Oral Glucagon-like Peptide-1 Receptor Agonists Research Articles

Effectiveness of switching from dipeptidyl peptidase-4 inhibitor to oral glucagon-like peptide-1 receptor agonist in Japanese participants with type 2 diabetes mellitus: Prospective observational study using propensity score matching.

Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period. Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'. In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m2 to 28.8 kg/m2. Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period. In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors.

Efficacy and tolerability of oral semaglutide in Japanese patients with type 2 diabetes mellitus: Analysis report from diabetes specialist clinics.

Glucagon-like peptide 1 receptor agonists (GLP1Ras) have emerged as pivotal agents in diabetes management and organ protection. However, their use is limited due to the necessity for injectable administration. The advent of the first oral GLP1Ra (oral semaglutide) in Japan since 2021 is expected to expand its usage. The aim of this study is to survey the efficacy and tolerability of oral semaglutide in clinical practice. We retrospectively analyzed 120 outpatients diagnosed with type 2 diabetes mellitus who had received oral semaglutide for >6 months. Changes in clinical parameters during oral semaglutide treatment from baseline to 12 months were analyzed. The inverse probability weighting method using the propensity score was used to evaluate the differences in clinical parameters at 6 months after treatment, based on the patients' obesity levels. Body weight (BW), glycated hemoglobin A1c (HbA1c), and alanine aminotransferase (ALT) levels at baseline decreased significantly after treatment compared with those at 12 months (P < 0.001, P < 0.001, and P = 0.03, respectively). The patients were divided into two groups using a cutoff baseline body mass index (BMI) of 30.3 kg/m2. Although no significant difference was observed, changes in body weight and HbA1c indicated a potentially greater decrease in the BMI ≧ 30.3 group than that in the BMI < 30.3 group (P = 0.07 and 0.13, respectively). Among 206 registered patients, 25 (12.1%) discontinued oral-semaglutide treatment owing to adverse effects, including gastrointestinal symptoms. Oral semaglutide treatment demonstrates efficacy and tolerability for managing type 2 diabetes mellitus in Japan. Significant improvements in metabolic factors induced by oral semaglutide are anticipated, particularly in obese patients.

What is the pipeline for future medications for obesity?

Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

SAT085 Oral Glucagon-like Peptide-1 Receptor Agonist As Adjuvant Treatment In HNF1A-MODY

Abstract Disclosure: D.T. Broome: Grant Recipient; Self; NIH U54DK118612-04. Research Investigator; Self; Fractyl Laboratories, Novo Nordisk. Maturity-onset diabetes of the young (MODY) is an inherited form of monogenic diabetes caused by a mutation in a single gene. HNF1A-MODY is the most common treatment-requiring form of MODY with a reported frequency of 1.2%1. Early genetic diagnosis leads to more precise treatment, and sulfonylureas have been recognized as first-line treatment in patients with HNF1A-MODY. Although sulfonylurea treatment is often effective early in the disease course, patients often experience sulfonylurea treatment failure. As a result, there has been recent investigation into additional treatment options that are effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have previously been published for use in patients with HNF1A-MODY2,3, and recognized as a potential effective treatment in patients with HNF1A-MODY. Although GLP-1 RAs have been reported for use as injectable agents, there is currently no evidence reporting their effectiveness as oral medications. In this report, we present a novel case of use of oral semaglutide as adjuvant treatment to sulfonylurea in a patient with HNF1A-MODY. A 48-year-old female with a history of diabetes since age 22, later confirmed as HNF1A-MODY at age 45 (Heterozygous HNF1A mutation, c.608G&amp;gt;A (p.Arg203His), NM_000545.5), was glimepiride for 3 years and without micro- or macrovascular complications. She developed a 15-lb weight gain, and her HbA1c increased to 7% (HbA1c gradually increasing from 5.4% to 7.0% over 3 years) despite her taking glimepiride 4 mg twice daily prescribed by her primary care physician. Thereafter, her primary care physician prescribed oral semaglutide 3 mg once daily for 4 weeks, which was titrated to 7 mg once daily. After initiation of oral semaglutide, her glimepiride was reduced to 2 mg once daily, her HbA1c improved to 5.4%, and she lost 30 lbs over a 6-month timeframe. This is the first report demonstrating the benefits of oral GLP-1 RA treatment in a patient with HNF1A-MODY, and this clinical case provides further support of use GLP-1 RA use as adjuvant treatment to sulfonylurea in patients with HNF1A-MODY.

