BACKGROUND:Istradefylline, a selective adenosine A2A receptor antagonist, is approved as an adjunct to levodopa in Parkinson's disease, but its long-term effects on clinically meaningful outcomes are unclear. OBJECTIVE:We aimed to compare the association of istradefylline versus catechol-O-methyltransferase (COMT) inhibitors with mortality, treatment escalation, and disease progression in levodopa-treated Parkinson's disease. METHODS:We conducted a nationwide cohort study emulating a target trial using the DeSC claims database in Japan. Patients aged ≥50 years with levodopa-treated Parkinson's disease between 2014 and 2023 were included. Strategies were initiation of istradefylline versus COMT inhibitors. Primary outcomes were all-cause mortality, levodopa-equivalent daily dose (LEDD) escalation to ≥1100 mg, and dementia or psychosis. Secondary outcomes were fractures, cardiovascular events, pneumonia, and depression. Intention-to-treat and per-protocol effects were estimated using Cox models with propensity score-based overlap weighting. RESULTS:We identified 3190 istradefylline and 7986 COMT inhibitor initiators. In intention-to-treat analysis, istradefylline was associated with lower risks of mortality (hazard ratio [HR] 0.91; 95 % CI 0.84-0.99) and LEDD escalation (HR 0.83; 95 % CI 0.73-0.94). Associations were stronger in per-protocol analysis (mortality: HR 0.84, 95 % CI 0.72-0.97; LEDD escalation: HR 0.71, 95 % CI 0.59-0.84). Istradefylline was linked to higher fracture risk (intention-to-treat HR 1.13, 95 % CI 1.02-1.25; per protocol HR 1.23, 95 % CI 1.07-1.41). No differences were observed for dementia, psychosis, or other outcomes. CONCLUSIONS:Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A2A antagonists.

BACKGROUND:A subgroup analysis of the COVID-OUT trial's long-term outcome found that starting metformin within 3 days of coronavirus disease 2019 (COVID-19) diagnosis reduced post-COVID-19 condition (PCC) incidence by 63% in overweight or obese individuals. However, its generalizability remains uncertain. OBJECTIVES:To evaluate the effectiveness of metformin in preventing PCC in adults with overweight or obesity who had a recent COVID-19 infection. DESIGN:A retrospective cohort study using a sequential target trial emulation framework. DATA SOURCES:The United Kingdom primary care data from the Clinical Practice Research Datalink Aurum database from March 2020 to July 2023. PARTICIPANTS:Adults with overweight or obesity (body mass index ≥ 25 kg/m²) and a record of severe acute respiratory syndrome coronavirus 2 infection were included. Exclusions included metformin use in the prior year or metformin contraindications. MEASUREMENTS:The outcome was PCC, defined by a PCC diagnostic code or at least 1 World Health Organization-listed symptoms between 90 and 365 days after diagnosis, with no prior history of the symptom within 180 days before infection. The pooled hazard ratio and risk difference for the incidence of PCC were adjust for baseline characteristics. RESULTS:Among 624 308 patients, 2976 initiated metformin within 90 days of COVID-19 diagnosis. The 1-year risk difference for PCC in the intention-to-treat analysis was -12.58% (hazard ratio 0.36; 95% CI, 0.32-0.41), with consistent results in subgroup analyses. LIMITATIONS:Findings may not apply to individuals with a normal body mass index. CONCLUSIONS:Early metformin treatment in overweight or obese individuals may reduce PCC risk. Further research is needed to confirm causality and clarify metformin's role in PCC management.

