Dapagliflozin plus calorie restriction boosts remission rates in adults with type 2 diabetes and obesity

By Dr. Priyom Bose, Ph.D.Reviewed by Danielle Ellis, B.Sc.Jan 24 2025

A multicentre trial in China finds that combining SGLT-2 inhibitors with calorie restriction improves remission, weight loss, and metabolic health without added adverse effects

A recent BMJ study conducted a randomized trial to evaluate whether a combined therapy of dapagliflozin and calorie restriction had better effectiveness over only calorie restriction on the remission of T2D.

T2D prevalence and treatments

Approximately 422 million adults worldwide develop T2D. However, this condition can be reversed through weight management and dietary intervention.  The DiRECT trial findings indicated that intensive dietary intervention reduced 10% body weight in 46% of the diabetic participants.

Furthermore, these individuals underwent diabetes remission, which is defined as glycated hemoglobin (HbA1c) <6.5% after antidiabetic treatment. It must be noted that long-term adherence to a very low-energy diet could be challenging.

Although bariatric surgery exhibited a high efficacy in weight loss and diabetes remission, this approach is not widely accepted owing to its high cost and short- and long-term risks of adverse effects.

SGLT-2 inhibitors are oral drugs that restrict renal glucose re-absorption and elevate urinary glucose excretion, effectively reducing blood glucose levels (hyperglycemia) and energy deficit.

Dapagliflozin, an SGLT-2 inhibitor, entails a caloric loss of 280-320 kcal per day, along with urinary glucose excretion of approximately 70-80 g. This treatment caused a mean weight loss of 2-3 kg in patients with T2D. It must be noted that these T2D patients can regain weight due to metabolic adaption of compensatory hyperphagia, which could be overcome by calorie restriction.

About the study

The current study hypothesized that a combination of dapagliflozin calorie restriction would lead to a greater energy deficit and a higher decrease in blood glucose level compared to calorie restriction alone. To test this hypothesis, a double-blind, randomized, multicentre, placebo-controlled clinical trial was conducted in 16 centers in China.

Participants diagnosed with T2D within the last six years, between 20 and 70 years of age, and who had a body mass index (BMI) higher than 25 were recruited. At baseline, participants without undertaking any antidiabetic agents had HbA1c between 6.5% and 10%, and those taking metformin exhibited HbA1c less than 10%.

Individuals with serious cerebrovascular or cardiovascular diseases who underwent a weight loss of more than 5 kg within six months or used weight-reducing drugs within 30 days were excluded from the study cohort. Furthermore, participants with a history of bariatric surgery or other gastrointestinal surgeries within two years and diagnosed with cancer, liver dysfunction, or chronic kidney disease were excluded.

All eligible participants were randomly assigned into two groups, namely, placebo and treated. Depending on the group, participants either received 10 mg of dapagliflozin or placebo per day for 12 months. All participants were instructed to follow a calorie restriction diet with an energy deficit of 500~750 kcal per day. They were provided with protein shakes twice a day for the first three months to improve the targeted energy intake.

Participants were also instructed to increase their physical activity levels and maintain the intensity, for example, 150 minutes of brisk walking every week or more than 10,000 steps per day. After a minimum of four months of treatment, they were asked to stop taking dapagliflozin or placebo if the normal glycaemic index of HbA1c <6.5% and fasting plasma glucose <126 mg/dL was maintained for two months.

Study findings

A total of 328 participants met all eligibility criteria; their mean age was 46.7 years, and their mean HbA1c was 7.3%. Approximately 66% of the cohort were male, the mean BMI of the study cohort was 28.2, and 45% of participants were treated with metformin at baseline.

Among the selected participants, 165 individuals were randomly assigned to the treatment group and 163 participants in the placebo group. The median duration of the intervention in the dapagliflozin group was nine months, and the placebo group lasted for 12 months.

Approximately 44% and 28% of participants in the treatment and placebo groups, respectively, achieved diabetes remission. The analyses of long-term diabetes remission indicated a risk ratio for three and four months of diabetes remission of 1.64 and 1.74, respectively.

Participants belonging to the dapagliflozin group noted greater weight loss from the baseline than placebo group members. Furthermore, a significant improvement in metabolic risk factors was observed in the dapagliflozin group compared to the control group, including fasting plasma glucose, systolic blood pressure, BMI, HbA1c, HOMA-IR, triglycerides, and high-density lipoprotein cholesterol.

Both the study groups exhibited an improvement in diastolic blood pressure, waist circumference, HOMA-β, lean mass, total cholesterol, and low-density lipoprotein cholesterol.

Participants in the dapagliflozin group exhibited higher adherence to intervention than the placebo group. However, both groups exhibited similar compliance rates to the daily energy intake target, diet, and physical activity.

According to the safety profile, both study groups recorded a similar rate of mild/moderate adverse events. However, two participants of the dapagliflozin group required hospital admission for urinary tract infections.  

Conclusions

The current study highlighted that a greater likelihood of diabetes remission was associated with combined therapy of dapagliflozin and calorie restriction compared to a placebo. This combined treatment resulted in more efficient weight reduction and improvement in metabolic risk factors among individuals with T2D. This strategy ensures a long-lasting effect than intervention associated with a restricted diet alone.