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A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes.

ABSTRACT: Oral semaglutide (Rybelsus^®) is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) with 94% homology to human GLP-1. It is the first GLP-1RA developed for oral administration, and it comprises a co-formulation of the peptide semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which overcomes the challenges of peptide absorption in the acidic conditions of the stomach. Oral semaglutide is indicated for use as an add-on combination therapy (with other glucose-lowering agents, including insulin) or as a monotherapy (in patients who are intolerant to metformin) for type 2 diabetes when diet and exercise do not provide adequate glycemic control. In an extensive phase III clinical program including patients from across the disease spectrum, treatment with oral semaglutide resulted in effective glycemic control, reductions in body weight, and decreases in systolic blood pressure when used as monotherapy or in combination with other glucose-lowering therapies. Studies showed that oral semaglutide was well tolerated, with a safety profile consistent with the GLP-1RA drug class. The risk of hypoglycemia was low, and the most common adverse events were gastrointestinal, with nausea and diarrhea generally being the most frequently reported manifestations. Cardiovascular (CV) safety was shown to be noninferior to placebo and observations suggest that the CV profile of oral semaglutide is likely to be similar to that of subcutaneous semaglutide. The evolution of the GLP-1RA class to include an oral agent could facilitate the use of these agents earlier in the diabetes treatment cascade owing to wider acceptance from patients and healthcare professionals.

SUBMITTER: Andersen A

PROVIDER: S-EPMC8217049 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceGlucagon-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.ObjectivesTo compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.Design, setting, and patientsPhase 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.InterventionsOnce-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.Main outcomes and measuresThe 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.ResultsBaseline 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.Conclusions and relevanceAmong 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.Trial registrationclinicaltrials.gov Identifier: NCT01923181.

Project description:IntroductionInternational guidelines recommend treatment with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist for treatment intensification in type 2 diabetes mellitus (T2DM) patients with progression on metformin. In the randomised, controlled, Peptide Innovation for Early Diabetes Treatment (PIONEER) 2 trial, the SGLT-2 inhibitor empagliflozin was compared with the GLP-1 receptor agonist oral semaglutide, in addition to metformin. The aim of the current study was to assess the long-term cost-effectiveness of empagliflozin 25 mg versus oral semaglutide 14 mg, in addition to metformin, for T2DM patients in the UK.MethodsAnalyses were conducted from the UK healthcare payer perspective, using the IQVIA Core Diabetes model, with a time horizon of 50 years. Patients received either empagliflozin or oral semaglutide, in addition to metformin, until Hba1c threshold of 7.5% (58 mmol/mol) was exceeded, following which treatment intensification with insulin glargine in addition to empagliflozin or oral semaglutide plus metformin was assumed. Baseline cohort characteristics and 52-week treatment effects were derived from the PIONEER 2 trial. Treatment effects of empagliflozin and GLP-1 receptor agonists on hospitalisation for heart failure (hHF) were based on the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) real-world study. Utilities, treatment costs and costs of diabetes-related complications were obtained from published sources.ResultsDirect costs for empagliflozin plus metformin were considerably lower than those for oral semaglutide plus metformin (by more than GBP 6000). Compared with oral semaglutide plus metformin, empagliflozin plus metformin was a cost-effective treatment for T2DM patients in all scenarios tested. Probabilistic sensitivity analysis showed cost-effectiveness in > 95% of the iterations using a threshold of 20,000 GBP/QALY.ConclusionEmpagliflozin 25 mg is a cost-effective treatment option versus oral semaglutide 14 mg, when used in addition to metformin, for the treatment of T2DM patients in the UK.

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A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes.

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