AIM:Chemotherapy is given for early-stage breast cancer; however, some patients discontinue before completing all planned cycles. This study investigated the impact of early chemotherapy discontinuation on treatment outcomes. METHODS:This retrospective cohort study used a target trial emulation framework to conduct a causal analysis of the all-cause mortality impact of completing a standard course of chemotherapy. Early-stage breast cancer patients treated with chemotherapy in England between 01/01/2014 and 31/12/2015 were identified from the National Disease Registration Service and Systemic Anti-Cancer Therapy datasets. Five-year OS was estimated for patients completing greater than or equal to six chemotherapy cycles relative to discontinuing chemotherapy early (less than six cycles), representing standard treatment during the study period. A clone-censor-weight approach was used to account for time-related bias and baseline confounding. Absolute risk and hazard ratios (HRs) were calculated. RESULTS:A total of 10 253 patients were included: 68% (n = 7014) received greater than or equal to six chemotherapy cycles, and 32% (n = 3239) received fewer than six cycles. Individuals completing greater than or equal to six cycles showed superior 5-year OS compared with discontinuation less than six cycles (absolute risk difference -1.6, 95% confidence interval [CI], -3.2, -0.1; HR 0.85, 95% CI 0.74, 0.98). Subgroup analyses showed OS benefit in patients diagnosed at stage 2 relative to Stage 3 (HR 0.82, 95% CI 0.69, 0.98), ER+/HER2+ histology (HR 0.46, 95% CI 0.24, 0.96) and Non-White ethnicity (HR 0.56, 95% CI 0.34, 0.91) when receiving six cycles. CONCLUSION:Patients who completed greater than or equal to six cycles showed improved OS compared with those who discontinued before receiving six cycles. These findings support the identification and pre-emptive management of patients at high risk of discontinuing chemotherapy prematurely, to maximize treatment benefit.

AIM:To investigate the incidence of T2DM associated with finasteride and tamsulosin use in Chinese and UK populations. METHODS:Using the Exchange Xiamen PLatform Of Resident E-health Records (EXPLORER) database in China and the UK Biobank (UKB), this study included men aged 40-80 years diagnosed with benign prostatic hyperplasia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox models, incorporating overlap weighting. RESULTS:The EXPLORER cohort comprised 34,075 patients, with 21,399 untreated, 2,122 receiving finasteride monotherapy, 5,012 receiving tamsulosin monotherapy, and 5,542 receiving combination therapy. The UKB cohort comprised 11,905 patients, with 7,050 untreated, 492 receiving finasteride monotherapy, 3,105 receiving tamsulosin monotherapy, and 1,258 receiving combination therapy. Compared to patients receiving tamsulosin monotherapy, those receiving finasteride monotherapy showed a higher T2DM risk in the EXPLORER cohort (HR = 1.36 [95% CI: 1.15-1.60]), while no statistically significant association was observed in the UKB cohort (HR = 1.32 [95% CI: 0.96-1.82]). When compared to non-treatment, finasteride monotherapy was not associated with an elevated T2DM risk (EXPLORER: HR = 1.00 [95% CI: 0.89-1.13]; UKB: HR = 1.04 [95% CI: 0.77-1.41]), whereas tamsulosin monotherapy and combination therapy were associated with a reduced T2DM risk (EXPLORER: HR = 0.71 [95% CI: 0.64-0.80] and HR = 0.44 [95% CI: 0.40-0.49], respectively; UKB: HR = 0.67 [95% CI: 0.56-0.81] and HR = 0.45 [95% CI: 0.34-0.59], respectively). CONCLUSIONS:These findings suggest potential benefits of tamsulosin against T2DM and underscore the need for careful monitoring of T2DM risk in finasteride users.

Less than 20% of patients diagnosed with advanced lung cancer will survive beyond five years and half of these will suffer a serious adverse event (SAE) caused by systemic anticancer therapy (SACT) resulting in a hospital attendance. We applied counterfactual prediction models, grounded in causal inference, to estimate outcomes for hypothetical treatment scenarios. This approach was made possible using data linkage to gather necessary information on possible predictors and confounders. We aimed to develop and internally validate a risk prediction model for hospital admissions following the first dose of SACT in patients with advanced NSCLC. Adult patients diagnosed between 2016 and 2019 were included. Four treatment regimens were considered: Regimen A (double agent chemotherapy), Regimen B (chemotherapy + immunotherapy), Regimen C (immunotherapy), and Regimen D (single-agent chemotherapy). The outcome was any unplanned hospital admission within 30 days of SACT initiation. The cohort was developed by linking Hospital Episode Statistics, Cancer Registry, and SACT datasets. Model development involved multivariable logistic regression and counterfactual prediction methods. 20,076 patients were included, of whom 36% experienced the outcome. Logistic regression and penalised models both showed a modest AUC of 0.61. An ensemble machine learning approach did not outperform logistic regression. Counterfactual analysis showed that regimens A and C were associated with the lowest risk of hospital admission, while regimen D was linked to the highest risk. The LUCID score was made possible using data linkage, and provides a promising tool for predicting hospital admissions following SACT in advanced NSCLC patients.

