Keith R. Campbell, PharmD, MBA, CDE Distinguished Professor in Diabetes Care and Pharmacotherapy, Department of Pharmacotherapy, Washington State University College of Pharmacy, Pullman, Washington
Michael E. Cobble, MD, FNLA Director, Canyons Medical Center, Sandy, Utah, Adjunct Faculty, University of Utah School of Medicine, Salt Lake City, Utah
Timothy S. Reid, MD Department of Family Medicine, Mercy Diabetes Center, Janesville, Wisconsin
Mansur E. Shomali, MD, CM Clinical Associate Professor of Medicine, University of Maryland School of Medicine, Associate Medical Director, Diabetes and Endocrine Center, Union Memorial Hospital, Baltimore, Maryland
References
These preclinical and clinical data regarding pancreatic β-cell function must be viewed as preliminary, and require further investigation. If confirmed, the ability to alter the natural progression of β-cell loss in T2DM and/or to reduce insulin resistance would be of significant clinical value.
Incretin effects on other causes of T2DM
Both the GLP-1 agonists and the DPP-4 inhibitors affect other mechanisms involved in the pathogenesis of T2DM. Several trials have shown a significant reduction in fasting glucagon secretion with GLP-1 agonist37 or DPP-4 inhibitor treatment.43,46,47 The addition of exenatide or liraglutide to metformin, a sulfonylurea, or both for 26 weeks resulted in a reduction in fasting glucagon secretion of 12.3 and 19.4 ng/L, respectively (P=.1436), after 26 weeks.37 Addition of saxagliptin to a submaximal dose of a sulfonylurea resulted in a reduction of glucagon secretion of 0.8 ng/L compared with an increase of 4.5 ng/L with uptitration of the sulfonylurea alone for 24 weeks. A 2-week crossover trial comparing exenatide with sitagliptin showed that compared with sitagliptin, exenatide reduced postprandial glucagon by 12% (P=.0011)47 (FIGURE 2); in addition, exenatide slowed the gastric emptying rate by 44% (P<.0001), with a commensurate decrease in total caloric intake of 134 kcal with exenatide vs an increase of 130 kcal with sitagliptin (P=.0227).47
FIGURE 2Reduction in glucagon secretion with exenatide or sitagliptin47
Postprandial glucagon concentration during meal ingestion at baseline and after treatment with exenatide or sitagliptin. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Current Medical Research and Opinion. 2008, reprinted with permission of Taylor & Francis Group.
Summary
The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic β-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.
