Glycaemic and Cardiometabolic Effects of Oral Semaglutide in Patients Aged ≥65 Years with Type 2 Diabetes

Background: Oral semaglutide has shown efficacy in clinical trials worldwide; however, real-world evidence in Indian settings is scarce. The current study examined the effectiveness of oral semaglutide in patients with type 2 diabetes within the context of routine clinical practice in Indian settings. Methodology: This retrospective, multicenter, observational study assessed the effectiveness of oral semaglutide in adult patients with type 2 diabetes who had inadequate glycemic control (HbA1c ≥6.5). The included patients need to have ≥1 HbA1c report within 12 weeks of the study initiation. The primary end point was change in HbA1c% from baseline to end of study (EOS; 30 weeks), with secondary end points including changes in body weight, waist circumference, and body mass index (BMI). These end points were evaluated for patients who were on oral semaglutide at EOS. Results: Of 414 screened patients, 340 were included in the study, with 176 patients on oral semaglutide at EOS. A mean reduction of 0.96 ± 1.02% (P < 0.001) in HbA1c from baseline to EOS was observed, with greater reductions in patients with 5–10 years of diabetes. At EOS, 92.6% of patients achieved a target of ≥1% HbA1c reduction from baseline. In addition, significant reductions in body weight (6.04 ± 5.40 kg, P < 0.001), waist circumference (3.47 ± 5.42 cm, P < 0.001), and BMI (1.94 ± 1.42 kg/m2, P < 0.001) were observed at EOS. Conclusion: Oral semaglutide shows promise as a therapeutic option for glycemic control and weight management in diabetic patients in Indian settings. However, further randomized clinical trials in Indian patients are warranted to validate these findings and optimize further treatment strategies.

Disclosure: T. Wang: None. L. Liao: None. Objectives: To evaluate the efficacy and safety outcomes of oral semaglutide in Asian and non-Asian patients with type 2 diabetes mellitus(T2DM). Methods: Search several databases for randomized controlled trials (RCTs) of oral semaglutide in patients with T2DM. The primary outcomes included Participants who achieved HbA1c <7.0% (53 millimoles per mole [mmol/mol]), Participants losing 5% or more of baseline body weight, adverse events (AE), serious adverse events (SAE). Risk ratios (RR) and 95% confidence intervals (CI) were calculated to evaluate the outcomes. Results: This meta-analysis included 8 RCTs with a total of 5662 patients. Using a placebo as a control group, semaglutide was effective in controlling blood sugar and reducing body weight in both Asian and non-Asian subgroups. meanwhile, compared to non-Asians, semaglutide 3mg(Chi2 4.54, P=0.03, I2=78%, 2 subgroup), 7mg (Chi2 7.79, P=0.005, I2=87.2%, 2 subgroup), 14mg (Chi2 7.97, P=0.005, I2=87.4%, 2 subgroup) oral preparation can make the level of HBA1c in Asian race more reach the therapeutic target. In Asian or non-Asian subgroups, semaglutide significantly reduced patient weight compared to active medicine. And semaglutide did not increase the risk of adverse reactions, whether Asian or not. Conclusion: Oral semaglutide is more effective in Asians, and semaglutide 7mg or 14mg is preferred over other active medicines. Presentation: 6/3/2024

More than half of diabetes patients are Asians, and their tolerance to antidiabetic drugs may differ from that of non-Asians. Oral semaglutide has recently gained attention for its advantages in glycemic and body weight control. However, its effects across different ethnic groups remain unknown. All available databases of randomized controlled trials (RCTs) on oral semaglutide in patients with type 2 diabetes mellitus were included. These databases provided detailed patient information, including HbA1c levels, body weight, and adverse events (AEs and serious adverse events [SAEs]). Ten randomized controlled trials involving 7817 patients were included: six conducted in European and American populations and four in East Asian populations. In both the Asian and non-Asian patients' subgroups, oral semaglutide 3, 7, and 14mg was more effective in reducing HbA1c than placebo, and between-subgroups analysis showed that semaglutide 3, 7, and 14mg was more effective in reducing HbA1c in the Asian patients' subgroup than in the non-Asian patients' subgroup. There were no significant differences between subgroups in the number of patients achieving HbA1c < 5%. Non-Asian patients with type 2 diabetes showed significant weight reduction with 7mg and 14mg oral semaglutide, and Asian patients reduced body weight only with 14mg oral semaglutide. Between-subgroups analysis showed that 7mg oral semaglutide was more effective for weight reduction in non-Asian patients than in Asian patients. In the analysis of the efficacy of oral semaglutide at weeks 26 and 52 in Asian and non-Asian patients, in Asian patients, the hypoglycemic efficacy of oral semaglutide at 3-, 7-, and 14-mg doses at week 52 was significantly lower than that at week 26. In non-Asian patients, there was no significant difference in the reducing HbA1c efficacy of these doses of oral semaglutide at weeks 26 and 52. The weight-reduction efficacy of all doses of oral semaglutide did not change significantly with treatment duration in either Asian or non-Asian patients. Compared with sitagliptin, oral semaglutide was more effective in HbA1c reduction and weight reduction in both Asian and non-Asian patients. Subgroup analysis showed that compared with sitagliptin, Asian patients received oral semaglutide to achieve greater efficacy (HbA1c and weight reduction) than non-Asian patients. In the analysis of adverse events, oral semaglutide, as compared with placebo, was not associated with serious adverse events in either subgroup. The incidence of other (not including series) adverse events was significantly higher in non-Asian patients receiving 7mg and 14mg oral semaglutide. Oral semaglutide demonstrates superior efficacy in reducing HbA1c levels and a rapid onset of action in Asian patients. However, its efficacy appears to diminish with prolonged treatment in this population. Medium (7mg)-dose oral semaglutide was associated with greater weight reduction in non-Asian patients than in Asian patients, but this difference was eliminated with higher doses. Additionally, doses of 7mg or more of oral semaglutide are associated with a higher incidence of side effects in non-Asian patients.

Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP‐1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add‐on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard‐of‐care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes‐related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose‐lowering medications from the dipeptidyl peptidase‐4 inhibitor (sitagliptin) and sodium‐glucose co‐transporter‐2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP‐1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP‐1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP‐1RA treatment in the paradigm of T2D management.

Efficacy and safety of the glucagon-like peptide-1 receptor agonist oral semaglutide in patients with type 2 diabetes mellitus: A systematic review and meta-analysis

Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP-1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a post-hoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: –0.8%; 95% CI: –1.0, –0.6; p < 0.0001) and body weight (ETD: –2.5 kg; 95% CI: –3.2, –1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment.

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an important therapeutic option for type 2 diabetes mellitus (T2DM), available in both oral and subcutaneous formulations. While subcutaneous semaglutide has been available since 2017, oral semaglutide (approved in 2019) represents the first oral GLP-1 receptor agonist.This meta-analysis compared the efficacy and safety of oral versus subcutaneous semaglutide in patients with T2DM. We conducted a systematic literature search across PubMed, Embase, Cochrane Library, and Web of Science from inception to March 15, 2025. Four studies (one randomized controlled trial and three retrospective studies) with a total of 559 patients (257 receiving oral and 302 receiving subcutaneous semaglutide) met our inclusion criteria. The included studies were published from 2017 to 2024. All studies had a six-month follow-up duration. Outcomes included changes in HbA1c, body weight, and treatment discontinuation due to adverse effects. Pooled analysis indicated that subcutaneous semaglutide achieved significantly greater reductions in HbA1c compared to oral semaglutide (SMD: 0.21, 95% CI: 0.04 to 0.38) with low heterogeneity (I-square: 22%). For body weight reduction, subcutaneous semaglutide showed greater effectiveness, though the difference was not statistically significant (SMD: 0.12, 95% CI: -0.27 to 0.52) with high heterogeneity (I-square: 81%). Notably, patients receiving oral semaglutide had a significantly higher risk of treatment discontinuation due to side effects (RR: 1.79, 95% CI: 1.13 to 2.83) with no heterogeneity (I-square: 0%). While both formulations demonstrated clinical benefits, subcutaneous semaglutide appears to offer superior glycemic control with fewer treatment-limiting adverse effects. These findings likely reflect the differences in bioavailability and pharmacokinetics between the two formulations. However, the choice between formulations should consider individual patient factors, including treatment adherence, preference for injection versus oral administration, and specific comorbidities. Future studies should investigate whether modified dosing protocols could improve the tolerability of oral semaglutide while maintaining efficacy.

IntroductionThe PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension...

Objective This prospective observational study explored the changes in the daily glycemic profile after switching from injectable to oral semaglutide in patients with type 2 diabetes mellitus. Methods Patients with type 2 diabetes mellitus who were treated with once-weekly 0.5 mg injectable semaglutide and wished to switch to once-daily oral semaglutide participated in this study. Oral semaglutide was initiated at 3 mg and increased to 7 mg a month later, according to the package insert. Before and two months after the switch, participants wore a sensor for continuous glucose monitoring for up to 14 days. We also evaluated the questionnaire-based treatment satisfaction and the preference between the two formulations. Patients Twenty-three patients participated. Results Mean glucose levels significantly increased by 9 mg/dL on average, from 132±20 to 141±27 mg/dL (p=0.047), which was equivalent to a change of 0.2% in the estimated hemoglobin A1c (6.5±0.5% to 6.7±0.7%). The inter-individual variability assessed with standard deviation also significantly increased (p=0.004). The change in treatment satisfaction varied considerably among patients, with no specific trend in the overall population. After trying oral semaglutide, 48% of patients responded that they preferred the oral formulation, while 35% preferred the injectable formulation, and 17% had no preference. Conclusion The mean glucose levels increased by 9 mg/dL on average after switching from once-weekly 0.5 mg injectable semaglutide to once-daily 7 mg oral semaglutide, with an increased inter-individual variability. The change in treatment satisfaction considerably varied among patients.

