Tirzepatide (MOUNJARO): Another Diabetes Drug Seeking FDA Approval for Weight Loss

Some drugs developed and originally approved by the Food and Drug Administration (FDA) for type 2 diabetes continue to grab headlines and the broader attention of consumers because they also suppress appetite, leading to marked weight loss.[1] Two of these drugs, semaglutide (WEGOVY) and liraglutide (SAXENDA), have been approved by the FDA for chronic weight management. Both drugs are administered by injection and are of a class of drugs known as glucagonlike peptide1 (GLP1) receptor agonists (activators).[2],[3] Public Citizen’s Health Research Group has previously designated Saxenda as Do Not Use for all age groups, as discussed in the December 2020 and June 2023 issues of Worst Pills, Best Pills News for adults and adolescents, respectively.

In 2022, the FDA approved a related drug, tirzepatide (MOUNJARO), which also is administered by injection, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.[4] This review summarizes the evidence for the use of tirzepatide for diabetes and chronic weight management. It is important to note that as of midSeptember 2023, the FDA had not approved tirzepatide for chronic weight management.

Tirzepatide is used offlabel for chronic weight management often enough that demand for the drug has led to shortages and risky supply networks, including patients obtaining the drug from online “compounding pharmacies” that make only laboratorygrade (not sanctioned for human use) tirzepatide.[5] As is the case with offlabel use of drugs in general, Public Citizen’s Health Research Group strongly cautions against the offlabel use of tirzepatide for chronic weight management or any other condition.

Background on tirzepatide

As a GLP-1 agonist, like liraglutide and semaglutide, tirzepatide mimics a hormone involved in the metabolism of carbohydrates (simple and complex sugars, including glucose).[6] Additionally, and unlike liraglutide and semaglutide, tirzepatide also is a glucose-dependent insulinotropic polypeptide (GIP) agonist, which means it (among other hormonal/metabolic actions) specifically promotes postprandial (after a meal) insulin secretion in the body.[7] GLP-1 and GIP agonists more broadly are classified as incretin peptides. Among such hormones, GIP agonists are especially potent; however, the long-term clinical advantages, if any, of treatment of diabetes with GIP agonists, as compared with other medications, are not yet known.

The recommended starting dose of tirzepatide is 2.5 mg injected subcutaneously once weekly, with dose increases in 2.5-mg increments as needed after at least four weeks on the current dose, up to a maximum dosage of 15 mg subcutaneously once weekly. Tirzepatide has not been studied in patients with pancreatitis (inflammation of the pancreas), and it may lead to or exacerbate that serious condition. Additionally, tirzepatide is not indicated for use in patients with type 1 diabetes.

FDA review for type 2 diabetes

The FDA’s 2022 approval of tirzepatide for type 2 diabetes was principally based on five clinical trials where the primary endpoint was hemoglobin A1c (HbA1c) level changes after 40 to 52 weeks of treatment.[8] Comparators were placebo (two trials, both randomized and double-blind) and two different insulin formulations or semaglutide (these three trials were all randomized but open-label [not blinded]). All five trials only included patients whose blood glucose was uncontrolled and who had either not previously been treated with glycemic medications or such medications (including metformin alone or insulin and metformin together) were not working as hoped. Results across the five trials showed that tirzepatide reduced HbA1c levels from an average of just over 8% to approximately 6.2%. For people without diabetes, the normal range for HbA1c is between 4% and 5.6%. Levels of 6.5% or higher are associated with diabetes.

The declines in HbA1c levels in the tirzepatide groups were much greater than the declines in the placebo groups, somewhat greater than in the insulin groups, and slightly greater than in the semaglutide group. The FDA reviewers concluded that tirzepatide was “statistically superior” to all the other treatment options tested for glycemic control in adults with uncontrolled blood glucose. Importantly, none of the studies submitted to the FDA for the initial approval of tirzepatide addressed the durability or persistence of HbA1c declines beyond four weeks after each study’s completion.

The FDA assessed the safety of tirzepatide based on nine trials (including the five described above), aggregating data from about 7,760 patients, including about 5,410 patients randomized to treatment with the drug. Adverse effects associated with tirzepatide were those seen previously with GLP-1 agonists. These included gastrointestinal illnesses (nausea, diarrhea, vomiting). Gastrointestinal illnesses occurred in 40% of patients treated with tirzepatide and 20% of patients receiving placebo. As tirzepatide has not been studied in patients with severe gastrointestinal disease, its use is not recommended in these patients. In clinical trials, there were also increases in heart rate of one to three beats per minute on average; such increases in heart rate were especially evident in a subpopulation of Japanese patients.

