AIMS:Care home admission often reflects frailty and limited life expectancy, potentially altering the benefit-harm balance of glucose-lowering drug (GLD) treatment for type 2 diabetes (T2D). Real-world data on treatment patterns in this setting remain limited. We examined GLD use for T2D among Danish care home residents. MATERIALS AND METHODS:We conducted a nationwide, population-based drug utilisation study of all individuals admitted to Danish care homes between 2018 and 2023, using linked national health registries. RESULTS:Among 88 658 residents (median age: 84 years [IQR: 78-90]; 60% women), 13% (n = 11 101) used GLDs for T2D at admission, with 84% continuing treatment beyond 2 years. Residents using GLDs at admission had long-standing diabetes (median duration: 12 years [IQR: 6.8-15]), relatively low glycated haemoglobin levels (median: 6.9% [IQR: 6.3-7.8]; 52 mmol/mol [45-62]) with little change around admission, and 43% used more than one GLD class, most commonly metformin (70%) and insulin (36%; basal: 30%; bolus: 16%). Use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased over time but remained limited (13% and 24%, respectively, in 2023), despite a high prevalence of cardiorenal disease (84%), and did not differ by cardiorenal disease status. Overall GLD use remained stable around admission, but initiation spiked 3 months before admission (36 initiators/10 000 residents), often following hospitalisation (63%) and primarily involved bolus insulin initiated by hospital physicians. CONCLUSIONS:GLD use for T2D among Danish care home residents is high and shows limited deintensification and potential misalignment with guideline recommendations.
AIM:Oxytocin has been proposed to exert glucose-stabilising effects via modulation of pancreatic hormone secretion and to play a role in bone homeostasis. However, human data under controlled conditions are limited. We investigated the effects of intravenously infused oxytocin during a graded glucose infusion on glucose-regulating hormones and markers of bone turnover in healthy men. MATERIALS AND METHODS:In a randomised, placebo-controlled, double-blind, crossover study, healthy men received intravenous infusions of oxytocin (0.1 or 0.2 IU/min, or placebo [saline], respectively) on three separate days during a three-hour intravenous graded glucose infusion with increases every 30 min (2-12 mg/kg/min). The primary outcome was baseline-subtracted area under the curve for C-peptide concentrations. Secondary outcomes included concentrations of plasma glucose, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), carboxy-terminal collagen crosslink (CTX), procollagen Type 1 amino-terminal propeptide (P1NP) and serum triglycerides. RESULTS:Twenty men (age: 24.9 ± 3.2 years; BMI: 23.8 ± 1.5 kg/m2) were included. Peak plasma oxytocin concentrations: 193 ± 29 and 401 ± 66 pg/mL. Circulating concentrations of plasma glucose, C-peptide, glucagon, GIP, GLP-1, CTX, P1NP and triglyceride were similar across study visits. Neither oxytocin dose affected C-peptide response or any secondary metabolic outcomes compared with placebo. CONCLUSION:Acute intravenous oxytocin infusion resulting in supraphysiological plasma concentrations did not modulate pancreatic or gut hormone secretion, or markers of bone turnover during a controlled, stepwise glucose challenge in healthy men, suggesting limited acute metabolic and skeletal effects of oxytocin under these conditions.