Oral semaglutide in kidney transplant recipients with metabolic syndrome: three Japanese cases

BackgroundRenal transplant recipients with chronic kidney disease often develop post-transplant diabetes mellitus or metabolic syndrome (MetS), which are poor prognostic factors after renal grafts. Although recent studies have reported the protective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) on the heart and kidneys, few have assessed its effects in renal transplant patients. Moreover, to our knowledge there have been no studies on the effects of oral GLP-1RA (semaglutide) in renal transplantation recipients in Japan.Case presentationCase 1 was a 52-year-old male renal transplant recipient with MetS. Semaglutide was administered orally for 12 months, starting at 3 mg/day and titrating up to 14 mg/day. Over time, his HbA1c level decreased from 5.9 to 5.5% and weight from 100.6 to 96.3 kg. No adverse events were observed. Case 2 was a 62-year-old male renal transplant recipient with MetS. Oral semaglutide was started at 3 mg/day. However, the patient had severe nausea, and the dose was reduced to 1.5 mg/day and then gradually increased to 14 mg/day for 12 months. Over time, triglyceride decreased from 308 to 277 mg/dL and weight decreased from 75.4 to 63.2 kg. Case 3 was a 59-year-old male renal transplant recipient with MetS and fatty liver. Oral semaglutide was started at 3 mg/day and titrated up to 12 mg/day for 12 months. Over time, triglyceride decreased from 205 to 119 mg/dL and weight decreased from 79.1 to 76.4 kg. No adverse events were observed.ConclusionsIn all three patients, oral semaglutide significantly reduced body weight and improved metabolic parameters. Additional studies are needed to further evaluate the efficacy of oral semaglutide and the incidence of associated adverse events in a large number of renal transplant recipients.Trial registration: UMIN, UMIN000050853. Registered 14 April 2023—Retrospectively registered, https://center6.umin.ac.jp/cgi-bin/ctr/ctr_reg_rec.cgi

PCR6 The Association between Administration Method, Socio-Demographic Characteristics, and Patient-Reported Outcomes for Glucagon-like Peptide-1 Receptor Agonists Among Diabetes Patients in Japan: A Cross-Sectional Patient Survey

In recent years, oral glucagon-like peptide-1 receptor agonist (GLP-1 RA) has become available. While an oral GLP-1 RA could simplify treatment compared to GLP-1 RA injections, it may also require an increase in administration frequency. This study examines the association between administration method (dosage form and administration frequency), socio-demographic characteristics, and patient-reported outcomes (PRO) under a real-world setting.

Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have a more potent glycated hemoglobin (HbA1c)-lowering effect than existing therapies and are widely used for treating type 2 diabetes mellitus (T2DM). Once-daily oral semaglutide is the world's first oral GLP-1RA. This study aimed to provide real-world data on oral semaglutide in Japanese patients with T2DM and its effects on cardiometabolic parameters. This was a single-center retrospective observational study. We examined changes in HbA1c and body weight (BW) and the rate of achieving HbA1c < 7% after 6 months of oral semaglutide treatment in Japanese patients with T2DM. Furthermore, we examined differences in the efficacy of oral semaglutide with multiple patient backgrounds. A total of 88 patients were included in this study. Overall, the mean (standard error of the mean) HbA1c at 6 months decreased by -1.24% (0.20%) from baseline, and BW at 6 months (n = 85) also decreased by -1.44 kg (0.26 kg) from baseline. The percentage of patients who achieved HbA1c < 7% changed significantly from 14% at baseline to 48%. HbA1c decreased from baseline regardless of age, sex, body mass index, chronic kidney disease, or diabetes duration. Additionally, alanine aminotransferase, total cholesterol, triglyceride, and non-high-density lipoprotein cholesterol were significantly reduced from baseline. Oral semaglutide may be an effective option for the intensification of therapy in Japanese patients with T2DM who have inadequate glycemic control with existing therapy. It may also reduce BW and improve cardiometabolic parameters.

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial.

To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed. Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants. SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.

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...

The GLP-1RAs: From Evolution to Revolution

Research on incretin hormones has advanced considerably over the past few decades. Although the initial molecule – glucose-dependent insulinotropic polypeptide – failed to stimulate insulin secretion in patients with type 2 diabetes, it led to the discovery of glucagon-like peptide 1 (GLP-1). As GLP-1 impacts on various tissues and cells throughout the body, it allows patients with type 2 diabetes to benefit in many ways, in addition to lowering blood glucose levels. In a bid to harness these benefits pharmacologically, analogues were evolved from GLP-1 to produce a class of peptides known as GLP-1 receptor agonists (GLP-1RAs). The mechanism of action by which GLP-1RAs achieve their effects on lowering glucose levels, body weight, systolic blood pressure as well as lipid profiles, and improving cardiovascular and renal outcomes will be further discussed. With the advancement in research and development, the advent of scientific research and development has greatly accelerated the global implementation and local approved use of the first oral GLP-1RA, allowing the abovementioned benefits to be easily accessed. Oral GLP-1RA is set to bring about a revolution in the management of type 2 diabetes in Singapore.

