High-dose semaglutide improves glucose metabolism outcomes in overweight/obese patients with T2D

Treatment with a higher dose of semaglutide led to significantly improved glucose metabolism outcomes in patients with overweight/obesity and type 2 diabetes (T2D) compared with a lower dose of semaglutide or placebo, according to the STEP* 2 trial presented at EASD 2021.

“We know that over 90 percent of people with T2D have overweight/obesity, … [and] a higher dose of subcutaneous semaglutide 2.4 mg has been investigated in the global phase III STEP programme, and is now FDA-approved for weight management in people with overweight/obesity,” said study author Dr Sue Pedersen from C-ENDO Diabetes & Endocrinology Clinic Calgary, Calgary, Canada.

This phase III trial involved 1,210 patients (mean age 55.0 years, 50.9 percent female) with overweight/obesity (mean body weight 99.8 kg and mean BMI of 35.7 kg/m²) and T2D (mean HbA_1c 8.1 percent) who were on oral antihyperglycaemic drugs (OADs)** for ≥90 days before screening. Participants were randomized to receive subcutaneous semaglutide 2.4 mg (n=404) or 1.0 mg (n=403) or placebo (n=403) once weekly. Detailed glucose metabolism parameters were assessed, particularly HbA_1c, FPG***, FSI⁺, and HOMA-IR⁺⁺ and HOMA-β⁺⁺⁺. [EASD 2021, abstract 19]

At week 68, patients who received semaglutide 2.4 mg had a greater reduction in mean body weight from baseline compared with semaglutide 1.0 mg or placebo (9.6 percent vs 7.0 percent and 3.4 percent, respectively).

In addition, those on semaglutide 2.4 mg also achieved a greater reduction in HbA_1c than those on semaglutide 1.0 mg or placebo from baseline to week 68 (1.6 percent vs 1.5 percent and 0.4 percent, respectively).

In this post hoc analysis, a higher percentage of patients treated with semaglutide 2.4 mg achieved HbA_1c of ≤6.5 percent (67.5 percent vs 60.1 percent and 15.5 percent) and <7.0 percent (78.5 percent vs 72.3 percent and 26.5 percent) compared with semaglutide 1.0 mg or placebo.

Among those on metformin only or not on any OADs at baseline, significantly more patients achieved HbA_1c of ≤6.5 percent (77.0 percent vs 60.4 percent; p<0.001 and 18.8 percent; p<0.0001) and <7.0 percent (85.2 percent vs 73.0 percent; p<0.01 and 32.2 percent; p<0.0001) in the semaglutide 2.4 mg group vs the semaglutide 1.0 mg or placebo groups at week 68, “perhaps reflecting even better glycaemic lowering efficacy in this group at an earlier stage of T2D,” Pedersen noted.

With regard to achievement of HbA_1c and weight loss composite endpoints, almost half of the participants on semaglutide 2.4 mg achieved HbA_1c of <7.0 percent with weight loss of ≥10 percent (44.6 percent) or ≥15 percent (25.7 percent).

In addition, both semaglutide groups demonstrated no change or decrease in OAD use, though it was more evident in the 2.4 mg group, whereas those in the placebo group had an increase of 11.0 percent.

Improvements in FPG, FSI, HOMA-IR, and HOMA-β were observed in the semaglutide 2.4 mg group at week 68 (mean change from baseline, -2.1 mmol/L, -12.0 mmol/L, -33.0 percent, and 73.0 percent, respectively). “[Overall,] treatment with semaglutide resulted in improvements in insulin resistance and β-cell function, [the] two key mechanistic drivers of T2D and diabetes progression,” noted Pedersen.

“In conclusion, with semaglutide 2.4 mg weekly, more patients achieved the composite endpoints of HbA1c <7.0 percent with weight loss ≥10 percent or ≥15 percent [at week 68] vs semaglutide 1.0 mg or placebo, that was more pronounced in patients who were not on other oral diabetes medications, or on metformin only, at baseline,” said Pedersen, who also added that “more patients reduced OAD use during treatment with semaglutide 2.4 mg.”

“The safety of semaglutide was consistent with the GLP-1RA class in general and with that reported in the once-weekly subcutaneous semaglutide T2D trials,” she highlighted. 

*STEP: Semaglutide Treatment Effect in People with obesity

**OADs: Metformin, sulphonylurea, SGLT2i, or TZD

***FPG: Fasting plasma glucose

⁺FSI: Fasting serum insulin

⁺⁺HOMA-IR: Homeostasis Model Assessment of insulin resistance

⁺⁺⁺HOMA-β: Homeostasis Model Assessment of B-cell function