AIMS:To characterise postmarketing safety signals and medication-use risks associated with GLP-1 receptor agonists and the GIP/GLP-1 co-agonist tirzepatide in diabetes and obesity care using an integrated pharmacovigilance, utilisation-context, regulatory, and external-consistency framework. MATERIALS AND METHODS:FDA Adverse Event Reporting System (FAERS) data from 2021Q1 through 2026Q1 were processed using deleted-case exclusion, latest-case-version retention, and case-product deduplication with analysis at the GLP-1 primary-suspect case-product level. Primary-suspect records for semaglutide, tirzepatide, dulaglutide, liraglutide, exenatide, and lixisenatide were analysed using reporting odds ratios, proportional reporting ratios, and an approximate Information Component. Medicaid utilisation data, FDA labelling/Safety-Related Labelling Changes resources, FDA shortage and compounded-product communications, and Canada Vigilance reports provided contextual interpretation; no data source was used to estimate incidence, comparative risk, or causality. RESULTS:The final FAERS analysis set included 243 114 GLP-1 primary-suspect case-product records within 8 995 547 background reports. Tirzepatide accounted for 133 100 records, followed by semaglutide (55619) and dulaglutide (38406). Frequently reported terms included incorrect dose administered, nausea, injection-site pain, diarrhoea, vomiting, off-label use, and extra dose administered. Prioritised domains included gastrointestinal intolerance, medication-use/device events, impaired gastric emptying, pancreatobiliary events, renal/dehydration events, and hypoglycaemia. Canada Vigilance and FDA labelling/SrLC mapping showed descriptive visibility for most major domains, while medication-use terms reflected use-process rather than conventional adverse-drug-reaction issues. CONCLUSIONS:Multi-source pharmacovigilance can improve interpretation of GLP-1 postmarketing safety evidence in diabetes and obesity care. Findings should be interpreted as signal-prioritisation and medication-safety evidence, not as incidence, proof of causality, or population-level comparative risk, given the limited clinical interpretability of spontaneous-reporting data.
AIMS:Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert systemic cardiometabolic, renal and vascular effects that may influence retinal health, yet whether their effects on diabetic macular oedema (DMO) are stage-dependent remains unclear. We synthesized real-world, interventional and mechanistic evidence on responsiveness across disease stages and retinal phenotypes. MATERIALS AND METHODS:In this scoping review (PRISMA-ScR; prospectively registered, UMIN000061304), we searched PubMed, the Cochrane Library, ClinicalTrials.gov, WHO-ICTRP and Google Scholar for studies published from January 2014 to April 2026. Two reviewers independently screened and charted records. Heterogeneity precluded meta-analysis, so a qualitative meta-summary with exploratory E-value analyses was performed. RESULTS:Forty studies were included. Large administrative databases consistently associated SGLT2 inhibitor use with a 16%-35% lower DMO incidence (hazard ratio 0.65-0.84) and hazard ratios of 0.53-0.94 for diabetic retinopathy progression. In established DMO, observational studies reported hazard ratios of 0.39-0.81 for anti-vascular endothelial growth factor (VEGF) injections, corticosteroid therapy and repeat vitrectomy, with the first-vitrectomy estimate non-significant, and attenuation in severe non-proliferative or proliferative retinopathy. The only randomized trial (COMET) did not meet its primary endpoint; its fellow-eye and phenotype-specific subgroup analyses were exploratory and hypothesis-generating. Proposed mechanisms include suppression of microglial activation, oxidative stress and angiopoietin-2/VEGF signalling, although translational evidence remains preclinical. CONCLUSIONS:This predominantly observational evidence suggests that SGLT2 inhibitors may be associated with slower DMO disease kinetics across retinopathy stages, with reduced treatment burden most evident before severe retinopathy. Systemic SGLT2 inhibition may complement, rather than replace, anti-VEGF therapy, which remains the cornerstone of DMO management. These findings support prospective stage- and phenotype-stratified investigation.
