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July Blog- How does the efficacy of Rybelsus compare to DPP4s and SGLT2s in patients with T2DM?

By Christina Inteso posted 29 days ago

  

Title: How does the efficacy of Rybelsus compare to DPP4s and SGLT2s in patients with T2DM?

Author: Jiwoo Lee, PharmD Candidate 2024, Northeastern University School of Pharmacy

Reviewer: Courtney Cameron, PharmD, BCACP

What is Rybelsus?

Rybelsus (semaglutide) is the first oral GLP-1 RA approved by the FDA to improve glycemic control in patients with T2DM in conjunction with diet and exercise. The medication is available in 3mg, 7mg, and 14mg tablets; the manufacturer recommends initiating with 3mg once daily for 30 days and then escalating to 7mg. The dose can further be increased to 14mg in patients requiring additional glycemic lowering.1

Despite the more frequent dosing (daily) compared to some injectable GLP-1 RAs (weekly), oral administration of Rybelsus makes GLP1s hugely accessible to patients reluctant to self-inject medications. As a result, Rybelsus may have a similar place in therapy as other oral T2DM medications like DPP4s and SGLT2s to reach glycemic targets. This written commentary aims to: 1) compare oral GLP-1 RA to DPP4i 2) compare oral GLP-1 RA to SGLT2i and 3) investigate the CV outcomes of oral GLP-1 RA.

Rybelsus vs DPP4i (PINOEER 3 trial)

PIONEER 3 was a randomized, double-blind, double-dummy, parallel-group, phase 3a trial that evaluated efficacy and long-term adverse drug events of oral semaglutide compared to sitagliptin added onto metformin with or without sulfonylurea, in patients with T2DM.2 At baseline, all patients were taking metformin and about half were taking sulfonylurea.

Patients were randomized into once-daily oral semaglutide, 3mg (n = 466), 7mg (n = 466), 14mg (n = 465), or sitagliptin 100mg (n = 467). The primary endpoint was change in HbA1c and the key secondary endpoint was change in body weight from baseline to week 26. Outcomes were assessed through the lens of two estimands: treatment policy and trial product. Treatment policy estimand utilizes an intention to treat approach, whereas trial product estimand utilizes per protocol analysis. 

The results of the treatment policy estimand showed a statistically significant reduction in HbA1c for semaglutide 7mg (-0.3% [95% CI,–0.4% to –0.1%]) and 14mg (–0.5% [95% CI,–0.6% to –0.4%]) groups from baseline to week 26. There was also a statistically significant reduction in body weight for 7mg (–1.6 kg [95%CI,–2.0 to–1.1 kg] and 14mg (–2.5kg [95%CI,–3.0 to–2.0kg]). Results were similar in the trial product estimand. Outcomes for semaglutide 3mg daily were noninferior throughout the trial. 

It is worth noting that the reduction trends were not always consistent through the extended follow up of 78 weeks. The treatment policy estimand showed A1c change of -0.3 (at week 26) vs -0.1 (at week 78) for 7mg and -0.5 (at week 26) vs -0.4 (at week 78). Reversal of A1c change and weight loss was most prominent from week 52-78. Results were similar in the trial product estimand.

This trial effectively shows that oral semaglutide 7mg and 14mg showed a significantly greater reduction in HbA1c and body weight compared to sitagliptin in adults with T2DM on metformin with or without sulfonylureas.

Rybelsus vs SGLT2i (PIONEER 2 trial)

PIONEER 2 was a randomized, open-label, multinational 52-week trial that compared the efficacy and safety of oral semaglutide and empagliflozin in patients with T2DM uncontrolled on metformin (at least 1,500mg daily) alone.3

A total of 822 patients were randomized to once-daily treatment with oral semaglutide 14mg (n = 412) or empagliflozin 25 mg (n = 410). The primary endpoint was change in HbA1c and the key secondary endpoint was change in body weight from baseline to 26 weeks. Outcomes were assessed through the lens of two estimands: treatment policy and trial product. Treatment policy estimand utilizes an intention to treat approach, whereas trial product estimand utilizes per protocol analysis. 

Results in the treatment policy estimand showed that oral semaglutide resulted in superior reduction in HbA1c compared to empagliflozin at week 26 (–1.3% vs. –0.9% [–14 vs. –9 mmol/mol]) with estimated treatment difference of –0.4% [95% CI –0.6, –0.3] [–5 mmol/mol (–6, –3)]; P < 0.0001). Results were consistent in the trial product estimand. While superior weight loss was not detected at week 26, oral semaglutide showed significant benefit at week 52 in the trial product estimand (−4.7 vs. −3.8 kg; P = 0.0114). Weight loss results were not significant in the treatment policy estimand. This trial supports the superiority of oral semaglutide over empagliflozin in terms of HbA1c lowering and, to a lesser degree, body weight reduction.

