DPP-4 Antagonists: Benefits, Risks, and the Future

Take-home Points
•  Given their ease of administration, tolerability, and avoidance of weight gain and hypoglycemia, DPP-4 antagonists warrant consideration as second-line agents added to metformin(Drug information on metformin), or even as first-line treatment for patients who cannot tolerate metformin or for who the drug is contraindicated. All antihyperglycemic agents should be prescribed against the backdrop of therapeutic lifestyle counseling as the cornerstone of treatment.
• The efficacy of glucose control is comparable to existing classes of oral antidiabetic agents, yielding approximately 0.5% to 1% additional HbA1c reduction either as monotherapy or added to existing drugs/drug combinations.
•  Meta-analyses thus far across this class of medications suggest approximately a 30% relative reduction in major adverse cardiovascular events, but these analyses are based on relatively few patients studied, few cardiovascular events captured, and relatively short duration of exposure. Cardiovascular outcomes trials are presently underway, with a total planned enrollment across the class of 50,000 trial participants.

There are several questions yet to be answered:
•  What, if any, increased risk for pancreatitis and/or pancreatic cancer is associated with DPP-4 antagonists?
•  If such risk exists, are there differential risks between the drugs in the class?
•  Finally, if these risks exist, how are they balanced by the DPP-4 antagonists’ efficacy against micro- and macrovascular disease complications?

These concerns are being addressed systematically in ongoing trial programs.

Suggested Reading
• Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369.
• Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20:224-235.
• Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27 Suppl 3:s57-s64.
• Goossen K, Graber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab. 2012.
• Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diab Vasc Dis Res. 2012;9:109-116.