Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials.

BACKGROUND: Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. METHODS: Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. RESULTS: Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA1c and BW. CONCLUSIONS: Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. TRIAL REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

The Potential Role of Digital Health in Obesity Care.

Obesity is a complex, multi-factorial, chronic condition which increases the risk of a wide range of diseases including type 2 diabetes mellitus, cardiovascular disease and certain cancers. The prevalence of obesity continues to rise and this places a huge economic burden on the healthcare system. Existing approaches to obesity treatment tend to focus on individual responsibility and diet and exercise, failing to recognise the complexity of the condition and the need for a whole-system approach. A new approach is needed that recognises the complexity of obesity and provides patient-centred, multidisciplinary care which more closely meets the needs of each individual with obesity. This review will discuss the role that digital health could play in this new approach and the challenges of ensuring equitable access to digital health for obesity care. Existing technologies, such as telehealth and mobile health apps and wearable devices, offer emerging opportunities to improve access to obesity care and enhance the quality, efficiency and cost-effectiveness of weight management interventions and long-term patient support. Future application of machine learning and artificial intelligence to obesity care could see interventions become increasingly automated and personalised.

Recommendations from a Working Group on Obesity Care Competencies for Healthcare Education in the UK: A Report by the Steering Committee.

INTRODUCTION: Obesity significantly increases the risk of developing (or worsening) more than 200 chronic diseases, and it is also a risk factor for severe COVID-19. With the rising prevalence of obesity in the UK, there is a need to develop obesity care competencies that apply to healthcare professionals (HCPs) at all levels of the health service, to increase the capacity for contemporary, evidence-based treatment that is effective, compassionate, and avoids stigmatising patients. METHODS: A UK Obesity Care Competencies Working Group consisting of experts by profession and experts by experience was created to provide a framework of obesity care competencies for HCPs involved in specialist obesity care (tiers 2-4 in the UK). The framework was adapted from a set of competencies recently published by the USA-based Obesity Medicine Education Collaborative (OMEC) and was intended to be adaptable to nurses and allied health professionals, as well as physicians, owing to the multidisciplinary team approach used in healthcare in the UK. RESULTS: The UK Obesity Care Competencies Working Group developed a set of 29 competencies, divided into five focal areas, namely obesity knowledge, patient care and procedural skills, practice-based learning and improvement, professionalism and interpersonal communication skills, and systems-based practice. The working group recommends that the obesity care competencies are targeted at HCPs training as specialists. The competencies could be imported into existing training programmes to help standardise obesity-related medical education and could also be used to direct a new General Practitioner with Extended Role (GPwER) qualification. CONCLUSION: This list of obesity care competencies aims to provide an initial framework to improve education for HCPs and therefore to improve patient care in obesity. The acceptance and integration of these competencies into the healthcare system should provide a stepping stone toward addressing trends in health inequality.

Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis.

CONTEXT: No head-to-head trials have directly compared once-weekly (OW) semaglutide, a human glucagon-like peptide-1 analog, with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in type 2 diabetes (T2D). OBJECTIVE: We indirectly compared the efficacy of OW semaglutide 1 mg vs once-daily (OD) empagliflozin 25 mg in patients with T2D inadequately controlled on metformin monotherapy, using individual patient data (IPD) and meta-regression methodology. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: IPD for patients with T2D receiving metformin monotherapy and randomized to OW semaglutide 1 mg (SUSTAIN 2, 3, 8 trials), or to OD empagliflozin 25 mg (PIONEER 2 trial) were included. Meta-regression analyses were adjusted for potential prognostic factors and effect modifiers. MAIN OUTCOME MEASURES: The primary efficacy outcomes were change from baseline to end-of-treatment (~1 year) in HbA1c (%-point) and body weight (kg). Responder outcomes and other clinically relevant efficacy measures were analyzed. RESULTS: Baseline characteristics were similar between OW semaglutide (n = 995) and empagliflozin (n = 410). Our analyses showed that OW semaglutide significantly reduced mean HbA1c and body weight vs empagliflozin (estimated treatment difference: -0.61%-point [95% confidence interval (CI): -0.72; -0.49] and -1.65 kg [95% CI: -2.22; -1.08], respectively; both P < 0.0001). Complementary analyses supported the robustness of these results. A significantly greater proportion of patients on OW semaglutide vs empagliflozin also achieved HbA1c targets and weight-loss responses. CONCLUSIONS: This indirect comparison suggests that OW semaglutide 1 mg provides superior reductions in HbA1c and body weight vs OD empagliflozin 25 mg in patients with T2D when added to metformin monotherapy.

Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials.

AIM: To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes. MATERIALS AND METHODS: Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose-confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function. RESULTS: Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common. CONCLUSIONS: Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide.

CONTEXT: Semaglutide, a once-weekly glucagon-like peptide-1 analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: Three hundred and eleven sites in 30 countries. PATIENTS OR OTHER PARTICIPANTS: 2432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7 kg to 4.3 kg; P < 0.0001) and semaglutide 1.0 mg (4.5 kg to 6.1 kg; P < 0.0001) vs comparators (1.0 kg to 1.9 kg). There were greater reductions in IR with semaglutide 0.5 mg (27% to 36%) and semaglutide 1.0 mg (32% to 46%) vs comparators (17% to 28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70% to 80% and 34% to 94%, for semaglutide 0.5 mg and 1.0 mg, respectively, vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.

Obesity Treatment in the UK Health System.

In the UK, as in most other countries in the world, levels of obesity are increasing. According to the Kinsey report, obesity has the second largest public health impact after smoking, and it is inextricably linked to physical inactivity. Since the UK Health and Social Care Act reforms of 2012, there has been a significant restructuring of the National Health Service (NHS). As a consequence, NHS England and the Department of Health have issued new policy guidelines regarding the commissioning of obesity treatment. A 4-tier model of care is now widely accepted and ranges from primary activity, through community weight management and specialist weight management for severe and complex obesity, to bariatric surgery. However, although there are clear care pathways and clinical guidelines for evidence-based practice, there remains no single stakeholder willing to take overall responsibility for obesity care. There is a lack of provision of adequate services characterised by a noticeable 'postcode lottery', and little political will to change the obesogenic environment.