Noninsulin Antidiabetic Agents: Typical and Atypical Effects

Debra Gordon

doi:10.1177/155989771009016

Summary

The incretin mimemics—dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists—stimulate insulin secretion and inhibit glucagon secretion to stabilize serum glucose levels. They provide blood glucose reductions that are similar to other antidiabetic drugs, with no associated weight gain and, in the case of the GLP-1 agonists, some weight loss [Drucker DJ, Nauck MA. Lancet 2006; Russell-Jones D. Int J Clin Pract 2010].

Diabetes Mellitus

There is also some evidence from animal and human models that these compounds may provide β-cell preservation. In animal studies, they have been shown to increase neogenesis from islet precursor cells, induce β-cell replication from mature β-cells, prevent apoptosis in toxic environments, determine insulin biosynthesis that results in greater β-cell mass, improve β-cell functional status, and increase recruitment of dormant cells that do not respond to high glucose levels, thus increasing the actively recruiting β-cell mass [Brubaker PL, Drucker DJ. Endocrinology 2004; Holz GG, Kuhtreiber WM, Habener JF. Nature 1993].

In human studies, patients who received the DPP-4 inhibitor sitagliptin demonstrated a reduced proinsulin: insulin ratio, indicating greater processing of proinsulin to insulin and evidence of healthier β-cells [Riche DM et al. Am J Med Sci 2009].

In addition, 3-year results in patients who received exenatide or glargine insulin found increased insulin sensitivity in the exenatide patients over baseline but no change from baseline in the insulin group. Whether the weight loss from exenatide or some other mechanism of action is responsible for the improved insulin sensitivity remains to be determined [Bunck MC. Abstract #848, EASD 2010. Stockholm, Sweden].

Pancreatitis and Incretin Mimetics

A concern has been raised about the risk of severe pancreatitis in patients who take exenatide. These cases were reported as part of postmarketing surveys, although none were seen during clinical trials.

Studies have found that pancreatitis is significantly more prevalent in people with diabetes, with the risk related to traditional risk factors for the disease, including alcohol intake, obesity, hypertriglyceridemia, gallstones, and the use of certain antihypertensive drugs. An evaluation of a claims-based database that contained more than 40,000 individuals who received either exenatide or sitagliptin, matched against an equal number of patients who received metformin or glyburide initiators, found a relative risk of 1.0 (95% CI, 0.6 to 1.7, exenatide; 95% CI, 0.5 to 2.0, sitagliptin), providing no evidence of a direct association between the drugs and pancreatitis [Dore DD et al. Curr Med Res Opin 2009].

Incretin Mimemics and C-Cell Abnormalities

Concern has also been raised about the drug liraglutide, after animal studies found a slightly higher risk of C-cell abnormalities and C-cell medullary thyroid carcinoma, a cancer that is very rare in humans. However, further studies found significant differences in C-cell response to GLP-1 receptor agonist stimulation compared with human C-cell response. Specifically, rat C-cells demonstrated far greater calcitonin release and adenylate cyclase activation than human cells, in which no immediate response was seen after GLP-1 receptor activation [Knudsen B et al. Endocrinology 2010]. No cases of medullary thyroid carcinoma have been reported in humans who have taken liraglutide, and it is unlikely that any direct association between this rare form of cancer and the GLP-1 receptor agonist will be found.

Incretin Mimetics and Cardiovascular Effects

Studies that have been conducted in dogs, rats, and pigs using exenatide and liraglutide have found far smaller areas of necrotic tissue following induced myocardial infarction (MI) on animals who received exenatide or liraglutide at the time of MI [Timmers L et al. J Am Coll Cardiol 2009; Sauve M et al. Diabetes 2008; Bose AK et al. Diabetes 2005].

Although large human studies are pending, a small pilot study, involving 5 patients with type 2 diabetes and 5 without who arrived in the emergency department with acute MI and low left ventricular ejection fraction, found that those who were randomized to a 72-hour infusion of a GLP-1 receptor agonist demonstrated significantly improved left ventricular ejection fraction, global wall motion score indexes, and regional wall motion score indexes compared with controls (p<0.01 for all) [Nikolaidis LA et al. Circulation 2004].

There is also some evidence that the DPP-4 inhibitors may significantly reduce cardiovascular events in patients with diabetes compared with sulfonylureas [Filozof C & Gautier JF. Diabet Med 2010; Ferrannini E et al. Diabetes Obes Metab 2009]. This conclusion, however, is based on small numbers of events in studies that aimed at demonstrating improved glycemic control. Larger trials are needed to better characterize the benefits and risks of incretin-based antidiabetic medications with regard to cardiovascular outcome.

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