Abstract Background Less than 20% of patients diagnosed with advanced lung cancer will survive beyond five years and half of these will suffer a serious adverse event (SAE) caused by systemic anticancer therapy (SACT) that will result in a hospital attendance. As multiple different SACT treatments are available for patients, a risk score that predicts the likelihood of a SAE following each type of SACT treatment would improve both communication with the patient and shared decision making with all those involved in delivering care for patients. There are currently no risk scores available for use in those with advanced stage lung cancer. Aim The overarching aim of this research is to develop and internally validate a risk score that will calculate the individualised risk of SAEs for different SACT treatments for patients with late stage lung cancer. Methods Utilising linked cancer registry data (National Cancer Registration and Analysis Service (NCRAS), England) for over 20,000 late stage lung cancer patients, a risk score will be developed using a multivariable logistic regression model to predict the risk of an acute admission within 30 days of SACT administration. Model performance will be summarised using calibration and discrimination. Internal validation will be used to quantify the degree of optimism due to overfitting, using re-sampling bootstrapping. Heterogeneity will be assessed, and the model will be fine-tuned. Fine-tuning and interrogation will be used to evaluate differences in performance between hospitals. The clinical utility will be assessed through calculating the net benefit in preventing SAEs. Conclusion A developed risk score (under each treatment strategy) has real potential to support individualised treatment decisions and optimise management of SACT-induced SAEs for patients and reduce hospital attendances.

BackgroundConsumption of gabapentinoids has increased worldwide in recent years, and the association between its use and drug poisoning is of public health concern. This study aimed to investigate the association between gabapentinoid treatment and the risk of drug poisoning.Methods and findingsIn this within-individual study, we utilised data from the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) Aurum database linked to the Hospital Episode Statistics (HES) and Office for National Statistics (ONS). The analysis included individuals aged 18 or above who were prescribed gabapentinoids and had an incident all-cause drug poisoning event between 1st January 2010 and 31st December 2020. Using the self-controlled case series (SCCS) design, we assessed the risk of drug poisoning incidence in predefined risk periods: 90 days before treatment initiation, first 28, 29-56, 57-84 days, and the remaining treatment time. Concomitant use with opioids/benzodiazepines was also evaluated. Adjusted incidence rate ratios (aIRRs) were calculated using conditional Poisson regression. A case-case-time-control (CCTC) analysis was also conducted, with adjusted odds ratio (aOR) calculated to validate the findings from the main SCCS analysis. All analyses have adjusted for key time-varying confounders, including age, season, and concomitant use of opioids, antiseizure medications, psychotropic medications, and non-steroidal anti-inflammatory drugs (NSAIDs). 16,827 individuals met the inclusion criteria and were included in the SCCS analysis. The risk of drug poisoning, compared with the reference periods, increased during the first 28 days of gabapentinoid treatment (aIRR = 1.81, 95% confidence interval [CI] [1.66, 1.99]; p < 0.001), eventually dropped to 1.11 (95% CI [1.05, 1.17]; p < 0.001) in the remainder of the treatment period. Notably, the risk was doubled during the 90-day preceding treatment initiation (aIRR = 2.09, 95% CI [1.98, 2.21]; p < 0.001). Co-administration with opioids elevated the risk by 30%, while benzodiazepines increased it 2-fold. The CCTC analysis also detected an increased aOR of 1.36 (95% CI [1.12, 1.65]; p = 0.002) of receiving gabapentinoid treatment within 30 days prior to a drug poisoning event. The SCCS approach cannot completely exclude the effect of unmeasured time-varying confounders, such as transient changes in socioeconomic status, major life events, or illicit drug use, although the negative control analysis did not suggest meaningful residual confounding.ConclusionsThe results suggest that gabapentinoid is associated with an increased risk of drug poisoning. Close monitoring throughout gabapentinoid treatment journey for drug poisoning is needed, especially at the initial phase. Concomitant use with opioid or benzodiazepines should be avoided.

