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Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available. This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks' duration and having change from baseline in hemoglobin (Hb) A1c as the primary end point. The random effects meta-analyses models examined HbA1c, fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA1c values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA1c of −1.1% to −1.6% and −0.6% to −1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >–2.0 and −0.2 to −0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA1c and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.

Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.

Overweight and obesity represent addressable proximal drivers of chronic disease. 1 The prevalence of overweight and obesity is increasing around the world; by 2050, projections indicate that more than half the adult population worldwide will be living with overweight and obesity, most prominently in China (an estimated 627 million persons). 2 In China, the numbers of persons with overweight and obesity have increased dramatically over the past four decades, contributing to major increases in the risks of noncommunicable diseases — including type 2 diabetes, cardiovascular disease, and cancer — and premature death. 3 Dedicated interventional trials in Chinese populations are part of the . . .

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

ObjectiveIn SUSTAIN 7, once-weekly semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of semaglutide versus dulaglutide.DesignAnalyses by baseline age (<65, ≥65 years), sex (male, female), diabetes duration (≤5, >5–10, >10 years), HbA1c (≤7.5, >7.5–8.5, >8.5% (≤58, >58–69, >69 mmol/mol)) and body mass index (BMI) (<30, 30–<35, ≥35 kg/m2).Setting194 sites; 16 countries.ParticipantsSubjects with T2D (n=1199) exposed to treatment.InterventionsSemaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly.Primary and secondary outcome measuresChange in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety.ResultsHbA1c and BW reductions (estimated treatment difference ranges: –0.22 to –0.70%-point; –1.76 to –3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with semaglutide, decreased with increasing BMI.ConclusionsConsistently greater improvements in HbA1c and BW with semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of semaglutide across the continuum of care in a heterogeneous population with T2D.Trial registration numberNCT02648204.

We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes. This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m2, or at least 27 kg/m2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete. From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was –15·1% (SE 0·5) with oral semaglutide 50 mg versus –2·4% (0·5) with placebo (estimated treatment difference −12·7 percentage points, 95% CI −14·2 to −11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo. In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo. Novo Nordisk.

Weight bias involves negative attitudes and stereotypes towards individuals based on their weight, which can be explicit or implicit. This bias contributes to weight stigma, or the mistreatment and social devaluation of individuals based on weight. Weight stigma is linked to adverse physical and mental health outcomes, leading to reduced access and quality of healthcare for individuals with obesity. The American Diabetes Association (ADA)’s Obesity Association developed guidelines on recognizing and addressing weight bias and stigma. All healthcare professionals and staff should receive training on weight bias and stigma to improve care for individuals with obesity. Training should start early and continue throughout medical education and practice. Multicomponent training that combines education with hands-on learning is recommended to reduce explicit and implicit weight bias. Clinical practices, a potential source of stigmatization for people living with obesity, should be equipped with appropriate furniture and equipment to establish an inclusive environment. Privacy and sensitivity during anthropometric measurements are essential to minimize stigmatization. Healthcare professionals should use person-centered, non-judgmental language and engage individuals in shared decision-making to consider their health and goals. Asking permission to discuss weight and respecting individual preferences is crucial. The ADA’s Obesity Association encourages adopting these guidelines to reduce weight bias and stigma, emphasizing education, inclusive clinical environments, and effective communication to improve obesity care.

INTRODUCTION The evoke/evoke+ trials are investigating semaglutide in a population with early Alzheimer's disease (AD). Specific analyses of semaglutide safety data in older adults are limited; therefore, in the current analysis, we aimed to evaluate safety considerations with semaglutide in adults ≥ 65 years. METHODS Adverse event (AE) data from three semaglutide phase 3a programs in participants ≥ 65 years with type 2 diabetes and/or overweight/obesity were pooled. Change in body weight was also assessed in a smaller subset of participants ≥ 65 years. RESULTS The analysis included 3529 participants ≥ 65 years. Baseline mean age and body mass index in participants ≥ 65 years were 69.3 to 70.2 years and 29.7 to 35.4 kg/m2, respectively, compared to 47.8 to 58.5 years and 31.3 to 36.7 kg/m2 in the overall population. AEs with semaglutide occurred in 73.6% to 92.4% of participants ≥ 65 years versus 73.2% to 90.8% of the overall population. AEs with semaglutide leading to permanent discontinuation appeared to be more frequent in participants ≥ 65 years (9.3%–12.4%) versus the overall population (5.7%–8.7%). Gastrointestinal disorders were the most frequently reported AEs with semaglutide in participants ≥ 65 years (44.6%–73.8%) and in the overall population (39.1%–73.4%). Participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo. DISCUSSION Age ≥ 65 years did not appear to affect the safety considerations of semaglutide. The ongoing evoke/evoke+ trials will elucidate the balance of efficacy and safety in the treatment of early AD with semaglutide. Highlights This was a post hoc analysis evaluating adverse event (AE) data of semaglutide in people ≥ 65 years. The most common AE with semaglutide was gastrointestinal (GI). GI event rates were similar in people ≥ 65 years and the overall study populations.

Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes. This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0−10·5% (64−91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete. Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were −1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, −1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] −0·27, 95% CI −0·42 to −0·12; p=0·0006), and −2·0 percentage points (0·06) with 50 mg (ETD −0·53, −0·68 to −0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related. Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified. Novo Nordisk.