Higher-dose oral semaglutide may be beneficial option for type 2 diabetes, obesity
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Key takeaways:
- In OASIS 1, adults with obesity lost more than 15% of their body weight with oral semaglutide 50 mg.
- In PIONEER PLUS, adults with type 2 diabetes had a 2 percentage-point HbA1c reduction with 50 mg semaglutide.
SAN DIEGO — Oral semaglutide 50 mg induces more than 15% weight loss in adults with obesity at 68 weeks and can reduce HbA1c by 2 percentage points at 52 weeks for those with type 2 diabetes, according to data from two phase 3 trials.
As Healio previously reported, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk) as the first oral GLP-1 receptor agonist for adults with type 2 diabetes in 2019. The approval was for a dose of up to 14 mg. Earlier this year, oral semaglutide received a label update allowing it to be used as a first-line medication for type 2 diabetes.
At the American Diabetes Association Scientific Sessions, researchers presented data from the OASIS 1 and PIONEER PLUS randomized controlled trials in which participants received higher doses of oral semaglutide. The OASIS 1 trial analyzed the effects of oral semaglutide 50 mg among adults with overweight or obesity, whereas the PIONEER PLUS trial assessed oral semaglutide 25 mg and 50 mg compared with 14 mg for adults with type 2 diabetes and a baseline HbA1c of 8% or higher.
Vanita R. Aroda, MD, director of diabetes clinical research at Brigham and Women’s Hospital in Boston and associate professor of medicine at Harvard Medical School, said 25 mg and 50 mg oral semaglutide differ from the 14 mg dose that is currently available.
“For both OASIS 1 and PIONEER PLUS, a new formulation of oral semaglutide was used,” Aroda said during a presentation. “This new formulation had two excipients removed with slightly smaller tablet size, resulting in a higher bioavailability.”
Oral semaglutide 50 mg induces 15.1% weight loss in obesity
OASIS 1 was a randomized, double-blind, placebo-controlled phase 3 trial in which adults aged 18 years and older with a BMI of 30 kg/m2 or higher or a BMI of 27 kg/m2 or higher with at least one body weight-related comorbidity and one self-reported dietary weight-loss effort were randomly assigned, 1:1, to oral semaglutide 50 mg or placebo daily for 68 weeks as an adjunct to lifestyle intervention. The primary endpoints of the study were percentage change in body weight from baseline to 68 weeks and the percentage of adults who achieved at least a 5% weight loss. Researchers also analyzed how many adults achieved a 10%, 15% and 20% body weight reduction and changes in absolute body weight, BMI, waist circumference, cardiometabolic parameters and fasting lipids. The Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) and SF-36 acute version were used to measure physical function.
There were 667 adults enrolled in the study (mean age, 67 years; 74% non-Hispanic white; 73% women). In the treatment-policy estimand, adults in the semaglutide group lost 15.1% of their body weight at 68 weeks compared with a 2.4% weight loss for placebo (P < .0001). The percentage of adults who lost at least 5% of their weight was 85% in the semaglutide group and 26% with placebo.
“Oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Filip K. Knop, MD, PhD, professor of endocrinology and director of the Center for Clinical Metabolic Research at Gentofte Hospital, University of Copenhagen in Denmark, and consultant endocrinologist at Steno Diabetes Center in Copenhagen, said during a presentation.
Adults who received semaglutide had greater improvements in body weight, BMI, waist circumference, HbA1c, fasting plasma glucose, fasting serum insulin, blood pressure, fasting lipids and high-sensitivity C-reactive protein compared with the placebo group. The semaglutide group also had greater improvements in both physical functioning scores compared with placebo (P < .0001 for both).
Adverse events were reported by 92% of the semaglutide group and 86% of the placebo group. Serious adverse events occurred in 10% of those receiving semaglutide and 9% receiving placebo. Most adverse events for those receiving semaglutide were gastrointestinal (GI)-related and mild to moderate in severity. GI-related events with semaglutide peaked during dose escalation.
Most with type 2 diabetes achieve HbA1c less than 7% with oral semaglutide
PIONEER PLUS was a 68-week active-controlled, randomized, double-blind, phase 3b trial. Adults aged 18 years and older with type 2 diabetes, an HbA1c between 8% and 10.5% and a BMI of 25 kg/m2 or higher who were on stable daily doses of metformin, a sulfonylurea, an SGLT2 inhibitor or a DPP-IV inhibitor were enrolled. Participants were randomly assigned, 1:1:1, to oral semaglutide 14 mg, 25 mg or 50 mg. Adults continued their existing glucose-lowering medication except for those using DPP-IV inhibitors. The primary endpoint was change in HbA1c from baseline to 52 weeks. Researchers also analyzed the percentage of adults who achieved an HbA1c of less than 7% or 6.5% or less at 52 weeks. Changes in body weight, FPG, waist circumference and fasting lipids were analyzed. Researchers also calculated the proportion of participants who achieved a 5% or 10% weight loss at 52 weeks.