PURPOSE:Simulation studies are used in pharmacoepidemiology for evaluating statistical methods in a controlled setting, whereby a known data-generating mechanism allows evaluation of the performance of different approaches and assumptions. This study aimed to review simulation studies performed in pharmacoepidemiology. METHODS:We conducted a review of all papers published in the journal of Pharmacoepidemiology and Drug Safety (PDS) over the period 2017-2024. We extracted data on study characteristics and key simulation choices such as the type of data-generating mechanism used, inferential methods tested and simulation size. RESULTS:Among 42 simulation studies included, 34 (81%) were informing comparative effectiveness/safety studies. Twenty-two studies (52%) used simulation in the context of a clinical condition, and 36 (86%) used Monte-Carlo simulation. Inputs not derived from empirical data alone (n = 22, 52%) or in combination with real-world data sources (n = 19, 45%) were most often used for data generation. The complexity of simulations was often relatively low: although 31 studies (74%) generated data based on other covariates, time-dependent covariates (n = 3) and effects (n = 4) were rarely implemented. Bias was the most often used performance measure (n = 26, 62%), although notably 18 studies (43%) did not report uncertainty in the method. CONCLUSION:Simulations contributed a relatively small number of articles (3.2% of 1320) to PDS over 2017-2024. Greater focus on evaluating methods and inferential approaches, using simulation studies that are appropriately complex given clinical realities, may be beneficial to the pharmacoepidemiology field.

BACKGROUND:Guidelines recommend oral anticoagulation for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism. Outside the United States, apixaban is unlicensed for use in patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT). AIM:To compare thrombotic and safety outcomes in patients receiving either vitamin K antagonists (VKAs) or apixaban 2.5 mg twice daily in the context of ESRD and RRT. METHOD:Retrospective service evaluation comparing bleeding and thrombotic outcomes in patients treated with apixaban 2.5 mg BD or VKA in a tertiary anticoagulation clinic. Trough anti-Xa levels of apixaban patients were reviewed. Clinical features and outcomes were reviewed using electronic patient records. RESULTS:Fifty-five VKA and 33 apixaban patients were included in the analysis. There were no major bleeds in the apixaban cohort compared with 4 (7.3%) in the VKA cohort (χ2 = 2.667, p = 0.102). No difference in time to major or clinically relevant non-major bleeding (CRNMB) was found (χ2 = 1.252, p = 0.263). Rates of thrombotic events (all stroke) were 1 vs. 3 (1.1 and 7.1 events/100 patient-years) for VKA and apixaban, respectively (χ2 = 3.291, p = 0.070). Only one stroke was related to AF. Eighty-four of 85 trough anti-Xa levels analysed were below the upper limit of normal of the reference range for the general population. DISCUSSION:Our results suggest similar outcomes with VKA and apixaban in those receiving RRT, indicating apixaban may be a viable second-line treatment option in those for whom VKA may not be appropriate. Further investigation into the safety of the apixaban 5-mg regimen is warranted.

