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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.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

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)

BackgroundLevothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.MethodsA systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.ResultsSeven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age.ConclusionTreatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.

Purpose Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. Methods We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. Results Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (standard deviation: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). Conclusions SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

OBJECTIVE Reports of amputations associated with sodium–glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. RESULTS The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71–1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. CONCLUSIONS In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

The association between long-acting insulin analogs and colorectal cancer is uncertain, with previous studies reporting discrepant findings. To determine whether the use of long-acting insulin analogs is associated with an increased risk of colorectal cancer, when compared with use of intermediate-acting human insulins among patients with type 2 diabetes. We conducted a population-based study using the United Kingdom Clinical Practice Research Datalink (CPRD). We identified patients newly treated with either a long-acting insulin analog or an intermediate-acting human insulin between September 1, 2002 and January 31, 2018, with follow-up until January 31, 2019. Each long-acting insulin analog user was propensity score-matched to one intermediate-acting human insulin user, and a lag of 1 year was imposed. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of colorectal cancer, comparing long-acting insulin analogs with intermediate-acting human insulin. Secondary analysis was conducted to assess whether there was a duration–response relationship. A total of 10,734 new long-acting insulin analog users were matched to 10,734 new intermediate-acting human insulin users. After a median follow-up of 2.8 years, the use of long-acting insulin analogs was not associated with an increased risk of colorectal cancer, compared with intermediate-acting human insulin (1.80 vs. 1.87 per 1000 person-years, respectively; HR 0.96, 95% CI 0.70–1.34). There was no evidence of a duration–response relationship. The results of this population-based study indicate that use of long-acting insulin analogs is not associated with an overall increased risk of colorectal cancer.

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid‐simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy., Our study found that a low proportion of women with SCH were prescribed levothyroxine during pregnancy and that prescriptions varied by patient characteristics and geographical region.

Aims Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. Methods We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with sulfonylureas vs metformin. Results Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with sulfonylureas. Conclusions Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.

OBJECTIVE There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score–matched analysis to assess the impact of residual confounding. RESULTS During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45–3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11–6.16]). Similar results were obtained in the propensity score–matched analysis (HR 2.40 [95% CI 1.13–4.66]). CONCLUSIONS In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.

Background. Sodium glucose cotransport (SGLT)-2 inhibitors are the newest class of antihyperglycemic agents used as second- or third-line treatment in the management of type 2 diabetes. Although the use of SGLT-2 inhibitors has not been shown to cause nephrotoxicity, there have been case reports of SGLT-2 inhibitor use being associated with acute kidney injury. Case Presentation. A 72-year-old woman with a history of type 2 diabetes and no known chronic renal insufficiency presented to the emergency room with a 3-day history of nausea, vomiting, and increased somnolence. She was found to have potassium level of 7.4 (normal: 3.5-5.5) mmol/L and a markedly elevated creatinine level at 1154 (normal: 45-95) μmol/L. Imaging of the abdomen and pelvis did not reveal any findings of obstruction. Urine microscopy showed many granular casts. In the absence of other causes for her clinical presentation, the patient was diagnosed with acute kidney injury secondary to ischemic acute tubular necrosis, with canagliflozin use likely an important contributing factor. Conclusions. Physicians should inform patients to stop the use of SGLT-2 inhibitors when patients are unable to maintain hydration or during acute illness. Use of SGLT-2 inhibitors in managing type 2 diabetes should be done with caution among more vulnerable populations, including individuals with cognitive impairment and the elderly.

Introduction Hyperglycaemia is common during hospitalization; glycaemic targets in non‐critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events. Methods We conducted a retrospective cohort study on non‐critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0–7.0 mmol/L, 7.1–10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia 10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75–1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1–10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21–2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31–2.60). Conclusions Neither glycaemia of 4.0–7.0 mmol/L nor glycaemia of >10.0mmol/L during non‐critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets., Few studies have assessed the association between various glycaemic targets and adverse outcomes during hospitalization. Our study assessed whether glycaemia levels (ie 4.0–7.0 mmol/L, 7.1–10.0 mmol/L and >10 mmol/L) during early hospitalization is associated with an increased risk of adverse events and hypoglycaemia. Our results showed that the glycaemic targets defined in our study were not associated with an increased risk of adverse events during hospitalization; however, hypoglycaemia (ie

Background Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data. Methods Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age. Results The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths. Conclusions A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.

