How’s it different when GLP-1RAs are paired with the GIP RA?

“The GIP component of tirzepatide works in white and brown adipose tissue (WAT and BAT, respectively), and is thought to improve the clearance of dietary triglycerides (TG) and the long-term storage of lipids. Using high-fat diet-fed obese insulin-resistant mice, 14 days of tirzepatide reduced circulating TG levels and free fatty acids, and lowered hepatic fat content. Tirzepatide also improved systemic insulin sensitivity, with enhanced insulin-stimulated glucose deposition in skeletal muscle and adipose tissue. With GLP-1Ra, the insulin sensitizing effect has been shown to result mainly from weight-loss. Comparatively, the weight-loss effect of tirzepatide represented only 70% of the improvement in insulin sensitivity. Using GLP-1R knockout mice, tirzepatide resulted in improvements in insulin sensitivity, even without weight-loss, demonstrating that the weight-independent effects on insulin sensitivity are mediated via GIPR agonism. Looking at metabolic analysis, tirzepatide and long-acting GIPRa-induced genes are involved in the breakdown of glucose, lipids, and branch-changed amino acids in BAT, which may explain the improvements in peripheral insulin sensitivity. Notably, this effect was not observed in the rodent skeletal muscle or WAT… As expected with improvements in insulin sensitivity, fasting insulin levels decreased at 26 weeks with tirzepatide 10 and 15 mg treatment, compared to both placebo and dulaglutide 1.5mg. Tirzepatide 5, 10, and 15 mg also resulted in reduced glucose-adjusted glucagon levels (percent change), as compared to tirzepatide 1mg, dulaglutide, and placebo.19 Although the mechanism of dysregulated glucagon secretion in T2DM is not fully elucidated, elevated fasting glucagon levels contribute to hyperglycemia in diabetes progression.”

“The improvement in postprandial glucose elucidates the glucose-dependent insulin secretion seen with tirzepatide and is unlikely related to slowed gastric emptying given the improvement in postprandial glucose persisted at 40 weeks, by which time the transient effect of delayed gastric emptying has waned.”

“In SURPASS 3, although fasting serum glucose (FSG) improvement was similar in tirzepatide vs insulin degludec, notably, the effect of tirzepatide on FSG was apparent in all the treatment groups as early as week 2, suggesting that even the starting dose of 2·5 mg of tirzepatide is efficacious for hyperglycemia.”

Tirzepatide: Does the Evidence to Date Show Potential for the Treatment of Early Stage Type 2 Diabetes?

Therapeutics and Clinical Risk Management