BACKGROUND: Advanced biliary tract cancer (BTC) has a poor prognosis with limited options. Gemcitabine–cisplatin (Gem/Cis) is standard first-line therapy, but outcomes remain suboptimal. This meta-analysis evaluated the...BACKGROUND: Advanced biliary tract cancer (BTC) has a poor prognosis with limited options. Gemcitabine–cisplatin (Gem/Cis) is standard first-line therapy, but outcomes remain suboptimal. This meta-analysis evaluated the efficacy and safety of adding paclitaxel complex to Gem/Cis (Gem/Cis/P) in advanced BTC. METHODS: The PROSPERO-registered protocol (CRD420251177440) guided searches of PubMed, EMBASE, Cochrane Library, and Web of Science for clinical studies on Gem/Cis/P in BTC. Three reviewers independently selected studies, extracted data, and assessed quality. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a fixed-effects model when heterogeneity was low (I² ≤ 50% and p ≥ 0.1), otherwise a random-effects model was applied. All analyses were conducted with RevMan 5.3. RESULTS: Ten studies (1,401 patients) were included; four controlled studies (739 patients) were meta-analyzed. Compared with Gem/Cis, Gem/Cis/P significantly improved response rates: objective response rate (OR = 1.51; 95% CI: 1.08 ~ 2.11; p = 0.02), disease control rate (OR = 1.47; 95% CI: 1.04 ~ 2.08; p = 0.03), and partial response (OR = 1.77; 95% CI: 1.1 ~ 2.62; p = 0.005). However, no significant differences were observed in overall survival (HR = 0.86; 95% CI: 0.71 ~ 1.03; p = 0.11) or progression-free survival (HR = 0.86; 95% CI: 0.73 ~ 1.02; p = 0.08). Grade ≥ 3 adverse events were significantly higher with triplet therapy (OR = 1.79; 95% CI: 1.27 ~ 2.51; p = 0.0008), particularly neutropenia (OR = 1.65; 95% CI: 1.19 ~ 2.28; p = 0.003). CONCLUSION: Adding paclitaxel to gemcitabine–cisplatin improves response rates but not survival in advanced BTC, with increased toxicity. These findings highlight the need for careful patient selection and validation in large-scale trials.
PURPOSE: Osimertinib displays substantial inter-individual variability in both pharmacokinetics and pharmacodynamics. This study aimed to explore the exposure-response relationship of osimertinib, thereby to provide a ba...PURPOSE: Osimertinib displays substantial inter-individual variability in both pharmacokinetics and pharmacodynamics. This study aimed to explore the exposure-response relationship of osimertinib, thereby to provide a basis for personalized therapeutic strategies. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, and China Biology Medicine Literature Database separately through October 2024, with no study type restrictions. The Newcastle-Ottawa Scale was used for quality assessment, and data were extracted and recorded using Excel software. The meta-analysis was conducted using Stata software. RESULTS: A total of nine observational studies were included. Among them, five studies identified a correlation between steady-state trough concentration and progression-free survival, with three specifically demonstrating that the low steady-state trough concentration group had longer progression-free survival. One study observed a negative correlation between clearance and overall survival via Cox proportional hazards regression. Additionally, several studies reported correlations between exposure and adverse events, though conclusions varied substantially across studies. CONCLUSION: Multiple studies demonstrated that lower osimertinib steady-state trough concentration correlated with longer progression-free survival in Non-Small-Cell Lung Cancer, challenging the conventional assumption that higher drug exposure directly translates to superior efficacy. No consistent overall survival association exists. The relationships of adverse events remain unclear due to inconsistent study outcomes. These findings highlight the need for personalized dosing strategies through further research.