“Superiority in HbA1c and weight were assessed for both [semaglutide] 25 mg and 50 mg as compared to 14 mg,” Sue Pedersen, MD, FRCPC, a specialist in endocrinology and metabolism at C-endo Diabetes and Endocrinology Clinic of Alberta in Calgary, Canada, said during a presentation. “Hypotheses to compare oral semaglutide 25 mg vs. 50 mg were not prespecified, and no statistical comparison of these doses were conducted.”
There were 1,606 adults enrolled in PIONEER PLUS (mean age, 58.2 years; 58.3% men; mean HbA1c, 9%). In the treatment-policy estimand, HbA1c declined by 2 percentage points in the 50 mg semaglutide group and 1.8 percentage points in the 25 mg dose group compared with a 1.5 percentage-point reduction in the 14 mg group (P = .0006 for 25 mg vs. 14 mg; P < .0001 for 50 mg vs. 14 mg). An HbA1c of less than 7% was achieved by 63% of adults receiving semaglutide 50 mg and 51% of those receiving semaglutide 25 mg compared with 39% for the 14 mg dose group. The percentage of participants achieving an HbA1c of 6.5% or lower was 51% with the 50 mg dose, 40% with the 25 mg dose and 26% with the 14 mg dose.
In treatment policy estimand, adults receiving 50 mg semaglutide lost 8 kg of body weight at 52 weeks and those receiving 25 mg lost 6.7 kg of weight compared with a 4.4 kg weight loss for adults receiving semaglutide 14 mg (P < .0001 for both). The percentage of adults who lost at least 5% of their body weight at 52 weeks was 67% in the 50 mg group, 60% in the 25 mg group and 41% in the 14 mg group. A weight loss of 10% or higher was achieved by 37% of those receiving 50 mg, 29% of adults receiving 25 mg and 14% of those receiving 14 mg.
“The weight loss at the highest dose was actually similar to what was seen in STEP 2 with injectable semaglutide, but less than what was seen in OASIS 1 in people without type 2 diabetes,” Aroda said during a press conference. “That could be related to the intention of treating obesity vs. the intention of treating type 2 diabetes, but we have also seen in previously studies that weight loss tends to be a little bit less in people with diabetes.”
The 25 mg and 50 mg semaglutide groups also had greater reductions in FPG and waist circumference at 52 weeks than the 14 mg semaglutide group. Systolic and diastolic BP reductions were similar between the groups. All three groups experienced similar changes in fasting lipids, though a greater reduction in triglycerides was observed for those receiving semaglutide 50 mg compared with 14 mg.
Adverse events were reported by 76% of adults in the 14 mg group, 79% of those in the 25 mg group and 80% of those receiving 50 mg. GI disorders such as nausea, vomiting and diarrhea were most common. Serious adverse events were reported by 10% of the 14 mg group, 11% of the 25 mg group and 8% of the 50 mg group. There were 10 deaths in the trial, with all of them judged to be unrelated to semaglutide. Researchers reported no new safety concerns with 25 mg and 50 mg doses of semaglutide.
“Thinking to the future, oral semaglutide 25 mg and 50 mg doses could be a beneficial option to support individualized treatment goals for people with type 2 diabetes in need of treatment intensification,” Aroda said.
Oral semaglutide provides additional option for diabetes, obesity care
Sean Wharton, MD, PharmD, director of the Wharton Medical Clinic, assistant professor at the University of Toronto and adjunct professor at McMaster University and York University in Canada, said it is difficult to predict where higher-dose oral semaglutide will fall among the ever-growing number of medication options for diabetes and obesity care. However, he said he believed that oral semaglutide will find a niche.
“OASIS 1 and PIONEER PLUS have introduced the world to a medication for obesity and type 2 diabetes that is oral, relatively east to administer, is scalable and effective in terms of similar magnitude to an injectable semaglutide,” Wharton said during a presentation.
Wharton said the weight reductions and HbA1c improvements with oral semaglutide were similar to what was observed in trials for injectable semaglutide 2.4 mg (Wegovy, Novo Nordisk). He said the oral formulation provides a few key advantages over other injectable medications, including a potentially greater reach globally due to pills being easier to produce, ship and keep in storage than injectable medications.
“The global reach of a pill can increase access to care and may impact equity,” Wharton said.
In addition, Wharton said semaglutide 50 mg could be a long-term solution for impacting comorbidities, may give an additional treatment option to children and adolescents with obesity and may become a preventive measure for polygenic obesity.
