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New option for the treatment of Type 2 Diabetes: Rybelsus® (oral semaglutide)

Thursday, January 23, 2020  
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Alexandra Cerino, PharmD Candidate 2020, University of the Sciences in Philadelphia

Diane H. Quinn, PharmD, BCACP

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one of the options available for the treatment of type 2 diabetes. GLP-1RA products have varying homology to the endogenous GLP-1RA. GLP-1RA controls post-prandial glucose through increased insulin secretion and inhibition of glucagon secretion; as well as inhibiting gastric emptying and increased satiety.1 Until recently, these agents were only available as injectable products. On September 20, 2019 the FDA approved the first oral GLP-1RA Rybelsus® (oral semaglutide) in dosing strengths of 3mg, 7mg, and 14mg.2,3 When initiating Rybelsus®, it should be started at 3 mg orally once daily for 30 days. After 30 days, the dose should be increased to 7 mg orally once daily. If glycemic targets have not been met after 30 days of 7 mg orally once daily dosing, it is recommended to titrate to a maximum dose of 14 mg orally once daily. Rybelsus® is indicated as adjunctive therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes.3  The American Diabetes Association (ADA) 2019 guidelines recommend metformin and lifestyle management as first line therapy for the treatment of type 2 diabetes.4 Second line or adjunctive therapy is dependent on patient specific factors, which would guide the clinician to choose from varying drug classes, such as a GLP-1RA.4 The novel mechanism of oral semaglutide is its increased half-life due to high protein binding, which results in decreased renal clearance and a decreased metabolism of semaglutide.3  In contrast to Ozempic® (semaglutide) once weekly subcutaneous (SQ) injection, Rybelsus® is taken at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of water.3,5 When Rybelsus® is taken with food or beverages other than water the effect is decreased.3 The warnings and precautions for Rybelsus®  include the risk of thyroid C-cell tumors, pancreatitis, diabetic retinopathy complications, hypoglycemia risk with concomitant use of insulin and insulin secretagogues, acute kidney injury, and hypersensitivity. Some common adverse reactions reported from Rybelsus® were nausea, abdominal pain, diarrhea and other gastrointestinal effects.3 These warnings and adverse reactions are commonly seen with GLP-1RA products.

Rybelsus® was studied in ten different trials known as the PIONEER series, as illustrated in Table 1, which were all sponsored by Novo Nordisk.6 The PIONEER 1 trial was a randomized, double-blind trial that compared oral semaglutide (3 mg,7 mg,14mg) to placebo. Oral semaglutide demonstrated efficacy with significant reduction in hemoglobin A1c (HbA1c) compared to placebo.7 In PIONEER 2, Rybelsus® was compared to empagliflozin in patients with uncontrolled type 2 diabetes on metformin therapy. This was an open-label trial that enrolled 412 patients to oral semaglutide 14 mg orally once daily and 410 patients to empagliflozin 25 mg orally once daily. The eligibility criteria was an HbA1c of 7.0-10.5% and receiving a stable metformin dose. Patients were excluded if they previously received other medication for diabetes or obesity, renal impairment, microvascular complications, or a history of pancreatitis. The primary endpoint assessed the change in HbA1c and the secondary endpoint assessed change in weight (kg), both from baseline to week 26. The primary endpoint was evaluated for both non-inferiority and superiority. There was superiority demonstrated by oral semaglutide compared to empagliflozin at week 26 which was demonstrated by a significant reduction in HbA1c. This trial demonstrates that oral semaglutide at its maximally tolerated dose demonstrated a significant decrease in HbA1c in comparison to empagliflozin.8

However, in comparison at week 26 there was not a superiority demonstrated by oral semaglutide for weight loss. Overall, oral semaglutide exhibited more gastrointestinal side effects compared to empagliflozin.

The PIONEER 3 trial studied Rybelsus® vs. sitagliptin. The study screened 2,463 patients, and randomized 1,864 patients with uncontrolled type 2 diabetes that were receiving metformin therapy. The inclusion criteria of the population were patients with type II diabetes who had an HbA1c of 7.0-10.5% and taking a stable dose of metformin with or without a sulfonylurea. Patients were excluded if they previously received other medication for diabetes or obesity in the past 90 days, history of pancreatitis, renal impairment of microvascular complications. The primary objective of this trial was to assess the efficacy and long-term safety with three different doses of Rybelsus® orally once daily compared to sitagliptin 100 mg orally once daily when either was added to metformin with or without a sulfonylurea in patients with uncontrolled type 2 diabetes. Patients received either once daily oral semaglutide 3 mg, 7 mg, or 14 mg, or sitagliptin 100 mg. In addition to the randomized study drug, patients were also receiving metformin with or without a sulfonylurea which were maintained at stable doses. The primary endpoint was change in HbA1c and a secondary endpoint of change in body weight, both from baseline to week 26. A sample size calculation was conducted to determine a 90% power to calculate a superiority of oral semaglutide 7 mg and 14 mg compared to sitagliptin and a noninferiority of oral semaglutide 3 mg compared to sitagliptin 100 mg. A significant reduction in HbA1c and body weight was seen in Rybelsus®  7 mg and 14 mg when compared to sitagliptin 100 mg at week 26. A noninferiority of the oral semaglutide 3 mg compared to sitagliptin could not be determined. The most commonly demonstrated adverse effects with oral semaglutide were gastrointestinal, particularly nausea. Both sitagliptin and oral semaglutide 3 mg and 7 mg doses reported upper respiratory tract and urinary tract infections.  This demonstrated that Rybelsus® could be considered a better option when compared to sitagliptin in patients on metformin therapy with or without a sulfonylurea with uncontrolled type 2 diabetes.9

In PIONEER 4, a 52 week trial compared oral semaglutide to subcutaneous liraglutide, both being GLP-1RAs. This head to head study was different than PIONEER 2 and 3 because there were three treatment arms, with one being placebo. The patients in this study were randomized to oral semaglutide 14 mg once daily, liraglutide 1.8 mg SQ once daily, and placebo (2:2:1). Inclusion criteria included >18 years, HbA1c 7-9.5%, therapy with a stable metformin dose, and with or without concurrent therapy of a sodium-glucose co-transporter-2 inhibitor (SGLT2). Patients were excluded if they had received any other medication for diabetes or obesity in the past 90 days, except for an SGLT2 inhibitor, or short term insulin, renal impairment, microvascular complications, and a history of pancreatitis. The primary endpoint was to assess the change in HbA1c, and the secondary endpoint was change in weight, both from baseline to week 26. Superiority of oral semaglutide compared to liraglutide was assessed based upon a 90% power calculation. Superiority was assessed for oral semaglutide vs. placebo and both non-inferiority and superiority for subcutaneous liraglutide vs. oral semaglutide. Oral semaglutide demonstrated non-inferiority to liraglutide, but not superiority. There was superiority demonstrated by oral semaglutide to placebo at week 26. Since both of these agents are in the same class, it would be expected that oral semaglutide would demonstrate non-inferiority to subcutaneous liraglutide. When using GLP-1RAs it would be a matter of dosing and administration on which agent to choose based upon patient characteristics.10

The remaining PIONEER trials include four published trials and two ongoing.6 The PIONEER 5 trial evaluated oral semaglutide (dose escalation to 14 mg)  compared to placebo in patients with moderate renal impairment who were receiving background therapy with other glucose-lowering therapies such as, metformin, sulfonylurea, or insulin. A significant reduction in HbA1c was demonstrated by oral semaglutide compared to placebo and both groups had no significant changes in renal function throughout the trial.11 PIONEER 6 was a trial that evaluated the cardiovascular outcomes of oral semaglutide compared to placebo in patients with high-cardiovascular risk. Oral semaglutide showed non-inferiority to placebo in terms of cardiovascular risk which included death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke.12 The PIONEER 7 trial compared sitagliptin 100 mg to oral semaglutide flexible dose increases based upon HbA1c and tolerability, with an initial dose of 3 mg and a maximum of 14 mg. There were significantly more patients in the oral semaglutide group that achieved a mean HbA1c <7% compared to those in the sitagliptin 100 mg group.13 The last published trial, PIONEER 8, evaluated oral semaglutide (3mg, 7mg, and 14mg) compared to placebo in patients with uncontrolled type 2 diabetes on insulin with or without metformin therapy. Oral semaglutide significantly reduced HbA1c and weight compared to placebo.14

Based upon the data from the PIONEER trials, Rybelsus® has shown its place in therapy in comparison to other type 2 diabetes treatment agents. Due to GLP-1RAs new place in therapy according to the ADA 2019 guidelines, this agent provides another option to this class of primarily injectable agents.4  Future use and true placement in the therapy algorithm for Rybelsus® is yet to be determined with the pending publication of the ADA 2020 guidelines.

 

 References

  1. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1.Cell Metab. 2018;27(4):740-756.
  2. Drugs@FDA: FDA Approved Drug Products. accessdata.fda.gov. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213051. Accessed October 22, 2019.
  3. Rybelsus® (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk; 2019.
  4. American diabetes association. Standards of medical care in diabetes – 2019. Diabetes Care. 2019 Jan; 42 (Supplement 1):S1-S183.
  5. Ozempic® (semaglutide) [package insert]. Plainsboro, NJ: Novo Nordisk; 2017.
  6. McDermid E. A quick guide to the pioneer trials. Springer Nature. 2019 July 3; updated 2019 October. Accessed from: https://diabetes.medicinematters.com/semaglutide/cardiovascular-outcomes/a-quick-guide-to-the-pioneer-trials/16877792.
  7. Aroda VRosenstock JTerauchi YAltuntas YLalic NMorales Villegas EJeppesen OChristiansen EHertz C, Haluzík MPIONEER 1: Randomized clinical trial comparing the efficacy and safety of oral semaglutide monotherapy with placebo in patients with type 2 diabetes. Diabetes Care. 2019; 42 (9):1724-1732.
  8.  Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, Lingvay I, Søndergaard AL, Treppendahl MB, Montanya E. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019 Sep 17.
  9. Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, Serusclat P, Violante R, Watada H, Davies M. 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.
  10. Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, Pedersen KB, Saugstrup T, Meier JJ; PIONEER 4 investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019 Jul 6;394(10192):39-50.
  11. Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, Pratley R, Sathyapalan T, Desouza C; PIONEER 5 Investigators. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jul;7(7):515-527.
  12. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, Thomsen M, Vilsbøll T, Warren ML, Bain SC; PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851.
  13. Pieber TR, Bode B, Mertens A, Cho YM, Christiansen E, Hertz CL, Wallenstein SOR, Buse JB; PIONEER 7 investigators. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jul;7(7):528-539.
  14. Zinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, Pedersen KB, Tarp-Johansen MJ, Araki E; PIONEER 8 Investigators. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019 Sep 17.

 


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