Secondary CV prevention in persons with ASCVD
Results of CVOT for 4 GLP1-RA, conducted largely in persons with pre-existing cardiovascular disease (CVD), were available at the time of publication of the 2018 guidelines. All GLP1-RA were noninferior to placebo with respect to major adverse CV events (MACE: nonfatal myocardial infarction [MI], stroke or CV death). Hazard rates for MACE were lower for liraglutide and subcutaneous semaglutide and extended release exenatide (nonsignificantly) compared to placebo. There was no suggestion of any CV benefit for lixisenatide.
Lixisenatide was compared to placebo in 6,068 patients with type 2 diabetes and a recent CV event over a median 2.1 years of follow up (MACE or hospitalization for unstable angina: 13.4% vs 13.2%; HR 1.02, 95% CI 0.89-1.17) (4). Extended-release exenatide was compared to placebo in 14,752 participants with type 2 diabetes (73% with pre-existing CVD) over a median 3.2 years of follow up (MACE 11.4% vs 12.2%; HR 0.91, 95% 0.83-1.00) (5). The first GLP1-RA to demonstrate significant CV benefit was liraglutide (6). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial evaluated CV outcomes in 9,340 participants with type 2 diabetes, of whom, 81% had established CVD or stage 3 or higher CKD and 72% had CVD only (6). Over a median follow up of 3.8 years, liraglutide was associated with a significantly lower incidence of MACE than placebo (13.0% vs 14.9%; HR 0.87, 95% CI 0.78–0.97), with significantly fewer CV deaths in patients treated with liraglutide compared to placebo (4.7% vs 6.0%; HR 0.78, 95% CI 0.66-0.93).
Since the 2018 guidelines were published, subcutaneous semaglutide became available in Canada and CVOT have been published for oral semaglutide, dulaglutide and albiglutide. Trials for those agents are described below (see also Table 2).
Subcutaneous semaglutide was compared to placebo in the phase 3a Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) (7). Similar to the LEADER trial of liraglutide (6), patients were eligible if they had type 2 diabetes and an A1C of 7% or greater; and were age ≥50 years with established CVD or stage 3 or higher CKD or age ≥60 years with at least 1 CV risk factor (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle–brachial index of less than 0.9). SUSTAIN-6 enrolled 3,297 participants with a mean duration of type 2 diabetes of 13.9 years and mean A1C of 8.7% (7), and they were randomized to subcutaneous semaglutide 0.5 mg or 1.0 mg weekly or placebo. At baseline, 98% were on antihyperglycemic therapy, 83% had established CVD or stage 3 or higher CKD, and 59% had CVD only. After a median follow up of 2.1 years, the primary composite outcome of MACE occurred in 6.6% of participants treated with semaglutide and 8.9% of participants treated with placebo (HR 0.74, 95% CI 0.58–0.95), fulfilling statistical criteria for noninferiority (p<0.001); a posthoc test for superiority was also significant (p=0.02). While the main findings from this trial were similar to those for liraglutide from the LEADER trial (6), as the hypothesis for CV benefit superiority was not prespecified, the evidence for CV benefit of subcutaneous semaglutide was graded lower than for liraglutide.
Oral semaglutide, the first orally available GLP1-RA, was evaluated in the phase 3a Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (PIONEER 6) trial (8). This study compared once-daily oral semaglutide to placebo in participants at high CV risk defined as age ≥50 years with established CVD or CKD, or age ≥60 years with CV risk factors only. PIONEER 6 enrolled 3,183 participants with a mean age of 66.7 years, mean A1C of 8.2% and mean 14.9 years diabetes duration. Most participants (84.7%) had established CVD or CKD at baseline. Following a relatively short follow up of 15.9 months, the primary composite endpoint of MACE was similar in the 2 groups; 3.8% in the semaglutide group and 4.8% in the placebo arm (HR 0.79; 95% CI 0.57-1.11), indicating CV safety but not demonstrating superiority as the trial was not designed to test this hypothesis. Death from CV causes was lower with semaglutide; 1.4% compared to 2.8% with placebo (HR 0.51; 95% CI, 0.31 to 0.84). This striking finding should be interpreted with care because of the small number of events and the short duration of follow up. In addition, due to the hierarchy of statistical testing, this result must only be considered exploratory. Based on these findings, the benefit of oral semaglutide to reduce the composite MACE outcome remains unproven.
Finally, the CV outcomes of albiglutide were evaluated in the Harmony Outcomes trial (9). Albiglutide was compared to placebo in 9,463 patients with type 2 diabetes and established CVD, and MACE occurred in 7% of albiglutide-treated patients and 9% of placebo-treated patients (HR 0.78, 95% 0.68-0.90) after a median 1.6 years, fulfilling criteria for noninferiority and superiority of albiglutide. Albiglutide is no longer marketed and is, therefore, not included as a potential treatment choice in this update.
Primary CV prevention in persons with CV risk factors
In contrast to most cardiovascular outcome trials (CVOT), which mainly included participants with a history of CV disease, the majority of participants in the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial (10) had CV risk factors only. This trial enrolled 9,901 participants with type 2 diabetes who were age ≥50 years and either had a previous CV event or age ≥60 years and at least 2 CV risk factors (hypertension, tobacco use, abdominal obesity or dyslipidemia), and they were randomized to subcutaneous dulaglutide (a GLP1-RA) 1.5 mg weekly or placebo. The mean age of participants was 66.2 years, median duration of diabetes was 9.5 years, the median A1C was 7.2% with 25% having a baseline A1C less than 6.6%, and 68.5% did not have CVD at baseline. After a median follow up of 5.4 years, there was a lower incidence of MACE with dulaglutide compared to placebo (12.0% vs 13.4%; HR 0.88, 95% CI 0.79-0.99; p=0.026). The hazard ratio was similar in those with and without previous CV disease. All-cause or CV mortality did not differ between groups. Since the majority of participants in the trial had CV risk factors rather than pre-existing CVD and many participants would be considered to be at target for A1C, this trial provides evidence for prevention of MACE with dulaglutide in people with type 2 diabetes without established ASCVD and in individuals who may be at A1C target.
In summary, there is substantial evidence that GLP1-RA (with the exception of lixisenatide) are associated with a significant reduction in risk of MACE among patients with type 2 diabetes and established CVD (11) (see also Table 2). The most reliable evidence for CV benefit from individual clinical trials is for liraglutide, dulaglutide and semaglutide. While CV safety has been confirmed for all GLP1-RA, there is no evidence of CV benefit for lixisenatide. The CV benefits of exenatide-ER and oral semaglutide remain unproven. Based on these findings, our recommendations have been updated to include dulaglutide and subcutaneous semaglutide as options for patients with ASCVD. We also now have evidence suggesting GLP1-RA, particularly dulaglutide, can reduce the risk of MACE in people without established CVD. This evidence has led to a recommendation that a GLP1-RA with proven CV outcome benefit can be considered in patients aged 60 years or older with at least 2 CV risk factors, with the strongest evidence for dulaglutide followed by liraglutide and subcutaneous semaglutide.