Dataset Information

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.

ABSTRACT:

Importance

The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.

Objective

To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.

Design, setting, and participants

Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.

Interventions

A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.

Main outcomes and measures

The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).

Results

Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).

Conclusions and relevance

Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.

Trial registration

ClinicalTrials.gov Identifier: NCT03548987.

SUBMITTER: Rubino D

PROVIDER: S-EPMC7988425 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Background: In people with overweight or obesity, long-term maintenance of weight loss is challenging. Subcutaneous (s.c.) semaglutide, a glucagon-like peptide-1 analogue, has shown clinically-relevant weight loss in a phase 2 trial in people with obesity. STEP 4 investigated the impact of continued semaglutide 2.4 mg treatment, vs switching to placebo, on maintenance of weight loss in participants who reached 2.4 mg of semaglutide during a run-in period. Methods: This was a 68-week withdrawal trial (NCT03548987) in 902 subjects aged ≥18 years with body mass index (BMI) ≥30 kg/m2 (or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity), without diabetes. Following a 20 week run-in period, 803 subjects who reached the maintenance dose of once-weekly (OW) s.c. semaglutide 2.4 mg were randomized 2:1 to continue treatment with semaglutide 2.4 mg or switch to placebo for 48 weeks, both as adjunct to lifestyle intervention. The primary endpoint was percentage change in body weight between randomization (week 20) and week 68. Confirmatory secondary endpoints included change in waist circumference and systolic blood pressure. Two estimands were defined: treatment policy and trial product; results are presented for the treatment policy estimand, unless stated otherwise. Results: Mean body weight (±SD) was 107.2 ±22.7 kg at week 0 and 96.1 ±22.6 kg at randomization (week 20; mean change -10.6%). Randomized participants were mostly female (79%) and white (84%); mean age was 46 years and mean BMI was 34.4 kg/m2. Between weeks 20–68, estimated mean body weight change was −7.9% vs +6.9% for semaglutide 2.4 mg vs placebo (estimated treatment difference [ETD]: −14.8%; 95% confidence interval [CI]: −16.0, −13.5; p<0.0001), and -8.8% vs 6.5%, respectively, for the trial product estimand (ETD: -15.3%; 95% CI: -16.5, -14.1; p<0.0001). For participants randomized to continue semaglutide, the estimated change in body weight from week 0–68 was -17.4% (-18.2% for trial product estimand). Continued semaglutide treatment (weeks 20–68) led to clinically-relevant improvements in waist circumference, systolic blood pressure, BMI, HbA1c, FPG, and lipids (total cholesterol, LDL, VLDL, and triglycerides) vs switching to placebo (p<0.0001 for all). During the run-in period, 5.3% of participants discontinued treatment due to adverse events; during the randomized period, 2.4% (semaglutide) and 2.2% (placebo) discontinued. Nausea, diarrhea and constipation (mostly transient and mild-to-moderate) were the most frequent adverse events with semaglutide. Conclusion: In adults with overweight or obesity, continued treatment after dose escalation with OW s.c. semaglutide 2.4 mg until week 68 led to clinically-relevant weight loss, while switching to placebo led to significant weight regain; these data underscore the chronicity and relapsing nature of obesity, and the need for continued treatment.

Project description:ImportancePhase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.ObjectiveTo compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.Design, setting, and participantsRandomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).InterventionsParticipants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).Main outcomes and measuresThe primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.ResultsOf 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.Conclusions and relevanceAmong adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.Trial registrationClinicalTrials.gov Identifier: NCT04074161.

