Real-world data favour tirzepatide over semaglutide for weight loss

Tirzepatide appears to yield substantially greater reductions in weight than semaglutide in the real-world treatment of overweight or obesity in adults with or without diabetes, according to a study.

Electronic health record data from 18,386 propensity-score matched adults with overweight or obesity across the US showed that a significantly larger proportion of people taking tirzepatide than semaglutide achieved weight loss of ≥5 percent (81.8 percent vs 66.5 percent), ≥10 percent (62.1 percent vs 37.1 percent), or ≥15 percent (42.3 percent vs 18.1 percent). [JAMA Intern Med 2024;doi:10.1001/jamainternmed.2024.2525]

In Cox proportional hazards models, tirzepatide was associated with a greater likelihood of losing weight compared with semaglutide. This was true for weight loss of ≥5 percent (hazard ratio [HR], 1.76, 95 percent confidence interval [CI], 1.68–1.84), ≥10 percent (HR, 2.54, 95 percent CI, 2.37–2.73), and ≥15 percent (HR, 3.24, 95 percent CI, 2.91–3.61).

On-treatment weight reduction was also larger with tirzepatide at 3 months (difference, −2.4 percent, 95 percent CI, −2.5 percent to −2.2 percent), 6 months (difference, −4.3 percent, 95 percent CI, −4.7 percent to −4.0 percent), and 12 months (difference, −6.9 percent, 95 percent CI, −7.9 percent to −5.8 percent).

“To our knowledge, this study represents the first clinical comparative effectiveness study of tirzepatide and semaglutide in adults with overweight or obesity,” the investigators said.

“Comparative effect estimates were consistent in direction and significance between methodological approaches (propensity score matching, inverse probability of treatment weighting [IPTW], modified intention-to-treat [ITT] analyses),” they continued.

In terms of safety, the tirzepatide and semaglutide groups had comparable rates of gastrointestinal adverse events, including bowel obstruction (6.26 vs 5.54 per 1,000 person-years), cholecystitis (6.50 vs 5.06 per 1,000 person-years), cholelithiasis (11.89 vs 12.66 per 1,000 person-years), gastroenteritis (19.75 vs 20.07 per 1,000 person-years), gastroparesis (3.61 vs 4.81 per 1,000 person-years), and pancreatitis (3.84 vs 3.60 per 1,000 person-years).

Prior to propensity-score matching, adults who initiated tirzepatide (n=9,193) vs semaglutide (n=32,029) were younger (mean 51.9 vs 56.4 years), more likely to be female (70.5 percent vs 65.8 percent) and White (77.2 percent vs 73.6 percent), and less likely to have type 2 diabetes (T2D; 51.9 percent vs 71.5 percent). Mean baseline weight was similar in the two groups (110 vs 109 kg), with measurement performed a median of 4.0 days before treatment initiation. The mean duration of on-treatment follow-up was 165 days.

Advantage maintained

Both medications are indicated for type 2 diabetes (T2D) treatment, with tirzepatide having already been shown to produce greater weight-loss benefits than semaglutide in this population. The investigators conducted further analysis and found that this benefit extended to people without T2D.

People without T2D achieved larger reductions in body weight with both medications compared with those who had T2D, but tirzepatide still outperformed semaglutide in all analyses, the investigators noted. This finding is consistent with that seen in several clinical trials. [N Engl J Med 2021;384:989-1002; Lancet 2021;397:971-984; Nat Med 2022;28:2083-2091; Lancet 2023;402:613-626]

The underlying reasons for the greater weight-loss benefit among people without T2D are not clear, but the investigators pointed to the possibility that individuals with and without T2D may differ in their motivations for weight loss and potentially engage in other weight loss activities differentially. They also acknowledged that more than half of the people (54.2 percent) included in the study discontinued treatment.

“Additional research is needed to understand the complex relationships between motivations and outcomes for patients with and without T2D,” as well as to explore the factors for treatment discontinuation, including shortages, adverse events, and costs, they said.

The study was limited by the endpoint of weight loss being directly observable to patients and potentially resulting in informative censoring, as well as the possibility of unmeasured confounding attributed to the degree of motivation for weight loss, among others.