Oral GLP-1RA superior in reducing HbA1c compared to DPP-4 inhibitor in T2DM

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

Literature - Rosenstock J, Allison D, Birkenfeld AL, - JAMA 2019, doi:10.1001/jama.2019.2942

Introduction and methods

GLP-1RAs are associated with greater reductions in HbA1c and body weight in type 2 diabetes patients than DPP-4 inhibitors [1]. In addition, some GLP-1RAs provide CV benefit, whereas DPP-4 inhibitors do not improve CV outcomes [2-5]. Still, DPP-4 inhibitors are widely prescribed, due to oral formulation and safety profile [6]. Currently available GLP-1RAs are only administered through subcutaneous injection. Therefore, oral semaglutide was developed and has demonstrated reduction in HbA1c and body weight compared to placebo [7,8].

Now, oral semaglutide was compared with sitagliptin for efficacy, long-term adverse event profile, and tolerability in the PIONEER 3 trial, which enrolled type 2 diabetes patients (n=2463) (HbA1c level 7.0-10.5%) who took metformin with or without sulfonylurea. PIONEER 3 was a 78-week, randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3a trial conducted between February 2016 and March 2018.

Patients were randomized in a 1:1:1:1 ratio to oral semaglutide (3 [n=466], 7 [n=466], or 14 mg [n=465]) or 100 mg oral sitagliptin [n=467]. Primary endpoint was change in HbA1c, and key secondary endpoint was change in body weight, both from baseline to week 26. Additional secondary endpoints were change in HbA1c and body weight at week 52 and 78. Noninferiority testing was done for primary endpoint of HbA1c, prior to testing for superiority of HbA1c and body weight. Safety assessments included the number of adverse events and number of episodes of hypoglycemia. Tolerability was assessed as rate of discontinuation.

Main results

  • Mean changes in HbA1c at week 26 were –0.6%, –1.0%, and –1.3% for oral semaglutide, 3, 7, and 14 mg, respectively, and –0.8% for sitagliptin. The 7 and 14 mg oral semaglutide dosages were superior to sitagliptin in reducing HbA1c at week 26 (treatment differences of –0.3% (95%CI: –0.4% to –0.1%, P<0.001] and –0.5% (95%CI:0.6% to –0.4%; P< 0.001], respectively). 3 mg oral semaglutide dosage was inferior to sitagliptin in reducing HbA1c.
  • Mean changes in bodyweight at week 26 were –1.2 kg, –2.2 kg, and –3.1 kg for oral semaglutide, 3, 7, and 14 mg, respectively, and –0.6 kg for sitagliptin. The 7 and 14 mg oral semaglutide dosages were superior to sitagliptin in reducing bodyweight at week 26 (treatment differences of –1.6 kg [95% CI:–2.0 to –1.1 kg, P< 0.001] and –2.5 kg [95% CI: –3.0 to –2.0 kg, P<0.001], respectively). 3 mg oral semaglutide dosage was not noninferior to sitagliptin for body weight.
  • At week 78, HbA1c reductions were greater with 7 and 14 mg oral semaglutide vs. sitagliptin, but not for 3 mg dosage oral semaglutide. Body weight reductions at week 78 were greater for all dosages oral semaglutide vs. sitagliptin.
  • Proportion of patients experiencing ≥1 adverse event was similar across treatment groups (79.4%, 78.2%, 79.6% for 3, 7 and 14 mg semaglutide, respectively compared to 83.3% in the sitagliptin group). Most frequent adverse events were gastrointestinal disorders and infections.
  • Hypoglycemia episodes were experienced by 4.9%, 5.2%, and 7.7% of patients in the 3, 7, and 14 mg oral semaglutide groups, respectively, and by 8.4% in the sitagliptin group.
  • Discontinuation rates were 16.7%, 15.0%, and 19.1% for those who took 3, 7, and 14 mg oral semaglutide, respectively, and 13.1% for sitagliptin. Discontinuation rates due to adverse events were discontinuation for 5.6%, 5.8%, and 11.6% in the 3, 7,and 14 mg oral semaglutide groups, respectively, and 5.2% for sitagliptin.


Dosages of 7 and 14 mg oral semaglutide were superior to sitagliptin with respect to reductions in HbA1c after 26 weeks in T2DM patients uncontrolled with metformin and/or sulfonylurea. 3 mg oral semaglutide did not demonstrate noninferiority for HbA1 or body weight when compared to sitagliptin.

Editorial comment

In his editorial comment [10], Hirsch noted that it was not surprising that therapy with oral semaglutide resulted in greater reductions in HbA1c and weight compared to sitagliptin, as this was already reported for member of GLP-1RAs, including subcutaneous semaglutide. Notable were the comparable rates of adverse events and overall safety with oral semaglutide (discontinuation rate for adverse events was similar for 7 mg semaglutide and sitagliptin), as sitagliptin is one of the better-tolerated antidiabetic drugs. However, adverse gastrointestinal symptoms remain a limiting factor in the use of GLP-1RAs and the balance between clinical effectiveness and tolerability is challenging. In the end Hirsch mentioned that we should not overlook the development of oral formulation of a peptide-based drug. Here, an absorption enhancer was used and the technology used for semaglutide could be applied to other drugs, such as insulin.


1. Tran S, Retnakaran R, Zinman B, et al. Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2018;20:68-76.

2. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.

3. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019; 321:69-79.

4. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.

5. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311-322.

6. Hernandez AF, Green JB, Janmohamed S, et al; Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial. Lancet. 2018;392: 1519-1529.

7. Scott LJ. Sitagliptin: a review in type 2 diabetes. Drugs. 2017;77(2):209-224.

8. DaviesM, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318:1460-1470.

9. Aroda VR, Rosenstock J, Terauchi Y, et al. Effect and safety of oral semaglutide monotherapy in type 2 diabetes—PIONEER 1 trial. Diabetes. 2018;67:2.

10. Hirsch IB. The future of the GLP-1 receptor antagonists. JAMA 2019; 321:1457-1458

Find this article online at JAMA

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