Trumping Obesity With Tirzepatide

Obesity is a highly prevalent disease in the United States (US), with prevalence rates over 40% (1). Obesity-related complications most commonly include heart disease, stroke, and type-2 diabetes, leading to higher costs of medical care for obese individuals, contributing to over 170 billion dollars in healthcare costs in the US (2). To combat the rising obesity prevalence, there are several approaches to therapy, including lifestyle modifications (improvement in diet and exercise), medical therapy, and bariatric surgery. Of the treatment options mentioned above, there are a variety of FDA-approved medications for obesity. This includes phentermine-topiramate, naltrexone-bupropion, orlistat, and glucagon-like-peptide 1 (GLP-1) agonists. Phentermine-topiramate, a combination of a sympathomimetic and antiepileptic drug, and naltrexone-bupropion, a combination of an opioid antagonist and anti-depressant, help improve appetite suppression, contributing to 4-10% weight loss from baseline (3-4). Orlistat is a lipase inhibitor preventing fat metabolism, contributing to ~5% weight loss from baseline (5). While these options are affordable, their expected weight loss may be ineffective for certain individuals. Thus, a newer class of anti-obesity medications, GLP-1 agonists, have been more popular on the market.

GLP-1 agonists are weekly injectables that not only increase insulin secretion and reduce glucagon release, they also delay gastric emptying to help induce satiety. FDA-approved GLP-1 agonists for obesity include liraglutide and semaglutide, which contribute to 6.4% and 15.8% weight loss for baseline, respectively (6). However, GLP-1 agonists being injectable with low affordability, insurance coverage, and supply chain issues may limit access to these medications for obesity, particularly semaglutide (7).

Recently, in May 2022, tirzepatide, was FDA-approved for type-2 diabetes. The unique aspect of tirzepatide is that it is a dual GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) agonist, further augmenting its impact on weight loss. The SURMOUNT-1 trial, a phase 3 double-blind randomized controlled trial with over 2,500 participants, demonstrated a mean weight change from baseline of 15-20% (p < 0.05) for 5mg, 10mg, and 15mg of tirzepatide at 72 weeks (8). This trial was preceded by the SURPASS-2 trial which compared tirzepatide to semaglutide in type 2 diabetics (9). In this 40-week, open-label, phase 3 trial, tirzapetide had shown a greater weight reduction compared to semaglutide (with least-squares mean estimated treatment difference, −1.9 to −5.5 kg, respectively; p<0.001 for all doses of tirzapetide compared to semaglutide) (9). However, tirzepatide had greater adverse events compared to semaglutide (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). While tirzepatide seems to be the front-runner as an anti-obesity drug, it is only FDA-approved in type-2 diabetics, making it difficult for non-diabetic obese individuals to get access to this medication. However, like semaglutide, tirzepatide will likely breach the barrier in FDA-approval as an anti-obesity agent – because we know its ability to trump obesity!

References.

1. Bryan S, Afful J, Carroll M, et al. NHSR 158. National Health and Nutrition Examination Survey 2017–March 2020 Pre-pandemic Data Files. Published online June 14, 2021. doi:10.15620/cdc:106273
2. Ward ZJ, Bleich SN, Long MW, Gortmaker SL. Association of body mass index with health care expenditures in the United States by age and sex. Siegel R, ed. PLOS ONE. 2021;16(3):e0247307. doi:10.1371/journal.pone.0247307
3. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2010 Aug 21;376(9741):594] [published correction appears in Lancet. 2010 Oct 23;376(9750):1392]. Lancet. 2010;376(9741):595-605. doi:10.1016/S0140-6736(10)60888-4
4. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. The Lancet. 2011;377(9774):1341-1352. doi:10.1016/s0140-6736(11)60205-5
5. Anderson JW, Schwartz SM, Hauptman J, et al. Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16 week, double-blind, placebo-controlled trial. Ann Pharmacother. 2006;40(10):1717-1723.
6. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022;327(2):138–150. doi:10.1001/jama.2021.23619
7. Wegovy Supply. Novonordisk-us.com. Published 2021. Accessed June 10, 2022. https://www.novonordisk-us.com/products/product-supply-update.html1.
8. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. Published online June 4, 2022. doi:10.1056/nejmoa2206038
9. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. New England Journal of Medicine. 2021;385(6):503-515. doi:10.1056/nejmoa2107519