Therapeutics: tirzepatide for type 2 diabetes

The vast majority of people with diabetes have the type 2 form of the disease, in which symptoms are often exacerbated by the patient being overweight and taking insufficient exercise

Although various drug treatments are available, there remains a need for more effective options. Eli Lilly is developing an alternative, tirzepatide, which is a dual receptor agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1).1

In a randomised Phase II trial in patients with type 2 diabetes, 316 subjects (with a mean age of 57 and a mean BMI of 32.6) whose condition was poorly controlled by diet only or metformin treatment were enrolled.2

They were given once-weekly 1, 5, 10 or 15 mg subcutaneous doses of tirzepatide, 1.5 mg of the selective GLP-1 agonist dulaglutide or a placebo.

Significantly better efficacy was observed with tirzepatide than dulaglutide for both glucose control and weight loss. Between 33 and 90% of those given tirzepatide achieved an HbA1c target of less than 7% compared with 52% with dulaglutide and 12% with the placebo. The safety and tolerability profile was acceptable.

Another Phase II trial was done to evaluate three different dose escalation regimens. In the double-blind, placebo-controlled study, 111 patients were randomised to receive doses escalating from 4 to 12 mg, 2.5 to 15 mg in one of two different escalation patterns or a placebo.3

The absolute HbA1c change from baseline was greater in all treatment groups (more so in the higher dose groups), the incidence of nausea was reduced with the lower dose and greatest in the 15 mg dose group that was escalated more quickly.

This suggests that lower starting doses and smaller increments are associated with a better side-effect profile. This was used to inform the dosing regimen for the Phase III study (12,500 patients with type 2 diabetes) that is now under way.

Its effect on biomarkers of non-alcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes has also been investigated in a post-hoc analysis.4 Subjects were given once weekly doses of 1, 5, 10 or 15 mg of tirzepatide, 1.5 mg of dulaglutide or a placebo for 26 weeks.

Changes from baseline of alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18, procollagen III (Pro-C3) and adiponectin were all analysed. At 26 weeks, significant reductions from baseline were seen with all doses for ALT, all except 10 mg for AST, for all but the lowest dose for K-18 and with the highest dose for Pro-C3.

Adiponectin increased significantly for the two highest doses of tirzepatide. The highest doses may therefore have potential in NASH.

References

  1. T. Coskun, et al., Mol. Metab. 18, 3 (2018).
  2. J.P. Frias, et al., Lancet 392, 2180 (2018).
  3. J.P. Frias, et al., Diabetes Obes. Metab. 22, 938 (2020).
  4. M.L. Hartman, et al., Diabetes Care 43, 1352 (2020).

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