Gastrointestinal adverse effects
On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”
“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”
He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.
Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”
Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”
He noted that the semaglutide dose used in this study was larger than that used in diabetes.
“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
Just weight loss or other actions too?
Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.
“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”
In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.
Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.
Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”
She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”