Oral Semaglutide in the Management of Type 2 DM: Clinical Status and Comparative Analysis.

In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy. This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control, and comparative analysis of semaglutide with the second-line antidiabetic drugs. Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide, to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve Glycemic control in obese patients with a reduction in body weight. Still, in clinical practice, in the type 2 DM treatment paradigm, the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control. The review highlights the comparative analysis of semaglutide with the existing second- line drugs for the management of type 2 diabetes mellitus by stressing its benefits and adverse events.

Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials.

ObjectiveThe absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials.MethodsA previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5–10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes.ResultsThe model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes.ConclusionsThe updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state.ClinicalTrials.gov identifiersNCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01025-x.

Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses.

IntroductionThe efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups.MethodsData from patients in the PIONEER 3–5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients.ResultsIn total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: − 1.0 to − 1.5% and − 2.2 to − 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups.ConclusionOral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents.Trial RegistrationClinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8).Graphic Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-020-00994-9.

Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.

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.

Type 2 diabetes in the US managed care setting: the burden of disease and rationale for an oral glucagon-like peptide-1 receptor agonist.

Diabetes affects an estimated 34 million US adults, with type 2 diabetes (T2D) accounting for 90% to 95% of cases. The downstream consequences of uncontrolled T2D are substantial, including an increased risk of microvascular complications (eg, renal impairment, retinopathy, and peripheral neuropathy), cardiovascular disease, impaired quality of life, and death. Overall, diabetes places a significant strain on the US health care system, with 7.8 million hospitalizations annually among patients with diabetes, and $237 billion in direct medical costs. Injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been available for T2D for over a decade, and are recommended, in particular, for patients with a compelling need to minimize hypoglycemia risk, curtail weight gain, or promote weight loss, and for patients with established cardiovascular disease. Despite being associated with high glucose-lowering efficacy, weight loss, and a low risk of hypoglycemia, injectable GLP-1RAs are relatively underutilized, and are associated with suboptimal adherence and persistence. These challenges may relate in part to the injectable route of administration, given that injection-related concerns have been linked with a failure to intensify T2D therapy in a timely manner (ie, therapeutic inertia), and are cited by patients as a barrier to initiating and persisting with injectable treatments. The approval of the first tablet formulation of a GLP-1RA for T2D, oral semaglutide, has the potential to address these challenges. In this context, we review the burden of T2D in the United States, the role of GLP-1RAs, the challenges of therapeutic inertia and poor adherence, and the rationale for an oral GLP-1RA, focusing on considerations for managed care.

Preference for Oral and Injectable GLP-1 RA Therapy Profiles in Japanese Patients with Type2 Diabetes: A Discrete Choice Experiment.

IntroductionGlucagon-like peptide 1 (GLP-1) receptor agonists (RAs) approved to date are administered by injection; therefore, patient perceptions of an oral GLP-1 RA are unknown. This discrete choice experiment explored preferences for (unbranded) oral and injectable GLP-1 RA profiles among Japanese patients with type 2 diabetes (T2D).MethodsAn online survey was designed using literature review and qualitative interview findings, and administered to Japanese patients with T2D and HbA1c ≥ 7.0% receiving oral antiglycaemic medication (with no experience of injectable antiglycaemic medication). Therapy profiles were created using Japanese head-to-head trial data for orally administered semaglutide (7 mg and 14 mg), injectable dulaglutide (0.75 mg), and injectable liraglutide (0.9 mg). Profiles were not labelled. Choice tasks tested preference between hypothetical profiles, preference between profiles with actual trial data, and willingness to initiate treatment. Relative importance of attributes was determined using conditional logit regression.ResultsA total of 500 respondents were analysed: mean age 61.2 years; 93.8% male; mean HbA1c 7.6%; 78.2% with HbA1c ≥ 7.0 to < 8%; 89% with HbA1c above personal target. Mean BMI was 25.4 kg/m2; 49% had obesity (≥ 25 kg/m2). The treatment attribute with greatest importance was mode and frequency of administration (49.1%), followed by nausea risk (30.8%), weight change (11.3%), and HbA1c change (8.8%). Oral semaglutide 7 and 14 mg-like profiles were both preferred: the 7 mg-like profile was preferred over dulaglutide (by 91.0% of respondents) and liraglutide (by 89.4%); the 14 mg-like profile was preferred over dulaglutide (by 88.2%) and liraglutide (by 94.4%). Willingness to initiate treatment was also higher for orally administered semaglutide-like profiles: 62.4% with 7 mg and 64.0% with 14 mg, versus 13.6% and 11.0% with injectable GLP-1 RA-like profiles. Subgroup results were generally consistent with the overall sample.ConclusionJapanese patients with T2D appear to prefer oral GLP-1 RA profiles over injectable GLP-1 RA profiles, and administration appears to be the most important factor in this decision. This highlights the unmet need for an effective and orally administered GLP-1 RA for the treatment of T2D in Japan.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01561-1) contains supplementary material, which is available to authorized users.

