Effect of semaglutide 2.4 mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1-4 trials.

AIMS: To summarize the effects of semaglutide 2.4 mg on weight-related quality of life (WRQOL) and health-related quality of life (HRQOL), focusing on the confirmatory secondary endpoint of physical functioning. MATERIALS AND METHODS: The STEP 1-4 Phase 3a, 68-week, double-blind, randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with overweight/obesity. WRQOL and HRQOL were assessed by change from baseline to Week 68 in two different but complementary measures, the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT; STEP 1 and 2) and the SF-36v2 Health Survey Acute (SF-36v2; STEP 1-4). RESULTS: Superiority for semaglutide 2.4 mg over placebo based on IWQOL-Lite-CT and SF-36v2 physical functioning scores was confirmed in STEP 1 and 2 and in STEP 1, 2 and 4, respectively. At Week 68, a greater proportion of participants treated with semaglutide 2.4 mg than with placebo reached meaningful within-person change (MWPC) thresholds for IWQOL-Lite-CT Physical Function scores in STEP 1 (51.8% vs. 28.3%; p < 0.0001) and STEP 2 (39.6% vs. 29.5%; p = 0.0083) and the MWPC threshold for SF-36v2 Physical Functioning in STEP 1 (39.8% vs. 24.1%; p < 0.0001), STEP 2 (41.0% vs. 27.3%; p = 0.0001) and STEP 4 (18.0% vs. 6.6%; p < 0.0001). All other IWQOL-Lite-CT and SF-36v2 scale scores in STEP 1-4 were numerically improved with semaglutide 2.4 mg versus placebo, except for SF-36v2 Role Emotional in STEP 2. CONCLUSIONS: Semaglutide 2.4 mg significantly improved physical functioning, with greater proportions of participants achieving MWPC compared with placebo, and showed beneficial effects on WRQOL and HRQOL beyond physical functioning.

Impact of BMI and comorbidities on efficacy of once-weekly semaglutide: Post hoc analyses of the STEP 1 randomized trial.

OBJECTIVE: This study assessed the effects of semaglutide on body weight, cardiometabolic risk factors, and glycemic status in individuals categorized by baseline BMI with or without additional obesity-related comorbidities, including prediabetes and high risk of cardiovascular disease (CVD). METHODS: This was a post hoc exploratory subgroup analysis of the Semaglutide Treatment Effect in People with Obesity (STEP) 1 trial (NCT03548935), in which participants without diabetes and BMI ≥30 kg/m2 , or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity, were randomized to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks. For this analysis, individuals were categorized into subgroups based on baseline BMI <35 versus ≥35 kg/m2 (with no additional criteria, with ≥1 comorbidity, with prediabetes, and with prediabetes and high risk of CVD). RESULTS: Mean changes in body weight from baseline to week 68 with semaglutide were -16.2% and -14.0% in the subgroups with baseline BMI <35 and ≥35 kg/m2 , respectively (both p < 0.0001 vs. placebo). Similar changes were observed in individuals with comorbidities, with prediabetes, and with prediabetes plus high CVD risk. The beneficial effects of semaglutide on cardiometabolic risk factors were consistent across all subgroups. CONCLUSIONS: This subgroup analysis confirms that semaglutide is effective in individuals with baseline BMI <35 and ≥35 kg/m2 , including in those with comorbidities.

Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials.

OBJECTIVE: These post hoc analyses of the Semaglutide Treatment Effect in People with obesity (STEP) 1-3 trials (NCT03548935, NCT03552757, and NCT03611582) explored the effects of semaglutide (up to 2.4 mg) on kidney function. RESEARCH DESIGN AND METHODS: STEP 1-3 included adults with overweight/obesity; STEP 2 patients also had type 2 diabetes. Participants received once-weekly subcutaneous semaglutide 1.0 mg (STEP 2 only), 2.4 mg, or placebo for 68 weeks, plus lifestyle intervention (STEP 1 and 2) or intensive behavioral therapy (STEP 3). Changes in urine albumin-to-creatinine ratio (UACR) and UACR status from baseline to week 68 were assessed for STEP 2. Changes in estimated glomerular filtration rate (eGFR) were assessed from pooled STEP 1-3 data. RESULTS: In STEP 2, 1,205 (99.6% total cohort) patients had UACR data; geometric mean baseline UACR was 13.7, 12.5, and 13.2 mg/g with semaglutide 1.0 mg, 2.4 mg, and placebo, respectively. At week 68, UACR changes were -14.8% and -20.6% with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (between-group differences [95% CI] vs. placebo: -28.0% [-37.3, -17.3], P < 0.0001 for semaglutide 1.0 mg; -32.9% [-41.6, -23.0], P = 0.003 for semaglutide 2.4 mg). UACR status improved in greater proportions of patients with semaglutide 1.0 mg and 2.4 mg versus placebo (P = 0.0004 and P = 0.0014, respectively). In the pooled STEP 1-3 analyses, 3,379 participants had eGFR data; there was no difference between semaglutide 2.4 mg and placebo in eGFR trajectories at week 68. CONCLUSIONS: Semaglutide improved UACR in adults with overweight/obesity and type 2 diabetes. In participants with normal kidney function, semaglutide did not have an effect on eGFR decline.

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses.

AIMS: Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials. MATERIALS AND METHODS: STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4 mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more weight-related comorbidity, without diabetes. Pre-specified endpoints were changes in waist circumference, systolic/diastolic blood pressure (SBP/DBP), lipids, fasting plasma glucose (FPG), fasting serum insulin and antihypertensive/lipid-lowering medication use. Post-hoc assessments included non-high-density lipoprotein (HDL) cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR; STEP 1 only), atherosclerotic cardiovascular disease (ASCVD) risk (American College of Cardiology/American Heart Association algorithm; STEP 1 only) and cardiometabolic risk factors by weight loss achieved (<5%, 5% to <10%, 10% to <15%, or ≥15%) (STEP 1 only). RESULTS: Of the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p ≤ .001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p > .05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained over week 20-68 with continued semaglutide, but deteriorated following the switch to placebo (p < .001 [week 20-68]). Net reductions in antihypertensive/lipid-lowering medication use occurred with semaglutide versus placebo (both trials). CONCLUSIONS: Semaglutide may improve cardiometabolic risk factors and reduce antihypertensive/lipid-lowering medication use versus placebo in adults with overweight/obesity without diabetes. These potential benefits were not maintained after treatment discontinuation. GOV NUMBERS: STEP 1 NCT03548935, STEP 4 NCT03548987.

Once-Weekly Semaglutide in Adults with Overweight or Obesity.

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).