Heart rate rises most during REM sleep after semaglutide initiation: a matched longitudinal cohort study

Study Objectives.

Glucagon-like peptide-1 (GLP-1) receptor agonists raise resting heart rate. We asked whether, after semaglutide initiation, the increase is larger during rapid eye movement (REM) sleep than during non-rapid eye movement (NREM) sleep.

Methods.

In the Human Phenotype Project, an Israeli cohort of generally healthy adults aged 40 to 70 years, 96 of 494 self-reported semaglutide initiators had a home sleep study (WatchPAT; sleep stages estimated from peripheral arterial tone and actigraphy) before and at least three months after starting. Each was propensity-matched 1:1 to a never-user of GLP-1 drugs measured at the same visits. We estimated the initiators’ change minus their controls’ change (difference-in-differences). The REM minus NREM contrast was designated primary after an exploratory analysis.

Results.

Relative to controls (90 to 94 pairs), heart rate rose during nocturnal wake (+3.89 beats per minute [bpm], 95% confidence interval 2.35 to 5.44), NREM sleep (+4.82 bpm, 3.12 to 6.52) and REM sleep (+6.25 bpm, 4.42 to 7.91); the REM increase exceeded the NREM increase by 1.42 bpm (0.98 to 1.89). The excess persisted across matching designs and on a relative scale; the proportion of REM sleep did not change. Never-users with similar weight loss showed no REM sleep heart-rate rise (+0.40 bpm, −0.63 to 1.50). Heart-rate variability decreases disappeared after adjustment for heart rate.

Conclusions.

Semaglutide initiation was associated with higher heart rate throughout sleep, most during REM sleep, unexplained by weight loss. Clinic measurements may understate this effect. Confirmation with polysomnographic staging is needed.

Graphical Abstract

Statement of Significance

Glucagon-like peptide-1 receptor agonists lower body weight and cardiovascular risk but raise heart rate, an effect usually measured while patients sit awake in a clinic. Whether it differs between sleep stages has not been formally tested. After people started semaglutide, heart rate rose in every sleep stage estimated by a home sleep apnea test, most during rapid eye movement sleep; weight loss did not explain it. A higher sleeping heart rate on a wearable after starting the drug may therefore be an expected effect, not illness. Whether the rise matters for patients with heart disease, in whom rapid eye movement sleep can provoke ischemia and arrhythmia, requires prospective studies with dispensed exposure and electroencephalographic sleep staging.