Efficacy of oral semaglutide: overview of the PIONEER clinical trial program and implications for managed care.

The first tablet formulation of a glucagon-like peptide-1 receptor agonist(GLP-1RA), oral semaglutide, was approved in September 2019 for the treatment of adults with type 2 diabetes (T2D). This article reviews data from the PIONEER phase 3a clinical trial program, which assessed the efficacy and safety of oral semaglutide in more than 9500 patients at different stages on the disease trajectory (mean diabetes duration,3.5-15 years) and on a range of background treatment regimens(monotherapy, added to 1 or 2 oral glucose-lowering agents, or added to insulin). The studies compared oral semaglutide (doses of 3 mg, 7 mg, or14 mg) with placebo, and selected commonly used glucose-lowering agents (empagliflozin 25 mg, sitagliptin 100 mg, or liraglutide 1.8mg). Across the studies, oral semaglutide provided greater glycated hemoglobin (A1C) reductions than placebo, empagliflozin, or sitagliptinat 26 weeks, and similar A1C reductions as liraglutide. The proportion of patients achieving the A1C level recommended by the American Diabetes Association of less than 7.0% (53 mmol/mol) was greater with oral semaglutide (7 mg, 42%-69%; 14 mg, 55%-77%) than placebo (7%-31%)and active comparators (25%-62%), with durable target achievement. Oral semaglutide was associated with similar reductions in body weight as empagliflozin and greater reductions than placebo, sitagliptin, or liraglutide. Oral semaglutide was also efficacious in patients with T2D and moderate renal impairment. These findings indicate that oral semaglutide presents a valuable option for treating patients with T2D in a managed care setting, with the potential to expand the number of patients benefiting from GLP­1RAs.

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.

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.

Cardiovascular outcomes, safety, and tolerability with oral semaglutide: insights for managed care.

It is important to consider the safety profile of new medications in type 2 diabetes (T2D) when selecting the most appropriate treatment option for each patient. This can help ensure that patients achieve optimal response, that those experiencing adverse events are appropriately managed, and that treatment is tailored for those with pre-existing conditions such as cardiovascular disease (CVD), which is the leading cause of death in patients with T2D. The American Diabetes Association and American Association of Clinical Endocrinologists/American College of Endocrinology recommend a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter 2 inhibitor with proven cardiovascular (CV) benefit in patients with established CVD or those at high risk of CVD. Injectable semaglutide is approved by the FDA for reducing the risk of major CV events in adults with T2D and established CVD. In PIONEER 6, the CV safety of the first GLP-1RA tablet, oral semaglutide, was noninferior to placebo, and a longer-term study (SOUL; NCT03914326) powered to assess a potential CV benefit is ongoing. The safety and tolerability profile of oral semaglutide across the PIONEER clinical trial program was consistent with the GLP-1RA class. The most common adverse events were gastrointestinal (GI) (eg, nausea, diarrhea, and vomiting), which were typically mild to moderate and transient. In clinical practice, oral semaglutide expands the treatment options available to patients with T2D and can be considered in patient populations suitable for injectable GLP-1RAs.