OBJECTIVE: This study aimed to establish a population pharmacokinetic (PPK) model of trimethoprim-sulfamethoxazole (TMP/SMZ) in critically ill patients from Hainan, to identify key determinants of drug exposure, and to p...OBJECTIVE: This study aimed to establish a population pharmacokinetic (PPK) model of trimethoprim-sulfamethoxazole (TMP/SMZ) in critically ill patients from Hainan, to identify key determinants of drug exposure, and to provide a basis for individualized dosing optimization. METHODS: Twenty-eight ICU patients receiving TMP/SMZ therapy were enrolled. Plasma concentrations of TMP, SMZ, and the metabolite N-acetyl-sulfamethoxazole (NSMZ) at steady state were quantified using LC-MS/MS. Demographic characteristics, clinical laboratory indices, and genotypes of NAT2, CYP2C9*3, and GCLC were collected as key covariates. PPK modeling was performed using NONMEM 7.4. We compared one-compartment and multi-compartment structural models and assessed the influence of covariates on pharmacokinetic parameters. The final model was validated through multiple approaches, including goodness-of-fit (GOF) plots, normalized prediction distribution errors (NPDE), prediction-corrected visual predictive checks (pcVPC), and nonparametric bootstrap analysis. Monte Carlo simulations were then conducted to evaluate target attainment rates and toxicity risks of TMP, SMZ, and NSMZ under different dosing regimens. RESULTS: TMP pharmacokinetics were best described by a one-compartment model with first-order absorption, and no significant covariates were identified for interindividual variability. SMZ and its metabolite NSMZ were also fitted with one-compartment models. Covariate analysis indicated that body weight significantly influenced SMZ clearance (CL, P < 0.01), while the CYP2C9*3 genotype significantly affected NSMZ CL (P < 0.001). Model diagnostics showed good fit in GOF plots, with NPDE and pcVPC indicating stable predictive performance, and bootstrap success rate reached 100%. Monte Carlo simulations revealed that conventional dosing could result in TMP and NSMZ concentrations exceeding toxicity thresholds in some patients, whereas SMZ concentrations often remained below therapeutic levels. Considering both efficacy and safety, simulations suggested that 960 mg TID or 1440 mg BID regimens provide an optimal balance for TMP, SMZ, and NSMZ concentrations, supporting subsequent individualized dosing strategies. CONCLUSION: This study is the first to establish a PPK model of TMP/SMZ, including the metabolite of SMZ, in critically ill patients from Hainan, China. Body weight and CYP2C9*3 genotype were identified as key covariates influencing drug exposure, indicating that genetic information should be considered in individualized dosing. The findings provide a theoretical basis for optimized TMP/SMZ use in special populations and offer methodological and data support for future model-informed precision dosing (MIPD) applications.
PURPOSE: Liver cirrhosis is a chronic disease that can change the pharmacokinetics of many drugs. Physiologically-based pharmacokinetic (PBPK) modeling and simulation can help in predicting the disposition of many drugs...PURPOSE: Liver cirrhosis is a chronic disease that can change the pharmacokinetics of many drugs. Physiologically-based pharmacokinetic (PBPK) modeling and simulation can help in predicting the disposition of many drugs in special populations, including cirrhosis. Limited information is available on statins (simvastatin, rosuvastatin, and atorvastatin) and warfarin doses in cirrhosis. This study aims to use PBPK modeling to provide some guidance on the optimal doses of these medications in cirrhotic patients. METHODS: Initially, the developed PBPK models were evaluated against available clinical pharmacokinetic data from healthy subjects and patients with cirrhosis. Subsequently, simulations were extrapolated to predict drug exposures in various untested cirrhosis populations, stratified by Child–Pugh classes A, B, and C. Dose adjustments for cirrhotic patients were evaluated to achieve unbound drug exposures equivalent to those observed in healthy volunteers. RESULTS: The models effectively captured the pharmacokinetics of the studied drugs in healthy populations within an acceptable 2-fold range. The models indicated gradual increases in unbound drug exposure with disease progression. The simulation results suggested decreasing doses of simvastatin, rosuvastatin, and atorvastatin by approximately 61%, 65%, and 70% in CP-A, 85.5%, 76%, and 84% in CP-B, as well as 93.5%, 85%, and 92% in CP-C to match healthy exposure levels. Additionally, warfarin doses can be reduced by 33.3% and 66.6% of the healthy dose in CP-B and CP-C, respectively. CONCLUSION: PBPK models can help in predicting statins and warfarin disposition in patients with cirrhosis, aiding in clinical study design and expanding therapeutic options for those patients.
