1. Compared to sitagliptin and glimepiride, glargine and liraglutide were more effective in achieving target glycated hemoglobin levels in patients with type 2 diabetes.

2. All four medications, when used adjunctive to metformin, significantly decreased glycated hemoglobin levels.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Type 2 diabetes affects more than 30 million adults in the United States and more than 500 million adults worldwide. Most recommendations for the management of glycemia in persons with type 2 diabetes include metformin as the first-line medication to be used, with a second medication added when needed to achieve the glycated hemoglobin level of less than 7%. However, there is a gap in knowledge as to the comparison between the various choices for adjunctive glucose-lowering medications. These include insulin, sulfonylureas, glucagon-like peptide-1 agonists, and dipeptidyl-peptidase 4 inhibitors. Overall, this study found that all four medications (glargine, glimepiride, liraglutide, and sitagliptin) improved glycated hemoglobin levels when added to metformin, though glargine and liraglutide were more effective in achieving and maintaining target glycated hemoglobin levels. This study was limited by factors such as the exclusion of thiazolidinediones and sodium-glucose cotransporter-2 inhibitors, the trial being unblinded, and medication adjustments being made faster than adjustments would typically be made in the clinical setting. Nevertheless, these study’s findings are significant, as they demonstrate that glargine, glimepiride, liraglutide, and sitagliptin all improve glycated hemoglobin levels when added to metformin, though glargine and liraglutide provide the most significant benefit.

Click to read the study in NEJM

Relevant Reading: Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes

In-Depth [randomized controlled trial]: This multicenter, parallel-group, comparative-effectiveness clinical trial was conducted across 36 clinical centers. Patients who had type 2 diabetes that had been diagnosed at or after the age of 30 years, and had known diabetes for less than 10 years were eligible for the study. Patients who had a glycated hemoglobin level of over 8.5% or under 6.8% were excluded from the study. The primary outcome measured was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed. The secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%. Outcomes in the primary analysis were assessed via the intention-to-treat principle and Kaplan-Meier plots and Cox proportional-hazards models to assess differences among the treatment groups. Based on the primary analysis, the cumulative incidence of a glycated hemoglobin level of 7.0% or higher differed significantly among the four groups (p<0.001 among all four groups). The rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1 per 100 participant-years) were similar and lower than those with glimepiride (30.4 per 100 participant-years) and sitagliptin (38.1 per 100 participant-years). Among participants with higher baseline glycated hemoglobin levels, there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Overall, this study demonstrates that all four medications, when added to metformin, significantly decreased glycated hemoglobin levels. Though glargine and liraglutide were significantly more effective in achieving and maintaining target glycated hemoglobin levels.

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