Semaglutide’s health benefits may be linked to dose rather than weight loss
Higher doses of semaglutide were associated with significantly lower cardiovascular risk in patients with pre-existing cardiovascular disease, while the amount of weight loss achieved did not appear to predict subsequent cardiovascular protection, according to a large real-world analysis. This was according to a new article in the journal Nature.[1]
The findings raise the possibility that semaglutide's cardiovascular effects extend beyond weight reduction. This adds to growing clinical data showing how GLP-1 drugs are having a positive impact on patient health separate from weight loss outcomes.
"The degree of weight loss surprisingly did not correlate with cardiovascular protection as measured by all-cause mortality or multiple individual incident disease diagnoses," explained lead author Karthik Murugadoss, a data scientist with nference and its Metabolism Agentic Intelligence Atlas (MAIA) initiative. "In a direct comparison of semaglutide to other anti-diabetic medications, semaglutide was associated with reduced rates of multiple cardiovascular endpoints after treatment initiation."
He said the findings suggest a cardioprotective role of semaglutide which may be related to attained dose, but is not explained simply by the amount of weight loss achieved while on therapy.
Researchers analyzed de-identified electronic health record data from 47,199 patients with cardiovascular disease who were prescribed semaglutide. Of these, 12,519 had at least two years of follow-up and were included in an analysis examining semaglutide dose and weight loss, and cardiovascular outcomes over the next two years.
Patients who reached higher semaglutide doses (1.7 to 2.4 mg) experienced greater weight loss, averaging about 15% at the 2.4-mg dose compared with approximately 8% at 0.25 mg. Each 1-mg increase in maximum attained dose was associated with an estimated 3.15% greater weight loss.
However, the cardiovascular findings showed a different pattern. Compared with patients who remained at 0.25 to 1 mg, those reaching at least 1.7 mg had a 58% lower relative risk of all-cause mortality, a 49% lower risk of a composite of death, myocardial infarction or stroke, a 50% lower risk of incident cerebrovascular disease, and a 45% lower risk of incident heart failure during the following two years.
The level of weight loss was not significantly associated with all-cause mortality, composite cardiovascular events, cerebrovascular disease or heart failure. Greater weight loss was associated with improvements in hemoglobin A1c and blood pressure, suggesting that its metabolic benefits did not necessarily translate into the cardiovascular outcome differences observed with higher semaglutide doses.
Propensity-matched comparisons also favored semaglutide over other diabetes medications. Compared with metformin, semaglutide was associated with lower two-year rates of all-cause mortality, composite cardiovascular events, ischemic heart disease, cerebrovascular disease, hypertension and arrhythmias or conduction disorders. Similar patterns were observed in comparisons with DPP-4 and SGLT2 inhibitors.
Transcriptomic analyses found substantial GLP-1 receptor expression in cardiac tissue, with cardiomyocytes, endothelial cells and pericytes among the expressing cell populations. The heart had the second-highest prevalence-weighted GLP1R engagement potential after the pancreas and the largest aggregate GLP1R expression outside the pancreas, the authors wrote.
Overall, the results suggest that semaglutide's cardiovascular protection may be more closely related to therapeutic exposure or dose than to the amount of weight lost, supporting further research into potential direct cardiovascular mechanisms of GLP-1 receptor agonism.
"These studies from nference signal that longitudinal, AI-curated evidence can inform prospective studies in profound ways," said C. Michael Gibson, MD, professor of medicine at Harvard and CEO of the Baim Institute for Clinical Research, in a statement about the launch of the MAIA research projects in June. "The broad spectrum of weight-loss-independent benefits revealed by the first series of MAIA publications challenges long-held cardiometabolism assumptions that place glucose lowering and total body weight reduction at the center of therapeutic value. These findings reinforce that incretin biology is organ-specific, durable, and multidimensional."
The researchers cautioned that the retrospective study is subject to selection and ascertainment bias, unmeasured confounding and incomplete laboratory and physiologic data. The population also consisted exclusively of patients with pre-existing cardiovascular disease.
Another recent study showed semaglutide may be able to reduce a patient's risk of atrial fibrillation (AFib) beyond the impact on weight loss. This may be due to the drug helping reduce inflammation in cardiac tissue, opening a new research avenue for GLP-1s.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]