Calcium channel blockers (CCBs) and statins are commonly combined to prevent cardiovascular diseases (CVDs). However, their concomitant use may lead to drug-drug interactions (DDIs) and increased adverse effects (AEs). This systematic review and meta-analysis aimed to evaluate the evidence of adverse effects (AEs) associated with the calcium channel blockers (CCBs) and statins concomitant use. We searched MEDLINE, Embase, Web of Science, and CENTRAL from database inception to 4 April 2025. Eligible studies included randomized controlled trials (RCTs) and observational studies reporting AEs of CCB-statin combinations compared with CCB or statin treatment in adults. Outcomes assessed included CCBs- and statins-associated AEs, treatment discontinuation, hospitalization, and all-cause mortality. Meta-analyses of similar outcomes were performed to estimate pooled Odds Ratios (OR) with 95% confidence intervals (CI). Of 9,737 articles screened, 20 studies (n = 1,053,198) were included. Peripheral edema, myalgia, and discontinuation were most reported in 11, 7, and 9 studies, respectively. Meta-analyses demonstrated no significant differences in the risk of peripheral edema (OR 1.03, 95% CI 0.14-1.48), myalgia (OR 1.33, 95% CI 0.63-2.79), or discontinuation (OR 0.78, 95% CI 0.50-1.23 for CCB-statin vs. CCB; OR 0.97, 95% CI 0.68-1.38 for CCB-statin vs. statin). However, evidence of other AEs was inconsistent and limited. CCB-statin combination appears generally safe in a short-term use (3 to 6 months). Further research is warranted to clarify the long-term risk of AEs.

BACKGROUND:Statins, renin-angiotensin system inhibitors (RASIs) and beta-blockers are guideline-recommended cardiovascular medications post-myocardial infarction (MI) for secondary prevention, but evidence for people with dementia is scarce. OBJECTIVE:To evaluate the association between post-MI cardiovascular medication use and the risk of cardiovascular outcomes and mortality, focusing on people with dementia. DESIGN:Large retrospective cohort study using data from Australia, Finland, Taiwan, the UK and the USA. SUBJECTS:People with and without dementia. METHODS:Seven exposure groups were assigned using one or combinations of the three guideline-recommended medication classes-(i) statin, RASI and beta-blocker, (ii) statin and beta-blocker, (iii) statin and RASI, (iv) RASI and beta-blocker, (v) statin only, (vi) beta-blocker only and (vii) RASI only, based on medication records during a 60-day landmark period post-MI. Recurrent MI, major adverse cardiovascular event (MACE) and all-cause mortality were evaluated as outcomes. Jurisdiction-specific results were pooled together using meta-analyses. RESULTS:A total of 28 122 people with dementia and 260 360 people without dementia were included. Among people with dementia, using any single or two medications carried a similar risk of recurrent MI and MACE as using all three guideline-recommended medications, except that using RASI and a beta-blocker without a statin was associated with a lower risk of recurrent MI (HR 0.85; 95% CI, 0.75-0.96). Using a statin and RASI without beta-blockers resulted in similar all-cause mortality to using all three (HR 1.16; 95% CI, 0.97-1.39), while all the remaining single- or dual-medication regimens were associated with higher risks of all-cause mortality. CONCLUSIONS:For people with dementia, using one or two guideline-recommended medications appeared sufficient to protect against recurrent MI and MACE. Beta-blockers may not provide additional survival benefits over statins and RASIs.