AIMS:Cardiovascular, kidney and metabolic diseases are pathophysiologically interrelated and are conceptualised within the cardiovascular-kidney-metabolic (CKM) syndrome framework. However, evidence linking continuous glucose monitoring (CGM) to CKM syndrome remains limited. This study examined the association between time in range (TIR), the core CGM metric, and advanced CKM syndrome. MATERIALS AND METHODS:A total of 2497 adults aged ≥ 60 years with type 2 diabetes were included. CKM syndrome was defined according to the American Heart Association Presidential Advisory, with stages 3-4 classified as advanced CKM syndrome. RESULTS:Participants with advanced CKM syndrome exhibited significantly lower TIR levels than those with non-advanced CKM syndrome (p < 0.001). After multivariable adjustment, each 1-standard deviation decrease in TIR was independently associated with higher odds of advanced CKM syndrome (OR 1.28, 95% CI 1.16-1.42). Restricted cubic spline analyses demonstrated a linear inverse association between TIR and advanced CKM syndrome, with the estimated OR approaching unity at approximately 70%. The prevalence of advanced CKM syndrome increased progressively across TIR categories of > 70%, 50%-70% and ≤ 50% (p for trend < 0.001). Although TIR levels of 50%-70% exceed the currently recommended target of > 50% for older adults, this range remained associated with higher odds of advanced CKM syndrome compared with TIR > 70% (OR 1.40, 95% CI 1.12-1.75). Higher TIR was not associated with increased hypoglycemia exposure. CONCLUSIONS:Lower TIR was associated with advanced CKM syndrome, supporting the potential value of CGM-derived TIR in evaluating multisystem cardiovascular-kidney-metabolic burden in older adults with type 2 diabetes.
AIM:We investigated the contribution of antecedent gestational diabetes mellitus (GDM) or gestational hypertensive disorder (GHTD) to the risk of cardiovascular disease (CVD) among women with Type 2 diabetes mellitus (T2DM). METHODS:In a population-based cohort using the Ministry of Health of Ontario (Canada) healthcare administrative data, women without prior CVD with T2DM and a history of GDM or GHTD as of 1 January 2018 (n = 11 525, mean age: 43 years) were age-matched to three comparator cohorts (women with T2DM and no history of GDM or GHTD [n = 11 525], women without T2DM and without GDM or GHTD [n = 11 525] and men with T2DM [n = 11 525]). Incident CVD (coronary artery disease [CAD] and cerebrovascular disease) and heart failure (HF) were assessed until 31 December 2023. RESULTS:There were 1231 CVD events over a median follow-up of 6 years. Compared to women with T2DM but no history of GDM or GHTD, women with T2DM and a history of GDM or GHTD exhibited higher incident CVD (adjusted hazard ratio [aHR]: 1.19, 95% CI: 1.01, 1.41) and CAD (aHR: 1.35, 95% CI: 1.10, 1.66) risks. They also had higher CVD (aHR: 3.70, 95% CI: 2.79, 4.91), CAD (aHR: 4.96, 95% CI: 3.43, 7.19), cerebrovascular disease (aHR: 2.41, 95% CI: 1.54, 3.76) and HF (aHR: 4.95, 95% CI: 2.05, 11.94) risks versus women without T2DM and no history of GDM or GHTD. However, they had lower CVD, CAD, cerebrovascular disease and HF risks, compared to men with T2DM. CONCLUSIONS:Among women with T2DM, prior GDM or GHTD conferred a higher CVD risk.
AIM:Automated insulin delivery (AID) systems improve glycaemic outcomes in Type 1 diabetes; however, paediatric real-world data on newly introduced tubeless AID systems remain limited. We aimed to provide the first clinical evaluation of the A8 TouchCare Nano AID system with the APGO algorithm in children and adolescents with Type 1 diabetes. MATERIALS AND METHODS:In this prospective observational study, children and adolescents initiating TouchCare Nano AID therapy were followed for 6 months. Continuous glucose monitoring metrics were assessed at baseline and 1, 3 and 6 months. The primary outcome was change in time in range (TIR, 70-180 mg/dL). Secondary outcomes included time in tight range (TiTR, 70-140 mg/dL), time above and below range, glucose variability, insulin dose, achievement of ISPAD glycaemic targets and safety. HbA1c was measured at baseline, 3 and 6 months. RESULTS:Seventy-six participants (mean age 13.3 ± 3.2 years) completed follow-up. Mean TIR increased from 59.0% ± 15.6% at baseline to 74.2% ± 8.9% at 1 month and remained significantly higher at 3 and 6 months (all p < 0.05). TiTR significantly improved, whilst time above range decreased and time below range remained stable. More than half of participants achieved the ISPAD target of TIR > 70% at 6 months. Mean sensor glucose and glucose variability declined, and HbA1c decreased from 7.4% ± 0.8% to 6.9% ± 0.7% at 3 and 6 months (all p < 0.05). No episodes of severe hypoglycaemia or diabetic ketoacidosis were observed. CONCLUSIONS:In routine paediatric care, use of this tubeless AID system was associated with rapid and sustained improvements in glycaemic control without increased hypoglycaemia. TRIAL REGISTRATION:Clinicaltrials.gov: NCT07425912.
