BACKGROUND AND AIM:This network meta-analysis addresses the limited dose-specific comparative evidence by evaluating different doses of tirzepatide (TZP) versus dulaglutide (DULA) for glycemic control, weight loss, and safety in type 2 diabetes mellitus (T2DM). METHODS:Following PRISMA and Cochrane guidance, we searched major databases for RCTs comparing TZP and DULA in adults with T2DM. Efficacy outcomes included body weight change (Weeks 12 and 16) and mean HbA1c change (Weeks 12 and 24). Safety outcomes included mortality, cardiovascular events, and adverse events (AEs). SUCRA ranking was used and analysis performed in RStudio (v4.5.1). RESULTS:Four RCTs comprising 14,348 participants contributed to a seven-node network. However, Nicholls et al. 2025 had the majority of sample size (n = 13,165). TZP 15 mg achieved the greatest reduction in body weight at Week 16 (mean difference [MD] vs. TZP 5 mg: -2.68 kg; 95% CI -4.98 to -0.38), while TZP 1 mg (MD: 4.39 kg; 95% CI 1.28 to 7.51) and DULA 0.75 mg (MD: 3.10 kg; 95% CI 0.25 to 5.96) were associated with smaller reductions relative to TZP 5 mg. TZP 15 mg also produced the largest HbA1c reduction at Week 24 (MD vs. TZP 5 mg: -0.40%; 95% CI -0.62 to -0.19), compared with TZP 10 mg (MD: -0.23%; 95% CI -0.44 to -0.02) and DULA 1.5 mg (MD: 0.67%; 95% CI 0.25 to 1.09). No significant differences were observed between treatments for all-cause mortality or major cardiovascular events. Gastrointestinal AEs were more frequent with higher TZP doses, especially TZP 15 mg vs. TZP 5 mg for nausea, while serious AEs and severe hypoglycemia were similar across doses. CONCLUSION:Higher TZP doses potentially improve efficacy, while lower TZP/DULA doses enhance tolerability, supporting individualized T2DM care. However, these findings should be interpreted cautiously because several comparisons are indirect, many participants had not reached their maintenance dose, several safety outcomes were based on limited event counts, and significant inconsistency was observed for early body-weight outcomes.
INTRODUCTION:This study aims to develop a machine-learning-based risk prediction model for a long-term visual prognosis in patients with proliferative diabetic retinopathy (PDR) following pars plana vitrectomy (PPV). METHODS:We analysed 609 PDR patients (609 eyes) who underwent PPV at Shanxi Eye Hospital from January 1, 2022, to January 1, 2025. The dataset was randomly split into training and validation sets at an 8:2 ratio. Candidate risk factors were identified using LASSO regression, followed by multivariate logistic regression to determine independent predictors. Machine learning algorithms were then trained to construct the prediction model, with performance evaluated by AUC-ROC, accuracy, precision, recall, and F1 score. Calibration was assessed via calibration curves, and clinical utility by decision curve analysis (DCA). RESULTS:LASSO regression and multivariate logistic regression indicated that several factors influenced postoperative long-term visual prognosis. These included Renal Insufficiency (OR = 6.932, 95% CI: 3.394-14.158), Preoperative iris neovascularization (OR = 7.674, 95% CI: 3.699-15.920), Silicone oil tamponade (OR = 2.799, 95% CI: 1.641-4.707), Indirect bilirubin (IBIL) (OR = 0.902, 95% CI: 0.829-0.981) (p < 0.05). LightGBM was found to be the best for predicting postoperative long-term visual prognosis risk in PDR patients. The LightGBM model demonstrated good calibration in both training and validation sets. DCA of the validation set showed clinical net benefit at low-to-moderate risk thresholds, outperforming both 'treat-all' and 'treat-none' strategies. CONCLUSIONS:In conclusion, this study developed a machine learning-based prognostic model for long-term visual prognosis in PDR patients after PPV, visualized as a proof-of-concept web calculator to assist clinical staff in early risk identification and support personalised treatment planning, pending external validation and prospective evaluation.
