SELECT ‘legitimized obesity medical therapy’ for treatment of cardiometabolic disease
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Key takeaways:
- SELECT cemented weight pharmacotherapy as a path for CV risk reduction.
- Researchers presented multiple hypothesis-generating subanalyses of semaglutide across the cardiometabolic and renal spaces.
SAN ANTONIO — The disruptive SELECT trial not only bolstered the idea of medical obesity therapy as an avenue for heart disease prevention, its subanalyses continue to generate interesting new hypotheses, speakers reported.
SELECT was a randomized trial to evaluate once-weekly semaglutide 2.4 mg (Wegovy, Novo Nordisk) compared with placebo for the reduction of secondary major adverse CV events in a cohort of 17,604 adults with CVD and overweight or obesity without diabetes over nearly 40 months of follow-up (28% women).
As Healio previously reported, once-weekly semaglutide 2.4 mg was associated with significantly fewer secondary cardiovascular disease events in this patient population.
During a session at ObesityWeek, researchers presented five post hoc analyses evaluating cardiovascular outcomes across various SELECT subgroups.
Kicking off the session, Donna H. Ryan, MD, FTOS, MABOM, professor emerita at Pennington Biomedical Research Center at Louisiana State University, said the SELECT trial, the first study to show the cardiovascular benefits of an obesity medication in patients with obesity and prior CVD without diabetes, was an opportunity to evaluate semaglutide 2.4 mg compared with placebo on weight, glycemia, CVD and safety, and to examine intermediate endpoints such as inflammation.
“To summarize why SELECT is such a noteworthy study: No 1, it was designed with rigor. No. 2, it was executed with precision. What that means is that we have evidence that we can trust. And, it was the first time we actually demonstrated that medical treatment for obesity resulted in disease modification in the reduction of cardiovascular events,” Ryan said during the presentation.
Ryan said that while SELECT was not only attitude-changing in “legitimizing medical obesity treatment as a pathway for disease modification,” secondary analyses of the trial, such as those presented during the session, are interesting and hypothesis-generating.
Safety of semaglutide vs. placebo
Robert F. Kushner, MD, professor of medicine and medical education at Northwestern University Feinberg School of Medicine, presented safety data of semaglutide compared with placebo in the SELECT trial, with a focus on serious adverse events, all adverse events leading to treatment discontinuation and prespecified adverse events of special interest.
Kushner and colleagues reported a lower proportion of serious adverse events in the semaglutide arm of SELECT compared with placebo (33.4% vs. 36.4%; P < .001), which was primarily driven by cardiac disorders (11.5% vs. 13.5%; P < .001). However, the proportion of adverse events leading to treatment discontinuation was higher in the semaglutide arm compared with placebo (16.6% vs. 8.2%; P < .001), which was driven by gastrointestinal disorders (10% vs. 2%), according to the presentation.
The proportion of serious adverse events leading to treatment discontinuation were similar between the two groups (semaglutide, 3.6%; placebo, 4.1%).
In addition, suicide and/or self-injury serious adverse events were not common and occurred in a similar proportion of patients in both groups — 0.11% in both groups. Moreover, gallbladder-related disorders occurred in a higher proportion of the semaglutide groups compared with placebo (2.8% vs. 2.3%; P = .04), which was driven by cholelithiasis (1.4% vs. 1.1%). The proportion of patients who experienced cholecystitis was similar in both groups (0.6% vs. 0.6%).
“Compared to placebo, [serious adverse events] were lower in the semaglutide group, and were largely driven by CV events,” Kushner said during the presentation. “Consistent with other GLP-1 [receptor agonist] studies, gastrointestinal disorders were the most commonly reported [adverse events] leading to trial product discontinuation, with most occurring during the dose-escalation period.
“There were no unexpected safety concerns and no difference between groups in reporting serious psychiatric disorders, including suicide and self-injury. I did not [present these data] but] acute pancreatitis or malignant neoplasms were also no different between the two groups,” he said.
HF, CV outcomes by body weight and mortality
A. Michael Lincoff, MD, vice chairman for research at the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic, presented secondary analyses on the effect of semaglutide on death and heart failure and the relationship between weight loss and CV benefit.
Overall, semaglutide was associated with lower risk for all-cause death (HR = 0.81; 95% CI, 0.71-0.93), CV death (HR = 0.85; 95% CI, 0.71-1.01) and non-CV death (HR = 0.77; 95% CI, 0.62-0.95), the common cause of which was death from infection (HR = 0.71; 0.51-0.98), according to the study.