PURPOSE: To demonstrate how Model-Informed Precision Dosing (MIPD) enables the transition from empirical discontinuation to precise, safe, and rational treatment resumption, as illustrated by the management of a substant...PURPOSE: To demonstrate how Model-Informed Precision Dosing (MIPD) enables the transition from empirical discontinuation to precise, safe, and rational treatment resumption, as illustrated by the management of a substantial binimetinib overdose in a frail elderly patient. METHODS: We present the case of an 80-year-old female (50 kg) with BRAF V600R-mutated metastatic melanoma who inadvertently received 135 mg of binimetinib twice daily (270 mg/day) instead of the recommended 45 mg twice daily. In the absence of overdose guidelines, a multidisciplinary workflow integrating pharmacovigilance assessment and model-informed simulations was initiated. A population pharmacokinetic model of binimetinib was used to simulate the patient-specific washout and estimate the optimal timing for therapy resumption at the median steady-state trough concentration (Cmin, ss). A virtual population (n = 10,000) receiving the standard regimen was simulated, excluding the 5th and 95th percentiles to remove aberrant predictions. RESULTS: Aside from bilateral subretinal fluid not requiring discontinuation, no acute dose-limiting toxicities were observed. Simulations estimated a target median Cmin, ss of 103.1 µg/L (CV 47.8%; range 16.8–230.0 µg/L). The patient’s predicted time to return within this exposure target was ~ 37 h after the first overdose. Treatment was resumed at 36 h, omitting one scheduled dose. Measured binimetinib concentration at resumption was 52 µg/L, within the predicted variability range. The patient tolerated reinitiation, ocular findings resolved completely within two weeks. CONCLUSION: This case illustrates that MIPD provides a rational alternative to empirical prolonged discontinuation after medication errors. By quantifying exposure and variability, therapy resumption was optimized in a frail patient with high oncologic risk.
Hamzah KA, Kurmasha YH, Shweliya MA
… +10 more, Al-Shammari AS, Alsaadany KR, Nofal AA, Al-Ibraheem AMT, Al Sakini AS, Jena N, Naz S, Syed M, Demede M, Sattar Y
BACKGROUND: Acute ischemic stroke (AIS) carries high risks of recurrence, disability, and death despite standard therapy. The role of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to pro...BACKGROUND: Acute ischemic stroke (AIS) carries high risks of recurrence, disability, and death despite standard therapy. The role of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to provide cardiovascular benefits, but their role in the acute neurovascular phase of AIS remains uncertain. METHODS: We systematically searched PubMed, MEDLINE, Embase, Web of Science, and the Cochrane Library from inception to August 31, 2025, for studies initiating PCSK9 inhibitors during hospitalization or within 14 days of AIS symptom onset. Primary outcomes were early recurrent stroke/transient ischemic attack (TIA) within 30 days, early neurological deterioration (END) within 7 days, and functional independence (modified Rankin Scale [mRS] ≤ 2 at 90 days). Pooled risk ratios (RRs) and mean differences (MDs) were calculated using fixed-effect models when statistical heterogeneity was low (I² ≤50%) and random-effects models when heterogeneity was substantial (I² >50%). This review was prospectively registered in PROSPERO (CRD420251144202). RESULTS: Five studies (n = 1,842) met eligibility criteria. Early PCSK9 inhibitor use was associated with a lower risk of recurrent stroke/TIA (5 studies, n = 1,842; RR 0.38, 95% CI 0.26–0.54; I²=45.5%; low certainty), all cause mortality (3 studies, n = 1,061; RR 0.48, 95% CI 0.30–0.77; I²=0%; low certainty), and early neurological deterioration (2 studies, n = 533; RR 0.56, 95% CI 0.36–0.88; I²=0%; low certainty), and was associated with a higher likelihood of functional independence (mRS ≤ 2 at 90 days) (2 studies, n = 533; RR 1.31, 95% CI 1.15– 1.50; I²=0%; very low certainty). LDLC was significantly reduced (5 studies, n = 1,842; MD − 0.91 mmol/L, 95% CI − 1.26 to − 0.57; I²=93%; very low certainty). The certainty of evidence was downgraded primarily due to the risk of bias in included studies and imprecision. CONCLUSIONS: Early initiation of PCSK9 inhibitors after AIS was associated with a higher likelihood of favorable short-term clinical outcomes and substantial LDL-C reduction. These findings suggest that PCSK9 inhibitors may confer neurovascular benefits, warranting confirmation in larger trials.
