Effects of GLP-1 agonists on 10-year cardiovascular risk reduction in primary prevention: A 44-week open label prospective study.

The efficacy and safety of oral semaglutide for glycaemic management in adults with type 2 diabetes compared to subcutaneous semaglutide, placebo, and other GLP-1 RA comparators: A systematic review and network meta-analysis

BackgroundThe risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.MethodsThis is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrolment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.ResultsOf the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.ConclusionIn Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.

Use of Body Fatness Cutoff Points–Reply–I

To investigate the association between triglyceride levels and major adverse cardiovascular events (MACE) in primary and secondary prevention cohorts. This retrospective study was conducted with a nationwide health insurance claims database, which included approximately 3.8 million participants with medical checkups between January 2005 and August 2020 in Japan. The participants were classified into primary prevention (n=3,415,522) and secondary prevention (n=29,806) cohorts based on cardiovascular or cerebrovascular disease history. Each participant was categorized as having very low (triglyceride ＜50 mg/dL), low normal (50-99), high normal (100-149), or hypertriglyceridemia (≥ 150). The primary prevention cohort was further stratified into low-, intermediate-, and high-risk groups according to atherosclerotic cardiovascular diseases risk. Outcome was MACE, including acute myocardial infarction (AMI), unstable angina, ischemic stroke, and cardiac death. Over a mean follow-up of 3.25 years, 0.3% and 2.6% MACE occurred in primary and secondary prevention, respectively. Hypertriglyceridemia was associated with high risk of MACE in the primary prevention, but not in the secondary prevention. A significant interaction was observed between prevention categories and the association of TG levels with MACE in those with TG ＜150 mg/dL and ischemic stroke in those with TG ≥ 150 mg/dL. The population-attributable fraction for hypertriglyceridemia in primary prevention was 4.1% for MACE. In primary prevention, lower risks of AMI were observed in the lower TG category compared to the current threshold. This study suggests distinct triglyceride thresholds for MACE risk in primary and secondary prevention cohorts, requiring further prospective validation for clinical implementation.

Background Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1a), reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over the subcutaneous form. Our objective was to compare the value for money of the two modalities by assessing the cost needed to treat (CNT) to prevent MACE. Methods The CNT to prevent MACE was figured by multiplying the one-year number needed to treat (NNT) with either oral or subcutaneous semaglutide by the annual cost of therapy. Efficacy estimates and the resulting NNT figures were extracted from the published results of the SUSTAIN-6 and the PIONEER-6 trials for the injectable and oral versions of semaglutide, respectively. Drug costs were estimated as 75% of the United States national average drug acquisition cost listing in June 2021. We performed a scenario analysis to mitigate the primary differences between the populations in the two trials. Sensitivity analysis was performed to evaluate the effect of price changes of the interventions. Results The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 was $966,693 ($594,888-$5,035,302) compared to $948,689 ($463,465-∞) with oral semaglutide in PIONEER-6. The scenario analysis demonstrated a 17% lower CNT for oral semaglutide. The difference between CNTs was sensitive to price fluctuations of the two interventions. Conclusions Oral and subcutaneous semaglutide prescribed to prevent MACE in patients with T2DM provide similar value for money. The choice between both therapies should be guided mainly by patient preferences.

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.

Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation. The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death). Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63). Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

Semaglutide for the treatment of type 2 Diabetes Mellitus: A systematic review and network meta-analysis of safety and efficacy outcomes

Advances in the management of diabetes mellitus have come a long way in the 21st century. One of the most important developments in diabetes management has been the discovery of...

4559 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists have played a pivotal role in the management of type 2 diabetes (T2DM). At the same time, immune checkpoint inhibitor (ICI) therapy remains one of the mainstay treatments for metastatic renal cell carcinoma (mRCC). There has been a scarcity of research on the effect of GLP-1 receptor agonists on ICI efficacy in cancer patients. This study presents the first real-world analysis of the effect of GLP-1 receptor agonists on outcomes in mRCC patients receiving ICI therapy. Methods: Data was retrospectively collected from TriNetX, a national electronic health record database with 120 million US patients from over 70 healthcare organizations, from 2012-2024. We included patients ≥ 18 years old with T2DM and mRCC who underwent ICI therapy. Patients were then stratified into two cohorts: on GLP-1 receptor agonists prior to ICI therapy and not on GLP-1 receptor agonists. Patients in each cohort were then 1:1 propensity score matched (PSM) based on age, sex, race, type of ICI therapy used, comorbidities, other diabetic medications and staging. 1 year outcomes for mortality, major adverse cardiovascular events (MACE) and various immune‐related adverse events (irAEs) were reported. Results: A total of 2378 patients were identified who met the inclusion criteria. 535 (22%) were in the GLP-1 receptor agonist cohort compared to 2378 (68%) in the non GLP-1 receptor agonist cohort. After 1:1 PSM, 497 patients were in each group. Among both cohorts, 66% were male, 77% white and the average age was about 65 years old. After conducting Cox proportional hazard analyses, GLP-1 receptor agonist use was associated with lower mortality (HR, 0.49 [95% CI: 0.37-0.64]). Moreover, GLP-1 receptor agonist use had lower rates of irAEs, including pneumonitis (HR, 0.61 [95% CI: 0.43-0.85]), hematological complications (HR, 0.78 [95% CI: 0.64-0.95]) and renal complications (HR, 0.67 [95% CI: 0.54-0.84]). There was no significant difference in MACE or other irAEs between the two cohorts. Conclusions: Analysis of one of the largest US based databases showed that the use of GLP-1 receptor agonist in T2DM patients with mRCC undergoing ICI therapy, is associated with better overall survival and lower irAES such as pneumonitis, hematological and renal complications. There was no significant difference in MACE. To our knowledge, this is the first study to identify the impact of GLP-1 receptor agonists on the outcomes of mRCC patients undergoing ICI therapy. Further prospective studies are needed to validate these findings and to identify the underlying mechanisms.