Although patients with HF in the SELECT trial had higher rates of adverse events compared with those without HF, semaglutide was associated with lower risk for adverse CV outcomes (HR = 0.72; 95% CI, 0.6-0.87) and a composite of CV death, hospitalization or other urgent HF medical visit in patients with HF compared with placebo (HR = 0.79; 95% CI, 0.64-0.98).
Additionally, compared with the placebo group, in the semaglutide group, major adverse CV events were reduced in patients who lost a least 5% of their body weight by week 20 (HR = 0.67; 95% CI, 0.52-0.87) as well as in those who lost less than 5% or gained weight by week 20 (HR = 0.85; 95% CI, 0.72-1), Lincoff said, noting that this indicates semaglutide improves CV outcomes compared with placebo regardless of its effect on weight.
Glycemic and renal subgroup analyses
Ildiko Lingvay, MD, MPH, MSCS, professor of medicine at UT Southwestern Medical Center in Dallas, reported on the longer-term weight loss benefits of semaglutide as well as the glycemic and kidney benefits.
Lingvay reported that at 208 weeks, semaglutide was associated with an average weight loss of 10.2%, a waist circumference decrease of 7.7 cm and reduction in waist-to-height ratio of 6.9%, whereas those assigned to placebo averaged a 1.5% weight loss, a waist circumference decrease of 1.3 cm and 1% reduction in waist-to-height ratio (P for all < .0001).
At 156 weeks, a greater proportion of patients assigned to semaglutide had normoglycemia compared with those assigned placebo (69.5% vs. 35.8%; P < .0001), with a number needed to treat of 18.5 to prevent one case of diabetes, Lingvay said.
The researchers reported that the magnitude of weight reduction mediated approximately 24.5% of the progression to diabetes and 27.1% of diabetes regression.
Moreover, incidence of the composite endpoint of death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73m2, persistent 50% or more reduction in eGFR or onset of persistent macroalbuminuria, was lower with semaglutide compared with placebo (1.8% vs. 2.2%; HR = 0.78; 95% CI, 0.63-0.96; P = .02).
Participants treated with semaglutide had an eGFR benefit of 0.75 mL/min/1.73m2 (P < .001) compared with placebo and among patients with baseline eGFR of less than 60 mL/min/1.73m2, the benefit was larger at 2.19 mL/min/1.73m2 (P < .001), according to the study.
Inflammatory markers and CV outcomes
Jorge Plutzky, MD, Brigham and Women’s Hospital Pollin Center director, presented the results of a SELECT subanalysis overviewing the drug’s impact on inflammatory markers, specifically high-sensitivity C-reactive protein (hsCRP), which is associated with future CV risk.
In the SELECT trial, baseline hsCRP was similar between semaglutide and placebo groups, most of whom were on statins, according to the study.
Semaglutide was associated with 37.8% lower hsCRP at 104 weeks compared with placebo, which is significantly prognostic of future major adverse CV events such as myocardial infarction, CV death and all-cause mortality, and reduced CV risk in each hsCRP group as compared with placebo, Plutzky said.
In addition, more weight loss was associated with greater reductions in hsCRP among patients assigned to semaglutide.
The impact of semaglutide on hsCRP occurred early on in treatment and was independent of LDL, statin use and CVD entry criteria, according to the study.
Predictors of weight loss with semaglutide
Lingvay presented a study that evaluated models designed to quantify the relative contribution of baseline predictors of weight loss with semaglutide.
The researchers reported that the average percentage weight loss among SELECT participants assigned to semaglutide was 13.5%.
Lingvay reported that female sex, lower baseline eGFR, age and diastolic BP, and higher BMI were prognostic of greater peak percentage weight loss among patients assigned to semaglutide (R square = 0.0919). A model that only included sex as a predictor of weight loss provided 88% of predictive information provided by the full model (R square for sex alone = 0.0812), according to the study.
Moreover, Lingvay reported that participants who received the highest doses of semaglutide achieved the highest percentage of body weight loss, regardless of sex.
“Among SELECT study participants who remained on semaglutide for at least 1 year, the peak percentage body weight loss of 13.5%, but was achieved at a median of 19 months after initiation. So don’t rush it,” Lingvay said during the presentation. “Only 9% of the variability in peak body weight-loss could be explained using baseline characteristics. In fact, sex explained 8% of the variability. It’s not very helpful, but we suspected that.
Greater peak body weight loss was achieved with higher doses of semaglutide. So that confirms the dose-dependent relationship of body weight loss in this population.”
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Ryan DH, et al. SELECT cardiovascular outcomes trial: Old lessons and new learnings. Presented at: ObesityWeek; Nov. 3-6, 2024; San Antonio.
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