Jia M, Chai Y, Gao Y
… +10 more, Jing C, Zhu K, Zhu T, Wang L, Sun A, Yang J, Zhu Y, Feng Y, Cao Y, Li J
Eur J Clin Pharmacol
· 2026 Mar · PMID 41874642
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PURPOSE: Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahe...PURPOSE: Rivaroxaban, a new direct oral anticoagulant (DOAC), has demonstrated better efficacy and safety than traditional anticoagulants. Individualized anticoagulation is crucial in patients with a transjugular intrahepatic portosystemic shunt (TIPS) and portal vein hypercoagulability to avoid stent thrombosis. As TIPS shunts portal blood directly into the systemic circulation and may substantially affect the first-pass extraction/distribution of direct oral anticoagulants, no population prospective pharmacokinetic studies have been published in patients undergoing TIPS placement so far. The goal of this study was to establish a PopPK model for rivaroxaban in post-TIPS patients, investigate clinical covariate effects on PK, and provide an optimized dosing regimen. METHODS: In this single-centre prospective study, 39 adult patients underwent TIPS and received rivaroxaban 5 or 10 mg once daily thereafter. Population PK analysis was conducted in NONMEM with 131 plasma concentrations available from 38 evaluable patients (median age: 56 years; median body weight: 63.8 kg). Parameterized model was then applied to simulate steady-state exposure of 5, 7.5, 10, and 15 mg once daily regimen. RESULTS: The final PopPK model was based on a one-compartment with sequential zero-order followed by first-order absorption kinetics, and included the effects of an absorption lag time and linear elimination. The apparent clearance and volume of distribution were 7.48 L/h and 4.75 L, respectively. Based on patient-specific simulations of 38 subjects, at the 5 mg/day dose, an exposure within predefined limits was potentially preserved in 96.7% of the cases vs. 62.5% for the 10 mg/day (thresholds: AUCss,24 ≤ 1.77 mg·h/L and Cmax, ss ≤ 140 µg/L). This trend was confirmed by Monte-Carlo simulations in 1,000 virtual patients and suggests TDM when the higher dosage is given. CONCLUSIONS: This PopPK model provides an initial characterisation of rivaroxaban disposition in post-TIPS patients and reveals a markedly reduced apparent V/F relative to non-TIPS populations. The 5 mg once-daily regimen is generally safe, while the 10 mg dose may be considered with therapeutic drug monitoring to account for substantial inter-individual pharmacokinetic variability in post-TIPS patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR (ChiCTR2300073784); registered 20 July 2023.
Pharmacometrics, as the core discipline of model-informed drug development paradigm, quantitatively characterizes drug exposure-response dynamics using mathematical models. However, its traditional methodology, represent...Pharmacometrics, as the core discipline of model-informed drug development paradigm, quantitatively characterizes drug exposure-response dynamics using mathematical models. However, its traditional methodology, represented by nonlinear mixed-effects modeling, is inherently resource-intensive and often struggles to fully capture complex biological variability. The rapid advancement of artificial intelligence technologies offers a transformative data-driven paradigm, providing superior efficiency and predictive accuracy. Yet, the artificial intelligence approaches suffer from the “black box” constraint. This review detailed the deep, complementary integration of artificial intelligence and pharmacometrics, demonstrating how this synergy is necessary to satisfy the complex, triple demands of accuracy, efficiency, and regulatory explainability. We systematically explored innovative applications across the entire pharmacometrics workflow, including model optimization, covariate screening, virtual population generation, etc. In each section, we also presented specific application cases or workflows. Furthermore, we outlined current challenges in the implementation of artificial intelligence and proposed a vision for interdisciplinary and cross-institutional collaboration.
