Comparative Effectiveness of Common Glucose-Lowering Medications Used with Metformin

A US multicenter, parallel-group, comparative-effectiveness clinical trial showed that when added to metformin, insulin glargine and glucagon-like peptide-1 receptor agonist liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels than sulfonylurea glimepiride or dipeptidyl peptidase 4 inhibitor sitagliptin in patients with type 2 diabetes (T2D). However, the incidences of microvascular complications and mortality were not materially different among the 4 treatment groups. The trial randomized 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) with T2D of less than 10 years and a glycated hemoglobin level of 6.8 to 8.5% (50.8 to 69.4 mmol per mole) to receive one of the 4 drugs in addition to metformin and followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% (53 mmol per mole) or higher (the primary metabolic outcome) differed significantly among the groups; the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. Among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin, but no material differences across prespecified subgroups.  Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other groups. There were no material differences among the groups in the development of hypertension or dyslipidemia or microvascular outcomes. However, the incidence of any cardiovascular disease in the liraglutide group was lower than glargine, glimepiride, and sitagliptin groups. The findings are of great clinical importance and highlight the difficulty in achieving and maintaining recommended glycated hemoglobin levels in T2D as a glycated hemoglobin level of less than 7.0% was not achieved and maintained in most participants. Metabolic goals are often individualized clinically. Source: https://www.nejm.org/