Tirzepatide

Mechanism (as reported)

Across sources, tirzepatide is described as a dual GIP and GLP-1 receptor agonist; one review additionally describes effects on gastric emptying (GE), including substantial delay after the first dose and tachyphylaxis after subsequent doses. (PMID 35658024; PMID 34170647; PMID 37385275; PMID 38912654; PMID 37940101; PMID 35658024)

Key findings (each cites a source)

• A phase 3 randomized withdrawal trial (SURMOUNT-4) reported that withdrawing tirzepatide led to substantial regain of lost weight, while continued tirzepatide maintained and augmented initial weight reduction through week 88; the mean percent weight change from week 36 to week 88 was -5.5% with continued tirzepatide vs 14.0% with placebo, and 89.5% vs 16.6% maintained at least 80% of lead-in weight loss. (PMID 38078870) [PMID 38078870]
• In a phase 3 trial in adults with obesity (SURMOUNT-1), tirzepatide produced greater weight reductions at week 72 than placebo, and the most common adverse events were gastrointestinal, mostly mild to moderate and occurring primarily during dose escalation. (PMID 35658024) [PMID 35658024]
• In a phase 3 analysis of SURMOUNT-1 participants with obesity and prediabetes over 176 weeks, fewer participants were diagnosed with type 2 diabetes in tirzepatide groups than in placebo, and no new safety signals were identified; gastrointestinal adverse events were common and mostly mild to moderate. (PMID 39536238) [PMID 39536238]
• In a phase 3 trial in adults with obesity and type 2 diabetes (SURMOUNT-2), tirzepatide 10 mg and 15 mg resulted in greater bodyweight reductions at week 72 than placebo, and the most frequent adverse events were gastrointestinal-related (nausea, diarrhoea, vomiting) that were mostly mild to moderate, with fewer events leading to discontinuation (<5%). (PMID 37385275) [PMID 37385275]
• In two phase 3 randomized controlled trials in adults with moderate-to-severe obstructive sleep apnea and obesity (SURMOUNT-OSA), tirzepatide reduced the apnea-hypopnea index (AHI) at week 52 compared with placebo and improved multiple prespecified secondary endpoints; reported adverse events were mostly gastrointestinal and mostly mild to moderate. (PMID 38912654) [PMID 38912654]
• In an international randomized placebo-controlled trial in heart failure with preserved ejection fraction and obesity (SUMMIT), a composite endpoint of adjudicated cardiovascular death or worsening heart-failure event occurred less often with tirzepatide than placebo, and health status (KCCQ-CSS) improved at 52 weeks; discontinuation due to adverse events occurred in 6.3% with tirzepatide vs 1.4% with placebo, mainly due to gastrointestinal adverse events. (PMID 39555826) [PMID 39555826]
• A literature review assessing impacts of tirzepatide and GLP-1 receptor agonists on oral hormonal contraception reported that one of six included clinical trials (involving tirzepatide) showed a statistically significant reduction in area under the plasma drug concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax when tirzepatide was concomitantly administered with an oral hormonal contraceptive; the remaining five studies involving GLP-1 receptor agonists did not show statistically or clinically significant differences. (PMID 37940101) [PMID 37940101]
• In an open-label phase 3 trial comparing tirzepatide with semaglutide in patients with type 2 diabetes (SURPASS-2), tirzepatide groups had greater reductions in body weight than semaglutide, with the most common adverse events being gastrointestinal and reported as primarily mild to moderate in severity. (PMID 34170647) [PMID 34170647]