Pathways to Weight Loss
Wegovy —>Januvia—>Metformin Pharmacologic Pathway
Eat Better—>Walking—>Exercise Lifestyle Pathway
Injectable GLP-1 drugs like Wegovy (semaglutide), Saxenda (liraglutide), and Mounjaro (tirzepatide) are becoming almost universally known in society for their potential weight loss properties. Off label use of some of these drugs has practically gone viral. Elon Musk himself gives the drug Wegovy credit for his improved health and slimmer figure. The demand has been so high for these products that availability has become a serious issue. This is more than just a manufacturing backlog that has slowed international roll out; these are expensive products with sometimes subpar reimbursements from insurance companies. The margins have become so tight on dispensing some of these more expensive drugs that for smaller independent pharmacies it means potentially filling the prescription at a loss.
Insurance companies are not exactly happy to see all these expensive claims coming through either. So, they throw up every roadblock they legally can in order to avoid paying for these products. Prior authorizations, step therapy, and outright claim rejections are their first line of defense. Next are audits of the pharmacy for any reason possible to later claw back those claims. Further complicating the payment issue are drug coupons handed out by the manufacturers. Mounjaro has become notorious for coupons that appear to work initially but can be taken back later for a variety of reasons in the fine print that void the coupon, off label prescribing for one. Wegovy is the only drug in the class that currently has an FDA approved indication for weight loss, others have approval for diabetes so using them for weight loss is technically off label prescribing. You can see why it happens after all Wegovy is the same drug as Rybelsus they are both semaglutide except one is injectable and the other is an oral tablet, one has approval for weight loss the other diabetes despite being the same drug. They are both very expensive, so what are the options for the financially or insurance challenged?
Januvia (sitagliptin) is the first drug that comes to mind when I think of less expensive alternative products to the GLP-1 drugs because it causes an increase in GLP-1 by inhibition of DPP-4. A study comparing the drugs showed sitagliptin to be comparable with lower doses of semaglutide. The beneficial effect is provided by the same mechanism, an increase in GLP-1 either by preventing its metabolism with DPP-4 inhibitors or injecting it directly once a week. Januvia is brand only until 2027 and costs about 500 bucks a month which is not cheap but is better than 2000. It also provides a real bang for its buck. Januvia can lower A1C by up to a point which is significant. Regarding weight loss, the results seem mixed. A recent study comparing the two drugs showed substantially more weight loss with the higher dose semaglutide. With Januvia we are politely nudging the system towards where we want to go. By directly injecting GLP-1 we are kicking the door down and forcefully dragging the system where we want it. Because it is more of a brute force approach the GLP-1 drugs do cause gastrointestinal issues (despite being injectable) and have more potential for hypoglycemia. I do have theoretical concerns about the abuse of these products causing acute hypoglycemia which could precipitate a cardiovascular event. (1)
Sitagliptin has received attention as a potential covid therapy also. Molecular modeling has confirmed that the drug has the potential to bind and interact with two proteases 3CL and PL. Both proteases play a role in viral reproduction and inhibition of them has been proposed as a beneficial mechanism for the treatment of covid. Another study looking at diabetic patients with covid did show improved outcomes when sitagliptin was given in addition to metformin. A retrospective cohort study of 220 patients looked at DPP-4 inhibitors in diabetic patients with covid and there was a significant decrease in hospitalization duration but no statistical significance for survival.
Metformin has been the gold standard for treating diabetes and is so widely used that its weight reduction benefits, and safety profile are well documented. The best thing about it is the price, since it is such an old generic medication it is as cost effective as it gets. Titrate the dose up slowly over a week or two to prevent gastrointestinal distress. Other generic drugs with weight loss credentials using different mechanisms include Topamax (topiramate) a migraine medication and Wellbutrin (bupropion) an antidepressant and smoking cessation drug that has its own potential for abuse.
At their best all these products discussed are hyped to be exercise in a bottle. The reason they say that is because there are studies showing that exercise increases GLP-1. Animal studies have shown that GLP-1 is involved in exercise endurance and remodeling of skeletal muscle. So instead of paying for GLP-1 you can go farm it the old-fashioned way, building more muscle and moving that muscle to burn fat.
Wegovy $2,000
Rybelsus $1,000
Januvia $500
Gym $50
Metformin $10
Walking $0
Jacob Hyatt Pharm D.