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection. To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes. Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use. Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events. Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common. Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety. clinicaltrials.gov Identifier: NCT01923181.

IntroductionObesity increases the risk of type 2 diabetes mellitus and cardiovascular disease (CVD). Weight loss (≥5 %) reduces the risk of CVD. Glucagon-like peptide-1 receptor agonists (GLP1 RA) have shown clinically weight loss. Objectives: 1) To assess differences in the efficacy of weight loss and HbA1c; 2) to evaluate the safety and adherence during the titration phase. MethodsIt is a multicenter, prospective, and observational study on GLP1 RA naïve patients. The primary end point was the weight loss (≥5 %). Changes in weight, BMI and HbA1c were also calculated as co-primary endpoints. Secondary endpoints were safety, adherence, and tolerance. ResultsAmong 94 subjects, 42.4 % received dulaglutide, 29,3 % subcutaneous semaglutide, 22,8 % oral semaglutide. 45 % female and the mean age was 62. Baseline characteristics were body weight 99.3 kg, BMI 36.7 kg/m2 and Hba1c 8.2 %. Oral semaglutide achieved the highest reduction: 61.1 % of patients achieving ≥ 5 %, subcutaneous semaglutide 45.8 % and dulaglutide 40.6 %. GLP1 RA significantly reduced body weight (−4.95 kg, p < 0.001) and BMI (−1.86 kg/m2, p < 0.001), without significant differences between groups. Gastrointestinal disorders were the most frequently reported events (74.5 %). 62 % of patients on dulaglutide, 25 % on oral semaglutide and 22 % on subcutaneous semaglutide. ConclusionsOral semaglutide achieved the highest proportion of patients that lost ≥ 5 %. GLP1 RA significantly reduced BMI and HbA1c. Most of the reported adverse events were gastrointestinal disorders and they were reported in a major frequency in the dulaglutide group. Oral semaglutide would be a reasonable switch in case of future shortages.

Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.

Glucagon-like peptide-1 receptor agonists and their analogues have emerged as effective pharmacotherapies for obesity. To assess the short-term cost-effectiveness of subcutaneous tirzepatide, semaglutide, liraglutide, and oral semaglutide for managing obesity or overweight in patients without diabetes. A decision tree model was developed using a 68-week time window with consideration of serious adverse events and treatment discontinuation from a US payer's perspective. The study population were adults with obesity or overweight with at least 1 weight-related comorbidity but without diabetes. Clinical data were obtained from clinical trials. Model utilities, disutilities, and the costs of serious adverse events were sourced from published literature. Medication costs were assigned from Red Book. All costs were calculated in 2024 US dollars. The incremental cost-effectiveness ratio was calculated based on the cost per quality-adjusted life-year (QALY) gained. A willingness-to-pay threshold of $150,000 per QALY was used. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the effect of parameter uncertainty on the results. In the base-case analysis, both subcutaneous tirzepatide and oral semaglutide were cost-effective vs subcutaneous liraglutide and subcutaneous semaglutide. Compared with oral semaglutide, subcutaneous tirzepatide was cost-effective, with an incremental cost-effectiveness ratio of $34,212 per QALY gained. Sensitivity analyses indicated the results were highly sensitive to medication costs and the effectiveness of medications. The probabilistic sensitivity analysis suggested that subcutaneous tirzepatide was most likely to remain cost-effective, with a 98% probability at a willingness to pay of $150,000 per QALY compared with other medications. Subcutaneous tirzepatide and oral semaglutide were cost-effective therapies compared with subcutaneous liraglutide and subcutaneous semaglutide for the short-term management of obesity in adults without diabetes. At or under a willingness-to-pay threshold of $150,000 per QALY, subcutaneous tirzepatide was most cost-effective, surpassing oral semaglutide. These findings provide valuable insights for health care decision-makers in selecting antiobesity medications.

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.