Aims Aim of this study is to describe changes in the utilization of basal insulins (glargine, detemir, degludec, neutral protamine Hagedorn [NPH]) among individuals with type 2 diabetes between 2003 and 2018 in the United Kingdom (UK). Materials and methods Using the UK Clinical Practice Research Datalink (CPRD) Aurum, we created three study cohorts of individuals with type 2 diabetes: (1) all users of antidiabetic drugs (n = 686,170); (2) initiators of antidiabetic drugs (n = 382,247); and (3) initiators of basal insulins (n = 85,369). Trends in prescription rates were determined using Poisson regression overall and stratified by sex, cardiovascular disease history, and obesity. Crude and adjusted Cox proportional hazards models were used to obtain hazard ratios (HRs) and confidence intervals (CI) comparing rates of treatment change between classes of basal insulins, with an intention-to-treat exposure definition. Results During the study period, prescription rates of insulin analogues increased in the all-user cohort from 118.3 (95% CI: 116.4, 120.2) prescriptions per 1000 person-years in 2003 to 579.4 (95% CI: 576.9, 582.0) in 2018. Prescription rates of NPH decreased from 770.5 (95% CI: 765.0, 775.3) in 2003 to 457.7 (95% CI: 455.5, 460.0) in 2018. Compared to initiators of NPH, initiators of detemir were more likely to change treatment (adjusted HR: 1.31, 95% CI: 1.25, 1.37) while glargine initiators were less likely to change treatment (adjusted HR: 0.85, 95% CI: 0.82, 0.88). Conclusions Basal insulin prescription evolved between 2003 and 2018. Our study provides insight into the evolving use of basal insulin among individuals with type 2 diabetes in the UK.

The United States Food and Drug Administration is considering replacing cardiovascular outcome trials (CVOTs) of antidiabetic drugs with trials that better represent patients with type 2 diabetes. However, designing such representative trials requires understanding the underlying target populations (i.e., populations intended to receive the drug in the real-world setting). Thus, we used the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial as a motivating example to illustrate how different target populations impact trial representativeness. Using the United Kingdom Clinical Practice Research Datalink, we identified three target populations: 1) all patients with type 2 diabetes; 2) patients prescribed liraglutide; 3) patients who would have been eligible to receive liraglutide based on treatment stage (i.e., patients with poorly controlled diabetes eligible to receive a second-to-fifth line antidiabetic drug). We then examined the representativeness of the LEADER trial by applying its eligibility criteria to each target population. The target populations of patients with type 2 diabetes (n=279,763), those prescribed liraglutide (n=14,421), and those eligible to receive liraglutide based on the treatment stage (n=85,610) differed substantially in terms of hemoglobin A1c, body mass index, prevalence of heart failure, and chronic kidney disease. Applying the LEADER trial eligibility criteria to these target populations resulted in the inclusion of 19.1%, 20.7%, and 34.8% patients, respectively. This study highlights how real-world data can be used to define different target populations. Explicitly defining these target populations can help in the design of future trials of antidiabetic drugs.

