1. GLP-1 Agonist:When to start ?
Dr. Ravi Kant
M.D (Medicine),P.Gd(Preventive cardiology),
Master (European and American Heart Association),
P.Gd.Diabetology (Boston University) 
Faculty
Department of Internal Medicine
All India Institute of Medical Sciences 
Rishikesh, Uttarakhand

2. OBSERVATION
In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion.

3. In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical o those achieved with oral glucose led to a insulin response that was only one quarter as great.

4. INCRETIN EFFECT
Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect.

6. WHAT ARE INCRETINS?
Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis.
Two Hormones:
Gastric inhibitory polypeptide (GIP) Glucagon-like peptide-1 (GLP-1).

7. WHAT ARE INCRETINS? Gastric Inhibitory Polypeptide (GIP)
Secreted by the K cells of the proximal gut.
type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target.

8. WHAT ARE INCRETINS? Glucagon-like peptide-1 (GLP-1)
secreted by L cells, primarily in the ileum and colon.
GLP-1 receptors are in islet cells and in the central nervous system, among other places.
GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV) .

9. ACTIONS OF INCRETINS

10. PROPERTIES OF GLP-1 AND GIP
Physiological Actions
GLP-1
GIP
Lower blood glucose
Yes
Glucose dependent stimulation of insulin secretion
Enhances β-cell glucose responsiveness
Increase β-cell gene expression and differentiation
Suppresses glucagon secretion
Extrapancreatic glucose-lowering actions
Stimulates β-cell expansion

11. DPP 4 INHIBITORS

13. ACTIONS OF GLP-1 THE PROBLEM
Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion).

14. THE SOLUTION Two options:
Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists.
Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the breakdown of GLP-1.

15. INCRETIN MIMETICS EXENATIDE
The first incretin-related therapy available for patients with type 2 diabetes.
Naturally occurring peptide from the saliva of the Gila Monster.
Has an approximate 50% amino acid homology with GLP-1.
Binds to GLP-1 receptors and behaves as GLP-1.

17. INCRETIN MIMETICS EXENATIDE
Resistant to DPP-IV inactivation. Following injection, it is measurably present in plasma for up to 10 hours. Suitable for twice a day administration by subcutaneous injection.

19. CLINICAL TRIALS OF EXENATIDE
Three pivotal randomized, double-blind, placebo-controlled, multicenter clinical trials were conducted to support the approval of exenatide (the AMIGO studies).
Patients with type 2 diabetes who had not achieved adequate glycemic control despite treatment with metformin, a sulfonylurea, or the combination of metformin and a sulfonylurea.
Patients were randomized to two well matched groups to receive either placebo or exenatide (5 and 10 (mcg) twice daily by subcutaneous injection).

21. WEIGHT LOSS WITH EXENATIDE
After Adding Exenatide:
The group that was on metformin alone lost about 3 kg of body weight at 30 weeks.
While the sulfonylurea group experienced a 1.5- to 2-kg weight reduction.
Patients receiving metformin and a sulfonylurea in combination along with exenatide lost an average of 2 kg.
Weight loss of up to 10 kg has been documented, but it varies from person to person.
Recently published findings have shown progressive weight loss continuing for 82 weeks. Patients convenience.

22. NAUSEA WITH EXENATIDE
Was seen uniformly across the clinical trials, although most episodes were mild-to-moderate in intensity and generally intermittent.
More frequent at the initiation of treatment and decreased over the course of several weeks.

23. INCRETIN MIMETICS RECENT ADVANCES
Liraglutide: Another GLP-1 analog with longer half-life, similar to exenatide with once-daily injection. Diabetes Care. 2007;30:
Long acting exenatide: Highly effective with once weekly injection. Diabetes Care. 2007;30:

24. Dipeptidyl Peptidase-IV Antagonists
The concept is to allow the endogenous GLP-1 to remain in circulation for a longer period.
DPP-IV inhibitors are oral, rather than injectable.
Weight neutral.
associated with a low incidence of hypoglycemia or gastrointestinal side effects. Diabetes Care. 2004;27:
Preliminary long-term studies suggest a durable effect on glycemia and improvement in some parameters of beta-cell function.

25. GLP-1 analogs and DPP-4 inhibitors
Physiological Actions
GLP-1
DPP 4 -
Administration
Injection
Oral
Mechanism of action
GLP-1 and GIP
Augmenting insulin secretion
+++ +
Suppressing glucagon levels ++
Risk of hypoglycaemia
Low
Gastric emptying
Delayed
Little or no effect
Weight loss
Yes No

28. DIPEPTIDYL PEPTIDASE-IV ANTAGONISTS SITAGLIPTIN AND VILDAGLIPTIN
Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval.
Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients.
They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin.
They look to be at least weight neutral.

29. SUMMARY
Insulin resistance and relative insulin secretory defect are key elements of the pathogenesis of type 2 diabetes.
GLP-1 deficiency is another key component in diabetic pathophysiology contributing to:
- Insulin secretory deficit.
- Excess of plasma glucagon.
- Postprandial hyperglycemia.

30. SUMMARY
Incretin mimetics offer a new approach in the management of type 2 diabetes.
Exenatide is the first agent in this class and is administered via injection twice a day.
In addition to improving glycemic control, exenatide has the unique benefit of causing weight loss that appears to be prolonged based on initial studies.

31. SUMMARY DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold.
They appear to be weight neutral and have a remarkable low incidence of adverse reactions.
Sitagliptin ad vildagliptin are the first of the DPP-IV inhibitors to receive FDA approval.
These promising new therapies should be undertaken in combination not only with existing oral antidiabetes medications as indicated, but also with other proven cardiovascular risk-reduction strategies, including lifestyle reduction and pharmacologic therapy, as needed.

32. THANK YOU