'Best in Class' Diabetes Drugs Compared in Head-to-Head Trial

Miriam E. Tucker

November 11, 2019

Oral semaglutide (Rybelsus, Novo Nordisk) lowered hemoglobin A1c more than empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in a recently published open-label, head-to-head comparison of the type 2 diabetes drugs. 

The findings from the PIONEER-2 trial were published online in Diabetes Care.

Semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, has been available as a once-weekly subcutaneous injectable since December 2017; the oral version, the first tablet form of a GLP-1 agonist, was approved by the US Food and Drug Administration in September.

Empagliflozin is an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that has been on the market since 2015.

Helena W. Rodbard, MD, medical director of Endocrine and Metabolic Consultants, Rockville, Maryland, and colleagues compared the effects of the two agents on A1c and body weight at 26 and 52 weeks among patients with type 2 diabetes in the Novo Nordisk funded study. 

At 26 weeks, oral semaglutide reduced A1c, but not body weight, significantly more than empagliflozin, but by 52 weeks, body weight was also reduced significantly more with the GLP-1 agonist, at least by one calculation.

Rodbard, who receives research funding from Novo Nordisk, told Medscape Medical News: "Both are great drugs. PIONEER-2 compares the two best in their classes. It's a very interesting study, comparing the highest dose of each titrated up. In that sense, it's a very pertinent and important trial...It's just very exciting to have so much to offer our patients."

She went on to explain that although "there is extensive experience with injectable semaglutide...many people still have reservations in terms of using injectable drugs." 

"Endocrinologists are used to instructing patients about injecting medications, but for primary care and other specialists, it's just so much easier to prescribe an oral medication than try to teach patients who aren't familiar with injections how to inject themselves," she said.

"I do think this is a gamechanger, in the sense that it should expand the market of people who would be willing to take a pill but do not want to take an injection, no matter how simple the injecting procedure is and how infrequently they need to take it, such as once a week," she added.

No CV Efficacy Data for Semaglutide

Asked to comment, Cecilia C. Low Wang, MD, told Medscape Medical News, "PIONEER-2 helps to answer one of the key questions about these new classes of type 2 diabetes therapies, which is the comparative efficacy and overall tolerability of GLP-1 agonists versus SGLT2 inhibitors."

"The A1c lowering and weight changes were positive results for oral semaglutide, and I think this trial shows that, for patients who are able to tolerate it, this therapy can provide benefits," said Wang, who is director of the Glucose Management Team at the University of Colorado Hospital, Aurora, and was not involved in the trial. 

However, she also pointed out, "Unfortunately, we do not have evidence that oral semaglutide would be preferable to empagliflozin in patients with established [atherosclerotic cardiovascular disease] or at high cardiovascular risk."

The cardiovascular outcomes trial PIONEER-6 "was designed to show noninferiority and not superiority, so we now know that oral semaglutide is safe in terms of cardiovascular risk, but we do not have evidence that shows it reduces cardiovascular risk," she emphasized.

This is in contrast to CVOT data for a number of other agents for type 2 diabetes, including empagliflozin in the EMPA-REG OUTCOME trial, which showed CV benefits in those at high risk.

"Therefore, in patients with established [atherosclerotic cardiovascular disease] or at high cardiovascular risk, the evidence still supports the use of empagliflozin or other agents that have demonstrated CV risk reduction over oral semaglutide," she asserted.

Superiority for Oral Semaglutide in A1c

In the new trial, 822 patients with type 2 diabetes uncontrolled on metformin were randomized to once-daily open-label treatment with 14 mg oral semaglutide or 25 mg empagliflozin for 52 weeks. Two estimands were used to assess efficacy: treatment policy regardless of trial product discontinuation or rescue medication, and trial product without rescue medication in all randomized patients.

At 52 weeks, 400 patients in the oral semaglutide and 387 patients in the empagliflozin groups had completed the trial.

At 26 weeks, there were A1c reductions of 1.3 percentage points for oral semaglutide versus 0.9 percentage points for empagliflozin, a significant difference for both noninferiority and superiority using the first estimand (P < .0001), and similarly with the second, with A1c reductions of 1.4 vs 0.9 percentage points (P < .0001).

Significantly greater A1c reductions with oral semaglutide compared with empagliflozin were also seen at week 52 using both estimands. And more patients achieved predefined A1c targets with oral semaglutide than with empagliflozin at weeks 26 and 52 (P < .0001).

Fasting plasma glucose was reduced with both treatments, with no significant difference between the groups.

At 26 weeks, weight loss was similar in both groups, at –3.8 kg with oral semaglutide versus –3.7 kg with empagliflozin (P = .76) using the treatment policy estimand, and –4.2 versus –3.8 kg (P = .14) using the trial product estimand.

But at 52 weeks, weight loss was significantly greater in the oral semaglutide group with the trial product estimand (–4.2 vs –3.8 kg; P = .01) although not the treatment policy estimand (–3.8 vs –3.6 kg; P = .62).   

Like the Injectable, Oral Semaglutide Associated With GI Side Effects

The overall number of adverse events and proportion of patients reporting side effects with the two drugs was similar, and most events were mild to moderate. Severe adverse events occurred in 6.6% of those taking oral semaglutide versus 9.0% with empagliflozin.  

The most common adverse event with oral semaglutide was nausea, which was usually mild to moderate and generally transient; no more than 10% of patients experienced nausea at any given time.

Mild-to-moderate female and male genital fungal infections were more frequent with empagliflozin (8.5% and 6.7%) than oral semaglutide (2.0% and 0%).

Adverse events resulting in drug discontinuation were more frequent with oral semaglutide than empagliflozin (10.7% vs 4.4%) and were primarily related to gastrointestinal symptoms (8.0% vs 0.7%). In both groups, premature discontinuations mainly occurred in the first 16 weeks of treatment.

Rodbard and colleagues conclude: "This trial provides a comparison of two increasingly used drug classes that are commonly added to metformin when glycemic control is not achieved. The principal limitation of the trial was the open-label design."

Diabetes Care. Published online October 7, 2019. Abstract

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