Oral Semaglutide In Patients Research Articles

Acceptability of the switch from parenteral to oral semaglutide in patients with type 2 diabetes mellitus and obesity: Patient satisfaction, and changes in HbA1c, body weight, systolic blood pressure and tryglicerides

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

PS-C17-9: RELEVANT BLOOD PRESSURE REDUCTION WITH ORAL SEMAGLUTIDE IN PATIENTS WITH TYPE 2 DIABETES AND OBESITY, INDEPENDENT OF PREVIOUS ANTIHYPERTENSIVE TREATMENT

Objective: The antihypertensive effect of oral semaglutide is apparently modest in published trials but it has not been explored in uncontrolled hypertensive patients. We sought to assess whether oral semaglutide may elicit a clinically relevant reduction of systolic blood pressure (SBP) in patients with type 2 diabetes (T2D), obesity and uncontrolled hypertension, and whether the attained SBP reduction is diluted by the previous antihypertensive treatment. Design and Methods: Retrospective analysis of the SBP and antihypertensive medication data were performed in consecutive patients with T2D and obesity who started therapy with oral semaglutide. Data were obtained from a baseline visit in which oral semaglutide was initiated, and a second visit after 3–4 months. Patients who initiated or changed antihypertensive medication simultaneously with oral semaglutide were excluded. Consent for anonymous analysis and reporting of data were obtained from all included subjects. Results: 50 patients with T2D (by usual clinical criteria) and obesity (BMI < 30 kg/m2) were included; their age was 56 ± 11 years. 32 (64%) were female, and their diabetes duration was 6.9 ± 2.9 years. 41 (82%) of them were diagnosed with hypertension (sitting office SBP > 140 and/or taking antihypertensive drugs). Globally there was a significant but modest reduction in SBP (149.8 ± 11.7 to 146.7 ± 12.4 mmHg, p = 0.041, paired t-test), but this reduction was strongly correlated with the baseline SBP (Pearson's r 0.39, p < 0.001). In the Figure (A) the reductions in SBP for patients with controlled SBP (< 140 mmHg), stage 1 (SBP 140–159 mmHg), stage 2 (160–179 mmHg) and stage 3 hypertension (> 180 mmHg) are shown (p = 0.0056 for differences among SBP categories, one-way ANOVA). The Figure (B) also shows the reductions in SBP for patients taking 0, 1, 2 or > 3 different antihypertensive drugs, but there are no significant differences (p = 0.2312, one-way ANOVA). In the second visit the number of patients with SBP < 140 mmHg had increased from 19 (38%) to 25 (50%). Conclusions: Treatment with oral semaglutide in patients with T2D, obesity and uncontrolled hypertension elicits a clinically significant decrease in SBP, enough to bring about acceptable SBP control in a relevant fraction. As expected, the reduction in SBP was strongly dependent on the baseline SBP. Interestingly, this reduction does not seem to be diluted by the use of multiple antihypertensive drugs, suggesting that oral semaglutide could be considered as an add-on in patients with apparent resistant hypertension.

Efficacy and safety of oral semaglutide in patients with non‐alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study

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.

Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study)

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...

Incorporating Treatment Pauses, Dosing Flexibility and Education to Support GLP-1RA Therapy Persistence

As the first oral GLP-1 receptor agonist (GLP-1RA), oral semaglutide may increase accessibility of GLP-1RA therapy in broader care settings. Understanding the management of GLP-1RA therapy when intolerability occurs, including gastrointestinal (GI) adverse events (AEs), is important to maintain treatment persistence. The PIONEER 6 trial (NCT02692716; N=3183) examined the efficacy and safety of oral semaglutide in patients with type 2 diabetes either ≥50 years with established cardiovascular/kidney disease or ≥60 years with cardiovascular risk factors. While 27% of patients temporarily discontinued semaglutide on ≥1 occasion during the trial, 12% permanently discontinued due to AE(s). We evaluated medication management strategies within PIONEER 6 to assess their role in supporting treatment continuation. Patients taking semaglutide underwent dose escalation (initiation, 3 mg; 4 weeks, 7 mg; 8 weeks, 14 mg). Investigators could reduce the dose if AEs developed and re-escalate once symptoms resolved/diminished. Patients were educated to address GI AEs throughout the trial. Patients who discontinued treatment because of AEs were encouraged to resume treatment once the AE had ceased. If patients discontinued semaglutide for >21 days, re-escalation from a lower dose was recommended to mitigate GI AEs. Discontinuation mostly occurred during the initial dose escalation period. In total, 23% of patients receiving semaglutide had ≥1 treatment pause, of which, 72% had one pause. Median duration of treatment pause was 21 days. Importantly, 75% of patients restarted semaglutide after the first AE-related treatment discontinuation. These data highlight the role of treatment pauses, flexibility and education in mitigating potential AEs to support treatment persistence on GLP-1RAs.

