Zepbound Cardiovascular Impact Long-Term: What the Evidence Shows

What is tirzepatide approved to do?

Zepbound is a once-weekly subcutaneous injection of tirzepatide, a drug that activates both the GIP and GLP-1 receptors [1]. Its labeled uses, in combination with a reduced-calorie diet and more physical activity, are to reduce excess body weight and maintain weight reduction in adults with obesity or with overweight plus at least one weight-related condition, and to treat moderate-to-severe obstructive sleep apnea in adults with obesity [1].

Tirzepatide is also sold as Mounjaro, which is labeled for type 2 diabetes. The Mounjaro label includes a separate indication to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal heart attack, non-fatal stroke) in adults with type 2 diabetes at high risk for these events. Mounjaro is not labeled for weight loss.

What SURPASS-CVOT actually showed

SURPASS-CVOT was a double-blind, active-comparator noninferiority trial in adults with type 2 diabetes and atherosclerotic cardiovascular disease [2]. Participants received once-weekly tirzepatide up to 15 mg, or dulaglutide 1.5 mg, an agent that has been shown to reduce cardiovascular events [2].

Of 13,299 people randomized, 134 were excluded for not meeting inclusion criteria, leaving 6,586 on tirzepatide and 6,579 on dulaglutide, or 13,165 in the modified intention-to-treat analysis [2]. Mean age was 64.1 years, 29.0% were women, and mean BMI was 32.6 [2].

The primary endpoint was the composite of cardiovascular death, myocardial infarction or stroke [2]. It occurred in 12.2% of the tirzepatide group and 13.1% of the dulaglutide group: hazard ratio 0.92, with a 95.3% confidence interval of 0.83 to 1.01 [2]. The trial was designed so that an upper confidence limit below 1.05 would establish noninferiority, which it did (p=0.003), and an upper limit below 1.00 would establish superiority, which it did not (p=0.09) [2].

What a noninferiority result means

The comparator was an active drug with proven cardiovascular benefit rather than placebo, so the trial measured whether tirzepatide was at least as good as dulaglutide, not whether it beat no treatment [2]. Read from the confidence interval, the result is consistent with anywhere from a 17% relative reduction to a 1% relative increase in the composite endpoint [2].

The population matters too: these were adults with type 2 diabetes and established atherosclerotic disease, a different group from the adults with obesity who take Zepbound for weight management [1].

The weight trials were built around weight

SURMOUNT-1, a 72-week double-blind trial of 2,539 adults with obesity, or overweight plus a weight-related condition, and no diabetes, had weight-based coprimary endpoints: percentage change in weight and the proportion losing at least 5% [3]. Mean weight change at week 72 was -15.0% with 5 mg, -19.5% with 10 mg and -20.9% with 15 mg, versus -3.1% with placebo [3].

SURMOUNT-2, in 938 adults with obesity and type 2 diabetes, produced mean weight changes of -12.8% (10 mg) and -14.7% (15 mg) versus -3.2% with placebo at 72 weeks [4]. SURMOUNT-4 showed what happens when treatment stops: after 36 weeks of open-label tirzepatide and a mean 20.9% weight reduction, weight changed by -5.5% between weeks 36 and 88 with continued tirzepatide, versus +14.0% after switching to placebo [5].

Sleep apnea, oxygen burden and heart risk

Zepbound's sleep apnea indication was approved on 2024-12-20 [1]. In the two 52-week SURMOUNT-OSA trials, the apnea-hypopnea index fell by 25.3 events per hour versus 5.3 with placebo in people not using positive airway pressure (a difference of 20.0), and by 29.3 versus 5.5 in people already on PAP therapy (a difference of 23.8) [6].

Whether that translates into fewer heart attacks or cardiovascular deaths is unresolved. A 2024 commentary noted that the apnea-hypopnea index change is clinically relevant but that its impact on cardiovascular mortality remains unclear, while hypoxic burden, which tirzepatide reduced, predicts cardiovascular mortality across populations; the authors suggested the reduction might attenuate cardiovascular risk without demonstrating that it does [7].

Heart rate, blood pressure and label safety findings

Mean heart rate rose 1 to 3 beats per minute with tirzepatide [1].

In the pooled Zepbound weight-reduction trials, hypotension was reported in 1.6% of Zepbound-treated patients versus 0.1% of those on placebo, and it was more frequent in patients who were also taking antihypertensive medication (2.2%) than in those who were not (1.2%) [1].

The label also flags acute kidney injury from volume depletion, mostly in patients whose gastrointestinal reactions led to dehydration, and says to monitor renal function in patients reporting reactions that could cause volume depletion, especially during dose initiation and escalation [1]. No dose adjustment is needed for renal or hepatic impairment [1]. Aspiration during general anesthesia or deep sedation has been reported with GLP-1 receptor agonists, and the label instructs patients to tell healthcare providers about planned surgery or procedures [1]. Because tirzepatide delays gastric emptying, the label advises monitoring oral drugs that depend on threshold concentrations or have a narrow therapeutic index, such as warfarin [1].

The bottom line

In adults with type 2 diabetes and atherosclerotic disease, a large double-blind trial showed tirzepatide was as good as dulaglutide, itself an agent with proven cardiovascular benefit, on cardiovascular death, heart attack and stroke, but not better [2]. The Zepbound label findings on the heart and circulation are a small average rise in heart rate and a higher reported rate of hypotension, particularly in patients also taking blood pressure medication [1].