De Guio G, Wolf C, Petit-Jean E
… +7 more, Guendouz A, Vogel T, Bachellier P, Noll M, Couturier F, Michel B, Gourieux B
Eur J Clin Pharmacol
· 2026 Mar · PMID 41872387
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INTRODUCTION: Studies show that the medications patients take after being discharged from the hospital often do not match the prescriptions provided at discharge due to inappropriate changes made by patients or community...INTRODUCTION: Studies show that the medications patients take after being discharged from the hospital often do not match the prescriptions provided at discharge due to inappropriate changes made by patients or community healthcare professionals. AIMS OF THE STUDY: To involve a clinical medico-pharmaceutical team during the hospital stay of polymedicated surgical patients in reviewing chronic treatments in collaboration with general practitioners; to support patients post-discharge and ensure information is transmitted to community pharmacists and general practitioners; to assess the impact of this coordinated approach on treatment continuity 45 days post-discharge. METHOD: This is a prospective multicenter study. Included patients were aged ≥ 65 years, taking ≥ 3 medications for ≥ 3 months, and had a surgical stay of ≥ 1 day. Upon admission, medication reconciliation was performed, followed by a therapeutic review based on STOPP/START criteria, scientific society recommendations, and BEERS criteria. General practitioners were involved in this review process. At discharge, patients underwent medication reconciliation followed by phone calls (Day3, Day45). General practitioners and community pharmacists were informed of follow-up [Discharge = Day0, Day3 (pharmacists) and Day45]. RESULTS: Fifty-one patients completed the study [mean age 74.2 years ± 6.27 (standard deviation)]. Treatment reviews were performed in 39 patients (76.5%), with general practitioner involvement in 36 cases. Prescription re-evaluations applied 36 STOPP criteria, 13 START criteria, 9 scientific society recommendations, 9 internal hospital guidelines, and 28 clinical-pharmacological considerations. Average number of medications: Admission = 7.86 (3.05); Day0 = 7.12 (3.04); Day45 = 7.16 (3.04) [significant decreases between Admission and Day0 (p = 0.0011) and between Admission and Day45 (p = 0.0021)] and no significant changes between Day0 and Day45. BEERS medications: Admission = 1.69 (1.22); Day0 = 1.35 (1.16); Day45 = 1.35 (1.20) [significant decreases between Admission and Day0/Day45 (p = 0.0014)], and no significant changes between Day0 and Day45. CONCLUSION: This coordination model between hospital and community care, involving general practitioners during hospitalization, represents an innovative approach. It reaffirms the importance of interprofessional collaboration to ensure continuity of care from hospital admission to return home and through post-hospitalization follow-up.
BACKGROUND: Heart failure is a chronic and progressive condition affecting millions worldwide, often accompanied by psychological comorbidities such as depression and anxiety. These conditions adversely impact quality of...BACKGROUND: Heart failure is a chronic and progressive condition affecting millions worldwide, often accompanied by psychological comorbidities such as depression and anxiety. These conditions adversely impact quality of life, treatment adherence, and prognosis. Understanding how pharmacologic therapy influences mental health is essential for comprehensive care. METHODS: A scoping review was conducted using PubMed and other databases to identify studies published between 2000 and 2024 assessing the effects of heart failure treatments on depression and anxiety. Seventy studies, including randomized controlled trials and observational analyses, met the inclusion criteria. This scoping review was conducted in accordance with PRISMA-ScR guidelines. RESULTS: Findings revealed heterogeneous and often indirect associations between heart failure pharmacotherapies and mental health outcomes. Beta-blockers showed variable associations, with some studies reporting depressive symptoms potentially influenced by fatigue and sleep-related side effects. ACE inhibitors and ARBs have been associated with lower depression and anxiety symptom scores in some cohorts, though findings are heterogeneous and of uncertain clinical significance. ARNI therapy has been associated with improvements in quality-of-life measures that include mental health domains, while direct effects on depression and anxiety remain uncertain. Evidence for MRAs, diuretics, nitrates, and SGLT-2 inhibitors was limited or mixed, with mental health outcomes rarely assessed as primary endpoints. CONCLUSIONS: Current evidence suggests heterogeneous and largely non-causal associations between heart failure pharmacotherapy and mental health outcomes. Observed relationships may reflect improvements in heart failure symptoms and quality of life rather than direct neuropsychiatric effects. These findings underscore the importance of integrated psychocardiology approaches and highlight the need for heart failure–specific studies using standardized mental health endpoints.
