Tirzepatide is both a GIP and GLP-1 receptor agonist.
Tirzepatide activates glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP) receptors; it has already proven to reduce a patient’s hemoglobin A1c levels and has also been shown to lower body weight and improve insulin sensitivity markers in patients with type 2 diabetes. The two metabolites strongly associated with improved hemoglobin A1C levels were the branched-chain amino acids and 2-hydroxybutyric acid. The branched-chain amino acids are known to be associated with both obesity and insulin resistance. Researchers wanted to identify any trends in fasting branched-chain amino acid levels and other related metabolites with Tirzepatide. Branched-chain amino acids are suspected of causing hepatic lipogenesis, cardiac hypertrophy, and skeletal muscle lipid accumulation.
This study aims to examine the effects of Tirzepatide on biomarkers of improved insulin sensitivity and hemoglobin A1C levels. The significant importance was manipulated to adjust for the various amounts of metabolites detected. Data from the phase 2b trial was used to analyze plasma sample post-hoc. A targeted mass spectrometry metabolomics approach was used. The treatment arms were Tirzepatide 1, 5, 10,15 mg, dulaglutide 1.5mg, and placebo. The patients underwent fasted serum lab tests on weeks 4, 12, 26, and baseline. There were about 250 targeted metabolites. However, only a total of 193 metabolites were detected in Tirzepatide 15mg. The data were statistically analyzed using a mixed-model approach.
The circulating levels of branched-chain amino acids were dependent on the dose; significantly different from the baseline were Tirzepatide 5mg, 10mg, and 15mg. After 26 weeks of treatment with Tirzepatide metabolites, the percent change from baseline results was analyzed. A total of 45 metabolites were proved to be significantly crucial in the Tirzepatide 15mg treatment arm. At week 12, acetylcarnitine had a significant p-value of p=0.04. Leucine, isoleucine, and valine had substantial results that showed a reduction in serum levels from baseline. The p-value for the Tirzepatide arm was less than 0.01, and the p-value for the dulaglutide arm was less than 0.05. The branched-chain amino acid levels in this study were able to positively be linked to the Homeostatic Model Assessment of Insulin Resistance for isoleucine (Spearman correlation coefficient of 0.58; p-value=0.0011) leucine (0.49; p-value=0.009), and valine (0.46; p-value=0.015). The only biomarkers that significantly affected weight loss were valine in the Tirzepatide 15mg treatment arm.
The metabolic profile surpassed dulaglutide effects. Future studies should be conducted to gain further knowledge about fasting branched-chain amino acid levels and metabolic imbalances. Also, more studies should be done to explore Tirzepatide’s effects on weight loss.
- This study was able to suggest Tirzepatide has a unique effect on glycemic control compared to dulaglutide.
- The biomarkers observed were significantly linked to insulin sensitivity but not much with weight loss.
- This study proved that Tirzepatide interferes with branched-chain amino acid levels positively.
Effects of tirzepatide, a novel dual GIP and GLP-1 receptor agonist, on metabolic profile in patients with type 2 diabetes. EASD Virtual Congress.
Alexandria Bartley, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences