Stroke Protection from DPP-4 Inhibitors?

December 27, 2016
Veronica Hackethal, MD

Whether or not antihyperglycemics can decrease the risk of stroke has been a matter of debate.

Large randomized controlled trials do not support a protective role for gliptins against stroke, according to a systematic review and meta-analysis published online in Diabetes & Metabolism.1

“[O]ur analysis of the data derived from the three large RCTs showed that, in the long term, treatment with these agents [gliptins] actually had neutral effects on the risk of stroke,” wrote first author Fotios Barkas, MD, of the University of Ioanninna (Ioannina, Greece), and colleagues.

However, researchers also did an analysis of small, prospective trials, which suggested a nonsignificant trend toward decreased incidence of ischemic stroke with gliptins compared to placebo. The findings agree with preclinical animal studies, which have suggested a neuroprotective role for DPP-4 inhibitors, though the mechanisms remain unknown.2

Whether antihyperglycemics can decrease the risk of stroke has been a matter of debate. So far, only pioglitazone has been associated with decreased risk of stroke. The PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) and IRIS (Insulin Resistance Intervention After Stroke) trials found that pioglitazone was associated with decreased risk of stroke in high-risk patients with prior stroke and diabetes or insulin resistance.3,4

Past meta-analyses have failed to find a difference in stroke risk with DPP-4 inhibitors vs. placebo or comparator drugs. The current meta-analysis expands on past studies by including data from recently published large RCTs: SAVOR-TIMI, EXAMINE, and TECOS.

In the study, researchers searched Medline and Embase for English language studies published up to December 2015. They also used unpublished data from

The pooled analysis included 19 small RCTs covering 9278 patients and evaluating the safety and efficacy of gliptins. A separate pooled analysis included three multicenter double-blind RCTs that evaluated CV outcomes in 36,395 patients. Included trials had to have at least 100 patients and a follow-up of at least 12 weeks. Trials evaluated saxagliptin, alogliptin, vildagliptin, sitagliptin, and linagliptin. 

Key Results:

• Small RCTs: Non-significant trend suggesting decreased risk of stroke with DPP-4 inhibitors (odds ratio [OR]: 0.639, 95% confidence interval (CI): 0.336–1.212; P=0.170)

• Large RCTs: No difference in stroke risk with gliptin vs placebo (OR: 0.996, 95% CI: 0.850–1.166; P=0.958).

The authors noted several limitations, including small sample sizes and short follow-up in several studies. In addition, the study population of smaller studies showed a trend toward younger age and shorter diabetes duration, while large RCTs had a higher incidence of stroke. Doses of gliptins may not have been within the approved range, and patients may have been taking higher or lower doses than recommended.

Unlike the PROactive and IRIS trials which evaluated stroke risk with pioglitazone, trials of gliptins focused on combined CV outcomes and were not specifically designed to look at stroke risk in individuals with and without prior stroke. The discrepant results between animal, small RCTs, and large RCTs points to the need for trials specifically designed to assess stroke risk with gliptin use, according to the authors.

They concluded: “Future studies with stroke and/or stroke outcomes as an endpoint are now needed to assess any of the gliptin treatment-associated neuroprotective effects suggested by experimental models.”

Take-home Points

• A systematic review and meta-analyses of large RCTs has found no difference in stroke risk with gliptins vs placebo.

• A pooled analysis of small trials suggests a nonsignificant trend toward decreased stroke risk with gliptins vs placebo.

• Animal studies suggest a neuroprotective role for gliptins.

• Further studies are needed with specific stroke and/or stroke outcomes to evaluate possible neuroprotective effects of gliptins.

One or more authors has given talks, attended conferences, and/or participated in trials and advisory boards sponsored by various pharmaceutical companies.


1. Barkas F, et al. Dipeptidyl peptidase-4 inhibitors and protection against stroke: a systematic review and meta-analysis. Diabetes Metab. 2016 Dec 1. pii: S1262-3636(16)30540-7.

2. Darsalia V, et al. Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke. J Cereb Blood Flow Metab. 2015;35:718-723.

3. Wilcox R, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke. 2007 Mar;38(3):865-873.

4. Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016 Apr 7;374(14):1321-1331.

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