Once-Weekly Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Common OAD: a Subgroup Analysis from SUSTAIN 2-4 and 10.
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SUBMITTER: Capehorn M
PROVIDER: S-EPMC7193006 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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Once-Weekly Semaglutide Reduces HbA<sub>1c</sub> and Body Weight in Patients with Type 2 Diabetes Regardless of Background Common OAD: a Subgroup Analysis from SUSTAIN 2-4 and 10.
Capehorn Matthew M Ghani Yasmin Y Hindsberger Charlotte C Johansen Pierre P Jódar Esteban E
Diabetes therapy : research, treatment and education of diabetes and related disorders 20200319 5
<h4>Introduction</h4>Despite treatment with oral antidiabetic drugs (OADs), achieving effective glycaemic control in type 2 diabetes (T2D) remains a challenge. The objective of this post hoc analysis of data from the SUSTAIN 2, 3, 4 and 10 active-controlled trials was to assess the efficacy and safety of the once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide in patients on background treatment with metformin (MET), with or without a sulphonylurea (SU).<h4>Methods</h4>Data ...[more]
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Project description:BackgroundCardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.MethodsA post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs-SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O-including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE).ResultsIn the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]).ConclusionThese findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).
| S-EPMC9052629 | biostudies-literature
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: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: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: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:IntroductionThe efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups.MethodsData from patients in the PIONEER 3-5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients.ResultsIn total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: - 1.0 to - 1.5% and - 2.2 to - 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups.ConclusionOral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents.Trial registrationClinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8).
| S-EPMC7994454 | 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: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
Project description:OBJECTIVE:The aim of this study was to assess the cost effectiveness of semaglutide versus dulaglutide, as an add-on to metformin monotherapy, for the treatment of type 2 diabetes (T2D), from a Canadian societal perspective. METHODS:The Swedish Institute for Health Economics Cohort Model of T2D was used to assess the cost effectiveness of once-weekly semaglutide (0.5 or 1.0 mg) versus once-weekly dulaglutide (0.75 or 1.5 mg) over a 40-year time horizon. Using data from the SUSTAIN 7 trial, which demonstrated comparatively greater reductions in glycated hemoglobin (HbA1c), body mass index and systolic blood pressure with semaglutide, compared with dulaglutide, a deterministic base-case and scenario simulation were conducted. The robustness of the results was evaluated with probabilistic sensitivity analyses and 15 deterministic sensitivity analyses. RESULTS:The base-case analysis indicated that semaglutide is a dominant treatment option, compared with dulaglutide. Semaglutide was associated with lower total costs (Canadian dollars [CAN$]) versus dulaglutide for both low-dose (CAN$113,287 vs. CAN$113,690; cost-saving: CAN$403) and high-dose (CAN$112,983 vs. CAN$113,695; cost-saving: CAN$711) comparisons. Semaglutide resulted in increased quality-adjusted life-years (QALYs) and QALY gains, compared with dulaglutide, for both low-dose (11.10 vs. 11.07 QALYs; +?0.04 QALYs) and high-dose (11.12 vs. 11.07 QALYs; +?0.05 QALYs) comparisons. The probabilistic sensitivity analysis showed that for 66-73% of iterations, semaglutide was either dominant or was considered cost effective at a willingness-to-pay threshold of CAN$50,000. CONCLUSIONS:From a Canadian societal perspective, semaglutide may be a cost-effective treatment option versus dulaglutide in patients with T2D who are inadequately controlled on metformin monotherapy.
| S-EPMC6861407 | biostudies-literature