Project description:Abstract Background: Semaglutide is a long-acting, subcutaneous (s.c.), glucagon-like peptide-1 analogue that is currently being investigated for obesity management in adults with overweight or obesity in the phase 3 STEP clinical trial program. Varying degrees of weight loss were observed with once-weekly s.c. semaglutide 2.4 mg in STEP 1, and a post-hoc analysis was conducted to investigate weight loss in subgroups of participants based on their baseline characteristics. Methods: STEP 1 was a randomized, double-blind, placebo-controlled, phase 3 trial (NCT03548935). Adults aged ≥18 years with either body mass index (BMI) ≥27 kg/m2 with ≥1 weight-related comorbidity or BMI ≥30 kg/m2, without type 2 diabetes, were randomized 2:1 to 68 weeks’ treatment with once-weekly s.c. semaglutide 2.4 mg or placebo, as adjunct to lifestyle intervention. A descriptive evaluation of categorical weight loss with semaglutide from baseline to week 68 (≥20%, 15-<20%, 10-<15%, 5-<10%) by baseline characteristics (age, sex, race [White, Asian, Black or African American, other], body weight, BMI, waist circumference, and glycemic status [normo-glycemia, pre-diabetes]) was conducted. Mean percent weight loss with semaglutide from baseline to week 68 was analyzed separately by sex (male, female) and baseline body weight (≥115 kg, 100-<115 kg, 90-<100 kg, <90 kg) using a mixed model for repeated measurements analysis with treatment, subgroup (of sex or baseline body weight), and the interaction between treatment and subgroup as factors, and baseline body weight as a covariate, all nested within visit (based on the trial product estimand [treatment effect assuming treatment adherence and without use of rescue intervention] for the on-treatment period). Results: STEP 1 included 1,961 randomized participants (mean age 46 years, body weight 105.3 kg, BMI 37.9 kg/m2; 74.1% female). For categorical weight loss, the observed proportions of participants with ≥20%, 15-<20%, 10-<15%, and 5-<10% weight loss at week 68 were 34.8%, 19.9%, 20.0%, and 17.5% with semaglutide vs 2.0%, 3.0%, 6.8%, and 21.2% with placebo, respectively. The distribution of participants across weight loss groups did not appear to be affected by any baseline characteristics, except sex and baseline body weight. Mean percent weight loss at week 68 with semaglutide was greater among females than males, and in participants with lower vs higher baseline body weight. Sex and baseline body weight were independently associated with weight loss with semaglutide vs placebo at week 68 (p<0.001 for both tests for subgroup interactions). Conclusion: In STEP 1, weight loss with once-weekly s.c. semaglutide 2.4 mg was seen in all subgroups evaluated, and was generally not influenced by baseline characteristics. The exception was sex and baseline body weight; female sex and a low baseline body weight were associated with a greater response to semaglutide.

Project description:Background: Semaglutide is a long-acting, subcutaneous (s.c.), glucagon-like peptide-1 analogue that is currently being investigated for obesity management in adults with overweight or obesity in the phase 3 STEP clinical trial program. Varying degrees of weight loss were observed with once-weekly s.c. semaglutide 2.4 mg in STEP 1, and a post-hoc analysis was conducted to investigate weight loss in subgroups of participants based on their baseline characteristics. Methods: STEP 1 was a randomized, double-blind, placebo-controlled, phase 3 trial (NCT03548935). Adults aged ≥18 years with either body mass index (BMI) ≥27 kg/ m2 with ≥1 weight-related comorbidity or BMI ≥30 kg/m2, without type 2 diabetes, were randomized 2:1 to 68 weeks’ treatment with once-weekly s.c. semaglutide 2.4 mg or placebo, as adjunct to lifestyle intervention. A descriptive evaluation of categorical weight loss with semaglutide from baseline to week 68 (≥20%, 15-<20%, 10-<15%, 5-<10%) by baseline characteristics (age, sex, race [White, Asian, Black or African American, other], body weight, BMI, waist circumference, and glycemic status [normo-glycemia, pre-diabetes]) was conducted. Mean percent weight loss with semaglutide from baseline to week 68 was analyzed separately by sex (male, female) and baseline body weight (≥115 kg, 100-<115 kg, 90-<100 kg, <90 kg) using a mixed model for repeated measurements analysis with treatment, subgroup (of sex or baseline body weight), and the interaction between treatment and subgroup as factors, and baseline body weight as a covariate, all nested within visit (based on the trial product estimand [treatment effect assuming treatment adherence and without use of rescue intervention] for the on-treatment period). Results: STEP 1 included 1,961 randomized participants (mean age 46 years, body weight 105.3 kg, BMI 37.9 kg/ m2; 74.1% female). For categorical weight loss, the observed proportions of participants with ≥20%, 15-<20%, 10-<15%, and 5-<10% weight loss at week 68 were 34.8%, 19.9%, 20.0%, and 17.5% with semaglutide vs 2.0%, 3.0%, 6.8%, and 21.2% with placebo, respectively. The distribution of participants across weight loss groups did not appear to be affected by any baseline characteristics, except sex and baseline body weight. Mean percent weight loss at week 68 with semaglutide was greater among females than males, and in participants with lower vs higher baseline body weight. Sex and baseline body weight were independently associated with weight loss with semaglutide vs placebo at week 68 (p<0.001 for both tests for subgroup interactions). Conclusion: In STEP 1, weight loss with once-weekly s.c. semaglutide 2.4 mg was seen in all subgroups evaluated, and was generally not influenced by baseline characteristics. The exception was sex and baseline body weight; female sex and a low baseline body weight were associated with a greater response to semaglutide.

