Novel dual GIP and GLP-1 receptor agonist Tirzepatide showed promising results for both reduction in A1C and weight loss.
The pharmaceutical company Eli Lilly recently released the preliminary results of their novel investigational drug, Tirzepatide. Tirzepatide is a dual, Glucose-dependent insulinotropic polypeptide (GIP) and a Glucagon-like peptide-1 receptor agonist (GLP-1 RA). The mechanisms of mimicking the functions of incretin hormones represent a new class of medication to treat type 2 diabetes. GLP-1 RA is considered second-line therapy for patients with type 2 diabetes and has some advantages over other drug classes, including administering a medication less frequently and the benefit of losing weight. Tirzepatide is administered subcutaneously once a week as are other GLP-1 RA. Eli Lilly conducted some randomized clinical trials where they evaluated the safety and efficacy of Tirzepatide in patients with type 2 diabetes.
In SURPASS-3, they compared Tirzepatide with Degludec in patients with type 2 diabetes in 122 sites. The trial was a randomized clinical phase 3, open-label and parallel assignment trial. In the study, 1,444 participants were randomized in a 1:1:1 ratio using Tirzepatide in 5mg, 10mg, and 15mg, or degludec. The primary intervention was reducing HbA1C at week 52 compared to baseline while using Tirzepatide 10 mg and 15 mg. The secondary outcomes looked for changes in body weight from baseline at week 52, changes in fasting serum glucose, percentages of participants achieving an HbA1C < 7%, percentage of participants with >5% of weight loss, and hypoglycemic episodes. Participants were all adults with type 2 diabetes with HbA1C reported as ≥7% and ≤10% at baseline and BMI ≥25kg/m2.
In SURPASS-3, Tirzepatide showed a reduction in HbA1C by 2.37% and an average of 12.9kg weight loss when used at the highest dose, which is 15mg. At the same strength, results showed that 92.6% of participants achieved an HbA1C <7% while 48.4% of patients achieved an HbA1C <5.7%. They observed the same trend in the treatment regimen estimand. In terms of safety, the most commonly reported side effects were gastrointestinal. A lower percentage of patients reported hypoglycemic events compared to Degludec.
On the other hand, SURPASS-5 compared Tirzepatide with placebo in a randomized, double-blind, parallel assignment, and multicenter trial. In this study, 475 patients with type 2 diabetes were randomized in a 1:1:1 ratio using Tirzepatide 5mg, 10mg, 15mg, or placebo, and followed for 40 weeks. All interventions had insulin glargine with or without metformin. The inclusion criteria were similar to those on SURPASS-3; participants were all adults with type 2 diabetes treated with glargine once daily, HbA1C ≥7% and ≤10.5% at baseline, and BMI ≥ 23kg/m2. The primary and secondary endpoints were similar to those in SURPASS-3.
In SURPASS-5, Tirzepatide 15mg showed the highest reduction in HbA1C and weight loss with a 2.59% and 10.9kg reduction, respectively. 97.4% of participants taking Tizepatide 10mg achieved an HbA1C < 7%. Also, 62.4% of the Tirzepatide 15mg group participants showed a reduction in A1C < 5.7%. The safety profile was similar to SURPASS-3, and hypoglycemic events were higher in the arms, including Tirzepatide, compared to placebo. In the study, the treatment regimen estimand showed the same trend as the efficacy estimand results.
These findings represent a promising drug for our population with uncontrolled type 2 diabetes with chronic weight management. These studies were conducted in multiple centers from the data available, but they included a low number of participants. The safety analysis results from the trials showed similar side effects presented in GLP-1 RA. Data regarding kidney and urinary excretion still unknown. More studies are needed to determine the use of Tirzepatide as a weight-loss medication. The press releases’ data were statistically significant, and the official report will be published later this year on a peer review.
- Tirzepatide is a novel dual GIP and GLP-1 RA and represents a new class of medication for the treatment of type 2 diabetes, used once weekly subcutaneously.
- In the SURPASS-3 clinical trial the highest dose of tirzepatide (15 mg) reduced A1C by 2.37% and body weight by 12.9 kg (13.9%). 92.6% of participants achieved an A1C of less than 7% and 48.4% of participants achieved an A1C of less than 5.7%.
- Less hypoglycemic events were reported in participants taking Tirzepatide compared to Degludec.
Tirzepatide Significantly Reduced A1C and Body Weight in People with Type 2 Diabetes in Two Phase 3 Trials from Lilly’s SURPASS Program. Eli Lilly and Company, February 17, 2021,
A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes – ClinicalTrials.gov,
A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin ClinicalTrials.gov
Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy