Studies show benefits of glucagon-like peptide-1 receptor agonists
A commentary reviewed the findings of REWIND, PIONEER 6, and PIONEER 4 trials, which studied the cardiovascular and glycemic control effects of dulaglutide, semaglutide, and liraglutide.
Three different industry-funded studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recently analyzed in ACP Journal Club.
The REWIND trial, published by The Lancet on June 9, included 9,901 type 2 diabetes patients at least 50 years of age who had either a previous cardiovascular (CV) event or CV risk factors. They were randomized to weekly subcutaneous injection of dulaglutide or placebo. After a median follow up of 5.4 years, the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes was significantly lower in the dulaglutide group.
The PIONEER 4 trial, published by The Lancet on June 8, included 711 patients on a stable dose of metformin with or without a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. They were randomized to once-daily oral semaglutide, subcutaneous liraglutide, or placebo for one year. The study found oral semaglutide to be noninferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c levels, and superior to both in decreasing weight.
The PIONEER 6 trial, published by the New England Journal of Medicine on Aug. 29, included 3,183 patients at high CV risk who were randomized to oral semaglutide or placebo for 16 months. The study found that oral semaglutide did not increase risk for CV events compared with placebo.
The following commentary by Lorraine L. Lipscombe, MD, MSc, was published with all three study recaps in the ACP Journal Club section of the Sept. 17 Annals of Internal Medicine.
The REWIND, PIONEER 6, and PIONEER 4 trials provide evidence for benefits of GLP-1RAs for treating type 2 diabetes. GLP-1RAs have several benefits beyond glucose lowering, such as weight loss and negligible hypoglycemia risk, which make them an attractive treatment option for patients with type 2 diabetes. With results from REWIND, we now have evidence that 3 GLP-1RAs on the market are also associated with CV benefit in patients with, or at high risk for, CV disease.
Liraglutide was the first GLP-1RA shown to reduce risk for CV events in a population of whom the majority had CV disease and high CV risk (4-y placebo event rate 15%). A subsequent trial showed that subcutaneous semaglutide reduced risk for CV events in a lower-risk population (4-y placebo event rate 8.9%), and its weekly administration offered greater convenience than daily liraglutide for some patients. The REWIND trial showed that another weekly GLP-1RA, dulaglutide, reduced risk for major CV events in patients at substantially lower CV risk than in other trials—only 32% of patients had CV disease, and the 5-year placebo event rate was 2.7%. These findings suggest that the CV benefits of GLP-1RAs probably extend to patients with type 2 diabetes and CV risk factors, rather than only patients with CV disease.
As with the CV benefits of some SGLT2 inhibitors, the CV benefits of GLP-1RAs are probably not a result of glucose lowering alone. Both GLP-1RAs and SGLT2 inhibitors have beneficial effects on weight and blood pressure, and GLP-1RAs may also improve endothelial function, endothelial cell responses to ischemia, and platelet function.
All approved GLP-1RAs are administered by subcutaneous injection, which, along with cost and gastrointestinal side effects, remains a barrier to their use. However, evidence is accumulating for the safety and efficacy of oral semaglutide, the first orally administered GLP-1RA. It has been shown to be superior to the commonly used oral medication, sitagliptin, for HbA1c and weight reduction. Results of PIONEER 6 provide evidence of the CV safety of oral semaglutide. Patients who received oral semaglutide had nonsignificantly lower rates of CV events and death than placebo-treated patients, with relative risk reductions comparable to those of REWIND and other GLP-1RA trials. Although noninferiority was confirmed, statistically significant CV superiority was not shown. Because the trial was designed to test for noninferiority, its short duration (16 mo) and low number of events probably limited the power to determine a CV benefit of oral semaglutide.
PIONEER 4 was the first trial to directly compare oral semaglutide with another GLP-1RA. Compared with liraglutide, the most commonly used GLP-1RA, oral semaglutide showed a similar reduction in HbA1c and, surprisingly, greater weight loss. Gastrointestinal side effects and discontinuation rates were similar between the 2 treatments, making oral semaglutide—once it is approved—a comparably effective and tolerable GLP-1RA option for patients wanting to avoid injections. That it must be taken daily on an empty stomach with half a glass of water ≥ 30 minutes before food intake may be cumbersome for some patients, who may favor the convenience of weekly subcutaneous semaglutide or dulaglutide. Patients at higher CV risk may also prefer the weekly options due to their proven CV benefit.
The results of these trials add to the growing evidence regarding GLP-1RA treatment to help guide treatment decisions. These results further endorse the CV benefits of GLP-1RAs in lower-risk populations and provide support for oral semaglutide as a promising alternative to current subcutaneously administered agents. Whether oral semaglutide has comparable CV-lowering benefits to subcutaneous GLP-1RAs remains to be confirmed.