Weight-loss studies

Two randomized, double-blinded, placebo-controlled trials of tirzepatide for the treatment of obesity have recently been published.[9],[10] One trial, published in The Lancet, was of tirzepitide in adults with type 2 diabetes (938 patients), and the other trial, published in the New England Journal of Medicine, was of adults without diabetes (2,539 patients). Both studies enrolled only those who were substantially overweight (body mass index [BMI] ≥ 27 kg/m2) or obese (BMI ≥ 30). Testing tirzepatide dosages from 5 mg to 15 mg per week, both trials demonstrated significant weight-loss effects at 72 weeks of treatment, with smaller effects in the population with type 2 diabetes (approximately 13%–15% average weight loss in the diabetes trial and 15%–21% average weight loss in the nondiabetes trial; average weight loss was 3% in the placebo groups). Including data from both trials, adverse gastrointestinal effects evident in at least 10% of those on any tirzepatide dose and at more than double the rate observed with placebo were nausea, diarrhea, constipation, dyspepsia (indigestion) and vomiting.

Semaglutide and other new-generation anti-obesity medications, such as tirzepatide, advance on previous-generation medications because they have led to weight loss of 15%–20% or more in clinical trials. A major concern is that lifetime use may be required to prevent weight regain. Studies of tirzepatide are not yet available that assess the effects of either treatment for more than 72 weeks or discontinuing treatment. Studying the effects of discontinuing treatment is critically important. When patients treated with semaglutide stopped the medication, researchers found a substantial rebound effect.[11] Most of the weight that had been lost was quickly regained. Without insurance coverage, lifetime use of semaglutide, tirzepatide or other new-generation anti-obesity medications would be a major financial burden, given the high cost of these drugs. Moreover, additional safety issues associated with long-term use may emerge.

What You Can Do

For type 2 diabetes, Public Citizen’s Health Research Group has previously classified all GLP-1 receptor agonists as Do Not Use because of the limited benefits of the drug class and the serious adverse effects that can include cardiovascular risk, pancreatitis, and pancreas and thyroid cancers. If you are obese or overweight and considering the use of a new-generation anti-obesity medication that has been approved by the FDA, consult with your clinician. The discussion should include consideration of the adverse effects of the medications, the potential for substantial weight regain if a drug is stopped and the advantages of losing weight primarily through increased physical activity and a reduced caloric diet.
 

References

[1] Blum D. “The diabetes drug that could overshadow Ozempic.” The New York Times. April 11, 2023.

[2] Worst Pills, Best Pills News. Semaglutide (WEGOVY) for weight loss: substantial risks, including weight regain. August 2023. Accessed August 19, 2023.

[3] Worst Pills, Best Pills News. Liraglutide (SACENDA): a bad weight-loss choice at any age. June 2023. Accessed August 19, 2023.

[4] Blum D. “The diabetes drug that could overshadow Ozempic.” The New York Times. April 11, 2023.

[5] Chen E. “Mix-it-yourself Wegovy? Some are trying risky sources for weight-loss drugs.” STAT. January 18, 2023.

[6] Puchino F, Nguyen MD. Center for Drug Evaluation and Research. Application Number: 215866Orig1s000. Clinical Review. NDA 215866 (tirzepatide). May 13, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000MedR.pdf. Accessed August 8, 2023.

[7] Gupta K, Raja A. Physiology, Gastric Inhibitory Peptide. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546653/. Accessed August 8, 2023.

[8] Puchino F, Nguyen MD. Center for Drug Evaluation and Research. Application Number: 215866Orig1s000. Clinical Review. NDA 215866 (tirzepatide). May 13, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000MedR.pdf. Accessed August 8, 2023.

[9] Garvey WT, Frias JP, Jastreboff AM, et al. 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 Jun 26:S0140-6736(23)01200-X. doi: 10.1016/S0140-6736(23)01200-X. Epub ahead of print. PMID: 37385275.

[10] Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.

[11] Worst Pills, Best Pills News. Semaglutide (WEGOVY) for weight loss: substantial risks, including weight regain. August 2023. Accessed September 13, 2023.