Tirzepatide beats semaglutide in lowering diabetes risk and cardiovascular events in obesity patients

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Susha Cheriyedath, M.Sc.Aug 28 2024

Image Credit: Rimma Bondarenko / Shutterstock

In a new study, tirzepatide not only outshines semaglutide in cutting diabetes risk but also offers enhanced protection against major cardiovascular events, setting a new standard in obesity treatment.

In a retrospective cohort study published in the journal eClinicalMedicine, researchers compared the effects of tirzepatide and semaglutide on the incidence of type 2 diabetes (T2D) and major adverse cardiovascular (CV) outcomes in individuals with obesity, with or without pre-existing T2D. They found that compared to semaglutide, tirzepatide was associated with a lower risk of developing T2D and more significant weight loss in individuals without T2D and a lower risk of major adverse CV events in those with pre-existing T2D.

Background

Obesity is a significant global health issue affecting over 650 million adults and 340 million children and adolescents. It is a leading risk factor for T2D, contributing to increased morbidity, mortality, and substantial economic costs. Managing obesity involves a combination of behavioral, dietary, pharmacological, and surgical interventions, with surgery offering the most effective weight loss, though it carries risks and barriers to access.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide are increasingly used to manage obesity by reducing appetite and slowing gastric emptying. Semaglutide has shown more significant weight loss compared to earlier GLP-1 RAs. Tirzepatide, a newer dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), has shown even greater weight loss, crucial for reducing the risk of T2D and improving health outcomes in those with obesity or T2D. However, the effects of tirzepatide on the incidence of T2D and CV outcomes remain unclear. While concerns about semaglutide's potential link to suicidal thoughts have been disproven, the risk of suicidal ideation with tirzepatide has not been studied. Therefore, researchers in the present study used electronic medical records (EMR) to compare the effects of tirzepatide and semaglutide on incident T2D in individuals with obesity and studied their impact on complications and mortality in those with pre-existing T2D.

About the study

In the present cohort study, anonymized EMR data were obtained from the TriNetX database. The analysis included two cohorts: individuals without pre-existing T2D) and those with T2D. In the non-T2D cohort, participants were matched and compared after six months of treatment with either tirzepatide (cohort 1a, n = 6923) or semaglutide (cohort 2a, 6923), with a follow-up of 12 months to assess the incidence of T2D and changes in glycated hemoglobin (HbA1c), body weight, hypoglycemia, and acute pancreatitis. In both the groups, the mean age of participants was 47.5 years; 73% were female, and 73-74% were White. The mean follow-up period in the two groups was 302 and 312 days, respectively.

The T2D cohort was similarly split into cohorts 1b for T2D + tirzepatide (n = 4223) and 2b for T2D + semaglutide (n = 4223). In both the groups, the mean age of participants was 53.9-54 years; 60% were female, and 68-69% were White. The mean follow-up period in the two groups was 328 and 339 days, respectively. Matching and follow-up were similarly conducted to evaluate the time to a composite of adverse CV events, including mortality, cerebral infarction, coronary syndrome, heart failure, and the incidence of microvascular complications and suicidal ideation. The study aimed to establish temporal relationships between drug exposure and outcomes while controlling for potential confounders. The statistical methods used in the study include propensity score matching (PSM) with logistic regression, univariate survival analysis with hazard ratios (HR), log-rank test, Kaplan-Meier survival curves, and sensitivity analysis.

Results and discussion

In individuals without T2D, tirzepatide was found to be associated with a significantly lower risk of developing T2D. Compared to the semaglutide, the tirzepatide group also showed greater weight loss and HbA1c reduction over one year (p<0.001).

In individuals with T2D, tirzepatide was found to reduce the risk of a composite outcome of mortality and CV events, specifically lowering the risk of all-cause mortality and cerebral infarction, but it was associated with an increased incidence of diabetic neuropathy. No significant differences were observed in the rates of hypoglycemia, acute pancreatitis, or suicidal ideation between the groups.

This is the first real-world study to offer a large-scale comparative analysis between tirzepatide, a new GLP1/GIP dual agonist, and semaglutide, a potent, established GLP1-RA. However, the study is limited by its observational nature, non-randomized comparisons, potential data incompleteness, lack of dosage information, and short follow-up duration.

Conclusion

In conclusion, the present real-world study found that compared to semaglutide, tirzepatide significantly reduces the risk of developing T2D and major CV events in individuals with obesity and T2D. The finding suggests that tirzepatide could potentially be a more effective therapeutic option for managing obesity-related health risks and preventing complications in these populations. Further randomized controlled trials are needed to confirm these results and explore the effectiveness of dual incretin agonists in preventing T2D and CV disease in high-risk populations.