PURPOSE:To explore the clinical value of adrenal venous sampling (AVS) and CXCR4-directed 68Ga-pentixafor PET/CT in the subtype diagnosis of primary aldosteronism (PA), with postsurgical blood pressure control and biochemical cure as primary endpoints, and to compare the accuracy and practicability of the two methods. METHODS:A retrospective cohort study was conducted in PA patients undergoing unilateral adrenalectomy at West China Hospital between February 2023 and June 2025. Patients were divided into the AVS and CXCR4 imaging groups. The primary outcome was the clinical and biochemical success rate according to the Primary Aldosteronism Surgical Outcome (PASO) criteria. In the subgroup with both procedures, AVS was considered the reference standard to assess the diagnostic efficacy of CXCR4. RESULTS:A total of 160 patients completed the trial. According to the PASO criteria, the total biochemical success rate was 93.1%, among which the complete biochemical success rate in the AVS group was 84.1%, and in the CXCR4 group it was 93.1% (p = 0.091); the total clinical success rate was 82.5%, with a complete clinical success rate of 40.9% in the AVS group and 30.3% in the CXCR4 group (p = 0.412). There were no statistically significant differences between the two groups. In 16 patients with both examinations, CXCR4 showed a sensitivity of 70.0%, specificity of 83.3%, accuracy of 75.0%, and moderate agreement with AVS. CONCLUSION:CXCR4 showed no statistical difference from AVS in diagnostic and prognostic outcomes in this study. However, discordance in multinodular disease indicates that molecular imaging cannot fully reflect the heterogeneity of aldosterone secretion. This finding requires verification in a larger cohort.
BACKGROUND:Obesity, a major global health issue, heightens the risk of cardiovascular diseases, including major adverse cardiovascular events (MACE), heart failure (HF) and myocardial infarction (MI). This study provides the first network meta-analysis (NMA) integrating direct and indirect evidence to compare the cardiovascular efficacy of bariatric surgery (BS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in individuals with obesity. METHODS:A systematic review and NMA were performed in adherence to PRISMA guidelines. PubMed, Embase, Cochrane Library and Google Scholar were searched for studies published from January 2000 to September 2024. Eligible studies reported cardiovascular outcomes, specifically MACEs, HF and MI, in patients with obesity receiving BS, GLP-1RAs or control treatment. Fixed- and random-effects models were used to analyse hazard ratios (HRs) and risk ratios (RRs), with heterogeneity assessed with I2 and consistency through node-splitting analysis. RESULTS:Forty-three studies involving 932,380 patients were included BS was associated with significantly greater reductions in MACEs (HR 0.66; 95% CI 0.60-0.74), HF (HR 0.45; 95% CI 0.38-0.53) and MI (HR 0.53; 95% CI 0.45-0.63) compared with controls in random-effects models. GLP-1RAs reduced MACEs (HR 0.85; 95% CI 0.77-0.94) but showed non-significant effects on HF and MI. Despite high heterogeneity (I2: 66%-93%), directional consistency was observed across studies. CONCLUSIONS:BS demonstrated more consistent and statistically significant reductions in all cardiovascular outcomes compared to GLP-1RAs, which showed more variable efficacy, particularly for HF and MI. Nevertheless, GLP-1RAs remain effective evidence-based alternatives for cardiovascular risk reduction in patients who are not candidates for surgery, but future studies on newer GLP-1RAs are required. The high heterogeneity across studies highlights the need for cautious interpretation. These results may inform individualized treatment selection in patients with obesity at high cardiovascular risk.