BACKGROUND:Gabapentinoids are increasingly being prescribed in older adults (aged 60 years or older), but concerns have been raised that their adverse effects on the CNS can increase the risk of fractures. Previous studies have reported associations between gabapentinoid use and fracture, but many have not adequately addressed confounding by indication or examined risk across the treatment journey. Therefore, we aimed to investigate the temporal association between gabapentinoid treatment and fracture in older adults, and to assess whether concomitant opioid or benzodiazepine use further modifies this risk. METHODS:In this retrospective multinational population-based study, we used data from the UK Clinical Practice Research Datalink (CPRD) Aurum database and the South Korea National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). The analysis included individuals aged 60 years or older prescribed a gabapentinoid and who had a hospitalised fracture between Jan 1, 2010, and Dec 31, 2020, in the UK and between Jan 1, 2003, and Dec 31, 2019, in South Korea. The observation period for each included individual was divided into four mutually exclusive windows: 90 days before gabapentinoid treatment (pre-exposure window), first 60 days of treatment period (focal window 1), remaining time of the treatment period (focal window 2), and all other non-treatment periods (referent window), to capture how risk varied across the treatment course. Adjusted incidence rate ratios (aIRRs) with 95% CI of fracture during different risk windows were estimated using conditional Poisson models within each country, and the country-specific aIRRs for the same risk window were then pooled using a random-effects model. FINDINGS:We included 20 030 participants in CPRD and 2935 in NHIS-HEALS in the analysis. In the CPRD cohort, 15 366 (76·7%) were women and the mean age at event was 77·85 years. In the NHIS-HEALS cohort, 2007 (68·4%) were women and the mean age at event was 69·24 years. The pooled results showed an increased risk of fracture during the pre-exposure window (aIRR 2·92, 95% CI 1·61-5·28, p=0·0004). The aIRR was 1·31 (95% CI 1·00-1·71, p=0·051) in the first 60 days of the treatment period and did not increase for the remainder of the treatment period (0·84, 0·54-1·32, p=0·45). Concurrent prescription of opioids or benzodiazepines elevated the risk of fracture, with an aIRR of 3·15 (95% CI 2·85-3·48, p<0·0001) for opioids and 1·91 (1·50-2·44, p<0·0001) for benzodiazepines during the first 60 days of gabapentinoid treatment period. INTERPRETATION:The risk of fracture was the highest in the period before the commencement of gabapentinoid treatment and declined after initiation of treatment. The results do not support a sustained causal relationship between gabapentinoid use and risk of fracture in older adults but warrant fall and fracture-prevention measures around gabapentinoid initiation. The elevated fracture risk observed with concomitant opioid or benzodiazepine use highlights the need for careful review of concurrent sedating medicines when initiating gabapentinoids. FUNDING:UK National Institute for Health and Care Research; Hong Kong Innovation and Technology Commission; Ministry of Food and Drug Safety, South Korea.

BACKGROUND:Antipsychotic use in people living with dementia has been linked to serious adverse outcomes. Guidelines recommend limiting antipsychotic treatment to short-term use (<12 weeks), followed by tapering and cessation. However, antipsychotic treatment in routine practice often exceeds the recommended duration. The effect of discontinuing antipsychotics on reducing adverse outcomes in practice remains unclear. We aimed to use linked primary and secondary care data in England to investigate whether tapering or abrupt discontinuation of antipsychotics, versus continuation, affected the risk of stroke, death, fracture, delirium, and pneumonia in people living with dementia. METHODS:Using UK primary care data from the Clinical Practice Research Datalink, linked with hospital and mortality data from Jan 1, 1998, to March 31, 2021, we emulated two sets of target trials, one after 12 weeks of antipsychotic treatment and another after 24 weeks of antipsychotic treatment, to compare continuing treatment versus tapering treatment and continuing treatment versus abrupt discontinuation of treatment. Patients aged 65 years and older at incident dementia diagnosis with antipsychotic treatment duration of at least 12 weeks were included. Study outcomes were incidence of fracture, stroke, hospitalisation for delirium, hospitalisation for pneumonia, and all-cause mortality within 24 months. A negative control outcome of skin conditions was included to measure potential unmeasured confounding. A clone-censor-weight approach was used with a 6-month grace period allowed for discontinuing antipsychotics. Weighted pooled logistic regression models were used to estimate 24-month absolute risk differences (ARDs). FINDINGS:134 549 eligible patients had a new antipsychotic treatment after dementia diagnosis, of whom 24 822 (18·4%) had a treatment period of at least 12 weeks and 16 795 (12·5%) had a treatment period of at least 24 weeks and met the eligibility criteria. The mean age was 83·57 (SD 7·07) in the 12-week trial and 83·65 (SD 7·02) in the 24-week trial; 16 725 (67·4%) of 24 822 patients were female and 8097 were male in the 12-week trial and 11 523 (68·6%) of 16 795 patients were female and 5272 were male in the 24-week trial. Compared with continuation after 12 weeks of treatment, estimated risks of delirium and fracture under the tapering strategy corresponded to 24-month ARDs of -2·46% (95% CI -4·10 to -1·27) and -2·80% (-4·14 to -1·29), respectively. Estimated risks for stroke, pneumonia, and all-cause mortality were similar between strategies. No difference in risk was observed for the negative control outcome. Similar results were found after 24 weeks of treatment and in sensitivity analyses. INTERPRETATION:Irrespective of method, antipsychotic discontinuation decreased the risk of delirium and fracture. Antipsychotics can be discontinued safely when treatment duration has exceeded guideline recommendations without increasing the risk of death, stroke, or pneumonia in those living with dementia. FUNDING:PharmAlliance Research Clusters for Doctoral Training.