AIMS:We evaluated overall and sex-specific performance of established diabetes risk models for predicting incident dysglycaemia in African and European populations. MATERIALS AND METHODS:We externally evaluated the African Diabetes Risk model, Finnish Diabetes Risk model, Epidemiological Study on the Insulin Resistance Syndrome model and the personal and clinical Framingham models. Evaluation was performed in three prospective cohorts: the Research on Obesity and Diabetes among African Migrants (RODAM-Pros; migrant and non-migrant Ghanaians; n = 1607), the Middle-aged Soweto cohort (MASC; urban Black South Africans; n = 515) and the Västerbotten Intervention Programme (VIP; Sweden; n = 3044). Dysglycaemia was defined according to American Diabetes Association criteria. Discrimination (c-statistic) and calibration were assessed before and after recalibration. RESULTS:Dysglycaemia developed in 17.7% of RODAM-Pros participants, 35.0% of MASC participants and 27.5% of VIP participants, with median follow-up of 6.7, 6.7 and 9.9 years, respectively. All models demonstrated poor-to-modest discrimination (c-statistic < 0.7). Most models substantially underestimated risk. Recalibration eliminated systematic miscalibration and reduced calibration error to ≤ 2.3% in RODAM-Pros and VIP and ≤ 3.4% in MASC. Performance varied by sex and cohort. CONCLUSIONS:Existing diabetes risk prediction models can be applied to predict incident dysglycaemia in both Sub-Saharan African and European populations, but only after recalibration to local risk levels.
AIMS:To examine the association between initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of incident depression compared with dipeptidyl peptidase-4 (DPP-4) inhibitors among adults with newly diagnosed Type 2 diabetes receiving metformin. MATERIALS AND METHODS:We conducted a nationwide active-comparator new-user cohort study with a 90-day adherent-survivor landmark design, using the Korean National Health Insurance Service database linked with national health check-up and mortality data (2014-2022). Adults with newly diagnosed Type 2 diabetes receiving metformin who newly initiated SGLT2 inhibitors or DPP-4 inhibitors as add-on therapy were identified. This study was designed as a 90-day adherent-survivor landmark analysis. Propensity score matching was performed in a 1:1 ratio, yielding 10 013 matched pairs. The primary outcome was incident depression, defined as ≥ 2 outpatient or inpatient claims with ICD-10 codes F32-F33. The secondary outcome was suicide mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs) under intention-to-treat and as-treated approaches. RESULTS:Among 38 297 eligible participants, 300 depression events occurred among SGLT2 inhibitor users and 391 among DPP-4 inhibitor users in the matched cohort. Initiation of SGLT2 inhibitors was associated with a lower risk of depression compared with DPP-4 inhibitors (HR 0.85, 95% CI 0.73-0.99). Similar findings were observed in as-treated analyses (HR 0.80, 95% CI 0.65-0.98). Associations were generally consistent across clinically relevant subgroups and appeared more pronounced among older adults, females and individuals with greater comorbidity burden. Suicide mortality was infrequent in both groups. CONCLUSIONS:Among 90-day adherent survivors with Type 2 diabetes receiving metformin, initiation of SGLT2 inhibitors as add-on therapy was associated with a lower risk of incident depression compared with DPP-4 inhibitors.
