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.

Trial registration: ClinicalTrials.gov NCT03548935 NCT03611582 NCT03548987.

Figure 1

Glycemic status—changes in proportions of participants from week 0 to week 68 in participants with prediabetes at week 0 in STEP 1 (A), STEP 3 (B), and STEP 4 (C). Data are observed data during the in-trial period (regardless of treatment discontinuation or rescue intervention). Glycemic category was evaluated by the investigator based on all available relevant information (e.g., concomitant medication, medical records, and blood glucose parameters) in accordance with ADA definitions.

Figure 2

Glycemic status—proportion of participants with prediabetes at week 0 and normoglycemia at week 68 by weight-loss categories in STEP 1 (A), STEP 3 (B), and STEP 4 (C). Data are observed data during the in-trial period (regardless of treatment discontinuation or rescue intervention). Glycemic category was evaluated by the investigator based on all available relevant information (e.g., concomitant medication, medical records, and blood glucose parameters) in accordance with ADA definitions.

Figure 3

Effects on glucose metabolism (HbA_1c, FPG, HOMA-IR) and body weight in participants with prediabetes at week 0 (all studies). HbA_1c % to mmol/mol conversion formula: 10.929 ∗ (HbA_1c value in % –2.15) = HbA_1c mmol/mol; FPG mg/dL to mmol/L conversion formula: FPG value in mg/dL ∗ 0.0555 = FPG mmol/L. ETR, estimated treatment ratio (semaglutide 2.4 mg vs. placebo).