Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program

Abstract

OBJECTIVE This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks’ treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes. RESEARCH DESIGN AND METHODS STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0–68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc). RESULTS Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01). CONCLUSIONS STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks’ treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia.

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial

“…The reduction in fasting insulin and glucose with semaglutide is indicative of an increase in insulin sensitivity. Similar to the findings of other studies in the STEP trial program 7 , 27 , exploratory outcomes showed that in the semaglutide group 80% of participants with prediabetes at baseline reverted to normoglycemia by the end of the trial (compared with 37% of those receiving placebo), while 99% of participants with normoglycemia at baseline maintained normoglycemia at the end of the trial (compared with 86% with placebo). These findings suggest a potential beneficial effect of semaglutide on glycemic status, but whether semaglutide treatment delays or prevents progression to type 2 diabetes requires confirmation.…”

The National Clinical Care Commission Report to Congress: Leveraging Federal Policies and Programs to Prevent Diabetes in People With Prediabetes

“…Although other pharmacologic treatments have been shown to be effective for type 2 diabetes prevention, including weight loss medications (orlistat and phentermine-topiramate), thiazolidinediones, α-glucosidase inhibitors, and even insulin glargine, the NCCC did not recommend them for diabetes prevention. A more recent study has also highlighted the potential role of glucagon-like peptide 1-receptor agonists for type 2 diabetes prevention ( 74 ). Because every kilogram of weight lost is associated with an additional 7% decrease in risk of progression to diabetes ( 14 ), newer treatments, including once-weekly glucagon-like peptide 1-receptor agonists and new dual receptor agonists such as tirzepatide, have great potential to reduce weight and prevent type 2 diabetes if rigorously demonstrated to be safe and effective for this indication.…”

Real world effectiveness of subcutaneous semaglutide in type 2 diabetes: A retrospective, cohort study (Sema-MiDiab01)

“…HOMA-IR might also help to anticipate patient's response to incretin-based therapies. There is limited current evidence to establish whether HOMA-IR amelioration with GLP-1 is an independent outcome or a secondary result from weight loss and body recomposition (50,51). It is known that T2D is a chronic degenerative disease characterized by high risk of complications and an increasing social, economic and health burden worldwide (52,53); on the other hand, GLP-1 therapy is recognized as one of the key strategies to overcome clinical inertia in cardiorenal protection of T2DM patients (53,54).…”

“…HOMA-IR might also help to anticipate patient’s response to incretin-based therapies. There is limited current evidence to establish whether HOMA-IR amelioration with GLP-1 is an independent outcome or a secondary result from weight loss and body recomposition ( 50 , 51 ).…”