A randomized trial of dapagliflozin and metformin, alone and combined, in overweight women after gestational diabetes mellitus

Abstract

Women with a history of gestational diabetes mellitus are at a substantially increased risk of gestational diabetes mellitus recurrence and type 2 diabetes. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of pancreatic beta cell compensation for insulin resistance. Weight management after gestational diabetes mellitus could have a significant benefit in these women who are at a high risk of developing type 2 diabetes. This study aimed to evaluate the treatment efficacy of dapagliflozin and metformin, alone and in combination, on body weight and anthropometric, cardiovascular, and metabolic parameters in overweight women with a recent history of gestational diabetes mellitus. This was a prospective, single-blind, randomized, outpatient clinical trial with 3 parallel treatment groups. Overweight or obese (body mass index>25) females (n=66; ≥18-45 years) with gestational diabetes mellitus in pregnancy in the past 12 months were randomized in a single-blind manner to dapagliflozin, metformin, or dapagliflozin-metformin for 24 weeks. Body weight, height, body mass index, waist circumference, waist-to-height ratio, and blood pressure were determined at baseline and trial completion. Oral glucose tolerance tests were performed at baseline and 24 weeks to assess glycemia and mean blood glucose and calculate insulin sensitivity and secretion measures. Plasma lipid fractions, thyroid-stimulating hormone, and liver enzymes were also assessed in the fasting sample at the beginning and completion of the study trial. The study was completed by 49 participants (74%). Significant reduction of weight, waist circumference, and waist-to-height ratio and improved glycemia and insulin sensitivity index derived from oral glucose tolerance test were found with dapagliflozin-metformin vs metformin monotherapy. Both dapagliflozin and dapagliflozin-metformin therapy were superior to metformin in increasing high-density lipoprotein levels, reducing triglyceride concentrations, lowering the triglyceride-to-high-density lipoprotein cholesterol ratio, and improving glucose excursion after an oral glucose tolerance test. The early insulin response to a glucose challenge significantly improved with only dapagliflozin-metformin compared with single-drug treatments. This is the first report comparing the efficacy of a sodium-glucose cotransporter 2 inhibitor alone and in combination with metformin in this patient population. We found that combination dapagliflozin-metformin treatment over a 24-week period had a greater positive effect on body weight, waist circumference, and glycemic, cardiovascular, and metabolic parameters than metformin monotherapy in overweight or obese at-risk women with a recent history of gestational diabetes mellitus.