BACKGROUND:Commercial automated insulin delivery (AID) systems are increasingly used in pregnancies complicated by Type 1 diabetes, but the evidence is dispersed across trials, observational studies, case series and qualitative research. Existing syntheses have largely emphasised glycaemic efficacy and selected perinatal outcomes, with less attention to device platform, timing of initiation, psychosocial burden, clinician workload and implementation context. AIMS:To describe the protocol for a mixed-methods systematic review and meta-analysis evaluating the effectiveness, safety, feasibility, acceptability and implementation of commercial AID systems in Type 1 diabetes pregnancy. METHODS:MEDLINE, Embase, CINAHL, Scopus, Emcare, the Cochrane Library, CENTRAL and ClinicalTrials.gov will be searched from 1 January 2010, with an update search before final synthesis. Eligible evidence will include randomised and non-randomised comparative studies, observational cohorts, case series, qualitative studies and mixed-methods studies involving pregnant women with Type 1 diabetes using commercial AID systems, including off-label pregnancy use. Two reviewers will independently screen, extract and appraise studies and inter-rater agreement will be reported. Randomised and non-randomised comparative evidence will be synthesised separately and, where studies are sufficiently comparable, meta-analysed within study-design and comparator strata. Quantitative outcomes will include pregnancy-specific time in range, other continuous glucose monitoring (CGM) metrics, maternal and neonatal outcomes, diabetes-specific adverse events, psychosocial measures, cost, resource use, feasibility, implementation and early postpartum outcomes. Qualitative evidence will be synthesised thematically and integrated with quantitative findings using a convergent segregated approach. DISCUSSION:The review will clarify what is known about commercial AID use in Type 1 diabetes pregnancy and identify patient-, device-, clinician- and service-level factors relevant to implementation. TRIAL REGISTRATION:This systematic review protocol is registered with PROSPERO: CRD420251025194.
BACKGROUND AND AIMS:Diabetic foot ulcers (DFUs) can lead to amputation, especially when complicated by osteomyelitis (OM) or soft tissue infection. Although MRI is the standard imaging method, ultrasonography (US) is increasingly used because it is more accessible. This study compared the diagnostic performance of US and MRI in DFU-related infections. METHODS:In this descriptive cross-sectional study, consecutive adults with diabetes and suspected diabetic foot infection underwent both US and MRI. One ulcer per patient wasanalysed. US was compared with expert clinical assessment for cellulitis and with MRI for abscess and OM, following IWGDF recommendations. Diagnostic measures were calculated overall and by ulcer severity. RESULTS:Among 127 patients, most had advanced Wagner grades (3-5) and forefoot ulcers. Cellulitis was clinically present in all cases; MRI and US concordance with the clinical diagnosis was 100.0% and 99.2%, respectively. For abscesses, US showed 100% sensitivity but low specificity, resulting in moderate accuracy. For OM, US had very poor sensitivity (17.9%) despite high specificity, especially in severe ulcers. MRI detected no OM in moderate-grade ulcers. CONCLUSION:US showed near-complete concordance with MRI for cellulitis, though this was assessed in a study in which cellulitis was universally present, and US performs poorly for OM and cannot reliably exclude bone infection. It is best used as an initial triage tool, while MRI remains essential when OM is suspected. Because MRI is not a perfect reference standard, the findings reflect diagnostic concordance rather than absolute accuracy and support a tiered imaging approach.