AIMS:Incretin-based pharmacotherapy was initially developed to improve glucose-dependent insulin secretion and glycaemic control in type 2 diabetes, but its clinical interpretation has expanded substantially with cardiovascular outcome trials, kidney outcome data, obesity studies and next-generation polyagonist development. This narrative clinical review uses structured literature identification and outcome-stratified synthesis to evaluate incretin-based therapies as cardiometabolic interventions across diabetes, obesity, cardiovascular disease and chronic kidney disease. MATERIALS AND METHODS:The available evidence was interpreted according to therapeutic class, clinical domain, outcome maturity and safety boundaries, integrating clinical outcome evidence with receptor-network pharmacology. RESULTS:Selected GLP-1 receptor agonists are supported by hard cardiovascular and renal outcome data, whereas several dual, triple, amylin-linked and oral small-molecule strategies are currently supported mainly by glycaemic, weight-loss, metabolic or early translational endpoints. This distinction is clinically important because treatment positioning should depend on patient phenotype, outcome maturity and safety boundaries rather than mechanistic plausibility alone. In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, GLP-1 receptor agonists with proven cardiovascular outcome benefit should be prioritised when atherosclerotic risk reduction is a major treatment goal. In type 2 diabetes with chronic kidney disease, semaglutide has dedicated kidney outcome evidence. In obesity with cardiometabolic risk, high-magnitude and sustained weight reduction has become a clinically relevant therapeutic target. Receptor-network pharmacology, including GLP-1, GIP, glucagon and amylin receptor signalling, provides a useful explanatory framework for heterogeneous efficacy, tolerability and tissue-level effects. CONCLUSIONS:However, clinical use remains bounded by gastrointestinal tolerability, lean-mass preservation, treatment durability, discontinuation effects and long-term safety. This review therefore proposes phenotype-based clinical positioning rather than a prescriptive treatment algorithm.
AIM:Limited data on the link between various measures of glycemia and metabolism and autonomic dysfunction exist. We assessed the association of fasting plasma glucose [FPG], glycated haemoglobin [HbA1C], fasting insulin, and HOMA-IR and cardiac autonomic function measures separately for men and women in the Diabetes Prevention Program Outcomes Study (DPPOS). METHODS:We included DPPOS participants with ECG-based heart rate variability (HRV) measured at the 10-year examination. Resting heart rate (HR), standard deviation of all normal-to-normal intervals (SDNN), and root mean square of successive differences between normal-to-normal intervals (rMSSD) were measured. Multivariable linear regression models assessed the cross-sectional associations of FPG, HbA1C, and fasting insulin and HOMA-IR with cardiac autonomic function measures. RESULTS:Among 2266 participants (mean age 65 years, 68.2% women, 53.4% White, 43.7% with prediabetes and 56.3% with diabetes at the time of evaluation), HbA1C, FPG, fasting insulin and HOMA IR were positively associated with high resting HR in men and women. HbA1C and FPG were inversely associated with rMSSD (β [95% CI] per SD: -0.08 [-0.14, -0.03] and -0.08 [-0.13, -0.03]) and SDNN (-0.08 [-0.12, -0.03] and -0.07 [-0.11, -0.02]) among women, but not in men. Fasting insulin was inversely associated with rMSSD in the men (-0.09 [-0.18, 0.00]). HOMA-IR was inversely associated with rMSSD in men (-0.11 [-0.20, -0.02] and women -0.07 [-0.12, -0.02]). HOMA-IR was associated with SDNN only in women (-0.05 [-0.10, 0.00]). CONCLUSIONS:Markers of dysglycaemia are associated with worse ECG-based autonomic dysfunction in adults with prediabetes and diabetes in the DPPOS, more so for some glycaemic markers and in women.
