Nonglycemic Effects of Incretins

In addition to their beneficial effects on blood glucose, particularly postprandial glucose, as well as body weight and pancreatic beta cell function, the glucagon-like peptide-1 (GLP-1) receptor agonists (Exenatide, Liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (Sitagliptin, Vildagliptin) have other beneficial effects. These effects on blood pressure and blood lipids, although not making incretins suitable as primary therapy, may be important benefits to consider in selecting diabetes therapy, because patients with type 2 diabetes mellitus (T2DM) are at increased risk for cardiovascular disease.

Blood Pressure

GLP-1 receptor agonists and DPP-4 inhibitors produce modest reductions in systolic blood pressure and, in some cases, diastolic blood pressure. The importance of hypertension as a cardiovascular risk factor is well established. As concluded by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, each increment of 20/10 mm Hg above 115/75 mm Hg doubles the risk of cardiovascular disease.

Lipid Profile

the GLP-1 receptor agonists and DPP-4 inhibitors produce significant reductions in the triglyceride level. Exenatide and vildagliptin also produce significant improvements in total, LDL-, and HDL-cholesterol. The benefits on reducing cardiovascular risk by lowering total and LDL-cholesterol and raising HDL-cholesterol are well established. As such, they are important targets for treatment as recommended by the National Cholesterol Education Program Expert Panel - Adult Treatment Panel III

Conclusion

The GLP-1 receptor agonists and DPP-4 inhibitors lower blood pressure and improve the lipid profile, which, although not appropriate as primary therapy, makes them especially valuable treatment options for patients with T2DM. These improvements may help to reduce the risk of cardiovascular events. Various approaches can be taken to initiate and modify GLP-1 receptor agonist and DPP-4 inhibitor therapy to improve efficacy and tolerability based on patient characteristics and concomitant therapies.

References

1. Boschmann M, Engeli S, Dobberstein K, et al. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J Clin Endocrinol Metab. 2008. In press.
2. Viswanathan P, Chaudhuri A, Bhatia R, et al. Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract. 2007;13:444-450.
3. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428.
4. Vilsboll T, Zdravkovic M, Le Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608-1610.
5. Colagiuri S, Frid A, Zdravkovic M, et al. The once-daily human GLP-1 analog liraglutide reduces systolic blood pressure in patients with type 2 diabetes. Paper presented at: American Diabetes Association 68th Scientific Session; June 6-10, 2008; San Francisco, CA.
6. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48:592-598.
7. Chobanian AV, Bakris GL, Black HR, et al; for the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206-1252.
8. Blonde L, Rosenstock J, Sesti G, et al. Liraglutide: superior glycemia control vs exenatide when added to metformin and/or SU in type 2 diabetes. Paper presented at: Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism Annual Meeting; October 15-18, 2008; Montreal, Quebec, Canada.
9. Scott R, Wu M, Sanchez M, et al. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007;61:171-180.
10. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556-1568.
11. Bolli G, Dotta F, Rochotte E, et al. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2008;10:82-90.
12. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care. 2007;30:217-223.
13. Grundy SM, Becker D, Clark LT, et al. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed January 20, 2009.
14. Daniel A. Nadeau, MD. Incretin Benefits Beyond Glycemic Control. From Primary Care Education Consortium, Medscape Internal Medicine. Posted 03/19/2009. Available at: http://www.medscape.com/viewarticle/588945?src=mp&spon=18&uac=82830HJ
    

new approach in type 2 diabetes pharmacotherapy

A relatively new approach in type 2 diabetes pharmacotherapy is the result of understanding incretin physiology. Briefly, after eating a meal, certain gut hormones are released that sensitize the beta cell to secrete more insulin. One of the most important gut hormones is glucagon-like peptide-1 (GLP-1), which goes into the circulation and stimulates insulin secretion in a glucose-dependent manner.

