Pancreatic Safety of Tirzepatide and Its Effects on Islet Cell Function: A Systematic Review and Meta-Analysis

Overview

Journal Obes Sci Pract

Date 2024 Dec 25

PMID 39720158

Authors

A B M Kamrul-Hasan

Sunetra Mondal

Deep Dutta

Lakshmi Nagendra

Mohammed Ruhul Kabir

Joseph M Pappachan

Affiliations

Soon will be listed here.

Abstract

Background: Endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet cell function. GLP-1 receptor agonists (GLP-1RAs) have been associated with an elevated risk of acute pancreatitis. Data on the pancreatic safety of tirzepatide (a dual GLP-1 and GIP agonist) and its effects on islet cell function in randomized controlled trials (RCTs) are scarce. Moreover, no meta-analysis has comprehensively examined such effects of tirzepatide.

Methods: Electronic databases were searched for RCTs with tirzepatide as the intervention and a placebo or active comparator as the control. The primary outcome was adjudication-confirmed pancreatitis; secondary outcomes were the percent changes from baseline in serum pancreatic amylase, lipase, insulin, C-peptide, glucagon, and homeostasis model assessment of insulin resistance (HOMA2-IR).

Results: Seventeen RCTs with 18 published reports involving 14,645 subjects were analyzed. Over a follow-up duration of 12-72 weeks, tirzepatide had identical risks of pancreatitis to placebo (tirzepatide 5 mg: RR 2.04, 95% CI [0.27-15.69], = 0.49; 10 mg: RR 0.63, 95% CI [0.08-5.12], = 0.67; and 15 mg: RR 1.26, 95% CI [0.36-4.98], = 0.72). Tirzepatide was also associated with comparable risks of pancreatitis to insulin and GLP-1RAs. However, tirzepatide (at all doses) caused greater increases in pancreatic amylase and lipase than placebo and insulin. Individuals on tirzepatide 15 mg and GLP-1RAs had similar risks of having increased lipase levels. The percent reductions in fasting insulin were greater with tirzepatide 10 and 15 mg than with placebo. All doses of tirzepatide caused greater percent reductions in fasting insulin, C-peptide, and glucagon than GLP-1RAs. Compared to placebo and GLP-1RAs, the percent reductions in HOMA2-IR were greater with all doses of tirzepatide.

Conclusion: The meta-analysis provides evidence of the safety of tirzepatide regarding pancreatitis and establishes its positive effect on islet cell functions and insulin resistance.

References

Wadden T, Chao A, Machineni S, Kushner R, Ard J, Srivastava G . Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023; 29(11):2909-2918. PMC: 10667099. DOI: 10.1038/s41591-023-02597-w. View

Gastaldelli A, Cusi K, Lando L, Bray R, Brouwers B, Rodriguez A . Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022; 10(6):393-406. DOI: 10.1016/S2213-8587(22)00070-5. View

Abd El Aziz M, Cahyadi O, Meier J, Schmidt W, Nauck M . Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes Obes Metab. 2019; 22(4):699-704. DOI: 10.1111/dom.13924. View

Page M, McKenzie J, Bossuyt P, Boutron I, Hoffmann T, Mulrow C . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. PMC: 8005924. DOI: 10.1136/bmj.n71. View

Willard F, Douros J, Gabe M, Showalter A, Wainscott D, Suter T . Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020; 5(17). PMC: 7526454. DOI: 10.1172/jci.insight.140532. View

Rosenstock J, Wysham C, Frias J, Kaneko S, Lee C, Lando L . 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, randomised, phase 3 trial. Lancet. 2021; 398(10295):143-155. DOI: 10.1016/S0140-6736(21)01324-6. View

Lupi R, Del Guerra S, DAleo V, Boggi U, Filipponi F, Marchetti P . The direct effects of GLP-1 and GIP, alone or in combination, on human pancreatic islets. Regul Pept. 2010; 165(2-3):129-32. DOI: 10.1016/j.regpep.2010.04.009. View

Baggio L, Drucker D . Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007; 132(6):2131-57. DOI: 10.1053/j.gastro.2007.03.054. View

Forzano I, Varzideh F, Avvisato R, Jankauskas S, Mone P, Santulli G . Tirzepatide: A Systematic Update. Int J Mol Sci. 2022; 23(23). PMC: 9741068. DOI: 10.3390/ijms232314631. View

10.

Garvey W, Frias J, Jastreboff A, le Roux C, Sattar N, Aizenberg D . Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023; 402(10402):613-626. DOI: 10.1016/S0140-6736(23)01200-X. View

11.

Frias J, Davies M, Rosenstock J, Perez Manghi F, Lando L, Bergman B . Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021; 385(6):503-515. DOI: 10.1056/NEJMoa2107519. View

12.

Thomas M, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K . Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2020; 106(2):388-396. PMC: 7823251. DOI: 10.1210/clinem/dgaa863. View

13.

Rosenstock J, Frias J, Rodbard H, Tofe S, Sears E, Huh R . Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA. 2023; 330(17):1631-1640. PMC: 10548360. DOI: 10.1001/jama.2023.20294. View

14.

Tang Y, Zhang L, Zeng Y, Wang X, Zhang M . Efficacy and safety of tirzepatide in patients with type 2 diabetes: A systematic review and meta-analysis. Front Pharmacol. 2022; 13:1016639. PMC: 9774036. DOI: 10.3389/fphar.2022.1016639. View

15.

Wilson J, Nikooienejad A, Robins D, Roell W, Riesmeyer J, Haupt A . The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes Metab. 2021; 22(12):2451-2459. PMC: 7756479. DOI: 10.1111/dom.14174. View

16.

Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist K . 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. PMC: 6308032. DOI: 10.1016/j.molmet.2018.09.009. View

17.

Permana H, Yanto T, Hariyanto T . Efficacy and safety of tirzepatide as novel treatment for type 2 diabetes: A systematic review and meta-analysis of randomized clinical trials. Diabetes Metab Syndr. 2022; 16(11):102640. DOI: 10.1016/j.dsx.2022.102640. View

18.

Azoulay L, Filion K, Dahl M, Clemens K, Durand M, Hu N . Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis. JAMA Intern Med. 2016; 176(10):1464-1473. DOI: 10.1001/jamainternmed.2016.1522. View

19.

Lingvay I, Sumithran P, Cohen R, le Roux C . Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet. 2021; 399(10322):394-405. DOI: 10.1016/S0140-6736(21)01919-X. View

20.

Hartman M, Sanyal A, Loomba R, Wilson J, Nikooienejad A, Bray R . Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes. Diabetes Care. 2020; 43(6):1352-1355. PMC: 7245348. DOI: 10.2337/dc19-1892. View