A. Michael Lincoff, MD, Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University speaks about Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.
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CVD is a leading cause of morbidity and mortality in the United States. While it is widely accepted that obesity is a major risk factor for CVD, successful, long-term weight loss therapies and the effects of weight loss on lowering cardiovascular risk have remained elusive. Instead, drugs for managing lipids, hyperglycemia, blood pressure, heart disease, inflammation, and/or thrombosis have made progress in lowering CVD risk. Obesity has been linked to many of these problems, implying that sustained, successful weight loss may have a separate cardiovascular gain. GLP-1 receptor agonists (RAs) help people with diabetes lose weight, boost their glycemia, and reduce cardiovascular events. They can also have other cardioprotective effects. At a dosage of 2.4 mg subcutaneously (s.c.) once weekly, the GLP-1 RA semaglutide is in phase 3 trials as an obesity treatment. SELECT (Semaglutide Impact on Cardiac Disease and Stroke in Patients with Overweight or Obesity) is a randomized, double-blind, parallel-group study to see whether semaglutide 2.4 mg subcutaneously once weekly is better than placebo at preventing significant adverse cardiovascular events in patients with proven CVD and overweight or obesity but no diabetes when added to standard of care. SELECT is the first cardiovascular outcomes study to measure an antiobesity medication's superiority in reducing significant adverse cardiovascular conditions in this population. As a result, SELECT has the ability to advance novel approaches to lowering CVD risk while also addressing obesity.
Design and care of the overall sample
SELECT (NCT03574597, www.clinicaltrials.gov) is a randomized, double-blind, parallel-group, placebo-controlled study that compares semaglutide to placebo as an alternative to the standard of care for the prevention of major adverse cardiovascular events (MACE) in patients with existing CVD who are overweight or obese. Novo Nordisk is the main sponsor of the trial. Every participating center's institutional review board and ethics committee approved the trial protocol. Before any trial-related operation, all patients gave written informed consent.
Figure 1 portrays a high-level overview of SELECT's core design elements. Once-weekly subcutaneous (sc) semaglutide 2.4 mg or placebo is given to patients in a 1:1 ratio. Patients are started on a once-weekly dose of 0.24 mg, which is increased every four weeks (to doses of 0.5, 1.0, 1.7, and 2.4 mg/wk) before they hit the target dose of 2.4 mg after 16 weeks. To minimize the possibility of side effects, the procedure is versatile, allowing for prolonged escalation and treatment pauses if appropriate. The investigators will receive ongoing support from a Global Exert Panel, which is made up of local experts with experience in CVOTs and GLP-1RA use, and there will be a strong emphasis on educating and encouraging them during the trial. Since the most common side effects are gastrointestinal (nausea, vomiting, diarrhea, and constipation), manuals for clinicians and patients have been established and distributed. Overall, trial behavior places a heavy emphasis on maximizing trial product exposure. The management of cardiovascular risk factors is emphasized in the SELECT trial to ensure that patients meet international recommendations for quality of care. Investigators are given guidelines in the form of a standard-of-care document that is revised on a regular basis.
The patient is in touch with the investigator every 13th week during the trial to ensure retention and compliance, as well as to optimize care. During the first months of the study, site visits are more frequent to help the patient during the dose-escalation phase. Detailed tracking and recording of treatment pauses, missed visits, and possible loss of follow-up is done during the study. To ensure a high retention rate and ongoing support for investigators and patients involved in Pick, a number of mitigation steps have been introduced.
Numbers of people
Around 17,500 volunteers will be enrolled in the study from over 750 locations around the world, including locations on all six continents (Africa, Asia, Oceania, Europe, and North and South America). The first patient was randomized in November 2018, and the trial is planned to last 5 years, despite being event-driven. Patients must be at least 45 years old, have a BMI of 27 kg/m2, and have a history of CVD. Prior myocardial infarction (MI), prior ischemic or hemorrhagic stroke, symptomatic peripheral arterial disease (PAD) with an ankle-brachial index of less than 0.85 at rest, prior peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease are all examples of proven CVD. Patients with hemoglobin A1c (HbA1c) ≥48 mmol/mol (6.5%); with a history of type 1 or type 2 diabetes; or who had suffered MI, stroke, hospitalization for unstable angina pectoris, or a transient ischemic attack within 60 days of screening are excluded. The full eligibility requirements can be found in Table I. Patients who acquire diabetes during the study are held in the study and given concomitant diabetes medication (excluding other GLP-1 RAs) at the investigator's discretion.