The report in the Journal of the American Medical Association Network Open advised that the findings suggested that treatment with tirzepatide could confer additional clinical benefits for patients with T2D.
Researchers from the Chi Mei Medical Center in Tainan, Taiwan, and colleagues noted that although tirzepatide—which is marketed as Mounjaro for diabetes treatment and Zepbound for weight loss—is known to have demonstrated benefits in improving cardiovascular risk profiles, the association of the medication with mortality and cardiovascular and kidney outcomes compared with GLP-1 RAs was previously unknown.
The retrospective cohort study used U.S. Collaborative Network of TriNetX data collected on adults with T2D initiating tirzepatide or GLP-1 RA between June 1, 2022, and June 30, 2023. The participants were excluded if they had stage 5 chronic kidney disease or kidney failure at baseline or had suffered myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation.
The study’s focus was on 14,834 patients treated with tirzepatide (mean [standard deviation (SD)] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125,474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67,474 [53.8%] female).
The primary outcome was defined as all-cause mortality, while secondary outcomes included MACEs, the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events.
The results indicated that, after a median (interquartile range) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. The researchers reported that tirzepatide treatment was associated with lower hazards of the following:
• All-cause mortality (adjusted hazard ratio [AHR], 0.58; 95% CI, 0.45-0.75), MACEs (AHR, 0.80; 95% CI, 0.71-0.91)
• The composite of MACEs and all-cause mortality (AHR, 0.76; 95% CI, 0.68-0.84)
• Kidney events (AHR, 0.52; 95% CI, 0.37-0.73), acute kidney injury (AHR, 0.78; 95% CI, 0.70-0.88)
• Major adverse kidney events (AHR, 0.54; 95% CI, 0.44-0.67).
“Treatment with tirzepatide was associated with greater decreases in glycated hemoglobin (treatment difference, –0.34 percentage points; 95% CI, –0.44 to –0.24 percentage points) and body weight (treatment difference, –2.9 kg, 95% CI, –4.8 to –1.1 kg) compared with GLP-1 RA,” the authors pointed out. “An interaction test for subgroup analysis revealed consistent results stratified by estimated glomerular filtration rate, glycated hemoglobin level, body mass index, comedications, and comorbidities.”
The study concluded that treatment with tirzepatide was associated with lower hazards of all-cause mortality, adverse cardiovascular events, acute kidney injury, and adverse kidney events compared with GLP-1 RA in patients with T2D. “These findings support the integration of tirzepatide into therapeutic strategies for this population,” the researchers added.
Background information in the study noted that cardiovascular and kidney diseases are prevalent in patients with diabetes and cause substantial morbidity and mortality. Among the many hypoglycemic agents evaluated for cardiovascular and kidney protection beyond their originally designed hypoglycemic effects, GLP-RAs have been found to improve kidney and cardiovascular outcomes, with new trials ongoing and results emerging.
“Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA, was developed in view of the synergistic effect of both receptors in achieving negative energy balance besides facilitating glucose-dependent insulin secretion,” the study explained. Past research has suggested tirzepatide’s superiority over semaglutide in reducing glycated hemoglobin (HbA1c) and weight (additional reductions of 0.15-0.45 percentage points in HbA1c and 1.9-5.5 kg in body weight) in patients with T2D.
“Compared with insulin glargine, tirzepatide has been shown to ameliorate annual estimated glomerular filtration rate (eGFR) decline by 2.2 mL/min/1.73 m2 and to reduce the urine albumin-to-creatinine ratio by 31.9%,” the authors explained. “Favorable effects on additional cardiovascular risk factors, including atherogenic lipoproteins and blood pressure, were also observed with tirzepatide compared with semaglutide (increase of 6.8%-7.9% vs. 4.4% in high-density lipoprotein cholesterol, decrease of 17.5%-23.7% vs. 11.1% in very-low-density lipoprotein cholesterol, and decrease of 4.8-6.5 mm Hg vs 3.6 mm Hg in systolic blood pressure). However, whether these metabolic improvements lead to benefits in survival and kidney or cardiovascular outcomes remains unclear.”
That uncertainty led to the current study, the authors wrote.
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