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Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (EX9536-4388) (SELECT)

Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT)

17609

The mean age of the subjects at baseline was 61.6 years and 72.3% of subjects were male. Around 10% were of Hispanic or Latino ethnicity. The most prevalent races were White (84.0% of subjects), Asian (8.2% of subjects) and Black or African American (3.8% of subjects). Most subjects were from the European region (38.0%) followed by North America (25.0%, hereof 20.7% recruited from sites in the United States). The majority (67.6%) of the subjects were enrolled in the trial based on prior MI only, 17.8% were enrolled based on prior stroke only, 4.4% were enrolled based on PAD only and 8.2% fulfilled more than one of these qualifying criteria

In total, 96.9% of randomised subjects in the FAS completed the trial (attended the FU visit or died while considered active in the trial). Vital status was available for 99.4% of subjects in the trial. A total of 543 randomised subjects (3.1%) did not complete the trial due to either withdrawal of consent or being LTFU. The number of non-completers was balanced between treatment groups and vital status was obtained for 434 (approximately 80%) of the non-completers at the end of the trial.

The safety profile of semaglutide 2.4 mg once weekly, added to standard of care, in subjects with established CVD and overweight or obesity was similar to the general population with overweight and obesity as evaluated in the phase 3a development weight management programme (STEP programme). No new safety concerns were identified.The key safety results are summarised below: Deaths -The proportion of subjects with SAEs having a fatal outcome and the corresponding event rate were lower with semaglutide 2.4 mg than with placebo. -The types of SAEs with a fatal outcome were generally similar with semaglutide 2.4 mg and placebo, whereas lower frequencies were observed with semaglutide 2.4 mg vs placebo for fatal events within the SOCs of Cardiac disorders, Infections and infestations, and General disorders and administration site conditions. Serious adverse events -The proportion of subjects reporting SAEs, including events with fatal outcome, were lower with semaglutide 2.4 mg than with placebo. -Most of the reported SAEs were of severe or moderate severity, had recovered at the end of the trial, and most were assessed by the investigator as unlikely related to trial product, both with semaglutide 2.4 mg and placebo. -The distribution of SAEs within each SOC was balanced or favouring semaglutide 2.4 mg. Safety focus areas -Generally, the evaluation of the safety focus areas showed that the safety profile of semaglutide 2.4 mg was consistent with the known safety profile of semaglutide. -The proportion of subjects reporting SAEs of Cardiovascular disorders (SOC) was lower with semaglutide 2.4 mg than placebo. -The proportion of subjects reporting SAEs Gastrointestinal disorders (SOC) was similar with semaglutide 2.4 mg than placebo. -Similar proportion of subjects in each treatment group reported AEs of acute renal failure (MedDRA search), malignant neoplasms (MedDRA search), pancreatitis (MedDRA search) and COVID-19 (MedDRA search). -The proportion of subjects reporting AEs of Gallbladder-related disorders (MedDRA search) was higher with semaglutide 2.4 mg than placebo, mainly driven by an imbalance in cholelithiasis (PT). Clinical laboratory evaluations -Overall, there were no noteworthy treatment group differences in haematology or biochemistry parameters (not part of a safety focus area). Safety in special groups and situations -The safety profile of semaglutide 2.4 mg was not affected to any clinically relevant extent by intrinsic factors (sex,baseline age, race, ethnic origin, baseline BMI, baseline kidney function, baseline HbA1c, baseline chronic HF status and baseline CVD status) or extrinsic factors (region). -There were no safety concerns for subjects within the semaglutide 2.4 mg group who lost 20% or more of their body weight during the trial, who had post-baseline hypotension, or who had increase in heart rate of >20 bpm during the trial, compared to those who did not. -Overall, the results from this trial were consistent with observations for the general population with overweight and obesity as evaluated in the phase 3a development weight management programme (STEP programme), in which it was concluded that no dose adjustment is warranted in any selected population.

