MACE Risk May Be Reduced with GLP-1 Drug in High-Risk Patients

Inside Precision Medicine Precision Medicine MACE Risk May Be Reduced with GLP-1 Drug in High-Risk Patients Facebook Twitter Linkedin ReddIt Treatment with GLP-1 drugs is well established to have a positive effect on patients with type 2 di

Many patients with these conditions also present with cardiovascular disease symptoms.

While GLP-1 drug treatment has shown improvements, there is little evidence directly comparing the impacts of these drugs, including tirzepatide marketed as Mounjaro with the current standard of care for cardiovascular disease to reduce the risk of major adverse cardiovascular events MACE .

Researchers from the United States and Germany published a paper in The BMJ to address this gap in the literature to provide guidance for both clinicians and regulators.

The team analyzed data from 52,971 patients in the United States who were over 40 years old, with type 2 diabetes, and established atherosclerotic cardiovascular disease.

The patients in this analysis were split into two groups, the first included those treated with tirzepatide 35,353 patients and the control group who were treated with a placebo proxy, sitagliptin 17,618 patients , as it has no documented cardiovascular effects.

The study focused on a main outcome of tracking MACE in patients as a combination of myocardial infarction, stroke, and all-cause mortality through a year of monitoring.

After one year, analysis found that the risk of MACE was 2.9% in the tirzepatide group compared with 4.4% in the sitagliptin group, equating to a 32% reduction between groups.

“For individual MACE components, tirzepatide was associated with a lower hazard for myocardial infarction, whereas ischaemic stroke showed no meaningful difference,” the study authors wrote.

Additionally, patients requiring hospitalization for infections were lower in the tirzepatide group compared with the sitagliptin group, as was infection-related mortality and all-cause mortality.

This study used “an approach benchmarked against randomized trials” with the aim of using large scale available data to assess tirzepatide’s effectiveness at reducing the risk of MACE, but it has also opened the door for investigation into the use of tirzepatide to reduce infection related events as well.

Further exploration into this at a patient level and the mechanism underlying this outcome is needed.

While this research presents a compelling option for the use of tirzepatide as part of standard of care practice, the authors acknowledge the study’s limitations.

“Although comprehensive propensity score weighting achieved well balanced groups for comparison, residual confounding from unmeasured factors which could partially explain the reduced risk of all cause mortality and rapid onset cardiovascular benefits cannot be ruled out.” Indeed, the authors of a related editorial, commenting on the study, explicitly point out that interpretation of the primary outcomes may be more nuanced.

They wrote that individual endpoints have mixed responses: while myocardial infarction risk was lower in tirzepatide treated patients, risk of stroke was not lower in that group.

“The study supports a cardiovascular signal, particularly for myocardial infarction, but its magnitude depends substantially on outcome definition” the authors of the editorial wrote.

They further point out that though the placebo proxy, sitagliptin, is a good choice, clinicians who chose to treat patients with a cardiovascular disease would also likely treat these patients additionally with additional medications like metformin and SGLT-2 inhibitors.

They noted that 21% of the patients were treated with SGLT-2 which was not accounted for in the study’s analysis, and post hoc analysis still showed a net positive effect of tirzepatide.

“This consistency is encouraging,” wrote the authors of the editorial.

“But it does not prove incremental benefit of tirzepatide over optimized SGLT-2 therapy: background treatment was not randomized, duration and adherence were incompletely observed, and the manuscript does not show a treatment-by-SGLT-2 interaction.” The study authors concluded that “this study shows how trial-anchored evidence from clinical practice can estimate the expected cardiovascular benefit of initiating tirzepatide beyond standard background treatment and inform shared decision making.” The further assert: “While awaiting accrual of further trial evidence for tirzepatide in cardiovascular indications, this study shows how randomized controlled trial evidence anchored in the real-world complements randomized clinical trials for timely regulatory and clinical decision making.” The editorial authors agree that the current study holds promise and is consistent with other similar studies of other GLP-1 drugs and stressed that further study is needed to develop best practices for treating patients.

They conclude: The signal is compelling; the causal and clinical placement questions remain open.” News & FeaturesCardiovascular diseasesDiabetesObesityPeptidesRandomized controlled trialRisk assessment Also of Interest News & Features | Breast Cancer Risk Criteria Miss Nearly All Women Who Later Develop Cancer News & Features | Can Blood-Cleansing Therapy Remove 'Forever Chemicals' and Microplastics?

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Peptides referenced: Tirzepatide, GLP-1.