Objective: Reports of amputations associated with sodium glucose co-transporter (SGLT) 2 inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase (DPP)-4 inhibitors among patients with type 2 diabetes. Research Design and Methods: This is a multicenter observational study using administrative healthcare databases from 7 Canadian provinces and the United Kingdom. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. Results: The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow up time of 11 months, the amputation rate among SGLT2 inhibitor users was 1.3 per 1,000 person-years and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared to DPP-4 inhibitor use was 0.88 (95% CI: 0.71-1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. Conclusions: In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes, compared to DPP-4 inhibitor use. While these findings provide some reassurance, studies with longer duration of follow-up are needed to assess potential long-term effects.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), uses angiotensin-converting enzyme 2 to invade human cells. However, recent evidence suggested that dipeptidyl peptidase 4 (DPP-4) may be used as a coreceptor when SARS-CoV-2 enters the target cells (1). Interestingly, upregulation of DPP-4 is associated with older age, respiratory or cardiovascular disease, and diabetes (2), all of which were reported to exacerbate COVID-19. Given the pathophysiological evidence, DPP-4 inhibitors were suggested to have beneficial effects on COVID-19. Given the high fatality rate of COVID-19 among patients with diabetes, there is an urgent need to understand the effect DPP-4 inhibitors may have on COVID-19. Therefore, we aimed to determine whether use of DPP-4 inhibitors reduces the risk of adverse COVID-19–related outcomes among patients with type 2 diabetes (T2D). We conducted a nationwide cohort study using the Health Insurance Review and Assessment Service database linked with the Korea Disease Control and Prevention Agency database, which covers the entire South Korean population of ≥50 million, from 1 January 2017 to 15 May 2020. We included patients who had a positive test result for COVID-19 as of 15 May 2020, had been diagnosed with T2D within the preceding 3 years before COVID-19 diagnosis (cohort entry), and had ≥1 antidiabetic prescription within the 180 days before cohort entry. We excluded patients aged

Introduction: The glycemic target for patients with diabetes in non-critical care hospitalization has not been well studied. The primary objective of this study is to determine the association between glycemic control during hospitalization and adverse events. The secondary objective is to assess the association between hypoglycemia and adverse events. Methods: We conducted a retrospective cohort study of patients with diabetes hospitalized on medicine wards from 2015 to 2018 in a tertiary care teaching hospital. Exposure was the average glycemia in the first 4 days of hospitalization, categorized into: ≥ 4.0 and ≤ 7.0 mmol/L (tight control),> 7 and ≤ 10.0 mmol/L (loose control, reference group), > 10.0 mmol/L (poor control). Hypoglycemia was defined as any glycemia< 4 mmol/L. Primary outcome was a composite of adverse events, including infection, thromboembolic events, acute kidney injury, and mortality. Logistic regression models were used to assess the relationship between glycemic control and the primary composite outcome. Results: A total of 1368 patients were included; 407 adverse events were recorded. Compared to loose glycemic control, tight and poor glycemic control was not associated with increased adverse events (tight control adjusted odds ratio [OR] 0.88, 95% confidence interval [CI] 0.63-1.23; poor control adjusted OR: 0.98, 95% CI 0.75-1.28). Any occurrence of hypoglycemia during hospitalization was associated with increased adverse events (adjusted OR 1.85, 95% CI 1.31-2.60). Conclusion: Tight and poor glycemic control during hospitalization was not associated with increased adverse events compared to loose glycemic control. The result for poor glycemic control was unexpected and may be due to lack of significant difference between the average glycemia in loose and poor glycemic control groups. Hypoglycemia was associated with increased adverse events, suggesting the importance of hypoglycemia prevention during hospitalization. Disclosure L. Deng: None. W. Aibibula: None. Z. Talat: None. K.B. Filion: None. S. Eintracht: None. K. Dasgupta: None. V. Tagalakis: None. A. Majdan: Advisory Panel; Self; Abbott, Insulet Corporation. Consultant; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Lilly Diabetes, Sanofi-Aventis. O. Yu: None.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are second- to third-line antidiabetes drugs that have been shown to have cardiovascular benefits. However, in premarketing trials of the SGLT2 inhibitor dapagliflozin, there were numerical imbalances in breast cancer events compared with placebo; all occurred within 1 year of randomization (rate ratio 2.47, 95% CI 0.64–14.10) (1). In contrast, no imbalances were observed in subsequent large cardiovascular outcome trials of dapagliflozin and other SGLT2 inhibitors (2–4). While the discrepant findings between the pre- and postmarketing trials could be due to chance, one hypothesis is that the early breast cancer imbalances are the result of an accelerated tumor-promoting effect of SGLT2 inhibitors. However, this is unlikely, given that sodium–glucose cotransporter proteins are not expressed in mammary tissue, and animal studies have failed to demonstrate that SGLT2 inhibitors have any neoplastic activity (5). Another hypothesis relates to the weight-lowering effects of SGLT2 inhibitors, which could facilitate the detection of existing breast lumps, thus leading to a transient overdetection of breast cancer. To date, this possible association has not been investigated in the real-world setting. We conducted a population-based cohort study using the U.K. Clinical Practice Research Datalink (CPRD) (protocol: 19_272). We identified all female patients newly treated with either an SGLT2 inhibitor (dapagliflozin, …