Project description:Abstract Background: Despite the increasing global adverse health impact of obesity, there are few pharmacological options for effective weight management. STEP 1 investigated the efficacy and safety of the glucagon-like peptide-1 analogue, subcutaneous (s.c.) semaglutide, for weight management in adults with overweight or obesity. Methods: This randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 129 sites across 16 countries (NCT03548935). Adults aged ≥18 years with either body mass index (BMI) ≥30 kg/m2 or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity, without type 2 diabetes, were randomized 2:1 to 68 weeks’ treatment with once-weekly s.c. semaglutide 2.4 mg or placebo, both as adjunct to lifestyle intervention. The co-primary endpoints were percentage change in body weight and achievement of weight loss ≥5%. Cardiometabolic risk factors, patient-reported outcomes, and safety/tolerability were also assessed. Two estimands were defined: treatment policy (effect regardless of treatment adherence and use of rescue intervention) and trial product (effect assuming treatment adherence and without rescue intervention); results are presented for the treatment policy estimand, unless stated otherwise. P values for parameters marked with # were not controlled for multiplicity. Results: 1961 randomized participants (mean age 46 years, body weight 105.3 kg, BMI 37.9 kg/m2; 74.1% female) were included. Mean body weight change from baseline to week 68 was −14.9% in the semaglutide group vs −2.4% with placebo (estimated treatment difference [ETD]: −12.4%; 95% confidence interval (CI): −13.4, −11.5; p<0.0001). Similar results were obtained with the trial product estimand: mean body weight change# was -16.9% for semaglutide vs -2.4% for placebo (ETD: -14.4%; 95% CI: -15.3, -13.6; p<0.0001). Participants were more likely to achieve weight loss ≥5%, ≥10%, ≥15%, and ≥20%# with semaglutide vs placebo (86.4% vs 31.5%, 69.1% vs 12.0%, 50.5% vs 4.9%, and 32.0% vs 1.7%, respectively; p<0.0001 for all). Greater improvements were seen with semaglutide vs placebo in waist circumference, BMI#, systolic and diastolic# blood pressure, glycated hemoglobin#, fasting plasma glucose#, C-reactive protein#, fasting lipid profile#, and self-reported physical functioning (p<0.05 for all). No new safety signals with semaglutide were observed. The most frequent adverse events with semaglutide were gastrointestinal disorders (typically transient and mild-to-moderate). Conclusion: In adults with overweight or obesity, once-weekly s.c. semaglutide 2.4 mg plus lifestyle intervention induced a mean weight loss of approximately 15% by week 68. Clinically beneficial weight loss of ≥10% was achieved by over two-thirds of participants and ≥20% by one-third of participants, along with associated improvements in cardiometabolic risk factors and physical functioning.

Project description:ImportanceWeight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.ObjectiveTo compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.Design, setting, and participantsRandomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).InterventionsParticipants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.Main outcomes and measuresThe co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.ResultsOf 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.Conclusions and relevanceAmong adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.Trial registrationClinicalTrials.gov Identifier: NCT03611582.

