Confirmatory Secondary Endpoint Research Articles

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.

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. 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). 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. 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.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. Novo Nordisk.

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.

Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction.

Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n=85), 50% to 59% (n=215), and≥60% (n=229). At 52weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95%CI:-2.7 to 12.8 points], EF 50%-59%: 9.8 points [95%CI: 5.0 to 14.6 points], and EF≥60%: 7.4 points [95%CI: 2.8 to 12.0 points]; P interaction=0.56) and body weight (EF: 45%-49%:-7.6 [95%CI:-10.7 to-4.4], EF 50%-59%:-10.6 [95%CI:-12.6 to-8.6] and EF≥60%:-11.9 [95%CI:-13.8 to-9.9]; P interaction=0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction=0.19), hierarchal composite endpoint (P interaction=0.43), and high-sensitivity C-reactive protein (P interaction=0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (Pinteraction=0.96). Semaglutide was well-tolerated across LVEF categories. In patients with HFpEF and obesity, semaglutide 2.4mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With HeartFailure and Obesity [STEP-HFpEF]; NCT04788511).

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I–III (body mass index (BMI) 30.0–34.9 kg m−2, 35.0–39.9 kg m−2 and ≥40 kg m−2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511.

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin

BackgroundInsulin icodec is an investigational once-weekly basal insulin analogue for diabetes management.MethodsWe conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded.ResultsEach group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, −1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, −1.35 percentage points]); the estimated between-group difference (−0.19 percentage points; 95% confidence interval [CI], −0.36 to −0.03) confirmed the noninferiority (P<0.001) and superiority (P=0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups.ConclusionsGlycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.)

Evoke and evoke+: design of two large‐scale, double‐blind, placebo‐controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease

AbstractBackgroundPreclinical, clinical, and real‐world evidence suggest benefits in Alzheimer’s disease (AD)‐related symptoms and reduced risk of dementia in type 2 diabetes following treatment with glucagon‐like peptide 1 receptor agonists (GLP‐1RA; Figure 1). The phase 3 evoke and evoke+ trials (NCT04777396 and NCT04777409, respectively) will assess the efficacy and safety of the oral GLP‐1RA semaglutide versus placebo in participants with early AD. Here, we present the design of these trials.Methodevoke and evoke+ are two randomized, double‐blind, placebo‐controlled trials (Figure 2) recruiting across 38 countries, with 2 further countries pending (Figure 3). In each trial, a planned 1,840 amyloid‐positive participants (aged 55 to 85 years) with mild cognitive impairment (MCI) due to AD (Clinical Dementia Rating [CDR] global = 0.5) or mild AD dementia (CDR global = 1.0) will be randomized (1:1) to oral semaglutide 14 mg once‐daily (escalated via 3‐ and 7‐mg doses over 8 weeks) or placebo for 156 weeks. Participants may use approved AD treatments if on a stable dose ≥3 months before screening. Other key inclusion criteria are: Mini‐Mental State Examination score ≥22 and Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index score ≤85. The key difference between the trials is the inclusion of ≥20% of participants with significant small vessel co‐pathology in evoke+. The primary endpoint is change in the CDR – Sum of Boxes score from baseline to week 104. Confirmatory secondary endpoints are change in Alzheimer’s Disease Cooperative Study‐Activities of Daily Living‐MCI score, and time to progression to dementia among participants with MCI at baseline. Exploratory endpoints include effects on neurodegeneration and neuroinflammation assessed by changes in plasma and cerebrospinal fluid biomarkers. After week 104, participants will continue their original randomized, double‐blind, placebo‐controlled treatment for a 52‐week extension phase followed by a 5‐week follow‐up, allowing assessment of the long‐term effects of semaglutide. A full list of endpoints is provided in Figure 4.ResultThe evoke and evoke+ read‐outs are expected in 2025.Conclusionevoke and evoke+ will be the first large‐scale phase 3 trials (Ntotal = 3,680) to investigate the hypothesized neuroprotective disease‐modifying effect of semaglutide in early AD.

Efficacy and safety of once-weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post-hoc analysis.

The 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. This 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). Change 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. In 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.

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes

Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. To 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. Randomized, 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). Participants 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). The 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. Of 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. Among 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. ClinicalTrials.gov Identifier: NCT04074161.

DUAL II China: Superior HbA1c reductions and weight loss with insulin degludec/liraglutide (IDegLira) versus insulin degludec in a randomized trial of Chinese people with type 2 diabetes inadequately controlled on basal insulin.

AimTo assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin.Materials and MethodsIn DUAL II China, a randomized, double‐blinded, multicentre, treat‐to‐target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)‐confirmed hypoglycaemic episodes (confirmatory secondary endpoints).ResultsOverall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (−1.9% vs. −1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: −0.92% [−1.09; −0.75], P < .0001), body weight change (−0.7 vs. +0.4 kg, respectively, ETD [95% CI]: −1.08 kg [−1.63; −0.52], P = .0002) and severe or BG‐confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed.ConclusionsIDegLira may be an efficacious and well‐tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs.

