Diabetes is an epidemic in the United States. According to the most recent CDC estimates, the disease affects approximately 25.8 million Americans, representing 8.3% of the total population. Over the course of several years, safer and more effective therapies and treatment options have emerged to improve patient management. A greater understanding of the pathogenesis of diabetes has led to the development of additional therapies to individualize treatment approaches.

Examining the Incretin System

Type 2 diabetes is a progressive disease that results from a complex process that includes declining b-cell function and insulin resistance. Other factors that play a role include unsuppressed glucagon and impaired incretin function. The role of the incretin system in diabetes has been studied for several decades, and therapeutic agents that target these hormones have become available. These incretin hormones are synthesized predominantly in the small bowel. The major incretins in humans are GLP-1 (glucagon-like polypeptide) and GIP (glucose-dependent insulinotropic polypeptide). These hormones can increase insulin secretion, reduce glucagon secretion, slow gastric emptying, and enhance early satiety, all of which may ultimately improve glucose homeostasis.

“The glucose-lowering effects of incretin-based therapies can provide the most beneficial improvements if they’re used early in the course of treatment.”

Native GLP-1 has a short half-life of approximately 3 minutes and is degraded by the dipeptidyl peptidase-4 (DPP-4) enzyme. Synthetic GLP-1 agonists are not degraded by this enzyme and provide pharmacologic levels of GLP. By achieving these levels of GLP-1, delayed gastric emptying and early satiety occurs. DPP-4 inhibitors delay the breakdown of endogenous GLP-1, and therefore provide levels of GLP-1 slightly higher than normal. Both of these agents lower fasting and postprandial glucose and lower A1C. Hypoglycemia, a complication that is frequently encountered with other glucose-lowering agents, is less common with the GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists and DPP-4 inhibitors are the incretins that are clinically available. The GLP-1 therapies are administered via injection, while the DPP-4 inhibitors are oral agents, which are taken once daily.

Important Considerations

Both the GLP-1 receptor agonists and DPP-4 inhibitors are effective therapies in drug-naïve patients as monotherapy and in combination with metformin, thiazolidinediones, sulfonylureas, and other agents. They lower fasting and postprandial glucose as well as A1C. The use of GLP-1 receptor agonists may result in weight loss. Data on the durability of these drugs are accumulating.

Research continues to accumulate on the long-term efficacy, safety, and durability of these agents. These studies include cardiovascular disease outcomes data, effects of GLP-1 agonists in cardiac contractility, and promoting islet cell survival in islet cell transplants. DPP-4 inhibitors are available in a single pill and in combination with metformin. They are currently being studied to formulate other combinations.

Initiate Early, Educate Thoroughly

The glucose-lowering effects of incretin based therapies can provide the most beneficial improvements if they’re used early in the course of treatment. There are more viable b-cells available earlier in the course of disease rather than later when the disease is well established with declining b-cell function. In particular, they can be used confidently after targets have not been achieved with metformin. The newer guidelines from the American Association of Clinical Endocrinologists recommend the use of GLP-1 and DPP-4 inhibitors throughout the course of disease. However, when A1C is above 9%, triple-drug combina­tion can be implemented.

It’s important to discuss the safety of incretin-based therapies prior to their use. This includes addressing the issues of renal safety, pancreatitis, medullary thyroid cancer, and other conditions listed and discussed in the product insert. Patients should collaborate with their healthcare team and engage in healthy lifestyle behaviors to optimize results.

 

References

Cobble ME, Freeman JS, Garber AJ, et al. The role of incretin therapy for type 2 diabetes in family medicine. J Fam Prac. 2008;57(Suppl 1):S2-S31. Available at: http://www.jfponline.com/ccp_article.asp?id=6684.

Garber AJ. Incretin-based therapies in the management of type 2 diabetes: rationale and reality in a managed care setting. Am J Manag Care. 2010;16(Suppl):S187-S194. Available at:http://www.ajmc.com/supplement/managed-care/2010/A292_10aug/A292_10aug_Garber_S187to194.

Campbell RK, Cobble ME, Teid TS, Shomali ME. Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies. J Fam Prac. 2010;59 (Suppl 1): S5-S9. Available at: http://www.jfponline.com/Pages.asp?AID=8943.

Holst JJ, LaSalle JR. An overview of incretin hormones. J Fam Prac. 2008;57(suppl):S4-S9.