To evaluate the efficacy and safety of oral PCSK9 inhibitors in adults with hypercholesterolemia by synthesizing evidence from randomised controlled trials.
This systematic review and meta-analysis followed PRISMA guidelines and was registered on PROSPERO (CRD420261303350). PubMed, Embase and Scopus were searched from inception to March 2026 for randomised controlled trials comparing oral PCSK9 inhibitors with placebo in adults with hypercholesterolemia. Primary outcomes were changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides. Secondary outcomes included other lipid parameters, adverse events and mortality. Random-effects models were used to calculate mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI). Quality of the included studies was assessed using the RoB2 tool and certainty of evidence was assessed using the GRADE approach.
Five randomised controlled trials (n = 4268) were included. Oral PCSK9 inhibitors significantly reduced LDL-C (MD −49.49 mg/dL; 95% CI −54.81 to −44.18; p < 0.00001) and triglycerides (MD −11.65 mg/dL; 95% CI −15.53 to −7.78; p < 0.00001). Significant reductions were also observed in non-HDL cholesterol, apolipoprotein B, lipoprotein(a) and total cholesterol. Dose-dependent effects were noted, with greater reductions at higher doses. No significant differences were observed in mortality or overall adverse events. Treatment discontinuation due to adverse events was lower with intervention.
Oral PCSK9 inhibitors were associated with clinically meaningful improvements in multiple lipid parameters while maintaining a favourable short-term safety profile. However, the available evidence is derived primarily from short-term randomised trials evaluating surrogate lipid outcomes. Larger randomised trials with longer follow-up and cardiovascular outcome data are needed to better define the long-term clinical role of oral PCSK9 inhibitors.
]]>Real-world glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies face substantial attrition rates in commercial digital weight loss services (DWLSs). Conversational artificial intelligence (AI) has been proposed to enhance patient support at production scale, but robust evidence of its effectiveness in improving medication retention is scarce.
To evaluate the effect of integrating an asynchronous AI patient support agent (Junebot) into a commercial DWLS on 6-month medication adherence and to assess the independent relationship of digital engagement on retention.
This retrospective analysis evaluated 16 556 adults prescribed semaglutide within an Australian DWLS between May 2024 and October 2025. The primary endpoint was 6-month medication adherence (≥ 6 orders fulfilled within 183 days). Analytical protocols featured a multivariate binary logistic regression on the full intention-to-treat cohort and three distinct 1:1 propensity score matching (PSM) sensitivity analyses to isolate era-based and tier-specific engagement effects.
Six-month adherence was higher post-Junebot than in the pre-Junebot control (53.2% vs. 47.3%; p < 0.001). However, the full cohort model (R
2 = 0.2236) revealed that the post-Junebot operational era was independently associated with an increase in the odds of attrition (OR: 1.178; 95% CI [1.052–1.318]; p = 0.004), a trend corroborated by the era-matched PSM model (OR of attrition: 1.309; p = 0.038). Non-automation factors dominated retention trajectories: high-intensity tracking during month 1 (> 25 tracks) dramatically predicted attrition (OR: 15.753; p < 0.001), alongside program pauses (OR: 2.508; p < 0.001) and higher program cost (OR: 2.458; p < 0.001). Within-cohort analysis demonstrated a profound, linear curve for active interaction; structured digital engagement spanning 50%–74.99% of weeks significantly optimised adherence odds across both medication-only (OR: 32.016) and medication plus health coaching cohorts (OR: 13.311).
Integrating an AI digital assistant did not independently improve medication adherence; programmatic costs, program pauses and initial tracking anxiety were stronger predictors of long-term retention. After matching post-Junebot cohorts, moderate, active digital engagement appeared to correlate with 6-month retention. Digital providers should prioritise proactive behavioural risk screening and financial accessibility over baseline AI integration.
