medwireNews: People with prediabetes and obesity are more likely to reduce their bodyweight and return to normoglycemia if treated with semaglutide than with placebo, the STEP 10 investigators report.
“The safety and tolerability profile of semaglutide 2.4 mg was consistent with previous studies and with the GLP-1 receptor agonist class,” say Barbara McGowan (Guy’s and St Thomas’ NHS Foundation Trust, London, UK) and co-workers in The Lancet Diabetes & Endocrinology.
They write: “These findings support the potential use of semaglutide 2.4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia.
The phase 3 randomized trial was conducted in Cananda, Denmark, Finland, Spain, and the UK in adults with a BMI of at least 30 kg/m2 and prediabetes, defined as a glycated hemoglobin (HbA1c) of 6.0–6.4% (42–47 mmol/mol), a fasting plasma glucose (FPG) of 5.5–6.9 mmol/L, or both.
A total of 71% of the 207 participants were women, 88% were White, and the average age at baseline was 53 years. The patients had an average weight of 111.6 kg, a BMI of 40.1 kg/m2, an average HbA1c of 5.9% (41.3 mmol/mol), and an FPG of 5.9 mmol/L.
Overall, 138 participants were randomly assigned to receive semaglutide 2.4 mg/week for 52 weeks alongside nine diet and physical activity counseling sessions, while 69 were instead given placebo with their counselling.
The co-primary endpoint of percentage change in bodyweight at week 52 was significantly better in the semaglutide-treated participants than controls, at an average decrease of 13.9% versus 2.7%. And semaglutide use was associated with significantly higher rates than placebo of patients achieving at least a 5%, 10%, and 20% loss of bodyweight (odds ratio [OR]=15.9, 32.7, and 39.6, respectively).
However, at week 80, 28 weeks after completion of treatment, the average decreases in bodyweight from baseline with semaglutide and placebo were 7.9% and 1.3%, respectively, and there was a “partial bodyweight regain from week 52 to week 80,” the researchers say.
These findings prompted Michael Bergman (VA New York Harbor Healthcare System, USA) to write in an accompanying comment: “[T]he considerable loss of benefit after stopping semaglutide 2.4 mg is not surprising and strongly suggests that prolonged therapy will be required.
“This raises questions about the long-term safety and cost-effectiveness of possibly lifelong treatment and the need for direct comparative data with bariatric surgery.”
The second co-primary endpoint of the proportion of participants who reverted to normoglycemia (HbA1c <6.0% [<42 mmol/mol] and FPG <5.5 mmol/L) at week 52 was also significantly higher with semaglutide than placebo (81 vs 14%, OR=19.8).
Of the participants who had reverted to normoglycemia at week 52 and had available data at week 80, 45% of 97 semaglutide-treated participants had regressed to prediabetes, as had 57% of nine controls.
Type 2 diabetes was diagnosed at week 52 in one (1%) person given semaglutide, who did not achieve a 5% decrease in bodyweight, and two (3%) of those given placebo. At week 80, the rates of type 2 diabetes had increased to 3% and 8%, respectively.
Serious adverse events (SAEs) occurred in 9% of the semaglutide arm and 9% of the placebo arm but only the former group experienced serious gastrointestinal side effects such as diarrhea, nausea, and vomiting (2 vs 0%). SAEs of special interest in the semaglutide-treated patients included neoplasms (3%), acute pancreatitis (1%), malignancy (1%), and acute gallbladder disease (1%). The malignancies were not considered to be related to semaglutide therapy.
“Results of STEP 10 add to existing evidence on the benefits of obesity management with pharmacotherapy on the progression of prediabetes, a condition that as of yet has few treatment options,” McGowan et al summarize.
Bergman notes that “as many patients with prediabetes will inevitably progress to type 2 diabetes given the substantial decline in β-cell function already present at the time of diagnosis, earlier identification of people at high risk is required.”
He concludes: “Fundamentally, more effort is required to mitigate progression to prediabetes, as presently defined, which might reduce the need for medication and enormous socioeconomic burdens.”
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Lancet Diabetes Endocrinol 2024; doi:10.1016/S2213-8587(24)00182-7
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