Addition of insulin glargine or liraglutide to metformin results in modest but significant decreases in glycated hemoglobin levels in patients with type 2 diabetes, reports the GRADE Study Research Group. Sitagliptin and glimepiride lowered A1c levels by smaller amounts.
The trial included 5,047 participants with type 2 diabetes of less than 10 years’ duration who had been on metformin therapy for a mean of 5 years. The cumulative incidence of A1c levels of 7.0% or higher were 26.5, 26.1, 30.4, and 38.1 per 100 participant-years for insulin glargine, liraglutide, glimepiride, and sitagliptin, respectively. Results were similar for incidence of A1c levels of 7.5% or higher. “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%),” the authors write. “Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.”
Editorial: “[A] shortcoming of the trial is the lack of information on plasma glucose levels in the participants, especially in the fasting state,” editorialists write while commenting on this and a companion report from the GRADE group. “The inclusion of participants with a glycated hemoglobin level of 6.8 to 8.5% at enrollment, which resulted in a mean glycated hemoglobin level of 7.5% at trial entry, meant that many of the participants probably had undisclosed fasting hyperglycemia, as inferred from the results of other studies that used continuous glucose monitoring. Thus, insulin glargine and the GLP-1 receptor agonist may have been more effective in the trial participants than they would be in patients with diabetes who do not have fasting hyperglycemia. Predominantly postprandial hyperglycemia apparently is limited to a glycated hemoglobin level below 7.0%. Thus, the glycemic outcomes are not surprising — all four tested options would appear to be reasonable additions to metformin in persons with type 2 diabetes who are at low cardiovascular risk, provided the glycemic phenotype is appropriately assessed. The high percentage of trial participants (approximately 50%) in whom the secondary metabolic target (a glycated hemoglobin level >7.5%) was met over the 5 years of follow-up is disturbing. This finding mirrors the unhalted, progressive nature of type 2 diabetes, which warrants regular glycometabolic assessment and adjustment of glucose-lowering therapy in these patients.”