INTRODUCTION:Interleukin (IL)-12 and IL-35 are heterodimeric cytokines that share the p35 subunit and have opposing inflammatory roles. Dysregulated IL-12/IL-35 p35 may reflect an imbalance between pro- and anti-inflammatory pathways linking metabolic dysfunction to cardiovascular risk in type 2 diabetes (T2D). However, the clinical significance of circulating IL-12/IL-35 p35 levels remains unclear. This study investigated the association between IL-12/IL-35 p35 levels and metabolic and atherogenic risk markers in T2D. METHODS:This cross-sectional study stratified 80 patients with T2D into Low and High IL-12/IL-35 p35 groups (n = 40/group) using a median split of plasma IL-12/IL-35 p35 (18.48 pg/mL). Laboratory parameters were measured using standard methods, and IL-12/IL-35 p35 concentrations were quantified by Enzyme Linked Immunosorbent Assay. RESULTS:Patients with High IL-12/IL-35 p35 had significantly elevated fasting glucose (p = 0.0318), triglycerides (p < 0.0001), triglyceride/HDL ratio (p < 0.0001), Triglyceride-Glucose (TyG) (p < 0.0001), and atherogenic index of plasma (AIP) (p < 0.0001). Circulating IL-12/IL-35 p35 levels positively correlated with triglycerides, AIP, Trig/HDL ratio and TyG index (all p < 0.0001), and negatively correlated with HDL (p = 0.0466). In the multiple linear regression analysis, IL-12/IL-35 p35 levels and TyG index (all p < 0.05) independently predicted atherogenicity after adjusting for glycaemic control. Receiver operating characteristic analysis demonstrated that IL-12/IL-35 p35 discriminated participants with high-risk AIP (AUC = 0.79, 95% CI: 0.68-0.89, p < 0.0001) and elevated TyG index (AUC = 0.78, 95% CI: 0.63-0.93, p = 0.0147). CONCLUSION:Elevated circulating IL-12/IL-35 p35 in T2D is associated with suboptimal glucose control and pronounced atherogenicity, suggesting altered activity within this immunoregulatory axis. These findings highlight the shared p35 subunit as a marker of immune imbalance and support its potential utility in identifying heightened atherogenic risk in T2D beyond the traditional markers. Future studies should directly quantify intact IL-12 and IL-35 to elucidate their individual contributions to the alteration of this immunoregulatory axis.
INTRODUCTION:Newborn screening (NBS) for congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21OHD) relies on elevated 17-hydroxyprogesterone (17OHP) levels but is limited by a high false-positive rate and difficulty in distinguishing classic from non-classic forms. To evaluate whether the suppression of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during mini-puberty can serve as an early biomarker of classic 21OHD. METHODS:We conducted a retrospective cohort study of 37 infants evaluated for suspected 21OHD between 2013 and 2025. Subjects were classified as classic (C), non-classic (NC), or false-positive (FP) based on biochemical and genetic confirmation. Neonatal serum LH and FSH levels were compared among groups, and receiver operating characteristic (ROC) analyses were performed. RESULTS:LH and FSH levels were significantly suppressed in classic 21OHD compared with NC and FP cases (p < 0.001). Gonadotropin concentrations demonstrated a stepwise pattern (C<NC<FP), although overlap limited the discrimination of non-classic disease. ROC analyses identified optimal cutoff values of 0.3 mIU/mL for LH (sensitivity 89.5%, specificity 83.3%) and 1.3 mIU/mL for FSH (sensitivity 94.7%, specificity 100%) for identifying classic 21OHD. Suppression was observed in both sexes and was particularly informative in male neonates. CONCLUSIONS:Suppressed LH and FSH levels during the neonatal period reflect the attenuation of mini-puberty and represent a characteristic endocrine feature of classic 21OHD. Gonadotropin measurement may provide a clinically accessible adjunct to NBS for the early identification of severe disease, particularly in male neonates and in the evaluation of 46,XX disorders/differences in sex development.