Project description:Abstract Background: Semaglutide, a glucagon-like peptide-1 analogue, is being investigated in people with overweight or obesity. A post-hoc analysis of the STEP 4 trial was conducted to identify whether early weight loss is predictive of later weight loss with maintenance once-weekly subcutaneous (s.c.) semaglutide 2.4 mg. Methods: STEP 4 was a randomized, double-blind, phase 3 withdrawal trial (NCT03548987). Adults aged ≥18 years with either body mass index (BMI) ≥27 kg/m2 with ≥1 weight-related comorbidity or BMI ≥30 kg/m2, without type 2 diabetes, underwent a 20-week run-in period. Participants reaching the maintenance dose of once-weekly s.c. semaglutide 2.4 mg at week 20 (regardless of weight loss achieved) were randomized 2:1 to semaglutide 2.4 mg or placebo, as adjunct to lifestyle intervention, for an additional 48 weeks. Percent change in body weight from week 0 to 68 was estimated using a mixed model for repeated measurements analysis with treatment, week 20 responder status, and the interaction between treatment and week 20 responder status as factors, and baseline body weight as a covariate, all nested within visit (based on the trial product estimand [treatment effect assuming treatment adherence and without use of rescue intervention] for the on-treatment period). Participants were considered responders if they achieved ≥5% weight loss at week 20. Whether the week 20 response to semaglutide predicted the achievement of clinically-relevant weight loss (≥5%) by week 68 was also assessed. Results: In STEP 4, 902 participants initiated semaglutide at week 0, of whom 803 were randomized at week 20 (semaglutide: n=535, placebo: n=268; characteristics at week 0 for all randomized participants: mean age 46 years, body weight 107.2 kg, BMI 38.4 kg/m2; 79.0% female; 83.7% white). For the 88.0% of participants randomized to semaglutide and who were responders at week 20, mean body weight change from week 0 to 68 was -19.7%. For non-responders at week 20, mean body weight change was -6.4% with continued semaglutide vs -0.3% with switch to placebo. Of all participants randomized to semaglutide, 86.2% achieved a clinically-relevant weight loss (≥5%) at week 68. Being a responder at week 20 was highly predictive of achieving this outcome (positive predictive value: 96.4%), whereas being a non-responder at week 20 had limited predictive value (negative predictive value: 42.9%). Conclusion: In the STEP 4 trial, the vast majority of participants who were randomized to the maintenance dose of once-weekly s.c. semaglutide 2.4 mg at week 20 had lost ≥5% body weight by week 68, with most achieving this by week 20. Overall weight loss with semaglutide was greater among early responders, but non-responders also achieved a clinically-relevant weight loss by week 68 if semaglutide treatment was continued.

Project description:Abstract Background: In people with overweight/obesity and type 2 diabetes (T2D), achievement of weight loss can be a challenge. STEP 2 investigated the efficacy and safety of semaglutide 2.4 mg for weight management in adults with overweight/obesity and T2D. Methods: This randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial was conducted at 149 sites across 12 countries (NCT03552757). Adults aged ≥18 years with body mass index (BMI) ≥27 kg/m2, T2D, HbA1c between 7–10% (53–86 mmol/mol), and receiving ≤3 oral glucose-lowering agents were randomized 1:1:1 to once-weekly subcutaneous (s.c.) semaglutide 2.4 mg or 1.0 mg, or placebo, as adjunct to a reduced-calorie diet and increased physical activity for 68 weeks. The co-primary endpoints were percentage change in body weight and proportion of participants achieving weight loss ≥5% for semaglutide 2.4 mg vs placebo. Cardiovascular risk factors, glycemia and safety/tolerability were also assessed. Two estimands were defined: treatment policy and trial product; results are presented for the treatment policy estimand, unless stated otherwise. Results: 1,210 participants (mean: age 55 years, body weight 99.8 kg, BMI 35.7 kg/m2, HbA1c 8.1%, diabetes duration 8.0 years; 50.9% female) were randomized. Mean body weight change from baseline to week 68 was −9.6% with semaglutide 2.4 mg vs −3.4% with placebo (estimated treatment difference [ETD]: −6.2%; 95% confidence interval [CI]: −7.3, −5.2; p<0.0001) and −7.0% for semaglutide 1.0 mg (ETD for semaglutide 2.4 mg vs 1.0 mg: −2.7%; 95% CI: −3.7, −1.6; p<0.0001). Similar results were obtained with the trial product estimand: mean body weight change −10.6% for semaglutide 2.4 mg vs −3.1% for placebo (ETD: −7.6%; 95% CI: −8.6, −6.6; p<0.0001) and 7.6% for semaglutide 1.0 mg (ETD vs semaglutide 2.4 mg: −3.1%; 95% CI: −4.1, −2.1; p<0.0001). Participants on semaglutide 2.4 mg were more likely to achieve weight loss ≥5%, ≥10%, ≥15% and ≥20% vs placebo (68.8% vs 28.5%, 45.6% vs 8.2%, 25.8% vs 3.2% and 13.1% vs 1.6%, respectively; p value for odds ratios <0.0001 for all). Mean change in HbA1c from baseline to week 68 was −1.6% for semaglutide 2.4 mg vs −0.4% for placebo (p<0.0001). Greater improvements with semaglutide 2.4 mg vs placebo were also seen in waist circumference, BMI, systolic blood pressure, fasting plasma glucose, C-reactive protein, and lipids (HDL, VLDL, free fatty acids, and triglycerides) (p<0.05 for all). The most frequent adverse events were gastrointestinal disorders (typically transient and mild-to-moderate), occurring in 57.5%, 63.5% and 34.3% of participants receiving semaglutide 1.0 mg, 2.4 mg and placebo, respectively. Conclusion: Semaglutide 2.4 mg, as adjunct to lifestyle intervention, was efficacious and well tolerated for weight management in adults with overweight or obesity and T2D, providing significantly greater weight loss vs placebo and semaglutide 1.0 mg at week 68.

