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Expert commentary

by John Wilding, DM, FRCP

Type 2 diabetes (T2D) is a complex condition; obesity is an important underlying causative factor and associates with insulin resistance and related metabolic abnormalities. Recent research shows that important metabolic changes associated with diabetes include higher levels of branched chain amino acids (BCAA), branched chain ketoacids (BCKA), and higher concentrations of triglycerides with saturated fatty acids; together these may contribute to insulin resistance, associated metabolic dysfunction, and increased atherogenic risk.1,2 Tirzepatide is a novel investigational medicine for the treatment of T2D and obesity that is a long-acting agonist at both the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors.

In a Phase 2 trial with tirzepatide in people with T2D, four doses (1, 5, 10, and 15 mg weekly subcutaneous injections) were compared with the GLP-1 receptor agonist (GLP-1RA) dulaglutide (1.5 mg weekly), and placebo on a background of metformin monotherapy. Tirzepatide was more efficacious at glucose lowering and weight loss than either comparator: HbA1c fell by 2.4% in the 15 mg tirzepatide group versus 1.1% with dulaglutide, and 0.7% with placebo, and weight loss was 11.3 kg with tirzepatide 15 mg versus 2.7 kg with dulaglutide, and 0.4 kg with placebo. These findings support its potential as a treatment for diabetes.3

The paper by Pirro and colleagues describes an analysis of the same trial focusing on metabolomic and lipidomic outcomes using state-of-the-art mass spectrometry.4 The most striking findings were that patients treated with tirzepatide had greater reductions in BCAA and BCKA in a dose-dependent manner; this was clearly associated with improvements in insulin sensitivity that were largely independent of changes in body weight, suggesting that tirzepatide was working as an insulin-sensitising agent. In the lipidomic analysis there were reductions in some lipid fractions – particularly saturated triacylglycerols that may be more atherogenic. Most of these effects were not seen with the GLP-1RA dulaglutide, suggesting that it is the GIP agonism that mediates these effects. GIP receptors are present in adipose tissue, and studies have shown that GIP inhibits lipolysis. Thus the combination of GIP and GLP-1 agonism may be key, as the increased lipolysis due to weight loss and its inhibition by GIP removes some of the substrate overload that is typically seen in T2D, and may explain why the overall therapeutic effects seems greater than the expected sum of the individual components. Phase 3 trials have confirmed tirzepatide as an effective glucose-lowering treatment in T2D, and a recent meta-analysis suggests it does not increase cardiovascular risk.5 The results of a large ongoing cardiovascular outcomes trial comparing tirzepatide with dulaglutide are awaited, and may confirm if the theoretical benefits of tirzepatide to reduce the risk of atherosclerotic cardiovascular disease on the basis of these interesting metabolic effects translate into clinical benefits for people with T2D.

 

References

  1. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009;9(4):311–26.
  2. Rhee EP, Cheng S, Larson MG, et al. Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J Clin Invest 2011;121(4):1402–11.
  3. Frias JP, Nauck MA, Van J, et al. Efficacy and Safety of LY3298176, a Novel Dual GIP and GLP-1 Receptor Agonist, in Patients With Type 2 Diabetes: A Randomised, Placebo-Controlled and Active Comparator-Controlled Phase 2 Trial. Lancet 2018;392(10160):2180–93.
  4. Pirro V, Roth KD, Lin Y, et al. Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab 2022;107(2):363–78.
  5. Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med 2022;28(3):591–8.
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