AIMS:The role of endogenous oestrogen exposure (EEE) in type 2 diabetes (T2D) remains understudied despite its potential importance. This study aimed to assess T2D incidence in women with different endogenous oestrogen durations. MATERIALS AND METHODS:At the initiation of the study, 6273 post-menarche women above 20 years were included. After applying the exclusion criteria, 3,411 women remained (2,754 premenopausal and 657 menopausal). Each woman's EEE was determined, and they were monitored for the incidence of T2D. Based on the EEE duration, hazard ratios (HRs) and 95% confidence intervals (CI) for the T2D event were reported using Cox proportional hazards regression models. RESULTS:The mean age and menarcheal age (standard deviation) of participants were 39.3(12.5) and 13.5(1.5) years, respectively. Finally, 30.9% (1053) of the women developed diabetes (819 (29.7%) premenopausal and 234 (35.6%) menopausal). The age and BMI-adjusted model's findings indicated that, overall, the EEE z-score was inversely associated with T2D incidence in postmenarcheal women [HR 0.91, 95% CI 0.85-0.97], meaning that the risk of T2D decreased by 9% for every 1-SD increase in the EEE z-score. Furthermore, after full adjustment for potential confounders, the association remained statistically significant (HR = 0.90, 95% CI: 0.84-0.96). CONCLUSIONS:The findings suggest that longer EEE duration may reduce the risk of T2D, emphasising the importance of reproductive history in health assessments.
BACKGROUND:Semaglutide and tirzepatide produce substantial weight loss during treatment, but the trajectory of weight regain after discontinuation remains uncertain. OBJECTIVE:To estimate post-discontinuation weight-regain trajectories and explore predictors of faster regain. METHODS:We used published timepoint-level aggregate data from studies evaluating weight change after discontinuation of semaglutide or tirzepatide to perform a Bayesian hierarchical longitudinal re-analysis. The model estimated weight loss at cessation, monthly regain rate, time to 50% regain, and time to return to baseline weight. Bayesian meta-regression examined medication type, magnitude of initial weight loss, and post-discontinuation behavioural or lifestyle support. Longer-term estimates assumed a constant linear regain rate. RESULTS:Six studies comprising 10 intervention arms and 1776 participants were included, with observed follow-up ranging from 4 to 52 weeks. Estimated weight loss at cessation was 15.35 kg (95% credible interval [CrI] 11.18-19.60), followed by regain of 1.04 kg/month (95% CrI 0.80-1.29). Based on the linear model, 50% of initial weight loss was projected to be regained by 7.50 months (95% CrI 5.05-10.57), with return to baseline weight by 15.00 months (95% CrI 10.10-21.13). Tirzepatide showed numerically faster regain than semaglutide in unadjusted analyses, but no clear independent drug-specific difference was evident after adjustment. Greater initial weight loss showed the strongest directional association with faster regain, although the credible interval included zero. Behavioural or lifestyle support was directionally associated with slower regain, but the estimate was imprecise. CONCLUSIONS:Weight regain after discontinuation of semaglutide or tirzepatide was rapid and clinically meaningful. Because estimates beyond 52 weeks were model-based extrapolations, they should be interpreted cautiously. Early monitoring and proactive maintenance planning may be warranted after treatment cessation.
BACKGROUND:The Omnipod 5 Automated Insulin Delivery (AID) System is safe and effective for individuals managing Type 1 diabetes (T1D). Longer-term studies may provide additional evidence of sustained effectiveness and safety of AID system use in T1D. METHODS:This 12-month extension study was conducted following a multicenter randomized controlled trial (RCT) where participants used either AID (Omnipod 5) or standard therapy (current non-automated pump therapy) for 13 weeks. Participants in France (n = 76) could transition to or continue with AID for an additional 12 months. Glycemic, safety, and psychosocial outcomes during or at the end of the extension phase were compared with baseline or end of RCT, as appropriate. RESULTS:Seventy-five participants enrolled in the extension phase. From RCT baseline to the end of the extension phase, time in range 70-180 mg/dL increased by 17.9% (p < 0.0001) or 4.3 h/day to 62.3%. Time above range > 180 mg/dL and mean sensor glucose decreased by 17.7% and 27.8 mg/dL (both p < 0.0001), respectively. HbA1c decreased from 8.33% to 7.18% (-1.14%; p < 0.0001). Glycemic improvements were maintained for those continuing with AID from the RCT intervention group and for those transitioning to AID from standard therapy. Diabetes Quality of Life-brief and Hypoglycemia Confidence Scale scores were maintained or improved at 6 and 12 months compared to RCT baseline. Adverse events were infrequent (12 per 100 person-years). CONCLUSIONS:Findings support the RCT results, demonstrating safety and sustained improvements in glycemic and psychosocial outcomes with the Omnipod 5 System in adults in France with T1D over 12 months. TRIAL REGISTRATION:ClinicalTrials.gov NCT05409131.
