GLP Agonists and DPP-IV Inhibitors

Zachary T. Bloomgarden, MD


August 10, 2007

In This Article

DPP-IV Inhibitors

Dr. Pratley discussed the role of DPP-IV inhibitors in the treatment of diabetes. Both GLP-1 and GIP have the amino acid alanine in the second N-terminal position, leading to inactivation by DPP-IV. It is interesting that more than half of secreted GLP-1 is degraded by local DPP-IV prior to absorption into plasma, suggesting that the glucose-lowering effect of GLP-1 is limited by its short half-life. DPP-IV belongs to a serine protease family also including DPP-VIII and -IX, and in vitro substrates of DPP-IV include GLP-1, GLP-2, GIP, enterostatin, gastrin-releasing peptide, neuropeptides Y, peptide YY, insulin-like growth factor-1, and a number of inflammatory peptides.

Fifty-five presentations at the American Diabetes Association (ADA) meeting addressed 12 different DPP-IV inhibitors, leading Dr. Pratley to observe that "we are going to be seeing even more . . . in the coming months." He reviewed long-term clinical data on sitagliptin and vildagliptin, both given once daily and both reaching Tmax after 2-3 hours, with > 1000-fold greater specificity for DPP-IV than for other related peptidases. The duration of DPP-IV inhibition is dose-dependent, with an 85% effect at 12 hours and a 40% effect at 24 hours after a 100-mg dose of vildagliptin.

During a 28-day study with vildagliptin, both GLP-1 and GIP levels were increased throughout the day, with a 50% reduction in glucagon and a robust decrease in glucose response to a standard meal.[7] Insulin levels showed no change, but given the lower blood glucose levels, the glucose-insulin dose-response curve can be considered to be shifted leftward. Insulin secretion itself is increased, with some evidence of increased insulin sensitivity, although this finding has been controversial.

In a comparative study of rosiglitazone and vildagliptin, both showed similar reductions in A1C, with a similarly greater response at higher baseline glucose levels.[8] In a 104-week trial comparing vildagliptin with metformin, both drugs achieved sustained glucose-lowering effects. Metformin showed a somewhat greater effect at 52 weeks but not at the end of the 2-year study.

It is interesting to note that both metformin and sitagliptin were reported in a presentation at the ADA meeting by Migoya and colleagues[9] to increase GLP-1. Metformin appeared to increase total GLP-1 secretion, whereas sitagliptin reduced GLP-1 inactivation, perhaps explaining why the combination has particularly desirable benefits. Indeed, sitagliptin has been studied in combination with both metformin and pioglitazone, and the effects have been additive. When the combination of sitagliptin with metformin was studied as initial treatment, the agents alone decreased A1C levels by 0.8% and 1.3%, respectively, whereas the combination decreased A1C levels by 2%, starting at a level of 8.8%.[10] Furthermore, a 52-week comparison of treatment with glipizide or sitagliptin in persons receiving metformin showed identical glucose-lowering effects.[11] However, there was more hypoglycemia and greater weight gain with the sulfonylurea.

In insulin-treated type 2 diabetes patients, the addition of vildagliptin led to a greater fall in A1C with less hypoglycemia, suggesting an additional potential for this agent.[12] Similarly, initial combination therapy with vildagliptin and pioglitazone decreased A1C by almost 2%.[13]

Side effects with the DPP-IV inhibitors are relatively few. Stein and colleagues[14] reported pooled safety data from 9 completed phase 2B and 3 studies, including 5141 persons receiving sitagliptin or a comparator, and hypoglycemia was considerably less frequent than with sulfonylureas. Side effects reported with significantly greater frequency with sitagliptin were nasopharyngitis in 12% vs 9%, contact dermatitis in 1% vs 0.4%, and osteoarthritis in 2% vs 1%.

Dr. Pratley suggested that some questions about the DPP-IV inhibitors remain to be addressed, including the relative importance of their effects on GLP-1 vs GIP, long-term efficacy, side effects, whether they are weight-neutral or associated with weight loss in certain circumstances, and their effects on other DPP-IV substrates.

Several new agents, such as saxagliptin and alogliptin, seem particularly interesting. Dr. DeFronzo and colleagues[15] studied 743 metformin-treated type 2 diabetes patients receiving placebo or saxagliptin 2.5 mg, 5 mg, or 10 mg daily, and demonstrated a 0.7% to 0.8% decrease in A1C levels from a baseline of 8%. Christopher and colleagues[16] reported that alogliptin appears to have considerably longer duration of effect compared with vildagliptin and sitagliptin. Elevated levels of GLP-1 and GIP may be sustained over a full 24 hours with alogliptin, potentially leading to greater effect on lowering of fasting glucose. It will be important to see whether clinical studies show important differences among these or other new agents.


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