Oral Semaglutide Tops Sitagliptin for Cutting HbA1c, Weight in T2D

NEW ORLEANS — Once-daily oral semaglutide showed greater effect for reducing HbA1 versus sitagliptin (Januvia) in patients with type 2 diabetes uncontrolled with metformin, with or without sulfonylurea, according to PIONEER 3 trial results.

Compared with 100-mg sitagliptin, investigational semaglutide significantly reduced HbA1c from baseline at a 7 mg/d dose (difference -0.3%, 95% CI -0.4% to -0.1%, P<0.001) and a 14 mg/d dose (difference -0.5%, 95% CI -0.6% to -0.4%, P<0.001) from baseline to 26 weeks, reported Melanie Davies, MD, of the University of Leicester in England, and colleagues.

The oral semaglutide was also superior to sitagliptin in reducing body weight from baseline with both the 7 mg/d dose (difference -1.6 kg or about 4 lbs, 95% CI -2.0 to -1.1 kg, P<0.001), and the 14 mg/d dose (-2.5 kg, 95% CI, -3.0 to -2.0 kg, P<0.001) from baseline to 26 weeks, they wrote in JAMA.

However, a 3 mg/d dose of semaglutide was not superior to sitagliptin in terms of HbA1c or weight loss, reported co-author Dale Allison, MD, of the Hillcrest Family Health Center in Waco, Texas, at ENDO 2019, The Endocrine Society annual meeting.

“I believe my colleagues, internists, and endocrinologists will look at this and be willing to offer their patients an option, [whether] they want to take a shot once a week or take a pill every day,” Allison told MedPage Today. “The efficacy is essentially the same and the tolerability is essentially the same as well.”

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend GLP-1 receptor agonists with proven cardiovascular benefit for patients with clinical cardiovascular disease who need further glycemic lowering, noted Irl Hirsch, MD, of the University of Washington School of Medicine in Seattle in an accompanying editorial.

However, the “adoption of the GLP-1RAs into clinical practice has been relatively slow,” Hirsch wrote, adding that these agents are expensive and require injection.

Hirsch said PIONEER 3 advances GLP-1RAs, but pointed out the higher rate of gastrointestinal (GI) adverse events with the 14 mg/d dose that “illustrates the difficult balance between clinical effectiveness and tolerability that has been a challenge in the development of GLP-1RAs.”

But prior evidence has shown adverse events may wane over time and could potentially be reduced with a slower escalation of dosage, he wrote.

For the 78-week, phase IIIa trial, researchers enrolled adult patients with type 2 diabetes and HbA1c levels from 7% through 10.5% who were taking a stable dose of metformin, with or without sulfonylurea, across 206 sites in 14 countries. Patients were excluded if they were being treated with diabetes or obesity medication other than metformin, sulfonylurea, or short-term insulin in the 90 days before screening, or had histories of pancreatitis, renal impairment, proliferative retinopathy, or maculopathy requiring acute treatment. They were blinded and stratified by country of origin and background medication. Changes in HbA1c were measured at 26, 52, and 78 weeks.

In total, 466 patients were randomized to 3 mg/d semaglutide, 466 to 7 mg/d semaglutide, 465 to 14 mg/d semaglutide, and 467 to 100 mg sitagliptin. About 53% of participants were male, the majority were white (71.1%), and the average age was 58. All of those in the trial were taking metformin and about half in each group were receiving sulfonylurea as well.

Researchers also measured body weight and HbA1c levels at 78 weeks, at which point semaglutide remained superior to sitagliptin. Fasting plasma glucose and mean self-measured whole-blood glucose were also significantly reduced in the 14 mg/d semaglutide versus the sitagliptin group at 26 and 78 weeks, respectively.

Overall, 5.6% of patients in the 3 mg/d semaglutide group prematurely discontinued the trial due to adverse events versus 5.8% in the 7 mg/d group, 11.6% in the 14 mg/d group, and 5.2% in the sitagliptin group. In the 14 mg/d semaglutide group, the majority discontinued the trial due to a GI adverse event, the most common of which was nausea. However, the majority of these events occurred during the dosage-escalation period, the authors reported.

Hypoglycemia and diabetic retinopathy-related adverse events also occurred, but at similar rates across treatment groups, the authors added.

There were nine deaths in the group of patients receiving semaglutide and three in the sitagliptin group, but the authors reported that they did not find a pattern indicating the deaths were related to treatment.

Study limitations included the high discontinuation rate, particularly observed in the semaglutide arm, and the failure to measure adherence to treatment. Sitagliptin might also not be an ideal comparator to this trial because DPP-4 inhibitors have “modest glucose-lowering effects and minimal effect on body weight compared with GLP-1RAs,” they stated.

The authors noted that “other trials within the PIONEER phase 3 program will assess oral semaglutide against other glucose-lowering medications and with flexible dosing of oral semaglutide.”

Hirsch pointed out that oral diabetes medications, such as metformin or pioglitazone generics, are relatively inexpensive and that sitagliptin will also soon be available in a less costly form.

“With greater amounts of medication expense in the United States being borne by patients, cost is increasingly a major factor in treatment decisions,” he cautioned, adding that “if history can predict the future, many patients who could benefit from this new agent may not have access to this drug unless the cost is substantially reduced.”

But “What should not be overlooked is the successful development of technology to permit oral availability of peptide-based drugs. The oral formulation of semaglutide requires an absorption enhancer that should be a model for other drugs,” including insulin, Hirsch stated.