OBJECTIVES:Diabetes mellitus (DM) is a chronic metabolic disorder characterized by insulin resistance, impaired insulin secretion, and increased cardiometabolic and inflammatory burden. Zinc plays a key biological role in insulin synthesis, storage, signalling and antioxidant defence; however, the clinical relevance and consistency of zinc supplementation effects in diabetes remain uncertain. METHODS:A systematic search of PubMed/MEDLINE, Web of Science, Scopus, CINAHL and Google Scholar was conducted to identify randomized controlled trials (RCTs) assessing zinc supplementation in individuals with diabetes, gestational diabetes or prediabetes. RESULTS:Eighteen RCTs involving 1023 participants met the eligibility criteria. Zinc supplementation significantly increased plasma zinc concentrations (MD = 7.80; 95% CI 4.33 to 11.26) and improved insulin resistance, as reflected by reductions in serum insulin (MD = -2.50; 95% CI -4.69 to -0.31) and HOMA-IR (MD = -1.10; 95% CI -2.05 to -0.15). Total cholesterol decreased modestly but significantly (MD = -5.70; 95% CI -7.50 to -3.89), representing a relatively small absolute reduction, while LDL cholesterol showed a modest increase (MD = 3.46; 95% CI 1.48 to 5.43), although the clinical relevance of this finding remains uncertain. Inflammatory and oxidative stress markers improved, including reductions in C-reactive protein (SMD = -0.91; 95% CI -1.43 to -0.38) and malondialdehyde (SMD = -0.76; 95% CI -1.34 to -0.18), alongside an increase in total antioxidant capacity (SMD = 1.79; 95% CI 0.68 to 2.91). CONCLUSIONS:Zinc supplementation was associated with improvements in insulin resistance, inflammatory status and oxidative stress markers in individuals with diabetes. TRIAL REGISTRATION:International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42025638646.
INTRODUCTION:Vitamin D (vitD) plays a role in metabolic regulation, including lipid metabolism and insulin sensitivity. During pregnancy, profound physiological changes in lipid handling and ketogenesis occur to support fetal development. However, the extent to which maternal vitamin D status influences these metabolic adaptations and fetal metabolic markers remains unclear. METHODS:In this secondary analysis, we examined lipid distribution throughout pregnancy-from before 20 weeks' gestation to delivery-in women with overweight or obesity, stratified by vitamin D status (deficiency, insufficiency, or sufficiency), assessing both maternal and cord blood. Main inclusion criteria were: age > =18 years, singleton pregnancy, < 20 weeks' gestation, BMI ≥ 29 kg/m2. Women with GDM < 20 weeks' gestation were excluded. In total, 962 pregnant women were divided into vitD deficient (< 30 nmol/L, n = 102), insufficient (30-50 nmol/L, n = 222) and sufficient (> 50 nmol/L, n = 638) groups. VitD levels and lipid concentrations were assessed at < 20, 24-28 and 35-37 weeks' gestation and in cord blood. RESULTS:Compared with vitD sufficient women, women with vitD deficiency had significantly larger increases in LDL-C throughout pregnancy and ß-OH-butyrate at 24-28 weeks' gestation, in adjusted analysis. VitD in cord blood was highest in offspring of mothers with vitD sufficiency. In cord blood, significantly higher ß-OH-butyrate was observed with vitD deficiency; lipid concentrations were similar between groups. CONCLUSIONS:Early vitamin D deficiency before 20 weeks of gestation was associated with altered metabolic trajectories during pregnancy, including greater increases in LDL cholesterol and ketone body concentrations in women with overweight or obesity, as well as higher cord blood ketone levels in their offspring. These findings suggest that early maternal vitamin D status may influence maternal and fetal metabolic adaptations, although causal relationships and clinical implications require further investigation. TRIAL REGISTRATION:Trial registered at ISRCTN registry (https://doi.org/10.1186/ISRCTN70595832) trial number ISRCTN70595832. Registration date 02/12/2011.
