RCT: Dapagliflozin Plus Calorie Restriction Achieves Higher Remission Rate of Type 2 Diabetes
30 Jan, 2025 | 10:10h | UTCBackground: Type 2 diabetes (T2DM) is often regarded as a chronic, progressive disease. Nonetheless, trials such as DiRECT have challenged this view by demonstrating that remission may be achieved through substantial weight loss. SGLT2 inhibitors—among them dapagliflozin—induce urinary glucose excretion and moderate weight reduction, yet their ability to promote sustained remission of early T2DM is not fully understood. Recent editorials highlight the promise of combining pharmacological therapies with dietary interventions while stressing the need to address cost, sustainability, and patient selection for best outcomes.
Objective: This study aimed to determine whether adding dapagliflozin (10 mg/day) to a moderate calorie restriction diet (energy deficit of 500–750 kcal/day) could increase T2DM remission rates in overweight or obese adults with a notably short median diabetes duration of 0.2–0.3 years, relative to calorie restriction alone.
Methods: Researchers conducted a multicenter, double-blind, placebo-controlled, randomized trial at 16 centers in China, recruiting 328 adults (20–70 years old, body mass index >25) with early T2DM (duration <6 years). Patients who were currently using any antidiabetic medications other than metformin were excluded. Participants were allocated to receive dapagliflozin 10 mg/day or placebo for 12 months. Both groups received dietary counseling and were instructed to maintain a calorie deficit of 500–750 kcal/day. When individuals achieved normoglycemia (fasting plasma glucose <110 mg/dL and HbA1c <6.5%) for two consecutive months, all antidiabetic medications—including dapagliflozin—were discontinued. The primary outcome was diabetes remission (HbA1c <6.5% and fasting plasma glucose <126 mg/dL for ≥2 months off medications). Secondary endpoints included changes in weight, body composition, blood pressure, insulin resistance (HOMA-IR), and lipid profiles.
Results: Over 12 months, 44% of participants in the dapagliflozin-plus-diet arm achieved remission, compared with 28% in the diet-alone arm (risk ratio 1.56, 95% CI 1.17 to 2.09; P=0.002). Mean weight loss was −5.0 kg in the dapagliflozin group versus −3.2 kg in placebo, with additional improvements in body fat, systolic blood pressure, HDL cholesterol, and triglycerides. Mild and moderate adverse events occurred at similar rates in both groups, and two patients in the dapagliflozin arm experienced serious urinary tract infections requiring hospitalization. No deaths occurred during the trial.
Conclusions: Dapagliflozin combined with moderate calorie restriction resulted in a significantly higher remission rate of early T2DM (median duration 0.2–0.3 years) compared with calorie restriction alone. This combined intervention also led to greater reductions in body weight and improvements in cardiometabolic risk factors, with an acceptable safety profile over 12 months.
Implications for Practice: For clinicians managing adults with relatively short-duration T2DM, the addition of dapagliflozin to a structured dietary program may offer a promising route toward remission. Nevertheless, cost considerations—particularly for long-term SGLT2 inhibitor therapy—require thoughtful assessment in routine practice. While the required weight loss was more modest than in some very-low-calorie interventions, maintaining remission may still depend on ongoing lifestyle modification. Providers should also evaluate patient eligibility carefully, noting that the greatest benefits may be realized in those with early-stage disease and minimal comorbidity.
Study Strengths and Limitations: Strengths include a randomized, placebo-controlled design across multiple centers, a feasible dietary regimen, and robust participant adherence. Limitations include a relatively short follow-up after drug discontinuation, potentially overestimating durable remission, and use of a two-month remission definition that may not reflect sustained outcomes. Furthermore, the study population had very early-stage diabetes (median duration 0.2–0.3 years), limiting applicability to patients with longer-standing disease or different ethnic backgrounds.
Future Research: Longer-term trials are needed to assess whether extending the period of drug or lifestyle support can sustain remission and to identify subgroups most likely to benefit. Additional research should also evaluate how discontinuing SGLT2 inhibitors might impact cardiovascular and renal outcomes over time. Comparisons with newer agents that produce greater weight loss (e.g., GLP-1 receptor agonists) could further clarify optimal approaches.
Reference:
- Liu Y, Chen Y, Ma J, et al. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial. The BMJ 2025; 388:e081820. DOI: https://doi.org/10.1136/bmj-2024-081820
- Hope D, Valabhji J. SGLT2 inhibitors and dietary calorie restriction for type 2 diabetes remission (Editorial). The BMJ 2025; 388:r40. DOI: https://doi.org/10.1136/bmj.r40