PURPOSE: To quantitatively compare the effectiveness of serum creatinine- and cystatin C-based equations in population pharmacokinetic (PPK) models in predicting renal function for mycophenolic acid (MPA) clearance in pa...PURPOSE: To quantitatively compare the effectiveness of serum creatinine- and cystatin C-based equations in population pharmacokinetic (PPK) models in predicting renal function for mycophenolic acid (MPA) clearance in patients with autoimmune diseases. METHODS: In this single-centre retrospective study, 176 plasma samples from 37 adult patients (≥ 18 years) with autoimmune diseases who received mycophenolate mofetil were analysed. Renal function was estimated using creatinine clearance (Ccr) based on the Cockcroft-Gault equation and Chronic Kidney Disease Epidemiology Collaboration equation (creatinine-, cystatin C-, and creatinine+cystatin C-based). The PPK model was developed using Phoenix NLME 8.1 software. Model diagnostics were performed using goodness-of-fit plots, and the model adequacy was assessed using visual predictive check and bootstrap methods. RESULTS: Plasma MPA concentrations were modelled using a two-compartment model with first-order elimination and a transit compartment for the absorption process. In the PPK analysis, MPA clearance was most effectively explained by the Ccr. Moreover, Ccr and albumin levels were identified as covariates significantly influencing MPA clearance. CONCLUSION: For adults with autoimmune diseases, creatinine-based equations (particularly Ccr) are superior in predicting MPA clearance. Cystatin C levels reflect glomerular filtration alone, whereas creatinine is eliminated via both glomerular filtration and tubular secretion. Since creatinine and a major MPA metabolite are eliminated by tubular secretion, Ccr is the optimal covariate in this analysis. However, cystatin C-based equations may better explain MPA clearance in paediatric patients or older adults with low muscle mass. Therefore, selecting the appropriate renal function equation according to patient characteristics is crucial for optimal mycophenolate mofetil dosing.
BACKGROUND: Heart failure (HF) remains a major global burden. Vericiguat, a soluble guanylate cyclase stimulator, has been tested across HF phenotypes. Given mixed trial results, an updated synthesis is needed to clarify...BACKGROUND: Heart failure (HF) remains a major global burden. Vericiguat, a soluble guanylate cyclase stimulator, has been tested across HF phenotypes. Given mixed trial results, an updated synthesis is needed to clarify its role in HFrEF and HFpEF. METHODS: We systematically searched three databases for RCTs comparing vericiguat with placebo in heart failure. Endpoints included cardiovascular death, heart failure hospitalization, their composite, all-cause death, and safety events. Pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using random-effects models. RESULTS: Five RCTs (12,877 patients) met the inclusion criteria. In HFrEF, vericiguat reduced the composite of cardiovascular death or heart failure hospitalization (Three RCTs, 11,520 patients; HR 0.91; 95% CI 0.85–0.97) and achieved a significant reduction in cardiovascular death (Two RCTs, 11,155 patients; HR 0.88; 95% CI 0.79–0.99). Effects on all-cause death were not significant in HFrEF (Two RCTs, 11,155 patients; HR 0.90; 95% CI 0.80–1.01). Across HFpEF trials, which were short-duration and not powered for hard outcomes, effects were neutral, reflecting insufficient evidence rather than a definitive lack of benefit. In the overall population, safety analyses showed no increase in serious adverse events (Five RCTs, 12,850 patients; RR 0.95; 95% CI 0.89–1.00). Symptomatic hypotension was more frequent (Five RCTs, 12,850 patients; RR 1.20; 95% CI 1.07–1.34), consistent with the drug’s hemodynamic effects, whereas rates of syncope were unchanged. CONCLUSION: Vericiguat provides a modest but consistent reduction in cardiovascular death or HF hospitalization in HFrEF, with no effect on all-cause death. Evidence in HFpEF remains inconclusive due to limited trial duration and event rates. Safety is acceptable, with hypotension as the main adverse effect. These results support its use as an adjunct in selected HFrEF patients.