BACKGROUND AND AIMS:Diabetic ketoacidosis (DKA) at type 1 diabetes diagnosis is common in low-resource settings and associated with prolonged hospitalisation. We aimed to identify determinants of time to discharge among children with new-onset DKA in Zambia. METHODS:We conducted a retrospective cohort study of children aged 0-16 years with newly diagnosed T1DM and DKA at the University Teaching Hospital, Lusaka (2018-2023). The primary outcome was time to discharge (days). We used Kaplan-Meier with log-rank tests and Cox regression. To address proportional hazards (PH) violation, we fitted a stratified Cox model (stratified by HbA1c, vomiting and DKA severity) for PH validation and a granulated Cox model with DKA severity (mild, moderate, severe) to estimate independent effects. PH was verified using Schoenfeld residuals. RESULTS:Among 353 children (mean age 8.3 years, SD 4.6), median stay was 5 days (IQR 4-8). Log-rank tests showed significant differences in discharge probability by DKA severity (χ2 = 70.32, p < 0.001) and vomiting (χ2 = 30.35, p < 0.001). In the granulated model, DKA severity was the strongest predictor of delayed discharge (moderate: HR = 0.01, p < 0.001; severe: HR = 0.01, p < 0.001), while infection was associated with faster discharge (HR = 1.51, p < 0.001). Ketonuria lost significance after DKA adjustment (HR = 0.90, p = 0.770), indicating a marker not an independent predictor. The stratified model confirmed PH satisfaction (global test χ2 = 5.62, df = 7, p = 0.584). Age, sex, polyuria, family history and residence were not significant. CONCLUSIONS:DKA severity is the strongest independent predictor of prolonged hospital stay in children with new-onset DKA. Ketonuria is a useful bedside marker but lacks independent effect beyond severity. Infection independently predicts faster discharge. These findings could inform risk stratification and resource allocation in similar settings.
INTRODUCTION:Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders arising from decreased insulin secretion and insulin sensitivity. Patients with T2DM take statins to prevent diabetic complications and mitigate mortality risk associated with this disease. Statins primarily function by blocking HMG-CoA, resulting in reduced cholesterol levels. Statins have been suggested to possess certain antidiabetic properties. However, the overall effects of statins remain controversial. The aim of this study was to investigate the mechanisms and triggering conditions for the development of statin-induced T2DM, despite their reported pleiotropic antidiabetic effects. METHODS:This paper is a narrative review. A thorough literature search was carried out across PubMed, Scopus and Google Scholar to identify studies relevant to the evaluation. RESULTS:In the cholesterol biosynthesis pathway (the mevalonate pathway), in addition to cholesterol, isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate are also produced. Inhibition of these metabolites largely mediates the diabetogenic action of statins. The effects of statins on insulin secretion appear to be largely independent of cholesterol. However, the inhibition of cholesterol synthesis in pancreatic beta cells reduces insulin secretion through impaired function of SNARE proteins and calcium channels. The most prominent effects of statins on insulin secretion and sensitivity are attributed to the suppression of isoprenoids, particularly Cdc42, Rac1 and Rab. Furthermore, studies have shown that statins directly affect the levels of some insulin-sensitivity-related factors, independent of the identification of isoprenoid-mediated pathways. CONCLUSIONS:Atorvastatin, simvastatin and rosuvastatin possess the most pronounced diabetogenic properties. In contrast, lovastatin, fluvastatin, pitavastatin and most notably pravastatin exert either neutral or advantageous effects with respect to glucose metabolism.
