Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

The Regulation of Metabolic Homeostasis by Incretins and the Metabolic Hormones Produced by Pancreatic Islets.

In healthy humans, the complex biochemical interplay between organs maintains metabolic homeostasis and pathological alterations in this process result in impaired metabolic homeostasis, causing metabolic diseases such as diabetes and obesity, which are major global healthcare burdens. The great advancements made during the last century in understanding both metabolic disease phenotypes and the regulation of metabolic homeostasis in healthy individuals have yielded new therapeutic options for diseases like type 2 diabetes (T2D). However, it is unlikely that highly desirable more efficacious treatments will be developed for metabolic disorders until the complex systemic regulation of metabolic homeostasis becomes more intricately understood. Hormones produced by pancreatic islet beta-cells (insulin) and alpha-cells (glucagon) are pivotal for maintaining metabolic homeostasis; the activity of insulin and glucagon are reciprocally correlated to achieve strict control of glucose levels (normoglycaemia). Metabolic hormones produced by other pancreatic islet cells and incretins produced by the gut are also crucial for maintaining metabolic homeostasis. Recent studies highlighted the incomplete understanding of metabolic hormonal synergism and, therefore, further elucidation of this will likely lead to more efficacious treatments for diseases such as T2D. The objective of this review is to summarise the systemic actions of the incretins and the metabolic hormones produced by the pancreatic islets and their interactions with their respective receptors.

Real-World Clinical Experience of Oral Semaglutide in a Secondary Diabetes Clinic in the UK: A Retrospective Observational Study.

INTRODUCTION: Oral semaglutide improves cardiovascular risk factors in people with type 2 diabetes (T2D) in clinical trials, though real-world evidence is limited. We aimed to determine the real-world impact of oral semaglutide on routinely collected clinical data in our practice. METHODS: People with T2D initiated on oral semaglutide in secondary care diabetes clinics at two hospital sites in Wales (United Kingdom) were included. Data were collected on reasons for oral semaglutide initiation and changes in bodyweight, blood pressure, glycemic control, and lipid profiles over follow-up at 3-6 months, and at 6-12 months. Data were collected to determine the safety of oral semaglutide. RESULTS: Seventy-six patients were included, with a median age 59.3 [51.4-67.6] years, and 38 (50.0%) patients were female. The most common reasons for oral semaglutide were need for weight loss and improved glycemia (69.8%), and improved glycemia alone (25.0%). Oral semaglutide associated with significantly reduced bodyweight (- 3.3 kg), body mass index (BMI) (- 0.9 kg/m2), glycated hemoglobin (HbA1c) (- 11 mmol/mol), and total cholesterol (- 0.4 mmol/l) by 3-6 months follow-up. At 6-12 months, there was a significant reduction in systolic blood pressure (- 7.0 mmHg), in addition to sustained reductions in other metabolic parameters. By 12 months, 18 (23.6%) patients had discontinued the drug, largely resulting from gastrointestinal disturbance, but there were no serious events in this cohort. CONCLUSIONS: Oral semaglutide was effective in improving cardiovascular risk factors in this real-world population living with T2D, and no serious events were identified related to oral semaglutide in this patient group.

Real-World Use of Oral and Subcutaneous Semaglutide in Routine Clinical Practice in the UK: A Single-Centre, Retrospective Observational Study.

INTRODUCTION: Semaglutide, the only glucagon-like peptide-1 receptor agonist (GLP-1 RA) available in subcutaneous and oral formulation for treatment of type 2 diabetes (T2D), has demonstrated clinically significant improvements in glycaemic control and weight in clinical trials. This study aimed to gain insights into the use of both formulations and evaluate their clinical effectiveness in a secondary care clinic in Wales. METHODS: This was a retrospective observational analysis of adults with T2D initiated on oral or subcutaneous semaglutide. Changes from baseline in glycated haemoglobin (HbA1c), weight and other metabolic parameters were evaluated. RESULTS: At baseline, participants (n = 103) had a mean age of 57.3 years, mean HbA1c of 79.1 mmol/mol (9.38%), mean weight of 111.8 kg and body mass index (BMI) of 39.6 kg/m2 (no statistically significant differences between oral and subcutaneous groups). At 6-month follow-up, statistically significant improvements in HbA1c (- 19.3 mmol/mol [- 1.77%] and - 20.8 mmol/mol [- 1.90%]), body weight (- 9.0 kg and - 7.2 kg), and BMI (- 3.3 kg/m2 and - 2.5 kg/m2) were observed for oral and subcutaneous semaglutide, respectively. No statistically significant differences between the formulations were observed, and safety profiles were comparable. CONCLUSIONS: Both formulations of semaglutide provided clinically and statistically significant reductions in HbA1c and weight in real-world practice. Oral GLP-1 RA may offer a practical and effective option for the management of T2D.

Effects of Once-Weekly Semaglutide on Kidney Disease Outcomes by KDIGO Risk Category in the SUSTAIN 6 Trial.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by Kidney Disease: Improving Global Outcomes (KDIGO) as risk-based treatment for hyperglycemia, weight management, and cardiovascular (CV) risk reduction in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). The aim of this post hoc analysis was to assess treatment effects of once weekly semaglutide on kidney disease outcomes by KDIGO risk category and on changes in KDIGO risk category, compared with placebo. Methods: Participants with T2D and established CV disease or at high CV risk treated with once weekly semaglutide or placebo in SUSTAIN 6 (NCT01720446) were stratified by baseline KDIGO risk category (low [n = 1596], moderate [n = 831], high [n = 445], very high [n = 366]). Treatment effect was analyzed for a kidney disease composite end point (macroalbuminuria, serum creatinine doubling and estimated glomerular filtration rate [eGFR] < 45 ml/min per 1.73 m2, kidney replacement therapy, or death due to kidney disease) from baseline to 2 years. Results: The treatment effect of semaglutide versus placebo was consistent across KDIGO categories for the kidney disease composite end point (hazard ratio [95% confidence interval (CI)]: 0.35 [0.07-1.72], 0.42 [0.25-0.72], 0.87 [0.45-1.71], and 0.72 [0.42-1.23] for low, moderate, high, and very high risk categories, respectively; P interaction = 0.28). Participants receiving semaglutide were more likely to move to a lower KDIGO risk category (odds ratio: 1.69; 95% CI: [1.32-2.16]) and less likely to move to a higher KDIGO risk category versus placebo (odds ratio: 0.71; 95% CI: [0.59-0.86]). Conclusion: Once weekly semaglutide versus placebo reduced risks of kidney disease end points and improved risk categories irrespective of baseline KDIGO risk.

SGLT2 Inhibitors - The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.