Semaglutide Seems to Reduce MACE & Death Rates for Certain Participants

SOURCE: Semaglutide Reduces MACE, Death in Participants With CVD, Overweight/Obesity, and Impaired Kidney Function

A recent subgroup analysis from the SELECT trial has demonstrated that semaglutide (Wegovy) significantly reduces major cardiac events, including death, in adults with overweight or obesity and cardiovascular disease (CVD), regardless of kidney function. The analysis revealed that participants with impaired kidney function experienced a 31% reduction in major adverse cardiovascular events (MACE) and a 33% lower risk of MACE or death from any cause when treated with semaglutide.

“These findings have important clinical implications,” said Dr. Helen Colhoun from the University of Edinburgh, presenting the results at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting. She noted that both reduced eGFR (estimated glomerular filtration rate) and albuminuria are well-established risk factors for cardiovascular events, and that individuals with impaired kidney function are at increased risk for CVD. The results suggest that semaglutide effectively reduces this risk.

SELECT Trial Overview

The SELECT trial previously reported a 20% reduction in the risk of MACE or cardiovascular-related death in people with overweight or obesity, CVD, but without diabetes, who were treated with semaglutide over three years. These participants also experienced an average weight loss of 9.4%.

In the study, 17,604 adults with a BMI of 27 kg/m² or higher (mean BMI of 33 kg/m²) and a history of CVD were enrolled from 41 countries. Participants received either weekly semaglutide (2.4 mg) or a placebo, with a median follow-up period of 3.5 years.

Of the total population, 11.1% of those taking semaglutide had impaired kidney function (eGFR < 60 mL/min/1.73 m²), compared with 10.7% on placebo. Additionally, 12% of semaglutide users had elevated levels of albuminuria (UACR of 30 to < 300 mg/g), compared with 11% of those on placebo.

The primary endpoint of the trial was MACE (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), while a secondary endpoint was the combined effect on MACE and death from any cause.

Consistent Cardiovascular Benefits

Participants with normal kidney function (eGFR ≥ 60 mL/min/1.73 m²) who were treated with semaglutide had an 18% reduction in MACE (6.0% versus 7.3% for placebo) and an 18% reduction in MACE or death from any cause (7.5% versus 9.0%). In contrast, those with impaired kidney function saw even greater benefits, with a 31% reduction in MACE (9.7% versus 13.5%) and a 33% reduction in MACE or death (12.6% versus 17.9%).

Dr. Colhoun highlighted that the results for those with impaired kidney function were just as promising as for those with normal kidney function, reassuring clinicians about the drug’s efficacy in this high-risk group.

Semaglutide also reduced MACE risk by 20% in individuals with either normal albumin levels or albuminuria. For participants with a UACR < 30 mg/g, the MACE event rate was 5.9% with semaglutide compared to 7.3% with placebo. Among those with a UACR ≥ 30 mg/g, the event rate was 9.9% versus 12.3%.

No Additional Safety Concerns

Importantly, there were no new safety concerns for participants with reduced eGFR or albuminuria.

Commenting on the results, comoderator Dr. Fiona Gribble of the University of Cambridge remarked, “The data clearly show that semaglutide is effective in patients with impaired kidney function.” Fellow moderator Dr. Jens Holst of the University of Copenhagen added that while the greater effect size in individuals with impaired kidney function might be harder to interpret, the overall results are encouraging.

Holst also noted that the link between improved kidney function and reduced cardiovascular risk is increasingly recognized, with this study providing further evidence that addressing one condition can benefit the other.

UPDATE:

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist primarily used for the treatment of type 2 diabetes, chronic weight management, and reducing the risk of major adverse cardiovascular events (MACE). MACE typically includes cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Several clinical trials have explored the relationship between semaglutide and MACE. The SUSTAIN 6 and PIONEER 6 trials demonstrated that semaglutide could significantly reduce the risk of MACE in patients with type 2 diabetes at high cardiovascular risk. In SUSTAIN 6, semaglutide showed a 26% reduction in MACE compared to placebo, confirming its cardiovascular safety and providing evidence for potential benefits. PIONEER 6, which tested the oral form of semaglutide, also confirmed non-inferiority for cardiovascular safety while hinting at a reduction in MACE risk, though not statistically significant for superiority.

The SELECT trial extended these findings to populations with overweight or obesity and established cardiovascular disease but without diabetes. Results indicated a 20% reduction in MACE compared to placebo, highlighting semaglutide’s broad cardiovascular benefits.

Furthermore, the SOUL trial specifically investigated oral semaglutide in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease or chronic kidney disease. It confirmed a 14% reduction in MACE, supporting the use of semaglutide for cardioprotection in this specific patient subset.

Semaglutide’s mechanism of action includes insulin secretion enhancement, glucagon suppression, and reduction in appetite, which collectively contribute to weight loss, improved glycemic control, and cardiovascular benefits. While generally well-tolerated, side effects like nausea and gastrointestinal issues have been noted, especially in the early stages of treatment. These trials underscore semaglutide’s role not only in diabetes management but also in reducing cardiovascular risks across diverse patient populations.