Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials.
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SUBMITTER: Aroda VR
PROVIDER: S-EPMC7065219 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials.
Aroda Vanita R VR Capehorn Matthew S MS Chaykin Louis L Frias Juan P JP Lausvig Nanna L NL Macura Stanislava S Lüdemann Jörg J Madsbad Sten S Rosenstock Julio J Tabak Omur O Tadayon Sayeh S Bain Stephen C SC
Diabetes, obesity & metabolism 20191114 3
<h4>Aim</h4>To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes.<h4>Materials and methods</h4>Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glu ...[more]
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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.
| S-EPMC8089676 | biostudies-literature
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.
| S-EPMC9067867 | biostudies-literature
Project description:AIM:To investigate treatment satisfaction with semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, versus placebo/active comparators in the SUSTAIN clinical trial programme. METHODS:In SUSTAIN 2-5 and 7, the Diabetes Treatment Satisfaction Questionnaire was used to evaluate patient-perceived treatment satisfaction, hyperglycaemia and hypoglycaemia. Post hoc subgroup analyses were conducted to explore the effects of gastrointestinal adverse events (GI AEs), weight loss (?5%) or achieving glycaemic (HbA1c?< 7%) targets on treatment satisfaction. RESULTS:Overall treatment satisfaction increased from baseline to end of treatment with all treatments across trials. Improvements were significantly greater with semaglutide versus comparators/placebo in SUSTAIN 2-5 (all P < 0.05), and generally greater in patients who achieved versus did not achieve weight loss and glycaemic targets, often with greater improvements with semaglutide 1.0 mg versus comparator/placebo in both weight loss groups. In SUSTAIN 7, improvements in overall treatment satisfaction were generally similar between semaglutide and dulaglutide, irrespective of weight loss or glycaemic control. In SUSTAIN 7, changes in overall treatment satisfaction score were generally lower in patients with versus without GI AEs at week 16 (except dulaglutide 0.75?mg), but similar by week 40. Perceived hyperglycaemia was significantly reduced from baseline to end of treatment with semaglutide versus all comparators/placebo (all P?<?0.05). No differences between treatments were observed for perceived hypoglycaemia. CONCLUSIONS:Semaglutide was associated with significantly greater (SUSTAIN 2-5) or similar (SUSTAIN 7) improvements in overall treatment satisfaction versus comparators/placebo. Improvements in overall treatment satisfaction were generally greater in patients achieving versus not achieving treatment targets. Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4), NCT02305381 (SUSTAIN 5) and NCT02648204 (SUSTAIN 7). EudraCT: 2012-004827-19 (SUSTAIN 2), 2012-004826-92 (SUSTAIN 3), 2013-004392-12 (SUSTAIN 4), 2013-004502-26 (SUSTAIN 5) and 2014-005375-91 (SUSTAIN 7).
| S-EPMC6771774 | biostudies-literature
Project description:IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice.Research design and methodsSEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus standard of care in US health-insured adults with T2D and physician-determined inadequate glycemic control. The primary end point is the proportion of participants achieving glycated hemoglobin (HbA1c) <7.0% at year 1; other key outcomes include glycemic control, weight loss, healthcare utilization, and patient-reported outcomes. Individual-level data will be collected from routine clinical practice and health insurance claims. The last patient last visit is expected by June 2023.ResultsBetween July 2018 and March 2021, 1278 participants were enrolled from 138 study sites across the USA. At baseline, 54% were male with mean±SD age 57.4±11.1 years and body mass index 35.7±8.0 kg/m2. Mean diabetes duration was 7.4±6.0 years and mean HbA1c was 8.5±1.6%. At baseline, concomitant antidiabetes medications included metformin, sulfonylureas, sodium-glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The majority of participants had hypertension and dyslipidemia. The trial design was self-assessed using the PRagmatic Explanatory Continuum Indicator Summary-2 tool by the study steering group and was scored 4-5 in all domains suggesting a highly pragmatic study.ConclusionsSEPRA, a highly pragmatic ongoing study, will provide data on the effects of once-weekly subcutaneous semaglutide in a real-world setting when used during routine management of T2D.Trial registration numberNCT03596450.Trial registration number
| S-EPMC10163526 | biostudies-literature
Project description:ObjectiveIn SUSTAIN 7, once-weekly semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of semaglutide versus dulaglutide.DesignAnalyses by baseline age (<65, ≥65 years), sex (male, female), diabetes duration (≤5, >5-10, >10 years), HbA1c (≤7.5, >7.5-8.5, >8.5% (≤58, >58-69, >69 mmol/mol)) and body mass index (BMI) (<30, 30-<35, ≥35 kg/m2).Setting194 sites; 16 countries.ParticipantsSubjects with T2D (n=1199) exposed to treatment.InterventionsSemaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly.Primary and secondary outcome measuresChange in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety.ResultsHbA1c and BW reductions (estimated treatment difference ranges: -0.22 to -0.70%-point; -1.76 to -3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with semaglutide, decreased with increasing BMI.ConclusionsConsistently greater improvements in HbA1c and BW with semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of semaglutide across the continuum of care in a heterogeneous population with T2D.Trial registration numberNCT02648204.
