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The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HTUsing the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5-24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs).The cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85-1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85-1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83-3.18).Median duration of SSRI use, in line with real-world SSRI prescribing, was relatively short.T2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

Aims To evaluate the effectiveness and safety of apixaban versus rivaroxaban among patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes mellitus (T2DM). Methods and Results Using the United Kingdom's Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository, and the Office for National Statistics database, we identified a cohort of patients with NVAF and T2DM newly treated with apixaban or rivaroxaban between 2013 and 2020. Propensity scores with standardized mortality ratio weighting were used to control for confounding. We used weighted Cox proportional hazards models to estimate separately the hazard ratios (HRs) with 95% confidence intervals (CIs) of ischemic stroke, major bleeding, and major adverse limb events associated with the use of apixaban compared with rivaroxaban. We also evaluated whether the risk was modified by age, sex, duration of diabetes, microvascular and macrovascular complications of diabetes, nephropathy, CHA2DS2-VASc and HAS-BLED scores, and by dose (standard vs. low dose). Results The cohort included 11,561 apixaban and 8,265 rivaroxaban users. Apixaban was associated with a similar risk of stroke (HR: 0.99, 95% CI: 0.79–1.23), and a 32% reduced risk of major bleeding (HR: 0.68, 95% CI: 0.59–0.78), compared with rivaroxaban. The risk of major adverse limb events was similar between apixaban and rivaroxaban (HR: 0.75, 95% CI: 0.54–1.04). Overall, the risk of ischemic stroke and major bleeding was consistent in stratified analyses. Conclusion Among patients with NVAF and T2DM, apixaban was associated with a similar risk of stroke and a lower risk of major bleeding compared with rivaroxaban.

To compare the risk of cardiovascular outcomes associated with long-acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes.We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long-acting insulin analogues or NPH insulin, defined using a time-varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long-acting insulin analogues versus NPH insulin, and in secondary analyses, by long-acting insulin molecule.Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow-up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person-years). Long-acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96).Current use of long-acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline-writing committees for recommendations of insulin treatment for type 2 diabetes.

SGLT2 inhibitors (SGLT2is) have been shown to reduce the risk of cardiovascular and mortality events in large cardiovascular outcome trials in patients with type 2 diabetes. However, their safety profile is controversial, with some trials reporting imbalances in bladder cancer events, all of which occurred relatively soon after randomization. To address this safety concern, we used 3 US healthcare claims databases and 1 UK primary care database (01/2013-12/2020) . In each database, we identified adults newly treated with either SGLT2is (total n=453,726) or GLP-1 receptor agonists (GLP1RAs, n=375,990) (comparison #1) , and SGLT2is (n=347,055) or DPP-4 inhibitors (DPP4is, n=854,141) (comparison #2) . Propensity score-based fine stratification was used to reweigh the cohorts, adjusting for a wide range of patient characteristics at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for bladder cancer in each database using Cox proportional hazards models. After a median follow-up of 1.8 years, use of SGLT2is may slightly reduce the risk of bladder cancer, compared to GLP1RAs [HR (95% CI) =0.90 (0.81-1.00) ]. Compared to use of DPP4is, SGLT2is are not associated with bladder cancer incidence [HR (95% CI) : 1.00 (0.91-1.11) ] after a median follow-up of 2.0 years (Table) . Overall, the results of this large international cohort study provide reassurance on the short-term effects of SGLT2is on bladder cancer incidence. Disclosure D.Abrahami: None. H.Tesfaye: None. H.Yin: None. O.Yu: None. R.W.Platt: Consultant; Amgen Inc., Biogen, Merck & Co., Inc., Nant Pharma, Pfizer Inc. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. L.Azoulay: Consultant; Pfizer Inc. Funding Canadian Institutes of Health Research (PJT-169040)