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Tirzepatide: Gaining Ground in the Diabetes World

Nebile Cayan, PharmD Candidate 2022¹
Keishla Chevere Espada, PharmD Candidate 2022¹
Abigail Henry, PGY1 Community-Based Pharmacy Resident¹
Kam Capoccia, Clinical Professor of Community Care^1
1Western New England University College of Pharmacy and Health Sciences

Background

Tirzepatide (LY3298176) is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist being investigated for the treatment of type 2 diabetes and chronic weight management. Tirzepatide is also being studied as a potential treatment for nonalcoholic steatohepatitis.¹

Tirzepatide demonstrates agonist activity at both the GLP-1 and GIP receptors. As a GLP-1 agonist, tirzepatide increases the activity of incretin, which stimulates insulin release from the pancreatic beta cells in a glucose-dependent manner, decreases glucagon release, delays gastric emptying and reduces appetite.² As a GIP agonist, the effects are similar to a GLP-1 agonist, by also increasing the activity of incretin and reducing appetite which leads to a reduction in food intake and body weight. Additional possible mechanisms of action of tirzepatide include the direct action of GIP on adipose tissue, such as increased insulin-dependent glucose uptake into adipose tissue. GIP agonist activity also contributes to lipolysis and lipogenesis in adipose tissues; thus, potentially increased metabolic flexibility by increasing fat utilization in a fasting state and reducing fat availability in the postprandial state.²

The multiple mechanisms of action of tirzepatide through the agonist activity at both GLP-1 and GIP receptors create a promising new tool in the management of type 2 diabetes.

Evidence

Preliminary data are available for the ongoing phase 3 (SURPASS) trials evaluating the safety and efficacy of tirzepatide. The preliminary data demonstrate that tirzepatide has a greater reduction in A1C and a greater reduction in weight when compared to placebo³, injectable semaglutide⁴, insulin degludec⁵, and insulin glargine⁶. The attached handout includes a one-page description of each of the SURPASS trials.

Recently published results

SURPASS-1⁷:

At 40 weeks, baseline A1C level decreased by 1.87 with tirzepatide 5 mg, 1.89 with tirzepatide 10 mg, and 2.07 with tirzepatide 15 mg, as compared with +0.04 with placebo group (all p<0.001) demonstrating statistical and clinical significance across all doses of tirzepatide. Of the individuals in the tirzepatide groups (5 mg, 10 mg and 15 mg), 87 to 92% achieved A1C <7%. A1C<5.7% was achieved in 31 to 52% of the patients who received tirzepatide and 1% of those in the placebo group.

The change of body weight from baseline at 40 weeks was decreased by 7.0kg with tirzepatide 5mg, 7.8kg with tirzepatide 10mg, and 9.5kg with tirzepatide 15mg, as compared with 0.7 kg in placebo group. Participants with ≥5% weight loss was achieved in 81 to 92% of the patients who received tirzepatide, as compared with 14% with placebo group. Of those in tirzepatide group, 37 to 55% achieved ≥10% weight loss, and 16 to 31% of those in tirzepatide group had ≥15% weight loss.

The most common adverse events in all groups were gastrointestinal. Nausea was reported by 12 to 18% in the tirzepatide groups, as compared with 6% in the placebo group. In the tirzepatide groups, 12 to 14% experienced diarrhea, as compared with 8% in placebo group.  Almost 60% of the total individuals experienced nausea and 54% experienced diarrhea. Hypoglycemia (<70 mg/dL) was reported in 6-7% of the individuals on tirzepatide, and 1% in the placebo group.

