In poorly controlled type 2 diabetes, oral semaglutide was noninferior to liraglutide for reducing HbA1c

Abstract

Question In type 2 diabetes poorly controlled by metformin, does oral semaglutide reduce hemoglobin (Hb) A1c compared with subcutaneous liraglutide or placebo? Methods Design Randomized placebo-controlled trial (Peptide Innovation for Early Diabetes Treatment [PIONEER] 4 trial). ClinicalTrials.gov NCT02863419, EudraCT 2015-005210-30. Allocation Concealed.* Blinding Blinded* (patients and clinical center staff). Follow-up period 52 weeks. Setting 100 clinical centers in 12 countries. Patients 711 adults 18 years of age (mean age 56 y, 52% men) who had type 2 diabetes and HbA1c 7.0% to 9.5%, and were receiving a stable dose of metformin (with or without a sodiumglucose cotransporter-2 [SGLT2] inhibitor). Exclusion criteria included estimated glomerular filtration rate <60 mL/min/1.73 m2, proliferative retinopathy or maculopathy requiring acute treatment, use of medication (other than metformin, an SGLT2 inhibitor, or short-term insulin) for diabetes or obesity in the past 90 days, or previous acute or chronic pancreatitis. Intervention Oral semaglutide, maintenance dose 14 mg/d, plus subcutaneous placebo (n =285), subcutaneous liraglutide, maintenance dose 1.8 mg/d, plus oral placebo (n =284), or oral plus subcutaneous placebos (n =142), once daily. Outcomes Change in HbA1c at 26 weeks. Secondary outcomes included change in HbA1c at 52 weeks and change in weight at 26 and 52 weeks. The prespecified noninferiority limit for the primary outcome was 0.4 (upper limit of the 2-sided 95% CI around the mean difference between groups). Patient follow-up 96% (intention-to-treat analysis). Main results The results are in the Table. Conclusion In type 2 diabetes poorly controlled by metformin, oral semaglutide was noninferior to subcutaneous liraglutide and superior to placebo for reducing hemoglobin A1c levels at 26 weeks. Oral semaglutide vs liraglutide or placebo in type 2 diabetes poorly controlled by metformin Outcomes Mean change from baseline Mean difference between groups (95% CI) Oral semaglutide vs liraglutide Change in HbA1c at 26 wk 1.2% vs 1.1% 0.1% (0.3 to 0.0) Change in HbA1c at 52 wk 1.2% vs 0.9% 0.3% (0.5 to 0.1) Change in weight (kg) at 26 wk 4.4 vs 3.1 1.2 (1.9 to 0.6) Change in weight (kg) at 52 wk 4.3 vs 3.0 1.3 (2.1 to 0.5) Oral semaglutide vs placebo Change in HbA1c at 26 wk 1.2% vs 0.2% 1.1% (1.2 to 0.9) Change in HbA1c at 52 wk 1.2% vs 0.2% 1.0% (1.2 to 0.8) Change in weight (kg) at 26 wk 4.4 vs 0.5 3.8 (4.7 to 3.0) Change in weight (kg) at 52 wk 4.3 vs 1.0 3.3 (4.3 to 2.4) Hb = hemoglobin; CI defined in Glossary. Criterion for noninferiority was met because the upper limit of the 2-sided 95% CI of the treatment difference was <0.4 (P =0.07 for superiority). Commentary The REWIND, PIONEER 6, and PIONEER 4 trials provide evidence for benefits of GLP-1RAs for treating type 2 diabetes. GLP-1RAs have several benefits beyond glucose lowering, such as weight loss and negligible hypoglycemia risk, which make them an attractive treatment option for patients with type 2 diabetes. With results from REWIND, we now have evidence that 3 GLP-1RAs on the market are also associated with CV benefit in patients with, or at high risk for, CV disease (1, 2). Liraglutide was the first GLP-1RA shown to reduce risk for CV events in a population of whom the majority had CV disease and high CV risk (4-y placebo event rate 15%) (1). A subsequent trial showed that subcutaneous semaglutide reduced risk for CV events in a lower-risk population (4-y placebo event rate 8.9%) (2), and its weekly administration offered greater convenience than daily liraglutide for some patients. The REWIND trial showed that another weekly GLP-1RA, dulaglutide, reduced risk for major CV events in patients at substantially lower CV risk than in other trialsonly 32% of patients had CV disease, and the 5-year placebo event rate was 2.7%. These findings suggest that the CV benefits of GLP-1RAs probably extend to patients with type 2 diabetes and CV risk factors, rather than only patients with CV disease. As with the CV benefits of some SGLT2 inhibitors (3, 4), the CV benefits of GLP-1RAs are probably not a result of glucose lowering alone (5). Both GLP-1RAs and SGLT2 inhibitors have beneficial effects on weight and blood pressure, and GLP-1RAs may also improve endothelial function, endothelial cell responses to ischemia, and platelet function (6). All approved GLP-1RAs are administered by subcutaneous injection, which, along with cost and gastrointestinal side effects, remains a barrier to their use. However, evidence is accumulating for the safety and efficacy of oral semaglutide, the first orally administered GLP-1RA. It has been shown to be superior to the commonly used oral medication, sitagliptin, for HbA1c and weight reduction (7). Results of PIONEER 6 provide evidence of the CV safety of oral semaglutide. Patients who received oral semaglutide had nonsignificantly lower rates of CV events and death than placebo-treated patients, with relative risk reductions comparable to those of REWIND and other GLP-1RA trials (1, 2). Although noninferiority was confirmed, statistically significant CV superiority was not shown. Because the trial was designed to test for noninferiority, its short duration (16 mo) and low number of events probably limited the power to determine a CV benefit of oral semaglutide. PIONEER 4 was the first trial to directly compare oral semaglutide with another GLP-1RA. Compared with liraglutide, the most commonly used GLP-1RA, oral semaglutide showed a similar reduction in HbA1c and, surprisingly, greater weight loss. Gastrointestinal side effects and discontinuation rates were similar between the 2 treatments, making oral semaglutideonce it is approveda comparably effective and tolerable GLP-1RA option for patients wanting to avoid injections. That it must be taken daily on an empty stomach with half a glass of water 30 minutes before food intake may be cumbersome for some patients, who may favor the convenience of weekly subcutaneous semaglutide or dulaglutide. Patients at higher CV risk may also prefer the weekly options due to their proven CV benefit. The results of these trials add to the growing evidence regarding GLP-1RA treatment to help guide treatment decisions. These results further endorse the CV benefits of GLP-1RAs in lower-risk populations and provide support for oral semaglutide as a promising alternative to current subcutaneously administered agents. Whether oral semaglutide has comparable CV-lowering benefits to subcutaneous GLP-1RAs remains to be confirmed.