Semaglutide found to cut risk of MACE in overweight or obese adults

11th August 2023

Semaglutide has been found to reduce the risk of major adverse cardiovascular events (MACE) by 20% in overweight or obese adults, its manufacturer Novo Nordisk has claimed.

According to headline results from the SELECT study, the anti-diabetic drug semaglutide was able to cut the risk of overweight or obesity experiencing a MACE by 20% compared to placebo.

This randomised, double-blind, placebo-controlled trial, the results of which are yet to be published in a peer-reviewed journal, was designed to evaluate the efficacy of semaglutide 2.4 mg versus placebo, as an adjunct to standard of care, for the prevention of MACE, in overweight or obesity with no prior history of diabetes.

The primary endpoint of the study was defined as the composite outcome of the first occurrence of MACE defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

Commenting on the findings, Martin Holst Lange, executive vice president for development at Novo Nordisk, said: ‘People living with obesity have an increased risk of cardiovascular disease but, to date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke or cardiovascular death. Therefore, we are very excited about the results from SELECT showing that semaglutide 2.4 mg reduces the risk of cardiovascular events.‘

He added: ‘SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.‘

Semaglutide and MACE

SELECT enrolled 17,604 adults across 41 countries at more than 800 investigator sites and was initiated in 2018.

All participants had pre-existing cardiovascular disease, including a prior myocardial infarction (76.3%) or stroke (23.3%). In addition, enrolled participants were aged ≥45 years with a body mass index (BMI) ≥27 kg/m².

In total 1,270 first MACEs accrued. The trial achieved its primary objective by demonstrating a statistically significant and superior reduction in MACE of 20% for people treated with semaglutide 2.4 mg compared to placebo. In the trial, semaglutide 2.4mg appeared to have a safe and well-tolerated profile in line with previous semaglutide 2.4mg trials.

Naveed Sattar, professor of metabolic medicine at the University of Glasgow, said: ‘More details are needed on the trials to give it proper consideration, including examination of safety aspects, but even here the top line report also sounded optimistic. 

‘The one thing to caution is we do not know to what extent the weight loss effects of semaglutide as opposed to its other direct effects on blood vessels or the heart, account for the 20% reduction in cardiovascular events, and more data are needed to try to work this out.‘

For now, however, this is a good result for patients, especially as progressively more are living with obesity and cardiovascular disease.‘

Novo Nordisk expects to file for regulatory approvals of a label indication expansion for semaglutide 2.4 mg in the US and the EU later in 2023. The detailed results from SELECT will also be presented at a scientific conference later in the year.

In March, NICE recommended Wegovy for use as part of a patient’s treatment for obesity in an NHS specialist weight management service and with the support of a multi-disciplinary team.

Artificial sweetener erythritol use in cardiac patients associated with increased MACE risk

13th March 2023

A higher intake of erythritol is linked to an increased risk of a major cardiovascular adverse event in those undergoing cardiac evaluation

Elevated plasma levels of the artificial sweetener erythritol, in patients undergoing cardiac risk assessment is associated with an increased 3-year risk of a major cardiovascular event according to the findings of an analysis by an international research group.

Low calorie artificial sweeteners are widely found in food and drinks and some of the most thoroughly tested and evaluated of all food additives. However, there is some evidence to suggest a significant association between intake of artificially sweetened soda consumption and obesity and to an increased risk of all-cause mortality. Nevertheless, a 2017 scoping review was unable to offer conclusive evidence for either beneficial or harmful effects of artificial sweeteners on several adverse health outcomes.

Erythritol is a sugar alcohol and commonly used as a sugar substitute and there is actually data indicating how acute consumption improves small vessel endothelial function whereas chronic use reduces central aortic stiffness. In contrast, other work suggests an association between erythritol and incident diabetes. Despite these findings, little is known about the relationship between erythritol and both cardiovascular disease and atherothrombotic complications and this was the purpose of the current study. Researchers initially measured plasma levels of the artificial sweetener among US patients undergoing elective diagnostic cardiac evaluation (which they referred to as the ‘discovery cohort’) and then compared the findings with results obtained from a second US and European cohort also undergoing cardiac evaluation.

