Patients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.

Summary Background Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. Findings The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and heart failure (1·22 [1·02–1·45]). Interpretation Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit–risk trade-off when counselling those on hydroxychloroquine treatment. Funding National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Depar...

BackgroundAntidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies.MethodsA review of MEDLINE and EMBASE identified case–control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups.ResultsA total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31–1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29–1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08–1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91–1.52) and sibling studies (0.96, 95% CI 0.65–1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13–1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14–1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31–2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77–1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70–1.11 (sibling studies).ConclusionsExisting observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0993-3) contains supplementary material, which is available to authorized users.

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AimsEvaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.MethodsWe searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non‐European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted.ResultsFrom 1246 screened articles, 229 were eligible for full‐text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill‐over effects were rarely evaluated. Two‐thirds used before–after time series and 15.7% before–after cross‐sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%).ConclusionWhilst impact evaluation of pharmacovigilance and product‐specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.

Background Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin.Methods New user cohort studies were conducted including 16 severe adverse events (SAEs).Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquineazithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA.Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included.No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45])