In type 1 diabetes, adding liraglutide to insulin increased hypoglycemia and hyperglycemia with ketosis
The study authors concluded that the negative effects observed would limit clinical use of liraglutide in patients with type 1 diabetes.
In patients already taking insulin for type 1 diabetes, adding liraglutide reduced HbA1c, body weight, and insulin dose but increased risk for hypoglycemia and hyperglycemia with ketosis, a trial found. Patients, who had an HbA1c between 7% and 10% at baseline, were randomized to placebo or a liraglutide dose of 0.6 mg/d, 1.2 mg/d, or 1.8 mg/d, with insulin dose managed using a treat-to-target approach. The study authors concluded that the negative effects observed would limit clinical use of this drug in patients with type 1 diabetes.
The study was published in the October 2016 Diabetes Care. The following commentary by Michael Tanner, MD, FACP, was published in the ACP Journal Club section of the Dec. 20 Annals of Internal Medicine.
Is there a medication other than insulin that can benefit patients with type 1 diabetes? Pramlintide, the only U.S. Food and Drug Administration–approved adjunct, is seldom prescribed because of gastrointestinal side effects and the need for thrice-daily injections in addition to the heavy treatment burden of basal bolus therapy. An ideal agent for type 1 diabetes would lower HbA1c levels and improve cardiovascular outcomes without causing hypoglycemia, weight gain, or diabetic ketoacidosis. Liraglutide, the once-daily, glucagon-like peptide-1 receptor agonist (GLP-1RA), was reported to be safe and effective in the LEADER trial of patients with type 2 diabetes.
The ADJUNCT ONE trial by Mathieu and colleagues randomized 1,398 patients with type 1 diabetes and suboptimal glycemic control to insulin plus placebo or 3 different doses of subcutaneous liraglutide. The results were analyzed on an as-treated (not intention-to-treat) basis. At 1 year, liraglutide 1.8 mg and 1.2 mg reduced HbA1c levels, insulin dose, and weight compared with placebo.
However, the trial found an increase in symptomatic hypoglycemia and 8 cases of diabetic ketoacidosis in the liraglutide groups compared with 0 in the placebo group. These results differ from the reduction in hypoglycemia found in the LEADER trial and led the manufacturer, Novo Nordisk, to announce in August 2015 that it would not apply for approval of liraglutide (Victoza) for use in patients with type 1 diabetes.
The strong tendency of insulin to cause hypoglycemia complicates the addition of a second therapeutic agent. Liraglutide, a seemingly hypoglycemia-proof GLP-1RA whose action depends on the presence of glucose, exacerbates hypoglycemic events in patients with type 1 diabetes. The ideal use of combination therapy—the standard of care in type 2 diabetes—remains to be determined for type 1 diabetes.