SURPASS-2⁸:

At 40 weeks, A1C level was reduced by 2.01% with tirzepatide 5mg, 2.24% with tirzepatide 10mg, and 2.30% with tirzepatide 15mg, as compared with 1.86% with semaglutide. All tirzepatide treatment doses were found to be statistically and clinically superior to semaglutide. The estimated treatment differences when compared to semaglutide were -0.15 percentage points for tirzepatide 5mg (p=0.02), -0.39 percentage points for tirzepatide 10mg (p<0.001) and -0.45 percentage points for tirzepatide 15mg (p<0.001). A1C <7% was achieved in 82 to 86% of the patients who received tirzepatide and in 79% of those who received semaglutide. An A1C <5.7% was achieved in 27 to 46% of those in the tirzepatide groups and 19% of those in the semaglutide group.

The mean reduction in body weight at 40 weeks was 7.6 kg with tirzepatide 5mg, 9.3 kg with tirzepatide 10mg, and 11.2 kg with tirzepatide 15mg, as compared with 5.7 kg with semaglutide. Body weight reduction of at least 5% was achieved in 65 to 80% of the patients who received tirzepatide and 54% of those who received semaglutide; 34 to 57% of those in the tirzepatide groups and 24% of those in the semaglutide group had weight reductions of at least 10%; 15 to 36% of those in the tirzepatide groups and 8% of those in the semaglutide group had weight reductions of at least 15%.

Adverse events were similar in all groups and the most frequent adverse events were gastrointestinal related. Nausea was reported in 17 to 22% of patients who received tirzepatide and in 18% who received semaglutide. Diarrhea was reported in 13 to 16% with tirzepatide and 12% with semaglutide. Vomiting was reported in 6 to 10% with tirzepatide and 8% with semaglutide. Decreased appetite was reported in 7 to 9% with tirzepatide and 5% with semaglutide. There was a higher incidence of serious adverse events among those who received tirzepatide than with semaglutide. The most frequent serious adverse event was coronavirus disease 2019–related pneumonia in all groups. Hypoglycemia (blood glucose <54 mg/dL) was reported in 3 patients (0.6%) who received tirzepatide 5mg, 1 patient (0.2%) who received tirzepatide 10mg, and 8 patients (1.7%) who received tirzepatide 15mg, as compared with 2 patients (0.4%) who received semaglutide.

Conclusion

Tirzepatide has promising data to support reduction in A1C as well as reduction in weight but not without gastrointestinal adverse events. Stay tuned for the release of future SURPASS trials and additional data of tirzepatide.

References 

1. Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalance and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):1-16.
2. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.
3. Lilly’s Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes. [Internet]. Cision PR Newswire. [cited 2021 May 27]. Available from: https://www.prnewswire.com/news-releases/lillys-tirzepatide-significantly-reduced-a1c-and-body-weight-in-people-with-type-2-diabetes-301188988.html
4. Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes. [Internet]. Cision PR Newswire. [cited 2021 May 27]. Available from: https://www.prnewswire.com/news-releases/tirzepatide-achieved-superior-a1c-and-body-weight-reductions-across-all-three-doses-compared-to-injectable-semaglutide-in-adults-with-type-2-diabetes-301239948.html
5. Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly’s SURPASS program. [Internet]. Cision PR Newswire. [cited 2021 May 27]. Available from: https://www.prnewswire.com/news-releases/tirzepatide-significantly-reduced-a1c-and-body-weight-in-people-with-type-2-diabetes-in-two-phase-3-trials-from-lillys-surpass-program-301229506.html
6. Lilly’s tirzepatide achieves all primary and key secondary study outcomes against insulin glargine in adults with type 2 diabetes and increased cardiovascular risk in SURPASS-4 trial. [Internet]. Cision PR Newswire. [cited 2021 May 27]. Available from: https://www.prnewswire.com/news-releases/lillys-tirzepatide-achieves-all-primary-and-key-secondary-study-outcomes-against-insulin-glargine-in-adults-with-type-2-diabetes-and-increased-cardiovascular-risk-in-surpass-4-trial-301295524.html
7. Rosenstock J, Wysham C, Frias JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial. Lancet 2021;398:143-155. DOI: https://doi.org/10.1016/S0140-6736(21)01324-6.
8. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. NEJM 2021 June 25. DOI: 10.1056/NEJMoa2107519.