Rybelsus in CVD

Though oral semaglutide is superior to DPP4i and SGLT2i in terms of glycemic control and weight management, it is also important to consider oral semaglutide’s cardiovascular benefit. SGLT2i and GLP-1 RA with proven cardiovascular benefit are the treatment of choice after metformin in patients with T2DM and ASCVD and/or CKD.4 Specific agents of choice include: liraglutide, semaglutide SC, and dulaglutide for GLP-1 RA and empagliflozin, canagliflozin, and dapagliflozin for SGLT2i.5,6

PIONEER 6 is a CV safety trial which evaluated cardiovascular outcomes of oral semaglutide in patients with T2DM.7 This was an event-driven, randomized, double-blind, placebo-controlled trial which included patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). 3183 patients were randomized to oral semaglutide or placebo group. The primary endpoint was the first occurrence of a MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). Results showed MACE occurred in 3.8% (61 of 1591) of oral semaglutide group compared to 4.8% (76 of 1592) in the placebo group. The hazard ratio was 0.79 (95% CI; 0.57 to 1.11; P<0.001 for noninferiority) and the authors concluded that CV risk profile of oral semaglutide was noninferior to that of placebo. While this trial does not support the role of Rybelsus in preventing MACE, PIONEER 6 demonstrates that Rybelsus does not independently cause MACE compared to placebo. 

Conclusion and Future Directions

PIONEER 2 and 3 trials showed results that favored oral semaglutide over DPP4i sitagliptin and SGLT2i empagliflozin in terms of HbA1c and body weight reduction. Therefore, practitioners may consider Rybelsus as a replacement for DPP4i or SGLT2i in patients not achieving glycemic or weight goals.

In terms of future directions, there is an ongoing CV efficacy trial for oral semaglutide (14mg daily) entitled SOUL.8 SOUL evaluates time to first occurrence of MACE as a primary outcome in patients with T2DM at least 50 years old who have one or more of CHD, CVD, symptomatic PAD, or CKD. The trial compares oral semaglutide to placebo and is expected to be completed in July 2024. This trial will help understand the degree of cardiovascular benefit that oral semaglutide has; it will further help determine the place in therapy the drug has in patients with T2DM and ASCVD and/or CKD.

Additionally, PIONEER TEENS investigates the efficacy and safety of oral semaglutide in children aged 10 to 17 years with T2DM. The estimated study completion date is 03/17/2026.9

In the near future, higher doses of Rybelsus are anticipated to enter the market. PIONEER PLUS, published in 2023, compared two higher doses of oral semaglutide – 25mg and 50mg daily – to the already approved 14mg daily over 52 weeks.10 The study was a global, multicenter, randomized, double-blind, phase 3b trial. Participants were randomly (1:1:1) assigned to once-daily oral semaglutide doses of 14mg, 25mg, or 50mg. The primary endpoint was a change in mean HbA1c from baseline to week 52. The results showed change of −1.5% (SE 0.05) with 14 mg, −1.8% (0.06) with 25 mg (estimated treatment difference [ETD] −0.27, 95% CI −0.42 to −0.12; p=0.0006), and −2.0% (0.06) with 50 mg (ETD −0.53, −0.68 to −0.38; p<0·0001). Adverse events occurred in 404 (76%) participants in the 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Therefore, authors concluded that oral semaglutide 25mg and 50mg were superior to 14mg in reducing HbA1c and body weight in adults with T2DM.

Practitioners should anticipate FDA approval of the two doses and consider therapy escalation in patients who fail to achieve glycemic control with the 14mg dose. 

Key Points:

  • Oral semaglutide at 7mg and 14mg daily has a marginally better effect on weight loss and A1c compared to sitagliptin 100mg daily in addition to metformin +/- sulfonylurea. However, degree of treatment effect with oral semaglutide was curiously not maintained through 52-78 weeks.
  •  Oral semaglutide at 14mg has a slightly better effect on A1c compared to empagliflozin 25mg daily in combination with metformin through 52 week follow up. Though, comparison of weight loss effects is likely not clinically significant.
  •  Oral semaglutide at a maximum dose of 14mg daily does not independently effect ASCVD risk.
  •  Oral semaglutide may soon be approved for higher dosing of 25mg and 50mg daily.  

References:

1. Rybelsus (semaglutide) [package insert]. Bagsværd, Denmark: Nono Nordisk; 2024. 

2. Rosenstock JAllison DBirkenfeld AL, et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With SulfonylureaThe PIONEER 3 Randomized Clinical TrialJAMA. 2019;321(15):1466–1480. doi:10.1001/jama.2019.2942

3. Rodbard HW, Rosenstock J, Canani LH, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-2281. doi:10.2337/dc19-0883

4. American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2024. Diabetes Care. 1 January 2024; 47 (Supplement_1): S158–S178. doi:10.2337/dc24-S009

5. Marx N, Husain M, Lehrke M, et al. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. AHA Journals. 2022;146:1882–1894. doi:10.1161/CIRCULATIONAHA.122.059595.

6. American Diabetes Association Professional Practice Committee; 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2024. Diabetes Care. 1 January 2024; 47 (Supplement_1): S179–S218. doi:10.2337/dc24-S010

7. Husain M, Birkenfield A, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes: The PIONEER 6 Randomized Clinical Trial. NEJM. 2019;381:841-851. doi:10.1056/NEJMoa1901118.

8. McGuire DK, Busui RP, Deanfield J, et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes Metab. 2023;25(7):1932-1941. doi:10.1111/dom.15058

9. A Research Study to Compare a New Medicine Oral Semaglutide to a Dummy Medicine in Children and Teenagers With Type 2 Diabetes (PIONEER TEENS). Clinicaltrials.gov. Updated March 20, 2023. Accessed April 10, 2024. https://clinicaltrials.gov/study/NCT04596631.

10. Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet. 2023;402(10403):693-704. doi:10.1016/S0140-6736(23)01127-3

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