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Featured Clinical Topic: De-Sema-nating the Best Semaglutide Formulation for Your Patient

19 Jan 2022 5:02 AM | Anonymous

De-Sema-nating the Best Semaglutide Formulation for Your Patient

By Kelly Williams, PharmD Candidate Class of 2023, UMKC School of Pharmacy and Jordan Rowe, PharmD, BCACP, BC-ADM, UMKC School of Pharmacy

Semaglutide, a glucagon-like peptide (GLP-1) receptor agonist, works by mimicking the effects of human GLP-1 to induce insulin secretion and augment the metabolism of blood sugar. Current American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) guidelines recommend GLP-1 agonists as a possible second-line therapy following first-line metformin for most patients, and the recent ADA 2022 update recommends that GLP-1 agonists may be appropriate initial therapy for those with certain risk or disease factors.1, 2 Semaglutide has been used on label for the last four years in the treatment of type 2 diabetes (T2DM) and off-label for weight management through its favorable glycemic profile, A1c-lowering, weight-reducing effects. Further data has shown additional benefits in secondary atherosclerotic cardiovascular disease (ASCVD) prevention. With the U.S. Food and Drug Administration’s (FDA) approval of Novo Nordisk’s third semaglutide formulation, Wegovy™, for weight management in early 2021, a clear, concise clinical decision support tool would be beneficial for providers who may be scratching their heads at the different forms of semaglutide and their appropriate uses. This article aims to describe the similarities and differences between three formulations of semaglutide (Ozempic®, Rybelsus®, and Wegovy™) and provide an overview given patient-specific factors.

 The first formulation of semaglutide approved was Ozempic®. On December 5th, 2017, Novo Nordisk approved Ozempic®, a once weekly 0.5 mg or 1 mg injection, as adjunctive therapy with diet and exercise for the treatment of T2DM in patients with or without cardiovascular complications.3  The results of the SUSTAIN trials skyrocketed Ozempic® to the public eye by demonstrating several eye-catching attributes, including significant weight loss, A1c lowering, and secondary ASCVD risk reduction.3 Ozempic® was studied as a once weekly injection, yielding another advantage over several other currently available once or multiple daily GLP-1 injections. Although the associated weight reduction is a particularly attractive feature of Ozempic® given the benefits of achieving a healthy weight in those with T2DM, the formulation is not FDA-approved for obesity or weight management. Consequently, Ozempic® would not be ideal in patients only seeking weight management or patients who do not feel comfortable with injection therapy. Analogous to all currently available semaglutide formulations, Ozempic® is not available as a generic and thus carries a significant price tag. Although patient assistance programs and coupons for Ozempic® are available, cost may direct prescribers away from semaglutide formulations and towards more cost-effective alternatives as Ozempic® average wholesale price (AWP) costs over $1000 for a one-month supply.4

Next came Rybelsus®, a once-daily oral alternative to Ozempic®. On September 20th, 2019, less than two years after the release of Ozempic®, Novo Nordisk announced Rybelsus® was FDA-approved as 7 mg or 14 mg tablets for the treatment of T2DM.5 A pioneer in its class, Rybelsus® was the first oral GLP-1 agonist, providing an option to patients unable or unwilling to use injections. The PIONEER trials showed that Rybelsus® had similar favorable A1c lowering and weight lowering effects to Ozempic®, although it failed to demonstrate superiority in secondary ASCVD risk reduction.6 Although current literature has not fully elucidated why Rybelsus® did not show a similar secondary ASCVD benefit profile like Ozempic®, some theories about the mechanism by which GLP-1 agonists reduce risk as well as the discrepancy between agents have been described. Proposed theories include differing kinetic concentration profiles between the oral and subcutaneous formulations are the root of the difference, or perhaps that there is no difference, and the duration of the PIONEER trials was simply not long enough to identify cardiovascular benefits.6 Comparable to Ozempic®, Rybelsus® is not advantageous for those only seeking weight reduction or weight management as the only FDA-indication for Rybelsus® is for the treatment of T2DM. Cost should also be considered with Rybelsus®, as similar to Ozempic®, the drug also has an AWP cost of over $1000 per month.4 It is noteworthy that both Ozempic® and Rybelsus® would likely have a lower price tag for insured patients compared to Wegovy™ as most insurance companies have relatively robust coverage for agents treating T2DM, while many plans have limited to no coverage for medications with indications for weight management alone.