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

ObjectivesTo evaluate the efficacy and safety of the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) oral semaglutide in the treatment of type 2 diabetes mellitus (T2DM) patients. Methods: Randomized controlled trials comparing oral semaglutide with placebo or other antihyperglycemic agents in T2DM patients were identified by searching PubMed, Embase, Cochrane Library and ClinicalTrials.gov. Risk ratios and mean differences with 95% confidence intervals were used to synthesize the results. Results: Ten relevant studies involving 8,536 patients were finally included. Compared with placebo, oral semaglutide significantly reduced hemoglobin A1c (HbA1c), body weight, fasting plasma glucose, self-measured plasma glucose (SMPG), serious adverse events and all-cause death and significantly increased the number of participants who achieved HbA1c < 7.0%. Compared with active comparators, oral semaglutide significantly reduced the level of HbA1c, body weight, and SMPG and significantly increased the number of participants who achieved HbA1c < 7.0%. Compared with placebo or active comparators, oral semaglutide did not increase the incidence of adverse events, hypoglycemia (severe or blood glucose-confirmed symptomatic), myocardial infarction, heart failure requiring hospitalization, stroke or acute pancreatitis but did increase the incidence of nausea, diarrhea and vomiting. Conclusions: Oral semaglutide has favorable efficacy and safety in the treatment of T2DM patients. Oral semaglutide may be superior to liraglutide, dulaglutide, empagliflozin and sitagliptin for T2DM patients who have obesity or poor adherence to injectable GLP-1 RAs.

The importance of patient-reported outcomes in type 2 diabetes: insight from the PIONEER program with oral semaglutide.

Patient-reported outcomes (PROs), including treatment satisfaction, patient well-being, and quality of life, are becoming increasingly important contributors to treatment decisions in clinical practice and the evaluation of health care services. PROs have been included in a number of clinical trials in patients with type 2 diabetes (T2D), including those investigating glucagon-like peptide-1 receptor agonists (GLP-1RAs). The first oral GLP-1RA, oral semaglutide, was approved in the United States in 2019. Four PROs were included in the PIONEER clinical study program that evaluated oral semaglutide in patients with T2D across the full diabetes disease spectrum. PRO findings in the PIONEER studies were generally similar for oral semaglutide and comparators, with some exceptions. Improvements in a number of the 36-item Short Form Survey domains were observed for oral semaglutide versus placebo, including general health, bodily pain, physical component summary, social functioning, and mental health. For general health and social functioning, differences significantly favored oral semaglutide versus empagliflozin, whereas role-physical and the physical component summary significantly favored empagliflozin compared with oral semaglutide. The Diabetes Treatment Satisfaction Questionnaire findings indicated that oral semaglutide improved feelings of unacceptably high blood sugars versus placebo (in PIONEER 4, 5, and 8) and sitagliptin (in PIONEER 7). Significant improvements in craving control and craving for savory were observed with oral semaglutide versus empagliflozin in the Control of Eating Questionnaire (in PIONEER 2). These data provide valuable information that can facilitate a patient-centered approach and guide decision-making in managed care to optimize each patient's treatment experience.