Father of three, Husband, Pharmacist, Realtor, Landlord, Independent Health and Medicine Reporter
www.pharmacoconuts.com
@Hyattjn
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Further reading and references
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649367/ (1)
Sanon VP, Sanon S, Kanakia R, Yu H, Araj F, Oliveros R, Chilton R. Hypoglycemia from a cardiologist's perspective. Clin Cardiol. 2014 Aug;37(8):499-504. doi: 10.1002/clc.22288. Epub 2014 Jun 4. PMID: 24895268; PMCID: PMC6649367.
https://pubmed.ncbi.nlm.nih.gov/36738369/
Zong Y, Wang X, Zhang Y, Tan N, Zhang Y, Li L, Liu L. Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice. Cardiovasc Drugs Ther. 2023 Feb 4. doi: 10.1007/s10557-023-07436-1. Epub ahead of print. PMID: 36738369.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145895/
Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials. Front Endocrinol (Lausanne). 2020 Apr 3;11:178. doi: 10.3389/fendo.2020.00178. PMID: 32308645; PMCID: PMC7145895.
https://pubmed.ncbi.nlm.nih.gov/36874737/
Benido Silva V, Pereira MT. Six-Year Complete Remission of Type-1 Diabetes Mellitus in an Adult Treated With Sitagliptin. Cureus. 2023 Jan 30;15(1):e34376. doi: 10.7759/cureus.34376. PMID: 36874737; PMCID: PMC9976506.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484814/
Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, Serusclat P, Violante R, Watada H, Davies M; PIONEER 3 Investigators. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Apr 16;321(15):1466-1480. doi: 10.1001/jama.2019.2942. PMID: 30903796; PMCID: PMC6484814.
https://pubmed.ncbi.nlm.nih.gov/36724745/
Sun X, Xu Y, Zhou J. DPP4 Inhibitor Sitagliptin Reduces Inflammatory Responses and Mast Cell Activation in Allergic Rhinitis. Pharmacology. 2023;108(2):166-175. doi: 10.1159/000528634. Epub 2023 Feb 1. PMID: 36724745.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524728/
Alomair BM, Al-Kuraishy HM, Al-Buhadily AK, Al-Gareeb AI, De Waard M, Elekhnawy E, Batiha GE. Is sitagliptin effective for SARS-CoV-2 infection: false or true prophecy? Inflammopharmacology. 2022 Dec;30(6):2411-2415. doi: 10.1007/s10787-022-01078-9. Epub 2022 Sep 30. PMID: 36180664; PMCID: PMC9524728.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639723/
Sadidi M, Zare A, Nasrollahzadehsabet M, Dastan F, Mosadegh Khah A, Jafari Asheyani M. The roles of dipeptidyl peptidase-4 inhibitors in prognosis of COVID-19 infection in patients with type 2 diabetes mellitus. J Res Med Sci. 2022 Aug 27;27:62. doi: 10.4103/jrms.jrms_71_22. PMID: 36353337; PMCID: PMC9639723.
https://pubmed.ncbi.nlm.nih.gov/36382241/
da Cruz Freire JE, Júnior JEM, Pinheiro DP, da Cruz Paiva Lima GE, do Amaral CL, Veras VR, Madeira MP, Freire EBL, Ozório RG, Fernandes VO, Montenegro APDR, Montenegro RC, Colares JKB, Júnior RMM. Evaluation of the anti-diabetic drug sitagliptin as a novel attenuate to SARS-CoV-2 evidence-based in silico: molecular docking and molecular dynamics. 3 Biotech. 2022 Dec;12(12):344. doi: 10.1007/s13205-022-03406-w. Epub 2022 Nov 7. PMID: 36382241; PMCID: PMC9640538.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699540/
Al-Kuraishy HM, Al-Gareeb AI, Albogami SM, Jean-Marc S, Nadwa EH, Hafiz AA, A Negm W, Kamal M, Al-Jouboury M, Elekhnawy E, Batiha GE, Waard M. Potential Therapeutic Benefits of Metformin Alone and in Combination with Sitagliptin in the Management of Type 2 Diabetes Patients with COVID-19. Pharmaceuticals (Basel). 2022 Nov 7;15(11):1361. doi: 10.3390/ph15111361. PMID: 36355535; PMCID: PMC9699540.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121144/
Mikhael EM, Ong SC, Sheikh Ghadzi SM. Efficacy and Safety of Sitagliptin in the Treatment of COVID-19. J Pharm Pract. 2022 May 17:8971900221102119. doi: 10.1177/08971900221102119. Epub ahead of print. PMID: 35581701; PMCID: PMC9121144.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294388/
Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021 Jul 7;12:645563. doi: 10.3389/fendo.2021.645563. Erratum in: Front Endocrinol (Lausanne). 2021 Nov 10;12:786732. PMID: 34305810; PMCID: PMC8294388.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393509/
Domecq JP, Prutsky G, Leppin A, Sonbol MB, Altayar O, Undavalli C, Wang Z, Elraiyah T, Brito JP, Mauck KF, Lababidi MH, Prokop LJ, Asi N, Wei J, Fidahussein S, Montori VM, Murad MH. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70. doi: 10.1210/jc.2014-3421. Epub 2015 Jan 15. PMID: 25590213; PMCID: PMC5393509.
https://pubmed.ncbi.nlm.nih.gov/35636559/
Wu L, Zhou M, Li T, Dong N, Yi L, Zhang Q, Mi M. GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochim Biophys Acta Mol Cell Res. 2022 Sep;1869(9):119300. doi: 10.1016/j.bbamcr.2022.119300. Epub 2022 May 27. PMID: 35636559.
