#VisualAbstract: Semaglutide 2.4 mg once a week decreases bodyweight in overweight or obese patients with type 2 diabetes

1. Change in mean bodyweight was -9.6% with semaglutide 2.4 mg vs. -3.4% with placebo.

2. Approximately two-thirds of patients on semaglutide 2.4 mg achieved a target HbA_1c of 6.5% or less.

 Evidence Rating Level: 1 (Excellent)

Study Rundown: There is strong overlap between weight gain and type 2 diabetes, with the majority of diabetic patients being overweight or obese by BMI measures. GLP-1 receptor agonists, which are known to elicit weight reduction in patients, are recommended as the second-line therapy for type 2 diabetes. Among GLP-1 receptor agonists that are currently available, semaglutide 1.0 mg has previously shown the greatest effect for weight loss. This multicenter, randomized controlled trial aimed to evaluate the safety and efficacy of weekly subcutaneous injections of semaglutide 2.4 mg vs. semaglutide 1.0 mg (the recommended dose) and placebo for weight reduction in overweight or obese adults with type 2 diabetes. Primary endpoints for this study were change in bodyweight at week 68 and loss of bodyweight by 5% or more from baseline (semaglutide 2.4 mg vs. placebo). Secondary endpoints included the proportion of patients who achieved 10-15% reduction in weight and changes in metabolic syndrome parameters (waist circumference, HbA_1c, and blood pressure). According to study results, the primary endpoint of weight loss was significantly greater in the semaglutide 2.4 mg group compared to placebo and semaglutide 1.4 mg. In addition, more patients on semaglutide 2.4 mg achieved weight reductions of 5% or greater. This trial was strengthened by a double-blind, placebo-controlled design with patients from different countries. However, given the difficulty of long-term weight management, a longer follow-up may be warranted to evaluate the sustainability of this weight-loss intervention. Overall, this study provided valuable insight into the use of high dose semaglutide for weight reduction in diabetic patients.

Click to read the study in The Lancet

Relevant Reading: Once-Weekly Semaglutide in Adults with Overweight or Obesity

In-depth [randomized controlled trial]: Between June 4 and Nov 14, 2018, 1595 patients were assessed across 149 outpatient clinics in 12 countries. Included patients were those ≥ 18 years of age with a body-mass index (BMI) ≥ 27 kg/m², HbA_1c of 7-10%, and a diagnosis of type 2 diabetes at least 180 days before screening. Patients with self-reported changes in bodyweight ≥ 5 kg within 90 days before screening and previous obesity treatment were excluded. Altogether, 1210 patients (404 in semaglutide 2.4 mg, 403 in semaglutide 1.0 mg, and 403 in placebo) were enrolled in the intention-to-treat analysis.

Among enrolled patients, the mean bodyweight was 99.8 kg (standard deviation [SD] 21.5) and the mean BMI was 35.7 kg/m² (SD 6.3). The mean weight reduction from baseline to 68 weeks was significantly greater for semaglutide 2.4 mg (-9.6%, SD 0.4) than for semaglutide 1.0 mg (-7.0%, SD 0.4) and placebo (-3.4%, SD 0.4). The estimated treatment difference between semaglutide 2.4 mg and placebo was -6.2% (95% confidence interval [CI] -7.3 to -5.2, p<0.0001). Furthermore, the primary endpoint of ≥ 5% reduction in baseline bodyweight at week 68 was also greater in the high dose semaglutide group (267 of 388, 68.8%) compared to low dose semaglutide (217 of 380, 57.1%, OR 1.62, 95% CI 1.21-2.18, p=0.0012) or placebo (107 of 376, 28.5%, odds ratio [OR] 4.88, 95% CI 3.58-6.64, p<0.0001). Similarly, more patients achieved reductions of 10%, 15%, or 20% at week 68 with semaglutide 2.4 mg. In terms of secondary endpoints, significant benefits in waist circumference and systolic blood pressure were observed among patients receiving semaglutide 2.4 mg than placebo. A similar trend was seen for HbA_1c at week 68 across all three groups (-1.6% for semaglutide 2.4 mg, -1.5% for semaglutide 1.0 mg, and -0.4% for placebo). High dose semaglutide was associated with more frequent adverse events (87.6%) than semaglutide 1.0 (81.8%) and placebo (76.9%). Findings from this study showed that semaglutide 2.4 mg is superior to semaglutide 1.0 mg and placebo for weight reduction in overweight and obese patients with type 2 diabetes.

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