PDB25 The Cost-Effectiveness of ORAL Semaglutide in Patients Treated with Currently Available GLP-1 Receptor Agonists - a UK Perspective

Oral semaglutide is now available in the United States and Canada, and received marketing authorisation in April 2020 from the EMA for use in Europe. There are already a number of glucagon-like peptide 1 receptor agonists (GLP-1RA) available in either once-daily or once-weekly injectable formulations; semaglutide is the first orally administered GLP-1RA. Unlike the majority of economic evaluations which focus on a specific comparator, the objective of this assessment takes a holistic, real-world approach and compares the cost-effectiveness of oral semaglutide with the currently prescribed GLP-1RA class. To inform the calculations, long-term economic evaluations were conducted in the IQVIA CORE Diabetes Model using the results of a published network meta-analysis and UK-specific costs of treatment and diabetes-related complications. The results of these model simulations were then weighted according to current country-specific GLP-1RA market shares (Feb–Apr 2020). Costs of diabetes treatments were taken from the Monthly Index of Medical Specialities, June 2020, with costs and impact on quality of life of diabetes-related complications taken from published sources. The UK standard discount rate of 3.5% was used. The use of oral semaglutide resulted in reduced lifetime costs and quality-adjusted life-years (QALY; £24,309 and 8.61, respectively) versus injectable GLP-1RAs (£24,561 and 8.59, respectively). These results show that oral semaglutide is dominant (less costly and more effective), with predicted savings of £251 and an increase of 0.03 QALYs per patient when compared with the current market-mix of GLP-1 RA treatments. The results of this analysis show that oral semaglutide is a cost-effective treatment option for patients for whom a GLP-1RA is appropriate. The comparison provided here is relevant to payers, as it demonstrates what they are currently paying versus the new oral formulation. Physician and patient preference is important when selecting which GLP-1RA to prescribe for a patient.

Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial

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...

Pharmacokinetics and Clinical Implications of Oral Semaglutide for Type 2 Diabetes Mellitus.

Since the approval of subcutaneous glucagon-like peptide-1 receptor agonists, this therapeutic class has become a preferred choice for the management of type 2 diabetes due to A1C reduction, minimal risk of hypoglycemia, weight loss, and cardiovascular benefit. An oral option, with gastrointestinal absorption, would overcome any potential fear of injection among patients. Oral semaglutide has been studied in randomized controlled trials within the PIONEER program. From a robust pool of literature with a global patient population, oral semaglutide has been an effective option as monotherapy and combination therapy to improve clinical outcomes, such as A1C and body weight from baseline to week 78, depending on the randomized controlled trial. In addition, a noninferiority result was observed with oral semaglutide versus placebo in a cardiovascular outcomes trial in patients with type 2 diabetes with established cardiovascular disease or risk factors. Similar to injectable glucagon-like peptide 1 receptor agonists, transient nausea and vomiting was seen with oral semaglutide. Overall, this new oral option may be a choice for patients with barriers to injectable therapy. This review evaluates and summarizes the pharmacokinetics, pharmacodynamics, and clinical application of oral semaglutide in patients with type 2 diabetes.

Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.

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

Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol [SE 0·8]) vs -0·2 percentage points (SE 0·1; -2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: -0·8 percentage points, 95% CI -1·0 to -0·6; p<0·0001) and bodyweight (estimated mean change of -3·4 kg [SE 0·3] vs -0·9 kg [SE 0·3]; ETD, -2·5, 95% CI -3·2 to -1·8; p<0·0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA1c -1·1 percentage points (SE 0·1; -12 mmol/mol [SE 0·8] versus -0·1 percentage points (SE 0·1; -1 mmol/mol [SE 0·8]; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p<0·0001); mean change in bodyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p<0·0001). More patients taking oral semaglutide than placebo had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a result (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group. Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class. Novo Nordisk A/S.

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AimsTo assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon‐like peptide‐1 receptor agonist.Materials and methodsPIONEER 6 is a multinational, randomized, placebo‐controlled, double‐blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once‐daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non‐fatal myocardial infarction or non‐fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non‐inferiority versus placebo for the primary endpoint (non‐inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event‐driven, with follow‐up continuing until accrual of at least 122 primary outcome events. There is no pre‐defined minimal duration.ResultsOverall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD.ConclusionsPIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.