Cardiovascular Outcomes of GLP-1 Receptor Agonist Therapies

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted in the gut in response to meal ingestion, targeting multiple tissues throughout the body. One of its main targets is pancreatic β-cells, resulting in increased insulin secretion and inhibition of glucagon production.1 Additionally, GLP-1 has been shown to delay gastric emptying and promote satiety and weight loss.2,3 In type 2 diabetes (DM2), insulin response to GLP-1 is impaired,4 making the GLP-1 receptor a desirable target for therapeutic antihyperglycemic agents. Exenatide (Byetta) was the first GLP-1 receptor agonist (GLP-1 RA) to gain FDA approval for the treatment of DM2. Since 2005, several more GLP-1 RAs have been approved, including liraglutide, lixisenatide, albiglutide and dulaglutide. GLP-1 RAs  have been shown to improve glycemic control when used as monotherapy as well as in combination with both oral anti-hyperglycemic agents and with basal insulin.5-12 The observed reduction in hemoglobin A1c (HbA1c) averaged between 0.5-1.5%.13

In response to the favorable effect of weight loss seen with GLP-1 receptor agonist use, liraglutide (Saxenda) was also approved for the treatment of obesity in 2014.14,15

Given FDA guidance for the assessment of cardiovascular (CV) safety, multiple clinical trials were designed to assess cardiovascular outcomes of GLP-1 RA therapy.16-19  Endpoints for major adverse cardiac events (MACE) were to be assessed based mainly on 3-point outcomes including death from all CV causes, non-fatal myocardial infarction, and non-fatal stroke. Several studies assessed additional endpoints, including hospitalization for unstable angina or heart failure.

At this time, there are 3 published CV safety outcome trials for the GLP-1 agents: liraglutide (LEADER),16 lixisenatide (ELIXA),17 and semaglutide (SUSTAIN-6).18  There is also an ongoing trial with exenatide (EXSCEL).19 All of these studies were randomized, double-blind, placebo-controlled trials conducted at multiple international centers. These studies enrolled patients with established CV disease and/or a high risk for CV events. All of these trials were powered to assess non-inferiority or to adequately detect differences between the drug and placebo. The upper bound for the 95% confidence interval (CI) was set to not exceed 1.3. Additionally, 2 of the studies--LEADER and ELIXA-were also designed to assess if the particular GLP-1 studied would reduce the incidence of CV outcomes.16,17

LEADER Trial

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results--A Long Term Evaluation (LEADER) trial investigated CV outcomes in 9340 patients with T2DM treated with liraglutide or placebo.16 Eligible patients had an HbA1c ≥7%, age ≥50 years with presence of CVD, or age ≥60 years with significant CV risk factors. Prior to enrollment, patients were either treatment-naïve to oral anti-hyperglycemic agents or on oral agents with or without the addition of basal or mixed insulin; exclusion criteria included prior treatment with short-acting insulin or GLP-1 RA. Patients were randomized to receive either liraglutide 1.8mg (or maximum tolerated dose) or placebo once daily. Median follow up for each group was 3.8 years. The primary composite CV outcome was occurrence of a 3-point MACE.

In the patients that received liraglutide, there was a reduction in both all-cause mortality (8.2% vs. placebo 9.6%; HR 0.85; 95% CI 0.74-0.97; P=0.02), and the 3-point MACE (13.0% vs. 14.9% in placebo group).16 However, even though these patients had a lower overall risk of death from CV causes, rates of nonfatal myocardial infarction and nonfatal stroke remained similar. There was also no difference between the groups in rates of hospitalization for heart failure. Subgroup analyses identified potential increased benefit with liraglutide treatment in patients with a reduced estimated glomerular filtration rate (eGFR) and previously established CV disease.

Elixa Trial

The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial included patients with DM2 who has experienced an acute coronary event within 180 days prior to randomization.17 Eligible patients (n=6068) were randomized to receive either lixisenatide (starting dose 10µg for 2 weeks, maximum dose 20 µg) or placebo and were followed for a median of 25 months. The composite outcome for this study was time to first event of a 4-point MACE (CV mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina) powered to detect both non-inferiority and superiority. Results revealed similar rates of occurrence of the primary composite outcome in both groups (13.4% of patients in the lixisenatide group and 13.2% in the placebo group), and no significant differences between groups when components of the primary outcome were assessed independently. There were also no significant differences between groups regarding hospitalizations for heart failure; this pattern persisted when analyzed with inclusion of hospitalizations for coronary revascularization.

SUSTAIN Trial

Recently, outcomes of participants with DM2 receiving semaglutide (SUSTAIN-6) were published.18 This was a non-inferiority trial comparing weekly administration of semaglutide (a long-acting GLP-1 RA, not yet approved in the United States to placebo. The primary outcome was a 3-point MACE. Enrolled patients (n=2735) were stratified by the presence of established cardiovascular disease, chronic kidney disease, or both. Even though the study was not specifically designed to test superiority, the semaglutide group had significantly lower rates of CV events compared to placebo (6.6% vs. 8.9%). This difference was explained by significantly more non-fatal stroke in the placebo compared to the semaglutide group (2.7% vs. 1.6%, HR, 0.61; 95% CI, 0.38 to 0.99; P = 0.04) while there were no differences in death from a CV cause or non-fatal MI.18   

For a summary of the GLP-1 Trials, see Table 1.

Commentary

Contrasting LEADER16 and SUSTAIN-6,18 ELIXA did not show a difference in all-cause and CV mortality between patients receiving GLP-1RA or placebo.17 The mechanisms for improved CV outcomes with semaglutide and liraglutide but not with lixisenatide are not clear. Previous animal studies and clinical trials showed possible CV benefits of GLP-1 therapy,20,21 potentially mediated through effects on CV risk factors including weight loss, reduction in blood pressure, improved lipid metabolism as well as direct effects on the vascular endothelium (ie, vasodilation, decreased inflammation). However, contrasting potential CV benefits, the SUSTAIN-6 trial reflected increased retinal complications against placebo very early in the trial, suggesting that aggressive glycemic control did not play a role.

All 3 trials had results that supported a reduction in both body weight and systolic blood pressure and an increase in heart rate.16-18 However, patients receiving semaglutide and liraglutide had more weight loss than the lixisenatide group. All studies showed improved glycemic control compared to placebo. In both LEADER and SUSTAIN-6, the differences in CV outcomes were apparent by 6 months,15,16 suggesting that glycemic control likely did not affect the CV outcomes.

To date, there have not been studies investigating use of GLP-1 RA therapy in primary prevention of CVD. The clinical trial, Effects of Liraglutide in Young Adults with Type 2 Diabetes (LYDIA), is ongoing and investigating changes in cardiac structure and function in younger (ages 18 to 40) obese patients with DM2 treated with liraglutide to determine effects on cardiac diastolic function.23

Currently, none of the cardiovascular outcome trials with a GLP-1 RA showed an increased risk in CV outcomes. However, recent trials with liraglutide and semaglutide indicated a lower incidence of adverse CV outcomes.16,18

Further studies are needed to determine potential patient populations that may benefit from GLP-1 RA therapy and to investigate mechanisms leading to improved CV outcomes.

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