Erythritol levels and incident MACE

In the discovery cohort with 1,157 patients, circulating levels of erythritol, were associated with incident (3-year) risk for major adverse cardiovascular events, including death or nonfatal myocardial infarction or stroke (adjusted hazard ratio, aHR = 2.95, 95% CI 1.70 – 5.12, p < 0.001) when comparing the highest vs lowest plasma erythritol levels. Subsequent analysis in the US cohort also confirmed an increased risk of MACE (aHR = 1.80, 95% CI 1.18 – 2.77, p = 0.007) as well as the European cohort (aHR = 2.21, 95% CI 1.20 – 4.07, p = 0.010). In fact, for every 1 μM increase in plasma erythritol levels, there was a 21% and 16% increase in the adjusted HR for MACE in the US and European validation cohorts respectively (p < 0.001 and p = 0.005).

In trying to better understand the potential mechanisms behind these effects, the researchers also found that erythritol heightened platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a small study with 8 healthy subjects, ingestion of the sweetener produced elevated plasma levels which remained high for hours after ingestion and remained substantially elevated for over two days.

Although recognising a limitation of the study in that the data were obtained from patients with a high prevalence of cardiovascular disease and with traditional risk factors, the authors concluded that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis.

Citation
Witkowski M et al. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 2023

High triglyceride:HDL cholesterol ratio and CTA risk score predict heart disease risk in stable angina

1st November 2021

A high triglyceride:HDL cholesterol ratio and CTA scores in patients with stable angina are associated with worse cardiac outcomes over time.

A high triglyceride-HDL cholesterol ratio (TG-HDL-C) and a high computed tomography angiography (CTA) score have been found to be independently associated with worse cardiac outcomes in a group of patients with stable angina. These are the findings of a multinational, prospective, observational study undertaken across seven European countries by a team from the Institute of Clinical Physiology, Pisa, Italy. Traditionally, for patients with known or suspected coronary artery disease, a standard lipid profile is conducted measuring total cholesterol, high density lipoprotein (HLD), low density lipoprotein (LDL) and triglycerides. While much attention has focused in treatment guidelines on a lowering of LDL cholesterol levels as means reducing cardiovascular risk, in recent years, emerging evidence suggests that a higher TG-HDL-C ratio is correlated with an increased risk of major CV events, even in the presence of low LDL cholesterol.

Nevertheless, whether the cardiovascular profile characterised by a high TG-HDL-C is associated with adverse events over the longer term is unknown and was the objective of the work undertaken by the Italian team. The study population came from the EVINICI cohort, in which patients with stable chest pain or equivalent symptoms and an intermediate risk of coronary artery disease, were referred for computed tomography and a smaller cohort were invited for a follow-up scan. For all participants, data on cardiovascular risk factors such as age, gender, family history of coronary heart disease, smoking status, co-morbidities etc were collected. In addition, measurement of cholesterol sub-fractions (e.g., HDL-C) and individual’s triglycerides levels were undertaken at baseline and after being followed up. The researchers set the primary outcome as a combination of major adverse events (AEs), including all-cause death and non-fatal myocardial infarction.

Findings

A total of 355 individuals with a mean age of 60 years (59% male) were included in the analysis. The overall baseline mean triglyceride:HDL cholesterol ratio was 2.78 and the mean CTA score 11.53. In addition, the majority of individuals had atypical chest pain (60%) or typical angina (25%).

A total of 154 patients were followed up over median duration of  4.5 years, during which time, 25 patients (7%) experienced a major AE including 8 deaths and 17 non-fatal myocardial infarctions. While over the follow-up period, mean LDL cholesterol levels were significantly reduced (106 vs 94, p = 0.0004), there was a significant increase in the TG-HDL-C ratio (2.49 vs 2.96, p = 0.0027), as well as an increase in mean CTA scores (11.02 vs 12.94, p < 0.0001). Using multivariate analysis, higher TG-HDL-C ratios were an independent predictor of prognosis (adjusted Hazard ratio, aHR = 2.51, 95% CI 1.09 – 5.81, p = 0.03) as was the CTA score (aHR = 1.06, 95% CI 1.03 – 1.11, p = 0.0006).

Commenting on these findings, the authors suggested that the TG-HDL-C ratio could be used as is a simple method to identify those individuals with a substantial residual coronary risk not tackled by current treatments. They concluded that a high triglyceride and  a low HDL-C levels are associated with coronary artery disease related outcomes independent of both LDL-C and treatments.

Citation

Csselli C et al. Triglycerides and low HDL cholesterol predict coronary heart disease risk in patients with stable angina. Sci Rep 2021