Background: It has been proposed that the weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve the detection of breast cancer in patients undergoing this treatment. Thus, this study aimed to determine whether the weight-lowering effects of GLP-1 RAs is associated with an increased detection of breast cancer among obese women with type 2 diabetes. Methods: Using the United Kingdom Clinical Practice Research Datalink, we conducted a propensity score-matched cohort study among female obese patients with type 2 diabetes newly-treated with antidiabetic drugs between 1 January 2007 and 31 January 2018. New users of GLP-1 RAs (n=5,510) were matched to new users of second- to third-line non-insulin antidiabetic drugs (n=5,510). Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with different GLP-1 RA maximal weight loss categories (10%). Results: Breast cancer incidence gradually increased with GLP-1 RA maximal weight loss categories, with the highest HR observed for patients achieving at least 10% weight loss (HR: 1.77, 95% CI: 1.12, 2.81). In secondary analyses, the HR for >10% weight loss was highest in the 2-3 years since treatment initiation (HR: 2.90, 95% CI: 1.21, 6.92). Conclusions: In this population-based study, the detection of breast cancer gradually increased with GLP-1 RA weight loss categories, particularly among those achieving >10% weight loss. These results suggest that significant weight loss with GLP-1 RAs may improve the detection of breast cancer among obese patients with type 2 diabetes.

Background Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS. Methods We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms. Results In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10− 59). But this CHD PRS was, at best, only weakly associated with traditional clinical risk factors, such as hypertension, hyperlipidemia, glycemic control, obesity and smoking. Conversely, in the angiographic cohort, the CHD PRS was strongly associated with multivessel stenosis (OR = 1.65; p = 4.9 × 10− 4) and increased number of major stenotic lesions (OR = 1.35; p = 9.4 × 10− 3). Conclusions Polygenic predisposition to CHD is strongly associated with atherosclerotic burden in individuals with type 2 diabetes and this effect is largely independent of traditional clinical risk factors. This suggests that genetic risk for CHD acts through atherosclerosis with little effect on most traditional risk factors, providing the opportunity to explore new biological pathways.

OBJECTIVE Previous studies suggested that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may initially worsen and possibly increase the risk of diabetic retinopathy. However, data on this possible association remain limited. Thus, this population-based study aimed to determine whether use of GLP-1 RAs is associated with an increased risk of incident diabetic retinopathy. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink (CPRD), we conducted a cohort study among 77,115 patients with type 2 diabetes initiating antidiabetic drugs between January 2007 and September 2015. Adjusted hazard ratios (HRs) and 95% CIs of incident diabetic retinopathy were estimated using time-dependent Cox proportional hazards models, comparing use of GLP-1 RAs with current use of two or more oral antidiabetic drugs. In an ancillary analysis, new users of GLP-1 RAs were compared with new users of insulin. RESULTS During 245,825 person-years of follow-up, 10,763 patients were newly diagnosed with diabetic retinopathy. Compared with current use of two or more oral antidiabetic drugs, use of GLP-1 RAs was not associated with an increased risk of incident diabetic retinopathy overall (HR 1.00, 95% CI 0.85–1.17). Compared with insulin, GLP-1 RAs were associated with a decreased risk of diabetic retinopathy (HR 0.67, 95% CI 0.51–0.90). CONCLUSIONS The associations with diabetic retinopathy varied according to the type of comparator. When compared with use of two or more oral antidiabetic drugs, use of GLP-1 RAs was not associated with an increased risk of incident diabetic retinopathy. The apparent lower risk of diabetic retinopathy associated with GLP-1 RAs compared with insulin may be due to residual confounding.