]]>Financial constraints often limit healthy eating among individuals with Type 2 diabetes (T2D) and lower socioeconomic status (SES). Produce Prescription Programs (PRx), which provide financial support for healthy foods, have shown promise in the United States but remain understudied in Europe. This study assessed the feasibility of a 3-month PRx intervention among adults with T2D and low SES, and explored its potential effects on dietary intake, metabolic outcomes and quality of life.
In this 3-month RCT, conducted in primary care in Rotterdam, the Netherlands, adults with T2D, BMI > 25 kg/m2 and low SES were assigned to either PRx or usual care. Both groups received three dietitian consultations and were advised to follow a Mediterranean diet. PRx additionally provided weekly plant-based food boxes, cooking workshops and educational support. Feasibility outcomes included recruitment, retention, adherence and acceptability. Exploratory efficacy outcomes included nutritional intake, anthropometric measures, metabolic outcomes and quality of life at three and 6 months.
Seventy-seven individuals were screened and 35 participants (57.3 ± 11.8 years; 74% female; BMI 32.6 ± 6.0 kg/m2) were included, of whom 17 were allocated to PRx. Participants collected an average of 10.9 out of 12 food boxes (91%) and attended 1.8 out of 3 workshops (59%). Among the 11 participants (69%) who completed the evaluation questionnaire, satisfaction scores ranged from 4.3 to 4.7 out of 5. Exploratory between-group comparisons favoured the PRx group for dietary intake, weight, BMI and physical quality of life, while no clear differences were observed for glycaemic outcomes. These findings were supported by favourable within-group changes in dietary and anthropometric outcomes in the PRx group, several of which appeared to be maintained at 6-month follow-up.
This pilot RCT demonstrates that a 3-month PRx intervention providing plant-based food boxes is feasible and acceptable among adults with T2D and low SES. As the first European RCT evaluating a PRx intervention in this population, it provides preliminary evidence of potential benefits for dietary, anthropometric and quality of life outcomes, warranting further investigation in adequately powered trials.
Trial Registration: OMON: NL-OMON57037; 8 October 2024
]]>Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved in the US for the treatment of Type 2 diabetes (T2D), weight loss and obstructive sleep apnoea. This study aimed to assess the utilisation and effectiveness of tirzepatide among individuals in a large US commercially insured population.
This retrospective, observational study used administrative claims and electronic health records from the Healthcare Integrated Research Database (HIRD). Adults with ≥ 1 prescription claim for tirzepatide (for obesity/overweight, without T2D), between November 2023–June 2024 and continuous medical/pharmacy enrollment for ≥ 12 months pre-index and ≥ 6 months post-index were included. Descriptive analyses included baseline demographic and clinical characteristics, treatment patterns and tirzepatide effectiveness (change from baseline in weight, BMI, cardiometabolic risk factors evaluated among persistent individuals) and were stratified by individuals who were GLP-1 RA naïve and individuals who switched to tirzepatide from a GLP-1 RA obesity medication.
Of the 22 512 individuals who initiated tirzepatide (mean age: 46 years, 73% female), 55% (n = 12 292) were adherent (PDC ≥ 80%) and 68% (n = 15 208) were persistent during the 6-month follow-up period. Of the overall population, 91% (n = 20 554) had ≥ 1 obesity-related complication at baseline, with dyslipidaemia, hypertension and anxiety being the most frequent complications. Clinically meaningful mean weight reduction (10.5%; n = 808) and numerical reductions in most cardiometabolic risk factors were observed among persistent individuals with available pre- and post-index measurements, including 12.0% body weight reduction in the GLP-naïve subgroup.
Over half of US adults with obesity or overweight who initiated tirzepatide were adherent (PDC ≥ 80%) and had a favourable persistence profile during a 6-month follow-up period. Persistent users achieved clinically meaningful weight reduction and numerical reductions in most cardiometabolic risk factors.