INTRODUCTION:Conventional single-agent drugs yield modest, plateauing weight loss and often lead to weight regain. Combination pharmacotherapy is a logical next step to target complementary pathways of weight control while reducing toxicity and treatment burden. This review synthesises mechanisms and clinical evidence for fixed-dose combinations, multi-agonist peptides, add-on regimens and multimodal strategies integrating pharmacotherapy with procedures. METHODS:We conducted a narrative review of clinical trials and observational studies on approved and emerging obesity pharmacotherapy combinations, focusing on mechanistic complementarity, efficacy, safety and practical implementation. Agents were mapped to three domains of energy homeostasis-homeostatic appetite regulation, hedonic-reward circuitry and peripheral metabolic effector pathways-to inform interpretation of combination strategies. RESULTS:Fixed-dose combinations such as phentermine-topiramate and naltrexone-bupropion yield greater weight loss than their individual components but also carry gastrointestinal, cardiovascular and neuropsychiatric risks. Multi-agonist peptides integrating GLP-1, GIP, glucagon, or amylin deliver double-digit weight loss and improve glycemic and cardiometabolic profiles, but increase the risk of gastrointestinal adverse events, requiring close monitoring. Add-on regimens that combine GLP-1 agonists with approved obesity medications or SGLT-2 inhibitors, and multimodal strategies that pair drugs with bariatric or endoscopic procedures, generally show additive rather than truly synergistic effects on weight loss. CONCLUSIONS:Available data suggest that combination pharmacotherapy can extend current approaches to precision obesity care, generally providing additive benefits alongside increased regimen complexity, costs and adverse-event risks. Thoughtful, phenotype-guided selection and comparative studies versus potent monotherapies, enriched by multi-omics and behavioural insights, may clarify which patients benefit most and sustainably from these strategies.
BACKGROUND:The atherogenic index of plasma (AIP) is a lipid-based indicator of cardiometabolic risk. We examined whether AIP is associated with prevalent type 2 diabetes mellitus (T2DM) and fasting blood sugar (FBS) in patients with premature coronary artery disease (PCAD) and explored whether this association differed across Iranian ethnic groups. METHODS:We analysed 2143 patients with angiographically confirmed PCAD from the Iran Premature Coronary Artery Disease (IPAD) study, of whom 1945 had valid AIP data. CAD was defined as ≥ 50% stenosis in the left main artery or ≥ 75% stenosis in another major coronary vessel. AIP was calculated as log10 (triglycerides/high-density lipoprotein cholesterol). Multivariable logistic regression was used to assess the association between AIP and prevalent T2DM, and generalized linear models were used to assess the association between AIP and FBS. RESULTS:In the fully adjusted model, including lipid-lowering medication use, participants in the highest AIP quartile had higher odds of prevalent T2DM than those in the lowest quartile (OR: 1.57; 95% CI: 1.14, 2.16; p = 0.005; P for trend = 0.002). Each 1-unit increase in AIP was associated with higher odds of prevalent T2DM (OR: 1.99; 95% CI: 1.26, 3.14; p = 0.003). Higher AIP was also associated with higher FBS; compared with the lowest quartile, the highest quartile had a 15.23 mg/dL higher FBS level in the fully adjusted model (95% CI: 7.61, 22.84; p < 0.001). In exploratory ethnicity-stratified analyses, the association was most evident in the Fars subgroup, while estimates in several smaller ethnic groups were imprecise. CONCLUSIONS:Higher AIP was associated with prevalent T2DM and higher FBS in patients with PCAD. Exploratory analyses suggested possible ethnicity-related heterogeneity, but these subgroup findings should be interpreted cautiously. Prospective studies are needed to determine whether AIP has predictive or clinical risk-stratification value in this population.
