American Diabetes Association 79th Scientific Sessions:

Oral Semaglutide Proves Most Effective in Patients with Type 2 Diabetes

with John B. Buse, MD

Results of the first oral glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide (Ozempic), for type 2 diabetes were reported as part of a session featuring data from a series of PIONEER studies1-5 during the American Diabetes Association Scientific Sessions.

Prescribing GLP-1 therapy has become a preferred choice for people with type 2 diabetes over the past 10 years, particularly in patients at high risk for cardiovascular disease (CVD).6 Several cardiovascular outcome trials have generated data showing demonstrated efficacy of the GLP-1 receptor agonists in preventing CVD events as well as lowering mortality.7

PIONEER Trials are a series of 8 studies comparing the first oral GLP1 to competitive agents.Since the PIONEER trial program began, more than 8,000 patients with type 2 diabetes  (T2D) have been enrolled in one of these randomized phase 3a studies to evaluate  clinical efficacy and safety of oral semaglutide in patients with T2D. These studies looked at patients who were taking different background treatments, including drug-naïve patients and those receiving metformin or insulin, and comparators such as placebo, sitagliptin, empagliflozin, liraglutide, and dulaglutide.1-5

Two scientific questions were addressed by defining two estimands in all randomized patients:

  • Treatment policy (regardless of study drug discontinuation or use of rescue medication
  • Study drug use without rescue medication

In these randomized, double blind, placebo controlled studies, patients were followed for 52 weeks to establish efficacy and safety of the first oral GLP-1, semaglutide.1-5 Endpoints established for the PIONEER trial series were reduction in hemoglobin A1c (HbA1c) of less than 7.0% (primary) and lower body weight (confirmatory secondary), from baseline to the midway point at week 26 and at the end of one year; cardiovascular risk was assessed separately.8

Oral Semaglutide Superior to Empagliflozin in Uncontrolled Type 2 Diabetes

In the PIONEER 2 trial,1 Eduard Montanya, MD, PhD, senior professor of medicine at the University of. Barcelona, Spain, and colleagues compared glucose control of  patients randomized to take either the GLP-1, oral semaglutide (14 mg once daily) or the sodium-glucose transport protein 2 inhibitor (SGLT2i) empagliflozin (25 mg once daily) in patients whose type 2 diabetes was uncontrolled by metformin in a 52-week open-label clinical trial.1

Endpoints for the PIONEER 2 study were change in hemoglobin A1c (primary) and body weight (confirmatory secondary) from baseline to week 26 in 411 patients taking the GLP-1 versus 410 receiving the SGLT2i.

Oral semaglutide proved superior to empagliflozin in reducing HbA1c at week 26 (1.3% vs 0.9% reduction in patients taking both oral semaglutide and empagliflozin, respectively) and even more significant at week 52 with more patients in the oral semaglutide group achieving HbA1c < 7.0% then empagliflozin (43.2% and 6.1%, respectively, P <  0.0001).1

Weight loss with oral semaglutide was not superior at week 26, but significantly greater at week 52: (-3.8 kg and -3.6 kg, respectively), according to Dr. Monanya.

Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor antagonists. Rates of adverse events were similar between oral semaglutide (70.5%) and empagliflozin (69.2%), the most frequent complaints observed with oral semaglutide being mild/moderate gastrointestinal events. Premature discontinuations due to adverse events were 11% (oral semaglutide) vs 4% (empagliflozin).1

Oral semaglutide provided superior reductions in HbA1c but not in body weight at week 26; and significant reductions in HbA1c and body weight at week 52 vs empagliflozin, said Dr. Montanya said.  

Oral Semaglutide Bests Liraglutide in Patients with Type 2 Diabetes

Richard E. Pratley, MD, director of the Florida Hospital Diabetes Institute and professor of medicine at the Sanford Burnham Medical Research Institute in Winter Park, Florida, and colleagues presented findings of the PIONEER 4 study at ADA 2019.

This study focused on patients with uncontrolled type 2 diabetes despite taking metformin who were then randomized to oral semaglutide 14 mg once daily (n=285), liraglutide 1.8 mg (n=284), or placebo (n=142) in this double-dummy trial.2

The treatment policy estimand was that oral semaglutide was noninferior (margin 0.4%) to liraglutide and superior to placebo in reducing HbA1c, and superior to both comparators in reducing body weight at week 26. “Differences in both HbA1c and body weight were significant at week 52,” said Dr. Pratley.