Lastly, on June 4th, 2021, Novo Nordisk announced Wegovy™ as a new semaglutide product to be FDA-approved for the exclusive indication of chronic weight management (in addition to diet and exercise) as a once-weekly 2.4 mg injection.7 Candidates for Wegovy should have a BMI of ≥30 kg/m2 or have one weight-related comorbidity (i.e. high blood pressure, high cholesterol, type 2 diabetes) with a BMI of ≥27 kg/m2.8  The STEP trials demonstrated that Wegovy™ showed significant weight loss and improved physical function.8  These trials did not show A1c-lowering effects in the general population, which is likely due to the trials excluding patients living with T2DM in all but the STEP 2 trial. In this instance, cost concerns are most dramatically at the forefront of clinical decision-making, as many insurance companies have limited to no coverage in medications indicated for weight management. Thus, Wegovy™ may incur the largest out-of-pocket expense by the patient of all semaglutide formulations with a price tag starting over $1600 per month AWP, regardless of strength.4

Given the similarity of Wegovy™ to its semaglutide predecessor, Ozempic®, the injectable dosage form of 2.4 mg once weekly begs the question whether two separate formulations are even necessary, as all semaglutide formulations are exclusively manufactured by Novo Nordisk. The SUSTAIN FORTE trial compared weekly Ozempic® 1 mg to Ozempic® 2 mg (not currently commercially available) for the purposes of assessing A1c lowering in patients with T2DM.9 The trial showed statistical superiority of the 2 mg dosage over 1 mg of Ozempic® in A1c reduction, although the absolute difference of 0.3% between the two dosages may or may not be considered clinically significant.9 The most substantial difference in study arms was in mean bodyweight change, mirroring results in the STEP trials.8, 9  This suggests that while the weight loss potential with semaglutide increases with escalating doses, the glycemic management benefits seem to plateau. It will be intriguing to see if the cardiovascular risk reduction will also be mirrored between the two injectable formulations, but the results of the SELECT trial, investigating secondary ASCVD risk reduction in patients using Wegovy™ for weight management, are not anticipated for several years.10

While differentiating between the three formulations of semaglutide may seem intimidating initially, this article hopes to help clarify key clinical pearls for their utilization in practice. The following decision support figure shown below may be beneficial in helping to determine which semaglutide formulation may be appropriate for your patient. 


  1. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocrine Practice. 2020;26(1):107-139.
  2. American Diabetes Association. Introduction: standards of medical care in diabetes—2022. Diabetes Care. 2021;45(Supplement_1)
  3. A quick guide to the SUSTAIN trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/type-2-diabetes/a-quick-guide-to-the-sustain-trials/12206922
  4. RED BOOK search - MICROMEDEX. Accessed January 11, 2022. https://www-micromedexsolutions-com.proxy.library.umkc.edu/micromedex2/librarian/CS/9C6AFE/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/94FAE0/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/redbook.FindRedBook?navitem=topRedBook&isToolPage=true
  5. FDA approves Rybelsus® (semaglutide), the first GLP-1 analog treatment available in a pill for adults with type 2 diabetes. Accessed December 5, 2021. https://www.prnewswire.com/news-releases/fda-approves-rybelsus-semaglutide-the-first-glp-1-analog-treatment-available-in-a-pill-for-adults-with-type-2-diabetes-300922438.html
  6. A quick guide to the PIONEER trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/cardiovascular-outcomes/a-quick-guide-to-the-pioneer-trials/16877792
  7. WegovyTM (semaglutide 2.4 mg), the first and only once-weekly GLP-1 therapy for weight management, approved in the US. Accessed December 5, 2021. https://www.globenewswire.com/news-release/2021/06/04/2242293/0/en/Wegovy-semaglutide-2-4-mg-the-first-and-only-once-weekly-GLP-1-therapy-for-weight-management-approved-in-the-US.html
  8. A quick guide to the STEP trials | diabetes.medicinematters.com. Accessed December 5, 2021. https://diabetes.medicinematters.com/semaglutide/obesity/quick-guide-step-trials/18854832
  9. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. The Lancet Diabetes and Endocrinology. 2021;9(9). doi:10.1016/S2213-8587(21)00174-1
  10. Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design. American Heart Journal. 2020;229:61-69. doi:10.1016/J.AHJ.2020.07.008 https://www.clinicaltrials.gov/ct2/show/NCT03574597.

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