Background and AimThis study aimed to clarify the efficacy and safety of oral semaglutide treatment in patients with non‐alcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM).MethodsThis was a single‐arm, open‐label pilot study. Sixteen patients with NAFLD who received oral semaglutide for T2DM were included in the analysis. Oral semaglutide was initiated at a dose of 3 mg once daily, and the dose was sequentially increased to 7 mg at 4 weeks and 14 mg at 8 weeks (maintenance dose) until the end of the 24‐week trial.ResultsBody weight and levels of liver‐related biochemistry, plasma glucose, and hemoglobin A1c decreased significantly from baseline to 12 weeks. These significant decreases were maintained until the end of the trial. Additionally, levels of the homeostasis model assessment‐insulin resistance and triglyceride significantly decreased at 24 weeks. Controlled attenuation parameter (CAP) values significantly decreased from baseline to 24 weeks. Changes in body weight were correlated with those in levels of alanine aminotransferase (r = 0.52) and CAP (r = 0.72). As for liver fibrosis markers, significant decreases from baseline to 24 weeks in levels of the fibrosis‐4 index, ferritin, and type IV collagen 7 s were found; however, the liver stiffness measurement did not significantly decrease. Most adverse events were grade 1–2 transient gastrointestinal disorders.ConclusionsOral semaglutide treatment in patients with NAFLD complicated by T2DM improved impaired liver function, hypertriglyceridemia, insulin resistance, and hepatic steatosis, as well as improving diabetic status and reducing body weight.

IntroductionIncretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on...

Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA), recently approved in the USA and other countries. This paper reviews data from clinical trials (PIONEER 1, 2, 3, and 7) comparing oral semaglutide (once-daily doses of 3, 7, or 14 mg) with either once-daily placebo, empagliflozin 25 mg, or sitagliptin 100 mg. After 26 weeks in PIONEER 1, patients randomized to 3, 7, or 14 mg doses of oral semaglutide monotherapy had statistically significant reductions in glycated hemoglobin (HbA1 c) of 0.9%, 1.2%, and 1.4%, respectively, versus 0.3% with placebo. In the active-comparator studies, oral semaglutide 14 mg provided better glycemic control than empagliflozin or sitagliptin after 26 weeks, with durable effects. Body weight reductions were significantly greater with oral semaglutide than with placebo and sitagliptin. However, body weight reductions with oral semaglutide 14 mg versus empagliflozin 25 mg were not significantly different. Gastrointestinal adverse events (AEs) with oral semaglutide were mostly mild-to-moderate, occurred early in the course of treatment, and abated over time. Across these trials, 5–13% and 15–20% of patients experienced nausea with oral semaglutide 7 and 14 mg, respectively, and 2.3–3.4% and 5.1–8.0%, respectively, discontinued treatment due to gastrointestinal AEs. Severe or blood glucose-confirmed symptomatic hypoglycemia occurred infrequently with oral semaglutide and was seen most often in patients taking concomitant sulfonylureas. Findings from these trials indicate that the addition of oral semaglutide reduces HbA1 c and body weight and is associated with a low risk of hypoglycemia. Oral semaglutide represents an additional option for treating people with type 2 diabetes in primary care, with the potential to expand the numbers of patients benefiting from GLP-1RAs beyond that currently seen with injectable formulations.

Real-world effectiveness of oral semaglutide on body weight, composition, and metabolic parameters in patients with obesity without diabetes.

Injectable therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin are high-efficacy options for people with type 2 diabetes (T2D) who require treatment intensification. In addition to high glycemic efficacy, GLP-1RAs offer weight loss benefits, and some agents have been shown to reduce cardiovascular risk. This article summarizes data from two clinical studies with the first oral GLP-1RA, oral semaglutide, in situations where injectable therapy is often considered, and provides guidance on use in primary care. PIONEER 4 compared oral semaglutide 14 mg with an injectable GLP-1RA, liraglutide 1.8 mg, or placebo in patients uncontrolled on oral glucose-lowering therapies. PIONEER 8 compared oral semaglutide with placebo in patients with T2D already on insulin therapy. Treatment with oral semaglutide gave similar reductions in glycated hemoglobin (HbA1 c) compared with liraglutide at 26 weeks, and significantly greater reductions at 52 weeks. Changes in body weight with oral semaglutide were significantly greater compared with liraglutide after 26 and 52 weeks. Adding oral semaglutide 7 or 14 mg to insulin resulted in significant reductions in HbA1 c and body weight at both 26 and 52 weeks compared with placebo, and facilitated a decrease in total daily insulin dosage. Oral semaglutide was associated with low proportions of patients experiencing severe or blood glucose-confirmed symptomatic hypoglycemia when added to oral glucose-lowering therapies, and did not increase the incidence of such events when added to insulin. The tolerability profile of oral semaglutide was consistent with that seen for injectable GLP-1RAs, with gastrointestinal side effects seen most frequently; most were transient and tended to occur during dose escalation. For patients requiring treatment intensification after oral therapy or as add-on to insulin, oral semaglutide provides effective glucose lowering and body weight loss, with low risk of hypoglycemia, thus broadening the range of therapeutic options for treatment of T2D in primary care.