BACKGROUND AND AIMS:Visceral fat area (VFA) is a key marker of central obesity and metabolic risk, but its assessment still depends largely on imaging. Existing VFA estimation equations often rely on conventional anthropometric or laboratory indices, and their increasing complexity may compromise model stability, generalizability, and practical implementation. We aimed to develop a parsimonious sagittal abdominal diameter (SAD)-based model for estimating VFA and to evaluate its performance in two independent cohorts. METHODS:In this cross-sectional study, we analysed two independent cohorts: NHANES 2011-2016 (N = 5655), in which reference VFA was derived from dual-energy X-ray absorptiometry (DXA, N = 3878), and a Chinese adult cohort (N = 3927), in which reference VFA was measured by computed tomography (CT, N = 190) in a subset of participants. Sex-specific regression models were developed separately in each cohort using prespecified anthropometric variables and were evaluated in terms of agreement with reference VFA, discrimination of metabolic risk, internal validation using bootstrap resampling, and sensitivity analyses. RESULTS:SAD was the strongest anthropometric predictor of VFA, with age providing additional explanatory value in both populations. The final equations differed slightly across cohorts: NHANES models included SAD, age, and height, whereas the Chinese models included SAD, age, and weight. Model fit was good, with R2 values ranging from 0.67 to 0.81. Agreement between estimated VFA and reference VFA was strong, with concordance correlation coefficients of 0.805-0.893 and mean absolute errors of 18.94-26.83 cm2. Estimated VFA showed discrimination comparable to reference VFA for identifying individuals with ≥ 2 non-adipose metabolic syndrome (MetS) components. Sensitivity analyses confirmed the robustness of the primary SAD-based model. We further developed an online calculator based on the SAD-eVFA model to improve its accessibility and real-world applicability. CONCLUSIONS:We developed parsimonious, cohort-specific SAD-based equations for estimating VFA. These equations demonstrated good agreement with reference VFA and effective discrimination for identifying individuals with ≥ 2 non-adipose components of MetS. This strategy may provide a feasible and potentially scalable framework for central obesity assessment in population screening, primary care, and individual health management.
BACKGROUND:Chronic inflammation and insulin resistance (IR) are key drivers of cardiovascular disease (CVD); however, their joint impact on cardiovascular risk remains poorly understood. METHODS:We developed the metabolic-inflammatory index (eMII) based on estimated glucose disposal rate (eGDR) in a derivation cohort (ELSA) and evaluated its transportability in two external validation cohorts (CHARLS, HRS). Multivariate Cox regression was utilised to assess the joint impact of IR and inflammation on long-term CVD risk. RESULTS:A total of 14,168 middle-aged and older adults were included (mean age 61.68 ± 9.67 years). In fully adjusted Cox models, low eGDR, elevated hs-CRP and their combined status were all associated with increased CVD risk, with the highest risk observed in participants with both poor metabolic function and high inflammation. Exploratory mediation analysis indicated that eGDR accounted for 41.14%, 46.50% and 75.47% of the inflammation-CVD association in ELSA, CHARLS and HRS, respectively. In terms of the new index-eMII, higher eMII levels were consistently linked to elevated CVD risk across all cohorts; compared with the lowest quartile, the highest quartile showed hazard ratios of 1.66 (ELSA), 2.28 (CHARLS) and 1.83 (HRS) (all p < 0.001). Lastly, incorporating eMII into traditional risk models showed potential for improving cardiovascular risk prediction, with a more noticeable reclassification benefit observed within CHARLS. CONCLUSIONS:eMII is a cross-population predictor of CVD, highlighting metabolic impairment as a key factor through which inflammation drives cardiovascular risk. It provides a practical perspective for observing joint metabolic-inflammatory burdens in middle-aged and older adults.
