Liraglutide had best outcomes in trial of second-line therapies added to metformin

Adding liraglutide to metformin was associated with lower risk of reaching a composite outcome of glycemic deterioration, weight gain, and hypoglycemia compared with sitagliptin, glargine, or glimepiride, new study results show.

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) randomized 5,047 participants (36% women; median age at baseline, 58 years) to one of four second-line therapies added to metformin. All participants had had type 2 diabetes for less than 10 years. Average follow-up was five years. The composite primary outcome was defined as the first occurrence of confirmed HbA1c level above 7.5%, a weight gain of 5% or more, or severe or recurrent nonsevere hypoglycemia in the four groups. Evaluations were performed quarterly and medications were titrated based on glycemic response, tolerability, or kidney function. Findings were published by Diabetes Care on Jan. 9.

Overall, 71% of participants reached the composite outcome. Patients randomized to glimepiride had the highest risk of reaching the composite outcome, at 81.4% (40 events per 100 participants per treatment year [PTY]), followed by those treated with glargine (71.9%; 29 per 100 PTY), sitagliptin (69.6%; 26 per 100 PTY), and liraglutide (60.3%; 19 per 100 PTY). The order remained the same for the outcomes of weight gain and hypoglycemia, except that there was no significant difference in weight gain between glargine and glimepiride or in hypoglycemia between liraglutide and sitagliptin. The risk of glycemic deterioration was lowest in patients in the glargine group compared with the other three groups (27%, 17%, and 39% lower vs. glimepiride, liraglutide, and sitagliptin, respectively). Additional analyses showed that patients who reached the composite outcome reported lower treatment satisfaction. Differences in risk of weight gain between medications also disappeared among patients who received rescue insulin (n=1,577).

Because the trial included free medication and care, including counseling on weight management and hypoglycemia, findings may be different in the real world, the study authors cautioned. The trial was also designed and implemented before sodium-glucose cotransporter-2 inhibitors and weekly glucagon-like peptide-1 receptor agonists came to market.

"Our results add evidence to support consensus guidelines that advise thinking beyond just glycemic control in considering second- and third-line therapy for patients with type 2 diabetes," the researchers concluded.