In addition, this pathway has the added benefit of suppressing glucagon secretion, which has a role in the pathophysiology of diabetes. GLP-1 is also involved in slowing gastric emptying and in working on the central nervous system causing early satiety, leading to some beneficial effects in glycemic control. The problem is that GLP-1 is very rapidly degraded through the very important enzyme, DPP-IV. This leads to rapid inactivation of GLP-1, making its use impractical in patients who have type 2 diabetes.

It is also interesting to note that in some animal models, and in in-vitro studies, there are some exciting observations that this pathway may also help beta-cell differentiation. This has been shown to increase beta-cell mass, and the formation of new beta cells, but is not yet proven in humans. It is an exciting new concept that is still being explored.

Coming back to this pathway of GLP-1 degradation through DPP-IV, one of the ways to use this physiologic knowledge is to develop a drug that might block DPP-IV activity, which has been done with the DPP-IV inhibitors. They sustain GLP-1 level in the circulation longer, which then stimulates pancreatic insulin secretion and suppresses glucagon secretion. Another strategy that one can employ is to develop a GLP-1-like substance synthetically that is not recognized by DPP-IV. That is the approach underlying the GLP-1 analogs that are not degraded through this pathway, and you can then use that substance in the treatment of type 2 diabetes.

These are the 2 concepts behind the development of the new drugs. Incretin mimetics, which are analogs of GLP-1, are synthetically produced. Exenatide is one of these drugs used to treat patients with type 2 diabetes. Because of the protein, you have to inject exenatide subcutaneously; you cannot give it orally. Another drug in this class, liraglutide, is under US Food and Drug Administration (FDA) review and might be approved in the near future.

The second way to use this physiology is to develop DPP-IV inhibitors. One such agent, sitagliptin, has been on the market for 2 years. There are several other drugs in this class undergoing clinical trials. This is an important area to pursue, and many of the pharmaceutical companies are trying to develop these agents that will be easy to use in the oral form to improve glycemic control.

exenatide, a twice-daily injection, you can lower A1C by about 0.8% to 1%. The main side effect is nausea, sometimes vomiting. There may be appreciable weight loss, which is a desirable side effect of this drug. We do not have another approved drug yet that improves glycemic control and results in weight loss at the same time. The only medication that came close to it was metformin, but metformin is relatively weight-neutral; it does not cause weight loss in most patients.

Sitagliptin has very similar effects on A1C reduction as exenatide, except it does not cause weight loss. This drug is weight-neutral, but at least it does not cause weight gain. Another advantage of these drugs is that they do not cause gastrointestinal side effects, such as nausea.

Both GLP-1 agonists and DPP-IV inhibitors are being utilized in the strategy of combination therapy to achieve better glycemic control.

Newer drugs in Treatment of Type 2 Diabetes

Incretins

Incretins are gastrointestinally secreted insulinotropic hormones that play an important role in glucose homeostasis as they are involved in augmentation of -cell secretion of insulin and in suppression of glucagon secretion by the cell. The incretin effect refers to the augmented release of insulin that is observed from oral ingestion of glucose when compared with intravenous glucose challenge, even though the glucose concentration achieved in plasma may be equivalent. There are two different gut hormones that are mainly responsible for the incretin effect, which may include glucose-dependent insulinotropic peptide and GLP-1. In contrast to glucose-dependent insulinotropic peptide, GLP-1 maintains a glucoregulatory function in individuals both with and without diabetes. For this reason, GLP-1 was identified as a potential therapeutic agent for diabetes treatment.

One of the major concerns for GLP-1 that limited clinical applicability is the rapid enzymatic degradation by DPP-4 and as such, requires continuous intravenous or subcutaneous infusion. To address the problem, two research approaches have been attempted. One is to modify the molecule to resist or delay degradation. Agents such as exenatide and liraglutide are GLP-1 receptor agonists that are resistant to DPP-4 inhibition. A second approach has been to inhibit endogenous DPP-4 activity, thus prolonging the circulating half-life of native GLP-1. Agents in the DPP-4 inhibitor class are represented by vildagliptin and sitagliptin