During a press conference, Knop said oral semaglutide will appeal to a subset of the population seeking diabetes or obesity medication.
“Patients [may] simply prefer an oral version compared to an injectable version, patients who have needle phobia, for instance,” Knop said. “My experience with the oral formulation of semaglutide for type 2 diabetes is that 20% to 25% would prefer an oral version of semaglutide over an injectable version.”
References:
- Aroda VR, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01127-3.
- Knop FK, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01185-6.
Perspective
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Semaglutide and other GLP-1 receptor agonists have been instrumental in reshaping the clinical management of type 2 diabetes by offering a weight-centric approach to improving glycemic control and reducing cardiovascular risk. Moreover, people living with obesity now have a treatment option that provides meaningful weight reduction when added to traditional lifestyle changes. Beneficial clinical outcomes of semaglutide on glycemic control were demonstrated in the SUSTAIN and PIONEER trials using injectable and oral semaglutide, respectively. Similarly, the results of the STEP trials showed superior weight reduction with injectable semaglutide compared to placebo.
Oral semaglutide is the first GLP-1 receptor agonist approved for the treatment of type 2 diabetes; although it did not show superiority in reducing major adverse CV events like its injectable counterpart, its popularity as a powerful treatment has recently soared. In fact, it is the drug manufacturer's second strongest driver of sales. Although oral semaglutide is currently not indicated for weight management, participants in the study lost an average of 8.4 lb on the current highest dose of 14 mg after 26 weeks of use.
The recently published results of oral semaglutide in the PIONEER PLUS and OASIS 1 phase 3 trials demonstrate the superiority of even higher doses of semaglutide regarding HbA1c reduction and weight loss. In the PIONEER PLUS study, the participants taking the 50 mg dose of oral semaglutide were 2.6 times more likely to reach an HbA1c of 7% and three times more likely to have an HbA1c of less than or equal to 6.5% compared with those taking the currently available 14 mg dose. The weight loss outcomes of both studies were equally impressive, showing a weight reduction of 8 kg and 15.5 kg after 68 weeks of treatment for people with and without type 2 diabetes, respectively.
Furthermore, both studies had a high (80%) completion rate among participants, suggesting good tolerability of the 50 mg semaglutide dose. Adverse event rates were similar in both trials and were mostly mild to moderate, most related to well-reported nausea and other gastrointestinal issues. Altered skin sensations and a higher incidence of benign tumors (not organ-specific) were reported in the OASIS 1, but not the PIONEER PLUS study. Although these studies were not designed to assess major adverse CV outcomes, the surrogate markers of CVD — namely plasma lipoprotein levels, blood pressure, weight circumference and high-sensitivity C-reactive protein — had all significantly improved at the end of the trial among those randomized to the higher semaglutide doses of 25 mg and 50 mg.
Overall, the outcomes of these important phase 3 oral semaglutide trials have demonstrated that a diverse population of individuals living with obesity and type 2 diabetes can tolerate higher doses while achieving positive outcomes. While injectable semaglutide has shown similar benefits, oral semaglutide can reach an even wider population of individuals, particularly those with disadvantaged social determinants of health. This is because oral semaglutide is stable at room temperature, making transportation to areas with limited health care access potentially more feasible. The oral administration also has the potential to make it more appealing to those who do not prefer or cannot administer injections, and the daily dosing may be more convenient for people who are more likely to take a daily rather than a weekly medication as part of their routine.
Like any drug, there are nuances associated with oral semaglutide, such as the recommended timing of administration and the requirement to take it on an empty stomach with minimal water. Adherence to these instructions is important to ensure adequate bioavailability of the drug and its efficacy. Furthermore, clinicians and patients should be aware of the potential impact of GLP-1 receptor agonists on the absorption and bioavailability of other medications, such as levothyroxine and others.
These practical inconveniences and reported adverse events are seemingly minor compared with the potential benefit for people facing the potentially devastating disease burden of type 2 diabetes and obesity. For too long, these diseases have led to social, economic and personal tragedies affecting billions worldwide. OASIS-1 and PIONEER PLUS results have opened the gates of hope and meaningful change to how clinicians and their patients approach diabetes and obesity care. The equitable accessibility of oral semaglutide to widespread groups of people is yet to be implemented. Still, the mere presence of an oral GLP-1 receptor agonist as effective as high-dose semaglutide will certainly be life changing. Finally, we may be on the brink of witnessing a new era where, like cancer, we aim for diabetes and obesity remission so we can live in a world where metabolic disease becomes history.
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Aroda VR, et al. Oral semaglutide for treatment of obesity and type 2 diabetes – Results from OASIS 1 and PIONEER PLUS trials. Presented at: American Diabetes Association Scientific Sessions; June 23-26, 2023; San Diego (hybrid meeting).
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