58 - Efficacy of Oral Semaglutide According to Background Medication: An Exploratory Subgroup Analysis of the PIONEER Trial Program

The global PIONEER program investigated the efficacy and safety of the first oral glucagon-like peptide-1 receptor agonist, oral semaglutide. Across PIONEER trials, patients with type 2 diabetes (T2D) were randomized to once-daily oral semaglutide (3, 7, 14 mg or flexibly dosed) or comparator. The present exploratory subgroup analysis evaluated the effect of background medications on glycated hemoglobin (HbA1c) and body weight (BW) reductions at the end of trial (week 26, 52 or 78) in 5 PIONEER trials (3–5, 7–8). Data were analyzed from patients who received oral semaglutide or comparator (sitagliptin, liraglutide or placebo) based on background medication received: metformin, sulphonylurea, sodium–glucose cotransporter 2 inhibitor, insulin or combinations. Baseline characteristics were generally similar across subgroups. Reductions in HbA1c and BW were greater for oral semaglutide vs comparators (except liraglutide, with similar HbA1c reductions), regardless of background medication (Table). In general, there were no statistically significant interactions between treatment and subgroups. Estimated treatment differences were consistent within each trial and background medication subgroups. These findings support the use of oral semaglutide across a broad population of patients with T2D in combination with other commonly used glucose-lowering agents.

957-P: Efficacy of Oral Semaglutide According to Background Medication: An Exploratory Subgroup Analysis of the PIONEER Trial Program

The global PIONEER program investigated the efficacy and safety of the first oral glucagon-like peptide-1 receptor agonist, oral semaglutide. Across PIONEER trials, patients with type 2 diabetes (T2D) were randomized to once-daily oral semaglutide (3, 7, 14 mg or flexibly dosed) or comparator. The present exploratory subgroup analysis evaluated the effect of background medications on glycated hemoglobin (HbA1c) and body weight (BW) reductions at the end of trial (week 26, 52 or 78) in five PIONEER trials (3-5, 7-8). Data were analyzed from patients who received oral semaglutide or comparator (sitagliptin, liraglutide or placebo) based on background medication received: metformin, sulfonylurea, sodium-glucose co-transporter 2 inhibitor, insulin or combinations. Baseline characteristics were generally similar across subgroups. Reductions in HbA1c and BW were greater for oral semaglutide vs. comparators (except liraglutide, with similar HbA1c reductions), regardless of background medication (Table). In general, there were no statistically significant interactions between treatment and subgroups. Estimated treatment differences were consistent within each trial and background medication subgroups. These findings support the use of oral semaglutide across a broad population of patients with T2D in combination with other commonly used glucose-lowering agents. Disclosure J.B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Neurimmune. Research Support; Self; American Diabetes Association, National Institutes of Health, Novo Nordisk A/S, Patient-Centered Outcomes Research Institute, Sanofi, Tolerion, Inc., vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings, Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg Therapeutics, Novo Nordisk A/S, Senseonics, Inc, vTv Therapeutics, Zafgen, Inc. M. Crowley: None. J.W. Eriksson: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. M. Gislum: Employee; Self; Novo Nordisk A/S. C.L. Hertz: Employee; Self; Novo Nordisk A/S. M. Kaiser: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes. A. Moeller Nielsen: Employee; Self; Novo Nordisk A/S. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Novo Nordisk A/S

21 - Effect and Safety of Flexible Dose Adjustment With Oral Semaglutide vs Sitagliptin in Type 2 Diabetes: PIONEER 7

Oral semaglutide is the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA). Flexible dose adjustment of oral semaglutide (3, 7 and 14mg) once daily (N=253) was tested vs sitagliptin (100mg; N=251) in a 52-week, randomized, open-label, phase 3a trial in patients with type 2 diabetes (T2D) uncontrolled on 1-2 oral glucose-lowering drugs (NCT02849080). Oral semaglutide dose could be adjusted every 8 weeks based on HbA1C (escalated if ≥7.0%) and tolerability. Endpoints at week 52: HbA1C <7.0% (primary); body weight change (secondary).