Overweight and obesity are global health concerns linked to impaired female fertility. Weight-lowering drugs are an alternative for achieving weight loss; however, their effect on natural female fertility is unclear. A systematic review and meta-analysis were conducted to summarise the literature on the effects of weight-lowering drugs on ovulation, conception, pregnancy and live birth rates. Inclusion criteria comprised interventional and observational studies involving women with overweight or obesity receiving weight-lowering drugs, compared with non-users, lifestyle modifications or other medications. MEDLINE, Embase, CINAHL, CENTRAL and ClinicalTrials.gov were searched, yielding 2731 records. After screening, seven clinical trials were included (n = 575), six of which were randomised. Sample sizes ranged from 40 to 120 women aged 25.9-29.7 years. Six trials evaluated orlistat, while one assessed semaglutide. In four trials, orlistat was associated with a higher ovulation rate than lifestyle modifications. A meta-analysis of ovulation rates comparing orlistat and metformin showed no significant difference (RR = 0.78, 95% CI: 0.41-1.49; p = 0.45). Two studies reported pregnancy rates: one found a higher rate with orlistat compared to lifestyle modifications (23.3% vs. 6.7%, p = 0.044), and another showed that adding semaglutide to metformin increased the pregnancy rate compared to metformin alone (35% vs. 15%, p < 0.05). Future studies should address current limitations and evaluate the effects of newer weight-lowering drugs on natural pregnancy and live birth rates in adequately powered studies.

Menopausal hormone therapy (MHT) is a mainstay treatment for menopausal symptoms. While international studies report rising MHT use, trends in Australia remain unclear. Using a 10% random sample of Pharmaceutical Benefits Scheme (PBS) data from 2014 to 2023, we analysed the prevalence of MHT dispensing among women aged 45-64. Overall prevalence of MHT dispensing remained stable (relative annual change: 0.42%, 95% CI -0.50 to 1.35). Use of transdermal and intrauterine device (IUD) MHT increased (5.89%, 95% CI 3.88-7.91 and 10.22%, 95% CI 9.48-10.95, respectively), and vaginal MHT decreased (-1.47%, 95% CI -2.30 to -0.63), while oral MHT appeared stable (0.66%, 95% CI -0.04 to 1.36). This study offers a clearer understanding of how MHT use in Australia has changed over the last decade.

AIMS:5α-Reductase inhibitors are prescribed for the treatment of benign prostatic hyperplasia (BPH) and their use is associated with increased risk of incident type 2 diabetes. This study assessed the long-term cardiovascular safety of 5α-reductase inhibitors in comparison with tamsulosin in people with co-existing BPH and type 2 diabetes. METHODS AND RESULTS:We performed a retrospective, population-based cohort study using Scottish Diabetes Research Network National Diabetes Dataset (SDRN-NDS) and IQVIA Medical Research Data (IMRD-UK). BPH patients ≥40 years with recorded type 2 diabetes mellitus and ≥2 prescriptions of 5α-reductase inhibitors or tamsulosin (2006-2021) were included. After 1:2 variable ratio propensity score matching, cause-specific Cox proportional-hazard models were used to compute the hazard ratio (HR) of incident major adverse cardiovascular events (MACE). A total of 11 969 patients were included in SDRN-NDS and 16 492 in IMRD-UK, with median follow-up durations of 3.8 (IQR: 1.7-6.8) and 4.8 (2.0-8.3) years, respectively. In SDRN-NDS, the HR of MACE in patients receiving 5α-reductase inhibitors relative to tamsulosin was 1.15 (95% CI 1.03-1.30, P = 0.007), driven by increased risk of myocardial infarction (MI) (HR 1.20, 1.03-1.40, P = 0.022). This was replicated in IMRD-UK, where HR was 1.26 (1.07-1.47, P = 0.008) for MACE and 1.33 (1.10-1.60, P = 0.005) for MI. We did not observe any increased risks in stroke, cardiovascular death, microvascular complications of diabetes, or faster progression to insulin-based therapies. CONCLUSION:Our retrospective data from two large cohorts suggest that the risk of MACE may be increased among patients with type 2 diabetes taking 5α-reductase inhibitors, potentially driven by increased risk of MI. This supports careful monitoring of macrovascular outcomes when prescribing 5α-reductase inhibitors in this population.