There is concern about the infection-related safety profile of sodium–glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs). We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models. Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89–3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14–4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96–1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93–1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10–1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20–0.72, I2 0%) but did not affect the risk of respiratory tract infections. SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.

The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of fractures is controversial. In the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin was associated with a significant increased risk of fractures compared with placebo (hazard ratio [HR] 1.26, 95% CI 1.04–1.52) (1). Possible mechanisms may involve elevated serum phosphate levels or reductions in bone mineral density (2). To date, three recent observational studies investigated this association, but these did not observe an increased risk of fractures (3–5). However, these studies had some limitations, including residual confounding, a limited outcome definition, or restriction to a single SGLT2 inhibitor. To address these limitations, we conducted a population-based cohort study using the U.K. Clinical Practice Research Datalink (CPRD). We first assembled a base cohort of all individuals, at least 40 years old, newly treated with antidiabetic drugs between 1 January 1988 and 31 December 2017. We excluded individuals with

OBJECTIVE Sulfonylureas have been associated with an increased risk of cardiovascular adverse events and hypoglycemia, but it is unclear if these risks vary with different agents. We assessed whether the risks of acute myocardial infarction, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia differ between sulfonylureas grouped according to pancreas specificity and duration of action. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, linked with the Hospital Episodes Statistics and the Office for National Statistics databases, we conducted a cohort study among patients with type 2 diabetes initiating monotherapy with sulfonylureas between 1998 and 2013. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, comparing use of pancreas-nonspecific, long-acting sulfonylureas (glyburide/glimepiride) to pancreas-specific, short-acting sulfonylureas (gliclazide/glipizide/tolbutamide). RESULTS The cohort included 17,604 sulfonylurea initiators (mean [SD] follow-up 1.2 [1.5] years). Compared with specific, short-acting sulfonylureas (15,741 initiators), nonspecific, long-acting sulfonylureas (1,863 initiators) were not associated with an increased risk of acute myocardial infarction (HR 0.86; CI 0.55–1.34), ischemic stroke (HR 0.92; CI 0.59–1.45), cardiovascular death (HR 1.01; CI 0.72–1.40), or all-cause mortality (HR 0.81; CI 0.66–1.003), but with an increased risk of severe hypoglycemia (HR 2.83; CI 1.64–4.88). CONCLUSIONS The nonspecific, long-acting sulfonylureas glyburide and glimepiride do not have an increased risk of cardiovascular adverse events compared with the specific, short-acting sulfonylureas gliclazide, glipizide, and tolbutamide. However, nonspecific, long-acting sulfonylureas glyburide and glimepiride have an increased risk of severe hypoglycemia.

Aim To assess the incidence of cardiovascular and hypoglycaemic adverse events associated with glimepiride compared with other second-generation sulphonylureas among patients with type 2 diabetes in a real-world clinical setting. Materials and methods We identified all sulphonylurea initiators between 1998 and 2017 in the UK Clinical Practice Research Datalink. Using a prevalent new-user design, glimepiride initiators were matched 1:4 with initiators of other second-generation sulphonylureas on calendar time, prior sulphonylurea use, and time-conditional high-dimensional propensity score. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for myocardial infarction, ischaemic stroke, severe hypoglycaemia, cardiovascular death, and all-cause mortality. Results Among 66 032 sulphonylurea new users, 6438 initiated glimepiride and were matched to up to 20 582 initiators of other second-generation sulphonylureas. During a mean follow-up of 1.3 years, glimepiride was associated with a similar incidence of myocardial infarction (HR 0.99, 95% CI 0.75-1.30) and ischaemic stroke (HR 0.96, 95% CI 0.72-1.27) compared with other second-generation sulphonylureas, while there was a non-significant trend towards a higher incidence of severe hypoglycaemia (HR 1.24, 95% CI 0.92-1.68). Glimepiride was also associated with a lower incidence of all-cause mortality (HR 0.77, 95% CI 0.67-0.89), and a non-significant but similar trend for cardiovascular death (HR 0.83, 95% CI 0.65-1.05). Conclusions Glimepiride was associated with a lower incidence of all-cause mortality compared with other second-generation sulphonylureas.