Project description:Background: In people with overweight/obesity and type 2 diabetes (T2D), achievement of weight loss can be a challenge. STEP 2 investigated the efficacy and safety of semaglutide 2.4 mg for weight management in adults with overweight/obesity and T2D. Methods: This randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial was conducted at 149 sites across 12 countries (NCT03552757). Adults aged ≥18 years with body mass index (BMI) ≥27 kg/m2, T2D, HbA1c between 7–10% (53–86 mmol/mol), and receiving ≤3 oral glucose-lowering agents were randomized 1:1:1 to once-weekly subcutaneous (s.c.) semaglutide 2.4 mg or 1.0 mg, or placebo, as adjunct to a reduced-calorie diet and increased physical activity for 68 weeks. The co-primary endpoints were percentage change in body weight and proportion of participants achieving weight loss ≥5% for semaglutide 2.4 mg vs placebo. Cardiovascular risk factors, glycemia and safety/tolerability were also assessed. Two estimands were defined: treatment policy and trial product; results are presented for the treatment policy estimand, unless stated otherwise. Results: 1,210 participants (mean: age 55 years, body weight 99.8 kg, BMI 35.7 kg/m2, HbA1c 8.1%, diabetes duration 8.0 years; 50.9% female) were randomized. Mean body weight change from baseline to week 68 was −9.6% with semaglutide 2.4 mg vs −3.4% with placebo (estimated treatment difference [ETD]: −6.2%; 95% confidence interval [CI]: −7.3, −5.2; p<0.0001) and −7.0% for semaglutide 1.0 mg (ETD for semaglutide 2.4 mg vs 1.0 mg: −2.7%; 95% CI: −3.7, −1.6; p<0.0001). Similar results were obtained with the trial product estimand: mean body weight change −10.6% for semaglutide 2.4 mg vs −3.1% for placebo (ETD: −7.6%; 95% CI: −8.6, −6.6; p<0.0001) and 7.6% for semaglutide 1.0 mg (ETD vs semaglutide 2.4 mg: −3.1%; 95% CI: −4.1, −2.1; p<0.0001). Participants on semaglutide 2.4 mg were more likely to achieve weight loss ≥5%, ≥10%, ≥15% and ≥20% vs placebo (68.8% vs 28.5%, 45.6% vs 8.2%, 25.8% vs 3.2% and 13.1% vs 1.6%, respectively; p value for odds ratios <0.0001 for all). Mean change in HbA1c from baseline to week 68 was −1.6% for semaglutide 2.4 mg vs −0.4% for placebo (p<0.0001). Greater improvements with semaglutide 2.4 mg vs placebo were also seen in waist circumference, BMI, systolic blood pressure, fasting plasma glucose, C-reactive protein, and lipids (HDL, VLDL, free fatty acids, and triglycerides) (p<0.05 for all). The most frequent adverse events were gastrointestinal disorders (typically transient and mild-to-moderate), occurring in 57.5%, 63.5% and 34.3% of participants receiving semaglutide 1.0 mg, 2.4 mg and placebo, respectively. Conclusion: Semaglutide 2.4 mg, as adjunct to lifestyle intervention, was efficacious and well tolerated for weight management in adults with overweight or obesity and T2D, providing significantly greater weight loss vs placebo and semaglutide 1.0 mg at week 68.