GIP and GLP-1 Receptor Agonist Tirzepatide Reduces CVD

Tirzepatide & CVD: dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1RAs create an additive effect for increased anti-inflammation and vascular protection.

Patients with T2D are often prescribed GLP-1RAs to decrease the risk of a major adverse cardiovascular event. This medication class has a mortality benefit attributed to lower blood glucose, increased weight loss, improved endothelial dysfunction, and reduced inflammation. Previous preclinical studies found that glucose-dependent insulinotropic polypeptide (GIP) also had anti-inflammatory and vascular protective properties. These findings led researchers to analyze a dual-therapy diabetes regimen that utilized the agonism of both GIP and GLP-1 receptors. In this study, individuals taking tirzepatide were evaluated to reduce biomarkers associated with cardiovascular disease (CVD) compared to dulaglutide.

This phase 2b, double-blind trial included 318 participants, age 18-75 years old. Inclusion criteria were BMI between 23-50 kg/m and T2D ≥ 6 months (HbA1c 7.0-10.5%) uncontrolled by diet, exercise, or continuous metformin. Patients were given either a placebo (N=51), Tirzepatide 1 mg (N=52), Tirzepatide 5 mg (N=55), Tirzepatide 10 mg (N=51), Tirzepatide 15 mg (N=53), or Dulaglutide 1.5 mg (N=54). All regimens were dosed subcutaneously once weekly for 26 weeks. During baseline fasting state, samples were collected at 4, 12, and 26 weeks. Biomarkers included hsCRP, GlycA, GDF-15, YKL-40, MCP-1, leptin, IL-6, ICAM-1, VCAM-1, and NT-proBNP. A log-transformation for models was used in biomarkers with a skewed distribution. Statistical significance was measured by a two-sided p-value (0.05).

This study found that Tirzepatide had a dose dependent decrease on hsCRP, with a statistically significant reduction at 15 mg (least squares mean [LSM] -36.2%, standard error [SE] 8.9). All doses of tirzepatide lowered GlycA, whereas placebo and dulaglutide increased GlycA. This difference was not statistically significant. Biomarker GDF-15 was reduced in all groups: Tirzepatide 1 mg (-11.6%, 5.3, p <0.05), 5 mg (- 9.4%, 5.1, p >0.05), 10 mg (-12.1%, 5.2, p <0.05), 15 mg (-12.9%, 5.8, p <0.05), and dulaglutide (-15.4%, 4.9, p <0.05). IL-6 levels were unaffected with all groups. MCP-1 levels were increased with Tirzepatide 5-mg and decreased with Tirzepatide 10-mg. Tirzepatide dose-dependently reduced YKL-40: 10-mg (-26.1%, 5.0, p <0.001), 15-mg (-30.8%, 5.3, p <0.001). There was no significant change with YKL-40 in placebo (10.8%, 7.6) or dulaglutide (-6.2%, 6.1). Tirzepatide significantly lowered ICAM-1: 5-mg (-4.5%, 2.2), 10-mg (-7.2%, 2.3), and 15-mg (-11.2%, 2.5). ICAM-1 levels were significantly lower with tirzepatide 15-mg versus placebo and dulaglutide. Leptin significantly decreased with tirzepatide 10-mg (-28.2%, 7.6) and 15-mg (-34.1%, 7.9). There was no significant difference with NT-proBNP in any group.

Fluctuations with ICAM-1 exhibited a significant correlation with changes in hsCRP, GlycA, and VCAM-1 in both groups. Changes in YKL-40 were associated with changes in VCAM-1 and NT-proBNP in dulaglutide only. Changes in leptin had a significant correlation with changes in GDF-15 only in the tirzepatide 15-mg group. Change in body weight was associated with 23% leptin variability in dulaglutide and 20% leptin variability in tirzepatide (10+15 mg combined). The leptin variability associated with bodyweight change increased with higher tirzepatide doses: 1 mg (6%), 5 mg (11%), 10 mg (18%), and 15 mg (18%). Change in body weight with tirzepatide (10+15 mg combined) was associated with 4% of the variability in ICAM-1 levels compared to 1% with dulaglutide. Bodyweight change with dulaglutide was associated with 13% of hsCRP and 21% of YKL-40 compared to 0% of hsCRP and 6% of YKL-40 with tirzepatide.

This trial found that patients with T2D taking tirzepatide exhibited a reduction in biomarkers associated with cardiovascular risk compared to placebo and dulaglutide. After 26 weeks, the treatment group saw a dose-dependent reduction in biomarkers hsCRP, YKL-40, ICAM-1, and leptin. The decline of leptin with individuals taking tirzepatide was more gradual at four weeks and did not level off after 26 weeks. Researchers believe tirzepatide may have been directly responsible for suppressing inflammation and improving endothelial function, independently from weight loss. Targeting these inflammatory biomarkers has been shown to reduce the risk of atherosclerotic cardiovascular disease in patients with T2D. Limitations of this study include the post-hoc design and storage of samples. The sample size was also not sufficiently powered. A future SURPASS- CVOT study will compare major cardiovascular events in patients with T2D and established cardiovascular disease taking tirzepatide or dulaglutide.

Practice Pearls:

• GLP-1RA and glucose-dependent insulinotropic polypeptide (GIP) dual therapy has anti-inflammatory and vascular protective properties, leading to a possible decrease in cardiovascular disease (CVD).
• Individuals with T2D taking tirzepatide exhibited a reduction in biomarkers associated with cardiovascular risk compared to placebo and dulaglutide. After 26 weeks, the treatment group saw a dose-dependent reduction in biomarkers hsCRP, YKL-40, ICAM-1, and leptin.
• A future SURPASS- CVOT study will compare major cardiovascular events in patients with T2D and established cardiovascular disease taking tirzepatide or dulaglutide.

References for “GIP and GLP-1 Receptor Agonist Tirzepatide Reduces CVD”:
Bray, Jonathan J H et al. “Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials.” Diabetes, obesity & metabolism vol. 23,8 (2021): 1806-1822. doi:10.1111/dom.14399. https://pubmed.ncbi.nlm.nih.gov/33830637/

Wilson, Jonathan M et al. “The Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Cardiovascular Risk Biomarkers in Patients with Type 2 Diabetes: a Post-Hoc Analysis.” Diabetes, obesity & metabolism, 10.1111/dom.14553. September 20. 2021, doi:10.1111/dom.14553. https://pubmed.ncbi.nlm.nih.gov/34542221/

Author: Kornelia Ilias, Pharm.D. Candidate, Creighton University School of Pharmacy and Health Professions