AIMS:People with Type 2 diabetes experience higher cardiometabolic risk, and both synthetic glucocorticoids and use of 5α-reductase inhibitors have been individually linked to increased risk of myocardial infarction. We tested whether the increase in risk is exacerbated by co-prescription of both drugs. MATERIALS AND METHODS:We performed a population-based cohort study in the Scottish Diabetes Research Network-National Diabetes Dataset (SDRN-NDS) and IQVIA Medical Research Data-UK (IMRD-UK). Patients with Type 2 diabetes aged ≥ 40 years receiving 5α-reductase inhibitors or tamsulosin, who were incident users of systemic glucocorticoids during 2006-2021 were included. We modelled the joint effect of 5α-reductase inhibitors and cumulative exposure to glucocorticoids on the risk of myocardial infarction using a time-varying Cox proportional hazards model. RESULTS:A total of 13 161 patients with Type 2 diabetes were included in SDRN-NDS and 15 084 in IMRD-UK. Mean age was 71.4 ± 9.6 and 72.3 ± 9.4 years, with mean follow-up of 4.7 (3.6) and 5.6 (4.0) years, respectively. Median (IQR) total glucocorticoids exposure was 210 (96-630) and 420 (200-1240) prednisolone-equivalent milligram. Risk for myocardial infarction was increased among users of 5α-reductase inhibitors (HR [95% CI]: SDRN-NDS, 1.21 [1.02-1.43]; IMRD-UK, 1.27 [1.02-1.59]) and per SD increase in cumulative glucocorticoid exposure (HR [95% CI]: SDRN-NDS, 1.09 [1.03-1.14]; IMRD-UK, 1.08 [1.01-1.15]). We did not observe a multiplicative interaction (SDRN-NDS, p = 0.44; IMRD-UK, p = 0.68) between the use of the two drugs. CONCLUSION:People with Type 2 diabetes exposed to 5α-reductase inhibitors or glucocorticoids are at an increased risk of myocardial infarction, although a multiplicative interaction between the use of the two drugs was not found.

BACKGROUND:Fluoropyrimidine chemotherapy is administered first-line for many gastrointestinal cancers. However, patients with cardiovascular disease commonly receive alternative treatment due to cardiotoxicity concerns. OBJECTIVES:This study sought to assess the risks of all-cause mortality and acute cardiovascular events with fluoropyrimidine treatment. METHODS:We conducted an observational cohort study applying a target trial emulation framework to linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. Adults diagnosed with tumors eligible for fluoropyrimidine-based chemotherapy as first-line therapy were included. All-cause mortality and a composite of hospitalization for acute cardiovascular events (acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) were compared in patients treated with fluoropyrimidine-based chemotherapy vs alternative management. Adjusted, weighted pooled logistic regression models were used to estimate the 1-year risk difference (RD). RESULTS:Among 103,110 patients (mean age 69.7 years, 59% male), the absolute risk of death at 1 year was significantly lower in fluoropyrimidine-treated patients (RD: -7.7%; 95% CI: -8.7% to -6.7%) with a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%). This was primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%), with no increased risk of acute coronary syndromes including in the subgroup of patients with pre-existing coronary artery disease. CONCLUSIONS:The markedly improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer significantly outweighs the small risk of cardiac arrhythmia and arrest. Oncologists should take this into consideration for decision making to avoid undue clinical conservatism, particularly in patients with cardiovascular disease.