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

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

A multicenter study in China found that combining SGLT-2 inhibitors with calorie restriction improved remission, weight loss, and metabolic health without additional adverse effects

A current oneBMJThe study conducted a randomized trial to evaluate whether combined therapy of dapagliflozin and calorie restriction had better efficacy than calorie restriction alone in 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 nutritional intervention. Direct trial results showed that an intensive nutritional intervention reduced body weight by 10% in 46% of diabetic participants.

Furthermore, these individuals underwent diabetes remission, defined as glycated hemoglobin (Hba1c) <6.5% after antidiabetic treatment. It is important to note that long-term adherence to a high energy diet could be challenging.

Although bariatric surgery demonstrated high effectiveness in weight loss and diabetes remission, this approach is not widely used due to its high cost and short- and long-term risks of adverse effects.

SGLT-2 inhibitors are oral drugs that limit renal glucose reabsorption and increase urinary glucose ion, effectively reducing blood glucose levels (hyperglycemia) and energy deficit.

Dapagliflozin, an SGLT-2 inhibitor, involves a caloric loss of 280-320 kcal per day and a urinary glucose release of approximately 70-80 g. This treatment caused a mean weight loss of 2-3 kg in patients with T2D. It is important to note that these T2D patients may regain weight due to the metabolic adaptation of compensatory hyperphagia, which can be overcome by calorie restriction.

About the study

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

Participants diagnosed with T2D between the ages of 20 and 70 in the past six years and who had a body mass index (BMI) over 25 were recruited. At baseline, participants without antidiabetic agents had HbA1c between 6.5% and 10%, and those taking metformin showed HbA1c of less than 10%.

Individuals with major cerebrovascular or cardiovascular disease who underwent weight loss of more than 5 kg within six months or used weight loss medications within 30 days were excluded from the study cohort. In addition, participants who had a history of bariatric surgery or other gastrointestinal surgery, history of cancer, liver dysfunction, or chronic kidney disease within two years were included.

All eligible participants were randomly assigned into two groups, namely placebo and treated. Depending on the group, participants 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. For the first three months, they were given protein shakes twice daily to improve targeted energy intake.

Participants were also instructed to increase their physical activity and maintain the intensity, for example, for 150 minutes per week or more than 10,000 steps per day. After at least four months of treatment, they were asked to stop taking dapagliflozin or placebo if the normal glycemic index of Hba1c <6.5% and fasting plasma glucose <126 mg/dl was maintained for two months.

Study results

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 people were randomly assigned to the treatment group and 163 participants to the placebo group. The median duration of intervention in the dapagliflozin group was nine months and the placebo group lasted 12 months.

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

Participants in the dapagliflozin group experienced greater weight loss from baseline than placebo group members. In addition, 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 study groups showed improvement in diastolic blood pressure, waist circumference, HOMA-β, lean mass, total cholesterol and low-density lipoprotein cholesterol.

Participants in the dapagliflozin group demonstrated higher adherence to the intervention than the placebo group. However, both groups showed similar compliance rates such as daily energy intake goal, diet and physical activity.

According to the safety profile, both study groups recorded a similar rate of mild/moderate adverse events. However, two participants in the dapagliflozin group required hospitalization 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 placebo. This combined treatment resulted in efficient weight reduction and improvement in metabolic risk factors in individuals with T2D. This strategy provides a more long-lasting effect than an intervention in the context of a restricted diet.

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