin Effect * * *

ng/mL 80 60 Subjects with diabetes

-60

0

60

120

180

240

Time (min) Data from Unger RH, et al. N Engl J Med 1971; 285:443-449

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal

Intestinal GIP and GLP-1 release

GIP-(1–42) GLP-1(7–36) Intact

DPP-4 Enzyme

Rapid Inactivation

Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes

GIP-(3–42) GLP-1(9–36) Metabolites

DIPEPTIDYL PEPTIDASE (DPP)-4 INHIBITORS

GIP and GLP-1 Actions

Deacon CF et al. Diabetes. 1995;44:1126–1131. *Meier JJ et al. Diabetes. 2004;53:654–662.

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Characteristics of Oral Antidiabetes Agents

DPP-4 Inhibitors (Sitagliptin) Advantages No hypoglycemia Oral administration*

Disadvantages Weight neutral* Expensive

*Compared to injectable GLP-1 agonist

Characteristics of Injectable Antidiabetes Drugs

EXENATIDE THE FIRST INCRETIN AGONIST

Glucagon-Like Peptide (GLP) – 1 Agonists Exenatide (Byetta) Advantages Weight loss No hypoglycemia

Disadvantages Initial nausea common Expensive

LEAD 6: Change in A1C at 26 Weeks

LIRAGLUTIDE THE SECOND INCRETIN AGONIST

6

EXENATIDE ONCE WEEKLY

EXENATIDE ONCE WEEKLY

Lancet 372:1240, 2008 Lancet 372:1240, 2008

EXENATIDE ONCE WEEKLY

SYMLIN (PRAMLINTIDE) Lancet 372:1240, 2008

Amylin Is Co-Secreted With Insulin Plasma Amylin (pM)

600

25 20

400

15 200 10 0

5 7 am

12 noon

5 pm

Time (24 h)

Type 2 Diabetes, Late Stage

Insulin Amylin

Midnight

60

40

Placebo or 100 µg/h pramlintide infusion

0

1

2

3

4

Time (h) Healthy male adults (n = 6)

Data from Kruger D, et al. Diabetes Educ 1999; 25:389-398

Insulin Sustacal®

30

50

30

Placebo Pramlintide

Type 1 Diabetes

Insulin Sustacal®

U Plasma Glucagon (pg/mL)

Meal

Plasma Glucagon (pg/mL)

Meal

30

Plasma Insulin (pM)

Meal

Pramlintide Reduces Postprandial Glucagon

20 10 0 -10 Placebo or 25 µg/h pramlintide infusion

-20 5

0

1

2

3

4

5

Time (h)

Type 2 diabetes: AUC1-4 h: P = 0.005 (n = 12) Type 1 diabetes: AUC1-5 h: P