Review: In type 2 diabetes, adding dipeptidyl peptidase-4 inhibitors to sulfonylureas increases hypoglycemia

Adding dipeptidyl peptidase-4 (DPP-4) inhibitors to sulfonylureas to treat type 2 diabetes was associated with a significantly increased risk of hypoglycemia, totaling 1 excess case of hypoglycemia for every 17 patients in the first 6 months of treatment, a systematic review and meta-analysis found.

The study was published by The BMJ on May 3 and summarized in the May ACP Diabetes Monthly. The following commentary by Michael Tanner, MD, FACP, was published in the ACP Journal Club section of the Aug. 16 Annals of Internal Medicine.

The enzyme DPP-4 degrades the incretin hormone glucagon-like peptide-1 (GLP-1). The gliptins, by inhibiting DPP-4, potentiate the action of GLP-1, increasing insulin secretion and decreasing glucagon secretion by the pancreas. Unlike sulfonylureas, the action of DPP-4 inhibitors depends on the presence of ingested glucose and fat; therefore, when used alone, risk for hypoglycemia is low (<1%).

DPP-4 inhibitors are generally well-tolerated oral medications that can be given to patients with diabetes and important comorbid conditions (e.g., those with glomerular filtration rate <30 mL/min who cannot safely take metformin and those with heart failure who cannot take thiazolidinediones). DPP-4 inhibitors can be used as an alternative to insulin to improve quality of life in hospitalized patients with mild diabetes, sparing them the pain of multiple daily fingersticks and small doses of preprandial insulin, with less risk for hypoglycemia.

The review by Salvo and colleagues included 10 trials published between 2007 and 2013 and evaluated the risk for hypoglycemia in 4,020 patients randomized to sulfonylurea plus a DPP-4-inhibitor compared with 2,526 randomized to sulfonylurea plus placebo. It showed about a 50% relative increase in incidents of hypoglycemia over 6 months when a DPP-4 inhibitor was added to a sulfonylurea (number needed to harm [NNH] 17). This NNH implies thousands of cases of hypoglycemia because of the widespread use of these agents. In 2012, >6.7 million patients in the USA filled prescriptions for sulfonylureas (single-ingredient or combination products) and >2.6 million received DPP-4 inhibitors.

It comes as no surprise that 2 drugs that stimulate insulin release cause more hypoglycemia than a single drug. An important implication for practice is that clinicians should warn patients and consider reducing the sulfonylurea dose when adding a DPP-4 inhibitor.