I. Semaglutide: A New Kid on the Block for Nonalcoholic Steatohepatitis, but a Long Way to Go for India: Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021 Mar 25;384:1113–1124. https://doi.org/10.1056/NEJMoa2028395. Epub 2020 Nov 13.

Authors have conducted a 72-week, double-blind phase 2 trial involving patients with biopsy biopsy-confirmed nonalcoholic steatohepatitis (NASH) and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH.

Weight Loss Maintenance With Once-Weekly Semaglutide 2.4 MG in Adults With Overweight or Obesity Reaching Maintenance Dose (STEP 4)

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.

Validation of a novel contact-free heart and respiratory rate monitor

There is a growing need for remote monitoring of patients due to a lack of resources and infection control. Current systems use sensors that require constant physical contact with the user, which may result in discomfort or lack of adherence. In the present study, we evaluated the accuracy of a new contact-free system to monitor heart and respiratory rate. Study participants were measured simultaneously using two devices: a contact-free optical system that measures nano-vibrations and movements (investigational device, “Gili Pro BioSensor”) and a standard reference bed-side monitor, inclusive of an electrocardiogram and capnograph modules (Mindray®). Co-primary endpoints included HR and RR accuracy in subjects without active arrhythmias for HR, and for all study populations for RR (i.e., for subjects with and without active arrhythmias). Confirmatory secondary endpoints included HR scored continuously for all study populations, inclusive of subjects with arrhythmias. The present study included 115 patients who completed study procedures. Mean age was 66 ± 14.6 (range 29–93) with 60% males, 31% obese patients (i.e., BMI > 30 kg/m2, range 17–44) and 56% measured in a chair. For the dichotomised accuracy analysis, both co-primary endpoint for HR and RR resulted in 100% accuracy (95% CI: HR 98.8–100%; RR 98.9–100%), whereas for the confirmatory secondary analysis, 99.1% of the HR measurements across subjects with and without active arrhythmias were deemed accurate (95% CI: 97.4–99.8%). The current study demonstrated over 99% accuracy in detecting heart and respiratory rate using a novel contact-free optical system.

A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis

BackgroundNonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.MethodsWe conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.ResultsIn total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.ConclusionsThis phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.)

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity

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. 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. 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. 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. 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]). 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%). 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. ClinicalTrials.gov Identifier: NCT03548987.

Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity

Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches. To 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. Randomized, 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). Participants 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. The 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. Of 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. Among 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. ClinicalTrials.gov Identifier: NCT03611582.

947-P: Semaglutide Added to Treatment or Changed from Other GLP-1 Receptor Agonist in Type 2 Diabetes: A Study to Evaluate Real-World Effectiveness

Objective: To evaluate real-world clinical outcomes of semaglutide on glycemic control and weight as an add-on to treatment or changed-on from other GLP-1 in patients with T2D who initiate treatment. Patients and Methods: To better understand the effectiveness of semaglutide on clinical outcomes in a real-world setting, this retrospective cohort study included eligible patients were at least 18 years old with uncontrolled T2D (HbA1c 6.5-11%) receiving stable therapy that initiated subcutaneous semaglutide 0.5 or 1.0 mg once weekly added to their therapy or after a change from other GLP-1. Primary endpoint was change from baseline in glycated Hb (HbA1c) and confirmatory secondary endpoint was change from baseline in body weight, both at week 24. Semaglutide was initiated as part of their diabetes therapy based in clinical practice. Results: in this study, were included 147 patients had a mean age of 60.3 ± 10.1 years, T2D duration of 14.0 ± 7.4 years, and baseline A1C of 8.3 ± 1.34%. Seventy-five were naïve in treatment with GLP-1 and seventy-four received previously another GLP-1 (liraglutide 1.8 mg daily or dulaglutide 1.5 mg once weekly). At 6 months follow-up, 145 patients who remained on-treatment showed an A1C reduction of 1.2 ± 1.15% (p&amp;lt;0.05), A1C lowering was seen in both groups: a reduction de 1.8±1.8% (p &amp;lt; 0.05) in patients that received GLP for first time and 0.6± 1.0%(p&amp;lt; 0.05) in group prior use of GLP-1. Mean weight reduction was 5.1 ± 4.6 kg (p &amp;lt; 0.001) in the group initiated GLP-1 for first time and 2.1±4.0 kg (p&amp;lt;0.01) in group that changed from another GLP-1. Four patients presented gastrointestinal adverse events to retire the treatment, all of them in the group that never had been treated with GLP-1. Conclusion: In this real-world study, patients initiating semaglutide had significant reductions in HbA1c and weight. The effect was reached whether patients received GLP-1 for the first time or if a change had been made from another GLP-1. Disclosure J. Ferrer-García: None. R. Albalat Galera: None. L. Arribas: None. M. Tolosa Torrens: None. A. Sánchez Lorente: None. A.J. Portilla: None. A. Artero: None. C. Sánchez-Juan: None.

Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial.

AimTo compare the effect of liraglutide or placebo added on to sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i) ± metformin on glycaemic control in patients with type 2 diabetes.Materials and MethodsPatients with type 2 diabetes on a stable SGLT2i dose ± metformin (with HbA1c 7.0%–9.5% and body mass index [BMI] ≥ 20 kg/m2) were randomized 2:1 to add‐on liraglutide 1.8 mg/day or placebo in this parallel, double‐blind, multinational trial. Primary and confirmatory secondary endpoints were changes in HbA1c and body weight from baseline to week 26, respectively. The proportions of patients achieving HbA1c (<7.0%) targets and safety events after week 26 were also assessed.ResultsOf 303 patients randomized (one in error), 280 completed treatment. Mean changes in HbA1c from baseline to week 26 with liraglutide (n = 202) and placebo (n = 100) were − 0.98% and − 0.30%, respectively (estimated treatment difference [ETD]: −0.68% [95% CI: −0.89, −0.48]; P < 0.001). Mean body weight changes from baseline were − 2.81 versus −1.99 kg, respectively (ETD: −0.82 kg [95% CI: −1.73, 0.09]; P = 0.077); 51.8% of liraglutide‐treated patients achieved HbA1c < 7.0% versus 23.2% receiving placebo (odds ratio: 5.1 [95% CI: 2.67, 9.87]; P < 0.001). More patients treated with liraglutide reported ≥1 treatment‐emergent adverse events (66.3%) versus placebo (47.0%).ConclusionsLiraglutide significantly improved glycaemic control compared with placebo in patients with type 2 diabetes, insufficiently controlled with SGLT2is with/without metformin, with no unexpected safety findings.

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial

Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478FundingThis trial was funded by Novo Nordisk (Bagsvaerd, Denmark)

Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial

Existing guidelines for management of type 2 diabetes recommend a patient-centred approach to guide the choice of pharmacological agents. Although glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors are increasingly used as second-line agents, direct comparisons between these treatments are insufficient. In the SUSTAIN 8 trial, we compared the efficacy and safety of semaglutide (a GLP-1 receptor agonist) with canagliflozin (an SGLT2 inhibitor) in patients with type 2 diabetes. This was a double-blind, parallel-group, phase 3b, randomised controlled trial done at 111 centres in 11 countries. Eligible patients were at least 18 years old and had uncontrolled type 2 diabetes (HbA1c 7·0-10·5% [53-91 mmol/mol]) on stable daily metformin therapy. Patients were randomly assigned (1:1) by use of an interactive web response system to subcutaneous semaglutide 1·0 mg once weekly or oral canagliflozin 300 mg once daily. The primary endpoint was change from baseline in HbA1c, and the confirmatory secondary endpoint was change from baseline in bodyweight, both at week 52. The primary analysis population included all randomly assigned patients, using on-treatment data collected before initiation of rescue medication. The safety analysis was done on a population that included all patients exposed to at least one dose of trial product. The trial was powered for HbA1c and bodyweight superiority under reasonable assumptions. This trial is registered with ClinicalTrials.gov, NCT03136484. Between March 15, 2017, and Nov 16, 2018, 788 patients were randomly assigned to semaglutide 1·0 mg (394 patients) or canagliflozin 300 mg (394 patients). 739 patients completed the trial (367 in the semaglutide group and 372 in the canagliflozin group). From overall baseline mean, patients receiving semaglutide had significantly greater reductions in HbA1c and bodyweight than those receiving canagliflozin (HbA1c estimated treatment difference [ETD] -0·49 percentage points, 95% CI -0·65 to -0·33; -5·34 mmol/mol, 95% CI -7·10 to -3·57; p<0·0001; and bodyweight ETD -1·06 kg, 95% CI -1·76 to -0·36; p=0·0029). Gastrointestinal disorders, most commonly nausea, were the most frequently reported adverse events with semaglutide, occurring in 184 (47%) of 392 patients; whereas infections and infestations (defined using the Medical Dictionary for Regulatory Activities, version 21.0), most commonly urinary tract infections, occurred more frequently with canagliflozin, in 136 (35%) of 394 patients. Premature treatment discontinuation because of adverse events occurred in 38 (10%) of 392 patients with semaglutide and in 20 (5%) of 394 patients with canagliflozin. One fatal adverse event confirmed unlikely to be caused by treatment occurred in the semaglutide group. Once-weekly semaglutide 1·0 mg was superior to daily canagliflozin 300 mg in reducing HbA1c and bodyweight in patients with type 2 diabetes uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices. Novo Nordisk.