]]>Animal models of prediabetes (Pre-DM) are essential for studying metabolic disease and testing therapies, yet high-fat diet (HFD) and HFD-plus-streptozotocin (STZ) protocols vary in feeding duration, STZ dose, and diagnostic criteria and rarely account for sex. We compared five protocols in male and female C57BL/6J mice to find the best balance of duration, cost, and phenotypic stability and to characterize how HFD and HFD-STZ differ in their effects on glucose and lipid metabolism.
Five-week-old mice were stratified by sex and assigned to three HFD-only groups (HFD-12w, -16w, -20w) and two STZ groups of differing cumulative dose (HFD-STZ-L, -H). Body weight, food and energy intake, body fat percentage, fasting blood glucose (FBG), OGTT, ITT, fasting insulin, serum lipids, hepatic Oil Red O, histopathology, liver and kidney safety, and per-animal cost were assessed.
HFD induced obesity of equal magnitude in both sexes (non-significant Sex × Diet interactions for body weight and fat mass). Glucose and hepatic-lipid metabolism showed clear sex dimorphism: in males these deteriorated by Week 12, whereas females required 16 weeks to reach the Pre-DM threshold, at a higher preset STZ dose. HFD-STZ-L matched HFD-12w in both sexes within a shorter cycle (overall success 73.3%). Notably, STZ reversed the HFD lipid phenotype, synchronously reducing body fat, serum lipids, and hepatic fat in females.
HFD-STZ-L is preferred for glucose and β-cell studies in both sexes; HFD-12w preserves the intact female obesity phenotype; HFD-20w is preferred for MASLD studies. Biological sex must be incorporated into model design and phenotype interpretation.
]]>While Type 2 diabetes mellitus (T2DM) is a known risk factor for cognitive decline, it remains unclear whether comorbid obesity merely parallels or synergistically correlates with this trajectory. We aimed to disentangle the specific neurotoxic impacts of adiposity from chronic hyperglycemia on cortical structure and function.
In this cross-sectional study, 102 matched participants (obese T2DM [n = 31], normal-weight T2DM [n = 40] and healthy controls [n = 31]) underwent high-resolution multimodal MRI, specifically Surface-Based Morphometry (SBM) and 2D-Regional Homogeneity (ReHo), to evaluate cortical thickness, area, and network synchronization.
Our analyses revealed that the obese T2DM cohort exhibited profound structural and functional vulnerability compared to normal-weight peers. High body mass index (BMI) robustly predicted severe cortical thinning in frontal-reward circuits and widespread functional dyssynchrony within the default mode network. Furthermore, SBM captured localized morphometric increases in the fusiform gyrus unique to obese T2DM patients, which we hypothesize may reflect an early, reactive phase of neuroinflammation. Crucially, chronological disease duration showed no significant correlation with these metrics.
Adiposity is profoundly associated with structural and functional neural disruption in T2DM. Comorbid obesity represents a prominent risk factor associated with brain morphometric patterns resembling advanced aging, highlighting the potential clinical importance of early weight management for neuroprotection.
]]>To evaluate and recalibrate commonly used 10-year cardiovascular disease (CVD) risk prediction models in two Chinese cohorts: the general population and adults with type 2 diabetes.
We analysed data from the Wuzhong subcohort of the China Kadoorie Biobank (CKB) and the Jiangsu Biobank for the Prevention and Control of Diabetes (JBPCD). After excluding participants with baseline CVD, baseline diabetes in CKB or missing predictors, 42 937 CKB participants and 14 125 JBPCD participants were included. We evaluated CKB-CVD, Globorisk, Framingham General CVD and WHO 2019 in both cohorts, and SCORE2-Diabetes in JBPCD. Performance of original and recalibrated models was assessed by 10-year inverse probability of censoring weighting (IPCW) C-statistic, calibration measures including the expected-to-observed (E/O) event ratio and Brier score. In JBPCD, overlap in high-risk classification was examined using a 20% predicted 10-year risk threshold.
