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

February 26, 2013
Payal Kohli, MD

Darren K. Mcguire, MD

Dipeptidyl peptidase-4 inhibitors, of the incretin class of antidiabetes drugs, are weight neutral, avoid hypoglycemia, and result in an average reduction in HbA1c of 0.5% to 1.0%

Will dipeptidyl peptidase-4 (DPP-4) antagonists find a secure position in the hierarchy of antidiabetes agents? Many signs point to “yes” for the fastest growing class of antihyperglycemic drugs: 
• Well tolerated
• Weight neutral
• Do not promote hypoglycemia
• Can be used in combination with traditional first-line agents
• Confer 0.5% to 1% additional reduction in A1C

Questions remain, however, about long-term safety of the DPP-4 inhibitors and their effects on cardiovascular outcomes, if any. In particular, an early signal for increased pancreatitis with some but not all members of this drug class, along with a small numeric excess of pancreatic cancer cases in some studies are now being systematically assessed for all  agents in the class. How should primary care physicians approach these agents and which patients might be candidates? 

DPP-4 Antagonists


In this short podcast, Dr Payal Kohli, host of CardiologyNow talks to Dr Darren McGuire about the DPP-4 antagonist class and the drugs’ benefits and risks as they are currently known. Dr Kohli is a cardiology fellow at the University of California San Francisco and Dr McGuire is Associate Professor of Medicine at UT Southwestern Medical Center, in Dallas; Associate of the Donald W. Reynolds Cardiovascular Clinical Research Center, and Director of the Parkland Hospital and Health System Outpatient Cardiology clinics. He is also senior editor of Diabetes and Vascular Disease Research, and associate editor of the American Heart Journal.

Take-home Points and Suggested Reading on next page...

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, 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.