| S-EPMC7670946 | biostudies-literature
Project description:BackgroundA once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking.MethodsIn this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68.ResultsA total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.ConclusionsAmong adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.).
| S-EPMC9997064 | biostudies-literature
Project description:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by Kidney Disease: Improving Global Outcomes (KDIGO) as risk-based treatment for hyperglycemia, weight management, and cardiovascular (CV) risk reduction in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). The aim of this post hoc analysis was to assess treatment effects of once weekly semaglutide on kidney disease outcomes by KDIGO risk category and on changes in KDIGO risk category, compared with placebo. Participants with T2D and established CV disease or at high CV risk treated with once weekly semaglutide or placebo in SUSTAIN 6 (NCT01720446) were stratified by baseline KDIGO risk category (low [n = 1596], moderate [n = 831], high [n = 445], very high [n = 366]). Treatment effect was analyzed for a kidney disease composite end point (macroalbuminuria, serum creatinine doubling and estimated glomerular filtration rate [eGFR] < 45 ml/min per 1.73 m2, kidney replacement therapy, or death due to kidney disease) from baseline to 2 years. The treatment effect of semaglutide versus placebo was consistent across KDIGO categories for the kidney disease composite end point (hazard ratio [95% confidence interval (CI)]: 0.35 [0.07-1.72], 0.42 [0.25-0.72], 0.87 [0.45-1.71], and 0.72 [0.42-1.23] for low, moderate, high, and very high risk categories, respectively; P interaction = 0.28). Participants receiving semaglutide were more likely to move to a lower KDIGO risk category (odds ratio: 1.69; 95% CI: [1.32-2.16]) and less likely to move to a higher KDIGO risk category versus placebo (odds ratio: 0.71; 95% CI: [0.59-0.86]). Once weekly semaglutide versus placebo reduced risks of kidney disease end points and improved risk categories irrespective of baseline KDIGO risk.
| S-EPMC11284422 | biostudies-literature
Project description:Aims/introductionThe etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program.Materials and methodsThis analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg).ResultsChange from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants. With once-weekly semaglutide, relative bodyweight was reduced from baseline to end of study by 4.0-7.3% in the overall populations, and 2.7-10.4% in Japanese participants. In the Japanese subpopulation, no new safety concerns were identified with once-weekly semaglutide, and there were no adverse events leading to death or severe hypoglycemic episodes.ConclusionsIn this post-hoc analysis, participants with type 2 diabetes initiating once-weekly semaglutide experienced improvements in glycated hemoglobin and bodyweight in both the overall and Japanese population, and no new safety concerns were identified among Japanese participants, supporting the efficacy of once-weekly semaglutide in this population.
| S-EPMC9720207 | biostudies-literature
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.
| S-EPMC8089593 | biostudies-literature
Project description:Aims/hypothesisIntra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning.MethodsAdults (age ≥18 years) with type 2 diabetes, HbA1c 53-91 mmol/mol (7.0-10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min-1 [1.73 m]-2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint.ResultsA subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.79 [95% CI -2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.78 [-1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [-0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups.Conclusions/interpretationIn individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.Trial registrationClinicalTrials.gov NCT03136484.FundingThis trial was supported by Novo Nordisk A/S, Denmark.
| S-EPMC6997246 | biostudies-literature