There are concerns that sodium-glucose co-transporter 2 inhibitors (SGLT2Is) may increase the risk of fractures in patients with type 2 diabetes. To date, large cardiovascular outcome trials have generated conflicting findings, and few real-world studies have been conducted to assess this association. As fracture risk in this vulnerable population is associated with increased mortality, there is an urgent need to address this safety issue using real-world data. Thus, the objective of this population-based cohort study is to determine if use of SGLT2Is is associated with an increased fracture risk in patients with type 2 diabetes. Using the UK Clinical Practice Research Datalink, a large primary care database, we identified a cohort of patients newly treated with antihyperglycemic drugs between January 2013 and December 2017. Use of SGLT2Is was modeled as a time-varying exposure and compared with use of dipeptidyl peptidase-4 inhibitors (DPP-4Is). Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs of incident fractures associated with use of SGLT2Is overall and according to specific SGLT2Is (dapagliflozin, empagliflozin, canagliflozin). We conducted several sensitivity analyses to address potential sources of bias. The cohort included 73,178 patients, which generated 153,179 person-years of observation. During follow-up, 1,973 patients were newly diagnosed with fractures (incidence rate: 12.9/1000 per year). Compared with DPP-4Is, SGLT2Is were not associated with an increased risk of fracture (HR: 0.97, 95% CI: 0.79-1.19). Similar findings were observed when stratifying on specific SGLT2Is, with HRs ranging between 0.67 and 1.42, with all CIs including the null value. The sensitivity analyses yielded highly consistent findings. The results of this large population-based study suggest that use of SGLT2Is is not associated with fracture incidence. This finding should provide reassurance on the safety of this class of drugs. Disclosure D. Abrahami: None. A. Douros: None. H. Yin: None. O. Yu: None. L. Azoulay: None. Funding Canadian Institutes of Health Research

The association between the use of testosterone replacement therapy (TRT) and prostate cancer remains uncertain. Thus, we investigated whether TRT is associated with an increased risk of prostate cancer in men with late-onset hypogonadism. We used the UK Clinical Practice Research Datalink to assemble a cohort of 12,779 men who were newly diagnosed with hypogonadism between January 1, 1995, and August 31, 2016, with follow-up until August 31, 2017. Exposure to TRT was treated as a time-varying variable and lagged by 1 year to account for cancer latency, with nonuse as the reference category. During 58,224 person-years of follow-up, a total of 215 patients were newly diagnosed with prostate cancer, generating an incidence rate of 3.7 per 1,000 person-years. In time-dependent Cox proportional hazards models, use of TRT was not associated with an overall increased risk of prostate cancer (hazard ratio = 0.97; 95% confidence interval: 0.71, 1.32) compared with nonuse. Results remained consistent in secondary and sensitivity analyses, as well as in a propensity score–matched cohort analysis that further assessed the impact of residual confounding. Overall, the use of TRT was not associated with an increased risk of prostate cancer in men with late-onset hypogonadism.

Purpose We assessed the risk of ischemic stroke, transient ischemic attack, and myocardial infarction associated with testosterone replacement therapy (TRT) among aging men with low testosterone levels. Methods Using the UK Clinical Practice Research Datalink, we formed a cohort of men aged 45 years or older with low testosterone levels and no evidence of hypogonadotropic or testicular disease, between 1995 and 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) of a composite of ischemic stroke/transient ischemic attack and myocardial infarction were estimated using time-dependent Cox proportional hazards models, comparing current use of TRT with nonuse. Results The cohort included 15,401 men. During 71,541 person-years of follow-up, 850 patients experienced an ischemic stroke/transient ischemic attack/myocardial infarction (crude incidence rate 1.19 [95% confidence interval (CI), 1.11-1.27] per 100 persons per year). Compared with nonuse, current use of TRT was associated with an increased risk of the composite outcome (HR 1.21; 95% CI, 1.00-1.46). This risk was highest in the first 6 months to 2 years of continuous TRT use (HR 1.35; 95% CI, 1.01-1.79), as well as among men aged 45-59 years (HR 1.44; 95% CI, 1.07-1.92). Conclusions TRT may increase the risk of cardiovascular events in aging men with low testosterone levels, particularly in the first 2 years of use. In the absence of identifiable causes of hypogonadism, TRT should be initiated with caution among aging men with low testosterone levels.