During a median follow-up of 11.96 years in the general population cohort and 10.03 years in the type 2 diabetes cohort, 3740 and 2794 ischemic heart disease or stroke events occurred, with 10-year risks of 6.04% and 19.72%, respectively. Discrimination was higher in the general population cohort than in the type 2 diabetes cohort (C-statistic 0.723–0.778 vs. 0.584–0.629). Original models were poorly calibrated, with systematic overprediction in the general population cohort (E/O 1.47–3.78) and heterogeneous miscalibration in the type 2 diabetes cohort (E/O 0.32–2.70). Recalibration markedly improved calibration and reduced Brier scores, with little change in discrimination. In the type 2 diabetes cohort, recalibrated CKB-CVD classified 48.4% as high risk, with an observed 10-year risk of 25.7%.
Widely used 10-year CVD risk models showed acceptable or modest discrimination but substantial miscalibration in Chinese populations, especially among adults with type 2 diabetes. Recalibration is essential before threshold-based clinical or public-health use.
]]>Chronic kidney disease (CKD) remains a leading complication of diabetes, and understanding population-level trends is crucial for prevention and healthcare planning. We examined national trends in CKD prevalence, incidence, and mortality among people with diabetes.
In this nationwide register-based cohort study, we identified people with diabetes in Denmark between 2016 and 2024 using linked national registers. CKD was defined by ≥ 2 measurements of estimated glomerular filtration rate < 60 mL/min/1.73 m2 and urinary albumin–creatinine ratio ≥ 30 mg/g, or a hospital diagnosis or procedure code. Annual CKD prevalence was calculated on 1 January each year. CKD incidence and mortality rates were calculated annually and reported per 1000 person-years (PY), separately for type 1 diabetes (T1D) and type 2 diabetes (T2D) and stratified by sex and age.
Between 2016 and 2024, CKD prevalence increased from 20.5% to 26.4% in T1D and from 24.8% to 37.3% in T2D. CKD incidence declined from 21.5 to 14.9 per 1000 PY in T1D and from 55.3 to 43.7 per 1000 PY in T2D, with the largest reductions in older people (aged ≥ 70 years with T2D [93.6 to 74.3 per 1000 PY]). Albuminuria prevalence increased, whereas incidence declined in both diabetes types. Mortality declined in people with and without CKD but remained substantially higher among those with CKD.
From 2016 to 2024, CKD incidence declined while prevalence increased among people with diabetes in Denmark. Mortality remained high among people with CKD, highlighting the ongoing clinical burden and need for improved prevention and early detection.
]]>The association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and the development of bowel obstruction/ileus remains unclear, and evidence for specific bowel obstruction/ileus subtypes remains limited. We examined the association between GLP-1RA use and the incidence of bowel obstruction/ileus subtypes across different subgroups of individuals.
Using the commercially available Japanese administrative claims DeSC database, we identified individuals aged ≥ 18 years with type 2 diabetes who newly initiated either GLP-1RAs or sodium-glucose cotransporter 2 inhibitors (SGLT2is) between April 2016 and February 2024. An active-comparator new-user design was adopted, designating GLP-1RA users as the exposure group and SGLT2i users as the control group. The primary outcome was bowel obstruction/ileus requiring tube decompression or surgery within 1 year. Secondary outcomes included specified small bowel obstruction, small bowel obstruction requiring surgery, paralytic ileus and colonic volvulus. Inverse probability weighting with propensity scores was used to adjust for confounding. Adjusted cumulative incidence was estimated using Kaplan–Meier methods; hazard ratios were estimated using Cox regression.
Among 298 124 eligible individuals, 25 779 and 272 345 were classified into the GLP-1RA and SGLT2i groups, respectively. The adjusted 1-year incidence proportion of the primary outcome did not significantly differ between groups (0.14% vs. 0.17%; difference −0.03%, 95% confidence interval (CI), −0.10% to 0.04%; hazard ratio 0.80, 95% CI, 0.52–1.24). No significant between-group differences were observed for the secondary outcomes.
GLP-1RA initiation in individuals with type 2 diabetes was not associated with an increased risk of bowel obstruction/ileus compared with SGLT2i initiation.
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