Superiority of semaglutide 2.4 mg vs placebo was confirmed for the primary endpoint of time to first EAC-confirmed MACE, comprising CV death, non-fatal MI and non-fatal stroke. - The primary analysis of time to first EAC-confirmed MACE resulted in an estimated HR of 0.80 [0.72; 0.90]95% CI (p<0.0001) for semaglutide 2.4 mg relative to placebo. - The result of the primary analysis of MACE was supported by all prespecified sensitivity analyses and consistent results were seen across all subpopulations investigated. - Time to first event analysis of other composite CV endpoints provided results consistent with the primary endpoint, supporting the robustness of the primary analysis. - All-cause death, non-fatal MI or non-fatal stroke: Estimated HR 0.80 [0.72; 0.88]95% CI -Expanded MACE (3-component MACE, UAP requiring hospitalisation or coronary revascularisation): Estimated HR 0.80 [0.73; 0.87]95% CI

Superiority of semaglutide 2.4 mg vs placebo was not confirmed for the confirmatory secondary endpoint of time to EAC-confirmed CV death:The confirmatory analysis of time to EAC-confirmed CV death resulted in an estimated HR 0.85 [0.71; 1.01]95% CI for semaglutide 2.4 mg relative to placebo. - Superiority of semaglutide 2.4 mg vs placebo for the confirmatory secondary endpoint of time to first EAC-confirmed composite HF outcome endpoint was not tested: The confirmatory analysis of time to first EAC-confirmed composite HF outcome endpoint resulted in an estimated HR 0.82 [0.71; 0.96]95% CI for semaglutide 2.4 mg relative to placebo. - Superiority of semaglutide 2.4 mg vs placebo for the confirmatory secondary endpoint of time to EAC-confirmed allcause death was not tested:The confirmatory analysis of time to EAC-confirmed all-cause death resulted in an estimated HR 0.81 [0.71; 0.93]95% CI for semaglutide 2.4 mg relative to placebo. - The potential effect of semaglutide 2.4 mg on kidney function in people with overweight and obesity was assessed by time from randomisation to first occurrence of a 5-component composite nephropathy endpoint, as a supportive secondary endpoint. The composite nephropathy endpoint comprised: onset of persistent macroalbuminuria (UACR >300 mg/g), persistent 50% reduction in eGFR compared with baseline (randomisation), onset of persistent eGFR <15 ml/min/1.73 m2, initiation of chronic renal replacement therapy (dialysis or transplantation) or renal death. The risk of deterioration in kidney function was lower with semaglutide 2.4 mg than with placebo (HR of 0.78 [0.63; 0.96]95% CI). - The 2-year treatment effect of semaglutide 2.4 mg vs placebo in subjects with established CV disease and overweight or obesity was evaluated on cardiometabolic risk factors. Beneficial effects in favour of semaglutide 2.4 mg vs placebo were seen for most cardiometabolic risk factors investigated.

This trial demonstrated superiority of semaglutide 2.4 mg once weekly vs placebo with a clinically relevant reduction of 20% in MACE risk in people with established CV disease and overweight or obesity. The safety profile of semaglutide 2.4 mg in subjects with established CV disease and overweight or obesity is in line with the safety profile previously reported for semaglutide. No new safety concerns were identified for semaglutide 2.4 mg.

Nov. 11, 2023

https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

Yes

-

Okada Takumi

Novo Nordisk Pharma Ltd.

Meiji Yasuda Seimei Bldg., 2-1-1, Marunouchi, Chiyoda-ku, Tokyo

JPHC_clinical_trials@novonordisk.com

clinical tiral infomartion register

Novo Nordisk Pharma Ltd.

Meiji Yasuda Seimei Bldg., 2-1-1, Marunouchi, Chiyoda-ku, Tokyo

+81-3-6266-1000

JPHC_clinical_trials@novonordisk.com

completed

Oct. 24, 2018

Interventional

Randomised, double-blind, parallel group, multi-center

treatment purpose

3

-Male or female, age >= 45 years at the time of signing informed consent
-Body mass index (BMI) >= 27 kg/m2
-Have established CV disease as evidenced by at least one of the following:
prior myocardial infarctionprior stroke(ischemic or haemorrhagic stroke) orsymptomatic peripheral arterial disease(PAD),as evidenced by intermittent claudication with ankle-brachial index(ABI)<0.85 (at rest),orperipheral arterial revascularization procedure, or amputation due to atherosclerotic disease

-Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
-HbA1c >=48 mmol/mol (6.5 %) as measured by the central laboratory at screening
-History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)

Both

Overweight or obesity

investigational material(s)
Generic name etc : NN9535
INN of investigational material : -
Therapeutic category code : 249 Other hormone preparations (including antihormone preparations)
Dosage and Administration for Investigational material : once weekly subcutaneously

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Reduction of risk of Major adverse cardiovascular events.

efficacy
Reduction of risk of other adverse cardiovascular events.

+81-72-696-0571

Aug. 17, 2018