Increase in pulse rate with semaglutide did not result in increased adverse cardiac events in subjects with type 2 diabetes in the SUSTAIN 6 cardiovascular outcomes trial


BACKGROUND: Type 2 diabetes (T2D) and elevated blood pressure (BP) are commonly associated with each other. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glucose control and produce small reductions in BP, but increase pulse rate. Beta-blockers, used to lower BP, are commonly used in patients with T2D; they reduce pulse rate. Semaglutide, a once-weekly GLP-1RA, has demonstrated robust reductions in cardiovascular (CV) events, HbA1c and body weight in SUSTAIN 6, a dedicated CV outcomes trial in subjects with T2D at high risk of CV events.

PURPOSE: To evaluate the effect of semaglutide on resting pulse rate in the SUSTAIN 6 trial and the effect of background beta-blocker use on pulse rate. Additionally to assess whether the increase in pulse rate with semaglutide leads to increased adverse cardiac events.

METHODS: In this post hoc analysis of SUSTAIN 6, subjects were stratified by beta-blocker use at baseline and at end of trial to evaluate the effect of beta-blocker use on pulse rate.

RESULTS: In total, 3,297 subjects were randomised to semaglutide 0.5 or 1.0 mg, or volume-matched placebo, for 104 weeks. Treatment arms were comparable in terms of pulse rate, BP, established CV disease (CVD) and beta-blocker use at baseline. At baseline, mean age of subjects was 64.6 years (standard deviation 7.4); 83.0% had established CVD, chronic kidney disease, or both.

At week 104, semaglutide increased the pulse rate (2.8 and 3.2 beats per minute [BPM] for 0.5 and 1.0 mg) compared with placebo (0.1 and 0.0 BPM for 0.5 and 1.0 mg); estimated treatment difference [95% confidence interval]: 2.75 BPM [1.75; 3.75] for semaglutide 0.5 mg versus placebo 0.5 mg; 3.20 BPM [2.20; 4.21] for semaglutide 1.0 mg versus placebo 1.0 mg; both p<0.0001. Changes to pulse rate were more pronounced in the comparatively fewer subjects who changed use of beta-blockers during the trial than in subjects with consistent use or no use of beta-blockers (Figure). Subjects who stopped beta-blockers during the trial had a comparatively higher pulse rate at study end than baseline; those who started them during the trial had a lower pulse rate than baseline.

Cardiac disorders occurred less frequently in the semaglutide arm (16.5%) vs the placebo arm (19.9%). The most common cardiac disorders with semaglutide were atrial fibrillation (2.4%), angina pectoris (1.8%) and congestive cardiac failure (1.5%); corresponding incidences with placebo were 3.4%, 3.0% and 2.2%.

CONCLUSIONS: In the SUSTAIN 6 trial, semaglutide increased pulse rate compared with placebo in subjects with T2D, as previously observed with other GLP-1RAs. This pulse rate increase did not result in increased adverse cardiac events. Initiating or stopping beta-blockers during the trial resulted in greater changes in pulse rate than consistent or no beta-blocker use.

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