Mounting Evidence that DPP-4 Inhibitors may Reduce Cardiovascular Risk

Web Exclusives
Wayne Kuznar

Premature mortality, frequently from cardiovascular disease, is a consequence of type 2 diabetes, especially when it is poorly controlled. Cardiovascular mortality increases with increasing levels of HbA1c.1 In addition to increasing the risk for macrovascular complications, poor glucose control is also a major risk factor for microvascular disease.2

Because patients with type 2 diabetes are at high risk of developing cardiovascular disease, the therapeutic choice should take cardiovascular risk potential into consideration, especially in those patients who have concomitant risk factors for cardiovascular disease.

Evidence is accumulating that dipeptidyl peptidase-4 (DPP-4) may have cardiac benefits either directly or mediated through increases in glucagon-like peptide-1 (GLP-1) bioavailability and signaling. Beneficial effects on blood pressure and lipid profiles have been observed with treatment with DPP-4 inhibitors.

A new meta-analysis goes one step further and suggests that treatment of type 2 diabetes using a DPP-4 inhibitor reduces the risk of adverse cardiovascular events relative to other oral antidiabetes drugs.3 The relative decrease in risk of cardiovascular events with the DPP-4 inhibitors was about 60%.

The evidence from the meta-analysis is strong enough to consider preferential use of DPP-4 inhibitors, especially among patients at higher risk for cardiovascular events, believes a co-author of the meta-analysis, James H. O’Keefe, MD, from Saint Luke’s Mid America Heart Institute in Kansas City.

“I am using DPP-4 inhibitors much more frequently now,” he says. “Often I use them as first- or second-line.”

The analysis included 18 randomized controlled trials (published and unpublished) identified through a search of electronic databases. The trials compared DPP-4 inhibitors to other oral hypoglycemic agents, and each was at least 24 weeks in duration. Altogether, there were 4,998 patients randomly assigned to DPP-IV inhibitors and 3,546 to a comparative oral diabetes drug.

DPP-4 inhibitors were associated with a 52% lower risk of adverse cardiovascular events and a 60% lower risk of nonfatal myocardial infarction or acute coronary compared with placebo or other oral hypoglycemic drugs. The risk of adverse cardiovascular events was not significantly different compared with placebo but when compared with other oral agents, including metformin, sulfonylureas, and thiazolidinediones, the risk for cardiovascular events was significantly lower with DPP-4 inhibitor therapy (relative risk [RR] =0.42).

Long-term use of DPP-4 inhibitors appeared more protective. In the trials of at least 52 weeks, DPP-4 inhibitors were associated with a 63% reduction in the risk of adverse cardiovascular events compared with controls. Those lasting less than 52 weeks showed a nonsignificant trend toward fewer events with DPP-4 inhibitors (RR = 0.78).

There was no significant heterogeneity within the group of pooled studies, the authors report.

Although this meta-analysis showed only a significant reduction in events associated with sitagliptin compared with other oral agents, other pooled safety studies of DPP-4 inhibitors show decreases in risk of major adverse cardiovascular events of 48% to 66% with saxagliptin, linagliptin, and alogliptin.4-6


  1. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001;322:15-18.
  2. Stratton IM, Adler AI, Weil AW, et al. Associaiton f glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412.
  3. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 2012;110:826-833.
  4. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16-27.
  5. Johansen OE, Neubacjer D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a prespecified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 2012;1:3.
  6. White WB, Bakris GL, Bergenstal RM, et al. Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): a cardiovascular safety study of dipeptidyl peptidase inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 2011;162:620-626.e1.
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Last modified: February 14, 2019
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