Falsetti L, Tarquinio N, Mucci L
… +7 more, Santini S, Guerrieri E, Giovenali L, Pierdomenico G, Zaccone V, Viticchi G, Moroncini G
Eur J Clin Pharmacol
· 2026 Mar · PMID 41811498
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BACKGROUND: Sodium-glucose transporter 2 inhibitors (SGLT2i) are widely used for diabetes management and have demonstrated benefits in treating acute and chronic heart failure (HF) and chronic kidney disease (CKD). Their...BACKGROUND: Sodium-glucose transporter 2 inhibitors (SGLT2i) are widely used for diabetes management and have demonstrated benefits in treating acute and chronic heart failure (HF) and chronic kidney disease (CKD). Their increasing application has revealed various side effects, although only a few are currently recognized as drug-related adverse events, based on ongoing observations. AIMS: This review synthesizes positive and negative side effects linked to SGLT2i and proposes management strategies. METHODS: A literature search of PubMed/EMBASE, Web of Science, and Google Scholar from the past 10 years identified randomized trials, meta-analyses, observational cohorts, and pharmacovigilance studies reporting SGLT2i-related events across genitourinary, endocrine, metabolic, hematologic, skeletal, and vascular domains. RESULTS: Data indicate an increased incidence of genital infections (GIs) in diabetic subjects, while associations with urinary tract infections (UTIs) are less consistent. Non-diabetic HF/CKD patients show modest increases in GIs and UTIs. SGLT2i modestly increase hematocrit and may reveal clonal erythrocytosis. Rare conditions like Fournier’s gangrene have been reported, though without a clearly increased risk in clinical trials: all the reported cases led to drug discontinuation. There is no conclusive evidence linking SGLT2i to fractures or osteoporosis, and risk of lower-limb amputation appears comparable to DPP-4 inhibitors, with some trend compared to GLP-1 receptor agonists, suggesting caution in patients with peripheral artery disease. Observational data suggest SGLT2i may protect against syncope and reduce acute kidney injury. CONCLUSIONS: Overall, SGLT2i are safe, with manageable adverse events such as GIs and UTIs. A thorough understanding of potential complications is essential for clinicians to optimize patients’ management.
PURPOSE: A systematic review was performed to assess the economic evaluation of sodium glucose transporters 2 (SGLT2) inhibitors vs GLP-1 receptor agonists (GLP-1RA) in treating type 2 diabetes. METHODS: The relevant stu...PURPOSE: A systematic review was performed to assess the economic evaluation of sodium glucose transporters 2 (SGLT2) inhibitors vs GLP-1 receptor agonists (GLP-1RA) in treating type 2 diabetes. METHODS: The relevant studies were searched in PubMed, Web of Science, Scopus, Embase, and Cochrane from the inception date to February 20, 2025. The titles, abstracts, and full texts were independently evaluated and screened by two authors. Additionally, the economic evaluation studies were assessed independently by two authors. RESULTS: 18 studies were included, evaluating oral semaglutide vs empagliflozin (n = 7), both oral semaglutide vs empagliflozin and subcutaneous semaglutide vs canagliflozin (n = 1), subcutaneous semaglutide vs empagliflozin (n = 4), liraglutide vs empagliflozin (n = 4), liraglutide vs dapagliflozin (n = 1), and subcutaneous semaglutide vs canagliflozin (n = 1). CONCLUSION: The results showed that when patients were assumed to receive initial therapies until HbA1c exceeded the target level and then treatment was intensified to basal insulin, GLP-1RA was cost-effective compared to SGLT2 inhibitors (semaglutide vs empagliflozin and liraglutide vs dapagliflozin). Empagliflozin demonstrated cost-effectiveness when the treatment with either empagliflozin or semaglutide would have continued indefinitely. Compared with empagliflozin, liraglutide may not be a cost-effective treatment option for patients with T2D who were not well-controlled with metformin.