AIM:Pathway-specific polygenic risk scores (psPRS) provide insights into the heterogeneity of type 2 diabetes. We aim to study whether psPRS for beta cell dysfunction, obesity and metabolic syndrome associate with risk of hyperglycaemic progression in Southeast Asian patients with type 2 diabetes. PARTICIPANTS AND METHODS:One thousand and fifty-nine insulin-naïve outpatients with type 2 diabetes were enrolled from a secondary hospital and a primary care facility. The psPRS were constructed as a weighted sum of risk alleles associated with specific metabolic pathways. Hyperglycaemic progression was defined as sustained insulin therapy lasting longer than 6 months. RESULTS:During a median of 11.2 (8.9-11.8) years of follow-up, 188 participants initiated sustained insulin therapy. One SD increment in psPRS for metabolic syndrome was associated with a 17% increased risk for hyperglycaemic progression after adjustment for clinical risk factors (adjusted HR 1.17 [1.02-1.36]). Consistent results were obtained when hyperglycaemic progression was defined as a composite of sustained insulin therapy and requirement for insulin treatments (HbA1c > 8.5% with two or more non-insulin medications). Adding metabolic syndrome psPRS onto clinical risk predictors (diabetes onset age, HbA1c, HDL cholesterol, eGFR, urinary albumin-to-creatinine ratio) did not improve risk discrimination (delta AUC -0.01 [95% CI -0.02 to 0.01], p = 0.50). Neither psPRS for beta cell dysfunction nor obesity was associated with the risk of hyperglycaemic progression. CONCLUSION:psPRS for metabolic syndrome is nominally associated with risk of hyperglycaemic progression in multi-ancestry Southeast Asian people with type 2 diabetes. The psPRS does not provide incremental value for prediction of hyperglycaemic progression beyond clinical risk predictors.
AIMS:To conduct indirect treatment comparisons (ITCs) of insulin efsitora alfa (efsitora) versus insulin icodec (icodec) in insulin-experienced individuals with Type 2 Diabetes Mellitus. METHODS:Efficacy, safety and patient reported outcomes were compared via matching-adjusted ITCs using results from randomised controlled trials: QWINT-3 versus ONWARDS 2 (basal-insulin experienced individuals) and QWINT-4 versus ONWARDS 4 (basal-bolus insulin-experienced individuals). RESULTS:In basal insulin-experienced participants, efsitora was comparable to icodec for change from baseline (CfB) in HbA1c (%) (efficacy estimand mean difference [MD] [95% CI]: 0.137 [-0.058, 0.333]), proportion of participants (PoP) discontinuing treatment due to adverse event (risk difference: -0.0002 [-0.0223, 0.0220]) and CfB in Diabetes Treatment Satisfaction Questionnaire-Change (DTSQc) (MD: 1.01 [-0.243, 2.27]). Efsitora exhibited significantly reduced weight gain (MD: -1.52 kg [-2.60, -0.447]) and had lower event rates of Level 2 or 3 hypoglycaemia (rate ratio: 0.436 [0.241, 0.786]) versus icodec, despite no significant difference in PoP with Level 2 or 3 hypoglycaemia (odds ratio [OR]: 0.581 [0.294, 1.14]). In basal-bolus insulin-experienced participants, efsitora was comparable to icodec: CfB in HbA1c (%) (MD: -0.0447 [-0.252, 0.163]); CfB in body weight (kg) (MD: -0.316 [-1.45, 0.817]); PoP with Level 2 or 3 hypoglycaemia (OR: 1.10 [0.698, 1.73]); event rate of Level 2 or 3 hypoglycaemia (rate ratio [95% CI]: 1.03 [0.759, 1.39]). CONCLUSIONS:These indirect comparisons suggest that efsitora had lower event rates of hypoglycaemia and less weight gain compared to icodec in basal insulin-experienced participants. Efsitora was comparable to icodec for all other endpoints.
