DPP-4 inhibitors, GLP-1 receptor agonists reduce hypoglycemia risk

Increased risk for hypoglycemia appears to be inevitable with intensive glycemic control in patients with type 2 diabetes, but there are steps that clinicians can take to minimize the risk when making antidiabetic drug choices, said Gabriele Perriello, MD, PhD, from the Department of Internal Medicine at the University of Perugia, Italy.
     The landmark United Kingdom Prospective Diabetes Study (UKPDS) showed that intensified treatment reduces the risk of complications in patients with newly diagnosed type 2 diabetes.
     “But the same study demonstrated for the first time that with intensified treatment of type 2 diabetes, we increase the risk of hypoglycemia,” Perriello said.
     In the UKPDS, Veterans Affairs Diabetes Trial, ADVANCE Trial, and ACCORD Trial, the risk of hypoglycemia was greater among patients on intensified therapy compared with standard glycemic control, he said.
     Severe hypoglycemia was also associated with an increase in overall mortality in ACCORD, with the overall death rate 3.3% among patients who experienced a severe hypoglycemic episode, compared with 1.2% for those with no serious episodes.
     Other risk factors for hypoglycemia, in addition to intensified treatment, include use of insulin secretagogues (sulfonylureas and glinides), older age, and diabetes of longer duration.
     Sulfonylureas in particular were associated with mild hypoglycemia in 39% of patients, severe hypoglycemia in 7% of patients, and a blood glucose level below 2.2 mmol/L (39.6 mg/dL) in observational studies. The incidence of hypoglycemia was similar between insulin- and sulfonylurea-treated patients, Perriello said.
     Individual factors that may increase the risk of hypoglycemia include impaired drug clearance (for example, with renal or hepatic impairment or failure), impaired counterregulatory capacity (as in Addison’s disease or with growth hormone deficiency), increased peripheral glucose uptake during exercise, decreased endogenous glucose production (as in liver failure), and impaired glucose absorption.
     Concurrent medications can also affect metabolism of sulfonylureas or other insulin secretagogues.
     In contrast to the sulfonylureas and glinides, agents associated with minimal risk for hypoglycemia include the DPP-4 inhibitors (eg, sitagliptin, linagliptin), and the injectable glucagon-like peptide-1 (GLP-1) receptor agonists (eg, exenatide). Evidence shows that addition of a DPP-4 inhibitor to insulin reduces the incidence of insulin-related hypoglycemic episodes, and combining a basal insulin with a GLP-1 receptor agonist can reduce both glycosylated hemoglobin and body weight without increasing risk for hypoglycemia, Perriello said.