The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial

Abstract

Aims/hypothesis We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA 1c . Methods The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m 2 , 30-70 years of age, and prediabetes (HbA 1c 39-47 mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). Results One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). Conclusions/interpretation Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain.

No effects of dapagliflozin, metformin or exercise on plasma glucagon concentrations in individuals with prediabetes: A post hoc analysis from the randomized controlled PRE‐D trial

“…As previously reported, 29 all three active interventions resulted in small reductions in HbA1c after 13 weeks of 1.1‐1.3 mmol/mol in the intervention groups compared with the control group. Furthermore, dapagliflozin reduced fasting serum insulin and postload insulin concentrations by 20%‐24%.…”

“…Of these, 28 in the dapagliflozin, 29 in the metformin, 27 in the exercise, and 28 in the control group completed the intervention and participated in the 13‐week visit. Twenty‐seven in the exercise group, 27 in the control group, 28 in the dapagliflozin group, and 29 in the metformin group participated in the follow‐up visit after 26 weeks 29 . Twenty‐six participants in the dapagliflozin and 25 in the metformin group took 80% or more of the administered medication.…”

“…Twenty‐six participants in the dapagliflozin and 25 in the metformin group took 80% or more of the administered medication. By comparison, 24 of the participants in the exercise group performed 80% or more of the prescribed exercise (both volume and intensity) 29 …”

“…The trial was registered with http://clinicaltrials.gov (NCT02695810). The primary outcome was the change in glycaemic variability (mean amplitude of glycaemic excursions) during continuous glucose monitoring; the sample size was calculated for the primary outcome 29 . The protocol, safety parameters and primary outcome of the PRE‐D trial have been described in detail elsewhere 28,29 …”

“…We performed a randomized controlled trial comparing the short‐term efficacy of three glucose‐lowering interventions (dapagliflozin [an SGLT‐2 inhibitor], metformin and exercise) in combination with dietary advice on glycaemic variability, HbA1c, body composition and cardiometabolic risk in overweight or obese individuals with prediabetes defined by HbA1c 28 . The main results from the study have been published elsewhere 29 . The current study examines whether the three interventions are associated with changes in fasting glucagon concentration and glucagon response to an oral glucose tolerance test (OGTT) in overweight individuals with prediabetes assessed by HbA1c.…”