The trial product estimand was that oral semaglutide demonstrated significant reductions in HbA1c and body weight vs liraglutide and placebo at weeks 26 (vs liraglutide 1.2% vs 1.1%, respectively; vs placebo 1.2% vs 0.2%, respectively); and at the one year completion (vs liraglutide 1.2% vs 0.9%, respectively; vs placebo 1.2% vs 0.2%, respectively).2

In addition to the favorable study outcomes, oral semaglutide exhibited comparable tolerability to liraglutide with 11% of patients discontinuing oral semaglutide), 9% of the cohort stopping liraglutide, and 4% of patients on placebo dropping out prematurely due to adverse events.2 This main complaint was related to gastrointestinal discomfort with 5% of patients on oral semaglutide versus 3% receiving liraglutide who exited due to nausea.

“Oral semaglutide was well tolerated in patients with type 2 diabetes were who were taking metformin with or without an SGLT2i,” Dr. Pratley reported. Oral semaglutide was noninferior to liraglutide and superior to placebo in reducing HbA1c, and superior in reducing body weight vs both liraglutide and placebo.

The proportion of patients who achieved HbA1c < 7.0% was significantly greater with the oral GLP-1 over liraglutide at both weeks 26 and 52 (65.3% vs 16.1%, respectively at the midway point, P < .0001 and 62.6% vs 18.3%, respectively, at one year, P < .0001.2   

Oral Semaglutide Effective in Patients with T2D and Renal Impairment

In this 26-week PIONEER 5 study, 163 patients were randomized to receive oral semaglutide (14 mg once daily) and 161 patients to the placebo. All participants were diagnosed with type 2 diabetes and moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 - 59 mL/min/1.73 m2).3

At baseline, all individuals were taking one or two glucose-lowering agents including metformin (≥1500 mg or maximum tolerated dose); a sulfonylurea (at least half of the maximum approved or maximum tolerated dose), or both; or basal insulin with or without metformin., according to Ofri Mosenzon, MD, MSc, attending physician, department of internal medicine, Hadassah Medical Center, Jerusalem, Israel, who presented the findings on behalf of her research team.

Oral semaglutide proved superior to placebo in reducing HbA1c and body weight.3 More patients taking oral semaglutide met the HbA1c endpoint, achieved more weight loss, and met composite targets with oral semaglutide. At follow-up, eGFR was unchanged in both groups.

At 26 weeks, oral semaglutide proved superior to placebo in decreasing HbA1c. Estimated mean change was -1 ± 0.1 percentage point, -11 ± 0.8 mmoL/mol with oral semaglutide vs -0.2 ± 0.1 percentage point, -2 ± 0.8 mmoL/mol with placebo. The estimated treatment difference was -0.8 (95% confidence interval -1.0 to -0.6 ± percentage points, P < 0.0001).3

Body weight was reduced by a mean of 3.4 ± 0.3 vs 0.9 ± 0.3 kg, respectively. These reductions represented an estimated treatment difference of -2.5 (95% confidence interval -1.0 to -0.6 percentage points (P < .0001).3

Fewer patients receiving oral semaglutide required rescue medication (4% vs 10%). Adverse events were more frequent with oral semaglutide (74% vs 65%), most often mild/moderate nausea (19% vs 7%). More patients receiving oral semaglutide discontinued prematurely (15% vs 5%), mainly due to nausea and vomiting.3

Dr. Mosenzon said that in patients with type 2 diabetes and moderate renal impairment, oral semaglutide provided superior glycemic control and body weight loss than placebo, did not appear to affect renal function, and was well tolerated, in line with the population and GLP-1 receptor antagonist class.

The net takeaway: Oral semaglutide is a potential new treatment option for patients with type 2 diabetes and moderate renal impairment, according to Dr. Mosenzon.

Flexible Dose Adjustment of Oral Semaglutide Compared to Sitagliptin 

John B. Buse, MD, PhD, professor of medicine, director of the Diabetes Care Center, and chief of endocrinology at the University of North Carolina School of Medicine, Chapel Hill, and colleagues presented findings from the PIONEER 7 trial, comparing flexible once daily adjustable dose of oral semaglutide (3 mg, 7 mg, 14 mg; n = 253) compared to sitagliptin (100 mg; n = 251) in a 52-week, randomized, open-label trial in patients whose type 2 diabetes was uncontrolled with one to two oral glucose-lowering medications.4

The oral semaglutide dose was adjusted (titrated up) every eight weeks based on tolerability and a HbA1c greater than or equal to 7.0%.

