SELECT Trial: Semaglutide Improves Glycemic Control For Patients at High Risk of Cardiovascular Disease

At the ADA 84th Scientific Sessions, new data from the SELECT (NCT03574597) trial shows semaglutide’s effect on glycemia, inflammation, and heart failure, demonstrating that the drug improved glycemic control in those at high risk of cardiovascular disease (CVD) and without diabetes.¹

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Previously reported data from the trial showed that weight loss was sustained over 4 years, which increased the confidence in safety and efficacy for patients using semaglutide. The findings also reported that there was a 20% reduction in major adverse cardiac events for adults who had a body mass index greater than 27 and pre-existing CVD.²

“More than 55% of semaglutide patients no longer qualified as having obesity [body mass indext (BMI) 30+]. The dataset adds significantly to the semaglutide evidence–the population had 75% men and most weight loss studies are predominantly in women,” Donna Ryan, MD, professor emeritus at the Pennington Biomedical Research Center, said in an interview with Pharmacy Times.2

There were 17,604 individuals enrolled in the trial from 41 countries between October 2018 and March 2021. In the session, Ryan reported that 97.1% of those receiving semaglutide completed the trial compared with 96.8% on the placebo. Further, approximately 77% of patients met the target dose of 2.4 milligrams subcutaneously weekly by 104 weeks at 2 years. For the primary outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, there were 569 events in the semaglutide arm compared with 701 events in the placebo arm, equaling a relative risk reduction of approximately 20%, according to Ryan.^1,2

“All subgroups that we looked at, there was this consistent benefit for the semaglutide treatment compared to placebo in terms of our primary end point,” Ryan said.¹

However, she reported that in the semaglutide group, there were 223 events of deaths due to cardiovascular events and 62 in the placebo group. Therefore, she stated that it’s not statistically confirmatory that semaglutide is associated with reduction in death from cardiovascular causes.¹

As for the glycemic outcomes, hemoglobin A1c (HbA1c) was evaluated at 20 weeks, and then annually after that. Investigators were observing the cumulative incidence of diabetes and the time to the first occurrence of a HbA1c greater than 6.5%. Further, at each time point, investigators classified the patient’s glycemia as normoglycemia (HbA1C of less than 5.7%), prediabetes (5.7% to 6.5%), and diabetes (6.5% or greater).^1,3

In this analysis, the majority of patients were aged 55 years to 75 years, with the majority being male and White. BMI was consistent with obesity, well controlled blood pressure, HbA1c of approximately 5.78% on average, and estimated glomerular filtration rate that was fairly normal, according to Steven E Kahn, MB, ChB, from the University of Washington, in the session.^1,3

For the baseline HbA1c at 20 weeks, the mean was approximately 5.8%. Kahn stated that semaglutide reduced HbA1c to below 5.5%, but overtime there was a slight increase of HbA1c. The results showed that semaglutide improved glycemic control in those at high risk of CVD but without diabetes, but over time HbA1c increased though it was parallel for both the treatment and placebo group.¹

However, individuals developed diabetes over time, but the semaglutide arm was significantly lower than the placebo arm, with an approximate 73% reduction risk in development of diabetes.¹

“if we looked at that subgroup that had the highest HgA1c to start with, so they're bordering right on the cut point for diabetes ... the cumulative incidence of diabetes is far greater, which makes total sense that [of] everybody this group that had the highest hemoglobin anyone sees at baseline,” Kahn said. “So that at about 3 years, 25% of them had developed diabetes in the placebo arm compared [with] about 5% in those individuals who were on semaglutide, [with a] hazard ratio of 0.23, or a 77% risk reduction.”¹

Kahn stated that, for those with prediabetes who received semaglutide, a smaller proportion progressed to diabetes, with a greater proportion regressing to normoglycemia. Further, the results showed that weight loss could explain about 30% of the beneficial effects of the drug on glycemia.¹

Additionally, at 20 weeks, 62% of individuals on semaglutide lost at least 5% of their body weight compared with 10% in the placebo group. However, the CV benefits with semaglutide were observed in both those who had significant weight loss and those who were overweight, so investigators concluded that weight loss was not the driving factor of CV benefits.¹

The reductions of MACE had no differences observed by investigators across the baseline HbA1c subgroups Further, the reduced likelihood of an event across HbA1c subgroups were observed with semaglutide across all CV end points, including MACE, MACE with all-cause mortality, individuals components of MACE, heart failure composite, and hospitalization and urgent care visits related to heart failure. Lastly, semaglutide reduced the risk of all-cause mortality in the subgroups.⁴

Overall, approximately 54% of individuals in the semaglutide group had a reduction in HbA1c of less than 0.3 percentage-points, according to the results of the sub analysis.⁴

Ildiko Lingvay, MD, MPH, MSCS, from the University of Texas Southwestern Medical Center, concluded that the CV benefits were independent of baseline HbA1c and the magnitude of change in hbA1c. Further, Lingvay said that the findings were anticipated across glycemic continuum, including those with normal hbA1c, and even when there was no improvement in HbA1c.¹

Of those with heart failure at enrollment, semaglutide showed the risk of MACE and heart failure composite was reduced. Further, the CV benefits with the drug were seen among patients with heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.¹

References

1. McGuire DK, Ryan DH, Kahn SE, Lingvay I, Plutzky J, Misra M. SELECT Trial—New Looks at Glycemia, Inflammation, and Heart Failure. Presented At: ADA 84th Scientific Sessions; June 21-June 24, 2024; Orlando, Florida.

2. Gallagher A. Semaglutide Shows Sustained Weight Loss Over 4 Years. Pharmacy Times. May 28, 2024. Accessed June 22, 2024. https://www.pharmacytimes.com/view/semaglutide-shows-sustained-weight-loss-over-4-years

3. Kahn SE, Deanfield JE, Jeppesen OK, Emerson SS, et al. Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial. Diabetes Care. 2024;47(00):1–10. doi:https://doi.org/10.2337/dc24-0491

4. Lingvay I, Deanfield J, Kahn SE, Weeke PE, et al. Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT. Diabetes Care. 2024;47(8):1–10. doi:https://doi.org/10.2337/dc24-0764