AIMS:Glucagon-like peptide-1 (GLP-1) receptor agonists can produce rapid weight loss, but this loss is frequently accompanied by disproportionate loss of lean mass, particularly during the early phase of GLP-1-treatment. Physical activity (PA), particularly resistance training, is the most effective behavioural strategy for enhancing fat reduction while preserving lean mass. Our primary aim was to evaluate whether a 12-week virtual GLP-1 lifestyle companion programme that includes PA coaching was associated with increased weight and fat loss coupled with preservation of muscle mass among adults with obesity who initiated GLP-1 therapy for weight loss ≤ 8 weeks prior to baseline. MATERIALS AND METHODS:In this quasi-experimental trial, 245 adults (151 intervention and 94 control) received either a virtual GLP-1 lifestyle companion programme with personalised, strength-focused PA coaching or usual care. Body composition was captured using home bioelectrical impedance analysis scales. Primary outcomes were 12-week between-group differences in change in weight, percent body fat and percent muscle mass. RESULTS:Participants in the GLP-1 lifestyle companion programme lost an adjusted mean of 6.0% of their baseline body weight versus 3.3% in the control group (between-group difference 2.8%, p < 0.001). Compared with controls, they also experienced a larger decline in body fat percentage (-3.3% vs. -1.6%, p < 0.001), a greater increase in muscle mass percentage (+0.6% vs. +0.2%, p < 0.01) and greater improvements in psychosocial and behavioural outcomes. CONCLUSIONS:Personalised, virtually delivered PA programming may meaningfully improve the quantity and quality of weight loss during GLP-1 therapy.
AIM:To characterise the pharmacokinetics (PKs) and safety of BM2216 sustained-release (SR) tablets after single-dose oral administration under fasted/fed conditions in healthy participants, assess the effect of food and dose proportionality, and compare the single and multiple-dose PK of BM2216 SR tablets with mirogabalin besylate tablets to estimate the bioavailability. MATERIALS AND METHODS:This was a single-centre, randomised, open-label, phase I study conducted in healthy adult participants aged 18-45 years old, consisting of three parts: Part 1 (Food effect and single-dose PK comparison): 18 participants were 1:1:1 randomised into three sequences: (1) 16.5 mg BM2216 (fasting 18:00, QD); (2) 15 mg mirogabalin besylate tablets (fasting 18:00/next-day 6:00, 7.5 mg/dose); (3) 16.5 mg BM2216 (post-high-fat dinner, QD). A 3-period crossover design with a 72 h washout period; Part 2 (Single-dose proportionality): 32 participants were equally assigned to four groups, receiving BM2216 SR tablets (5.5, 11, 16.5, or 33 mg) 30 min post-standard meal, respectively; Part 3 (Multiple-dose PK comparison): 16 participants were 1:1 randomised into two sequences: (1) BM2216 (post-dinner, 16.5 mg QD, four consecutive days); (2) 15 mg mirogabalin besylate tablets (fasting 18:00/next-day 6:00, 7.5 mg/dose, four consecutive days). Crossover was conducted with a 72 h washout period. PK parameters were calculated and compared using non-compartmental analysis. RESULTS:The most common adverse events (AEs) were dizziness (15.6%), increased bile acids (12.5%) and vertigo (12.5%). Dizziness appeared in both the 16.5 and 33 mg dose groups, while vertigo was only seen in the 33 mg group, no serious AEs occurred. Single postprandial doses (5.5-33 mg) exhibited linear PKs: Tmax median 3.00-5.02 h, with dose-proportional increases in Cmax, AUC0-t and AUC0-∞. Multiple doses (16.5 mg QD, 4 days) had Tmax,ss median 5.996 h, t1/2,ss mean 3.8075 h; The RAC,Cmax and RAC,AUC were 0.9965 and 1.0150, indicating no accumulation; high-fat meal significantly extending T1/2 by 3.5 h, increasing Cmax by 16%, delaying Tmax by 3 h and raising AUC by 30%. Postprandial BM2216 (16.5 mg) and fasting mirogabalin besylate (15 mg) had equivalent mirogabalin AUC; BM2216 showed good sustained-release properties. CONCLUSIONS:BM2216 SR was safe and shows linear PK (5.5-3 mg single dose). Due to significant food effect and comparable QD exposure to the reference drug, postprandial QD administration is recommended. These data support further efficacy trials in neuropathic pain patients.