At week 52, the final dosages for patients receiving oral semaglutide were:4

  • 3 mg: 9%
  • 7 mg: 30.2%
  • 14 mg: 59.4%  

Fewer patients receiving oral semaglutide needed rescue medication (3% vs 16%), Dr. Buse said. Oral semaglutide demonstrated superiority to sitagliptin in reducing HbA1c < 7.0 (62.8% vs 28.3%, respectively) as well as with respect to weight loss at week 52: -2.9 vs -0.8 kg, respectively.4

Adverse events were slightly more frequent in patients taking the oral semaglutide (78% vs 69%), but complaints were generally mild to moderate, transient nausea (21% vs 2%). Discontinuation due to adverse events (mostly gastrointestinal) was higher with oral semaglutide (9% vs 3%).4

Flexible dose adjustment of oral semaglutide led to superior glycemic control and weight loss at week 52 versus sitagliptin and was well tolerated with safety consistent with the GLP-1 receptor antagonist class.

“The results are clearly practice-changing,” Dr. Buse told EndocrineWeb. “Oral semaglutide is the first oral GLP-1 receptor agonist. This class represents the most weight loss, glucose-lowering drugs on the planet. The oral formulation will allow more patients to take advantage of that efficacy. There’s a reluctance to use this class in the primary care setting, and that barrier will be overcome with the advent of an oral GLP-1 receptor agonist.”

“In addition,” he said, “the oral and injected forms are more or less equally effective and tolerable, though the two formulations have not been compared. Oral semaglutide will be of particular advantage in patients with cardiovascular disease in addition to their type 2 diabetes,” said Dr. Buse.

Oral Semaglutide as an Add-On to Insulin Leads to Lower Insulin Dosing

Bernard Zinman, CM, MD, FRCPC, FACP, is professor of medicine at the Banting & Best Diabaetes Center at the University of Toronto, Canada, and colleagues led the PIONEER 8 trial in which patients whose type 2 diabetes was uncontrolled by insulin with or without metformin were randomized to:5

  • oral semaglutide at 3 mg (n = 184)
  • oral semaglutide at 7 mg (n = 182)
  • oral semaglutide at 14 mg (n=181)
  • placebo (N=184)

Total daily insulin dose was reduced by an optional 20% and capped at baseline level for weeks 0 - 26 and freely adjustable for weeks 26 - 52.

Oral semaglutide proved efficacious in reducing HbA1c. At trial completion, 15.6% of patients receiving 3 mg achieved a HbA1c < 7.0%, 25.4% at 7 mg, and 36.3% on 14 mg, as compared with a 4.7% in HbA1c in the placebo group (P < 0.001).5

Weight loss was greater in participants taking oral semaglutide (versus placebo ) at the end of one year, with patients receiving the lowest dose oral semaglutide (3 mg) having lost 0.8 kg; 2.0 kg weight loss on those taking 7 mg and a weight loss of 3.7 kg was achieved at the highest dose as compared to placebo: 0.5 kg (P < 0.001).5

The total daily insulin dose was significantly reduced from baseline with oral semaglutide vs placebo at weeks 26 (except 3 mg) and at completion, and the rate of hypoglycemia did not differ significantly vs placebo.

As has been the case, the most frequent adverse event experienced by patients taking oral semaglutide was nausea (11.4% - 23.2%   of patients vs 7.1% with placebo) and 7.1% - 13.3% of patients discontinued prematurely due to adverse events (vs 2.7% with placebo).5  

An add-on to insulin with or without metformin, oral semaglutide led to superior HbA1c and body weight reductions vs placebo at week 26, and achieved further reduction in insulin need at the end of the study, having shown good tolerance to treatment without increasing the rate of hypoglycemia significantly,5 said Dr. Zinman.

The PIONEER trial series was underwritten by Novo Nordisk. Dr. Montanya reported receiving fees from AstraZeneca, Novo Nordisk, Merck, Novartis, and Almirall. Dr. Buse reported research support from AstraZeneca, Novo Nordisk, Sanofi, and vTv Therapeutics. Dr. Pratley reported consultancy fees from  Sanofi, and Dr. Zinman reported receipt of fees from Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Janssen, Merck, and Novo Nordisk. Dr. Mosenzon reported fees research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Sanofi-Aventis.

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