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Am Fam Physician. 2015;92(11):1020a-1021

Clinical Question

Does adding sitagliptin (Januvia) to existing therapy for type 2 diabetes mellitus improve outcomes?

Bottom Line

The glass half full is that sitagliptin does not increase the risk of cardiovascular events in patients with type 2 diabetes. The glass half empty is that it does not reduce the risk, either. And that is the important message: In patients with a mean glycated hemoglobin level of 7.2%, adding sitagliptin at a cost of approximately $350 per month does not affect cardiovascular outcomes at all. (Level of Evidence = 1b)


To date, the only drug shown to reduce the risk of cardiovascular events or death in patients with type 2 diabetes is metformin. Sitagliptin is one of a class of dipeptidyl-peptidase-4 inhibitors that reduces glucose levels by decreasing glucagon levels and increasing insulin secretion. A previous meta-analysis found a 25% relative increase in the likelihood of hospitalization for heart failure with the use of these agents. In this study, the researchers recruited adults older than 50 years with type 2 diabetes; current treatment with metformin, pioglitazone (Actos), a sulfonylurea, or insulin; and a glycated hemoglobin level between 6.5% and 8.0%. Patients with two or more recent episodes of severe hypoglycemia were excluded, as were patients with impaired renal function. The patients were randomized to receive 100 mg of sitagliptin daily (50 mg if the glomerular filtration rate was 30 to 50 mL per minute per 1.73 m2) or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction or stroke, or hospitalization for unstable angina.

This was designed as a noninferiority (or “no worse than”) trial, with the stated goal of determining whether sitagliptin was no worse than placebo at causing cardiovascular events. However, the researchers also looked at whether sitagliptin was superior to placebo for preventing cardiovascular events. They recruited 14,735 patients and followed up for a median of three years. The groups were balanced at the beginning of the study, and the mean duration of type 2 diabetes was 12 years, with a mean glycated hemoglobin level of 7.2%. The drug did lower glycated hemoglobin levels a bit, by 0.4% after four months, but that decreased as time went on. There was no difference in the likelihood of the primary composite outcome, of a composite that did not include unstable angina, or of individual cardiovascular outcomes or mortality for both per protocol and intention-to-treat analyses. Death from any cause occurred in 7.5% in the sitagliptin group and in 7.3% in the placebo group, and hospitalization for heart failure occurred in 3.1% in each group.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Setting: Outpatient (any)

Reference: GreenJBBethelMAArmstrongPWet alTECOS Study GroupEffect of sitagliptin on cardiovascular outcomes in type 2 diabetes [published correction appears in N Engl J Med. 2015; 373(6):586]. N Engl J Med2015; 373( 3): 232– 242.

POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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