Case reports have suggested a link between dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic drugs used as second- to third-line treatments, and incidence of rheumatoid arthritis. Because the DPP-4 enzyme is involved in several immunologic processes and possibly in the pathophysiology of rheumatoid arthritis, further research is warranted. This population-based study aimed to determine whether use of DPP-4 inhibitors is associated with incidence of rheumatoid arthritis.Using the United Kingdom Clinical Practice Research Datalink, we conducted a cohort study among 144,603 patients with type 2 diabetes initiating antidiabetic drugs between 2007 and 2016. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for incident rheumatoid arthritis using time-dependent Cox proportional hazards models, comparing use of DPP-4 inhibitors with use of other antidiabetic drugs. We imposed a 6-month exposure lag period for latency and diagnostic delays. Secondary analyses included assessment of the duration-response relation and comparison with other second-line antidiabetic drugs, among others.During 567,169 person-years of follow-up, 464 patients were newly diagnosed with rheumatoid arthritis (crude incidence rate: 82 per 100,000/year). Compared with use of other antidiabetic drugs, use of DPP-4 inhibitors was not associated with an increased risk of rheumatoid arthritis (82 vs. 79 per 100,000/year; HR = 1.0; 95% CI = 0.8, 1.3), with no evidence of duration-response relation. The results did not change after using second-line antidiabetic drugs as the comparator group.In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis.

Objective To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes. Design Population based cohort study. Setting General practices contributing data to the UK Clinical Practice Research Datalink. Participants Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. Main outcome measures Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes. Results Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia. Conclusions Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.

Purpose The magnitude of the risk of severe hypoglycemia associated with sulfonylureas as the initial treatment for type 2 diabetes in the real-world setting is unknown. We assessed the risk of severe hypoglycemia associated with initiating monotherapy with sulfonylurea compared with metformin for the treatment of type 2 diabetes. Methods By using the UK Clinical Practice Research Datalink and Hospital Episode Statistics linked to the Office for National Statistics, we identified a cohort of patients with type 2 diabetes who initiated sulfonylureas or metformin monotherapy between April 1, 1998, and December 31, 2012, with follow-up until December 31, 2013. Sulfonylurea users were matched one-to-one to metformin users by high-dimensional propensity scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia, defined as requiring hospitalization, were estimated using Cox proportional hazards models comparing sulfonylureas with metformin monotherapy. Results The study cohort consisted of 14,012 initiators of sulfonylureas matched to 14,012 initiators of metformin. The mean treated follow-up time was 1.41 (standard deviation, 1.84) years. Use of sulfonylurea was associated with an elevated incidence of severe hypoglycemia compared with metformin as the initiating monotherapy for type 2 diabetes (incidence rate, 2.4/1000 person-years; 95% CI, 1.90-2.90; HR, 4.53; 95% CI, 2.76-7.45). Conclusions Sulfonylureas, when prescribed as the initiating monotherapy for the treatment of type 2 diabetes, is associated with a 4.5-fold increase in the risk of severe hypoglycemia. Given the negative consequences of this outcome, clinicians should consider alternative hypoglycemic agents when metformin is not tolerated or contraindicated.

Diabetes is a chronic disease associated with increased morbidity and mortality (1), mainly from cardiovascular disease (2–6). Treatment of diabetes includes normalizing hyperglycemia to attain glycemic targets and treatment of cardiovascular risk factors such as hypertension and dyslipidemia. This multifactorial intervention strategy has been shown to decrease cardiovascular and all-cause mortality among patients with type 2 diabetes (7). Nevertheless, mortality in diabetes remains elevated (2,5). A number of epidemiological studies have quantified the risk of death among patients with diabetes and assessed the causes of death (2–6), with highly varying results (Table 1). The South Tees Diabetes Mortality Study (2) found an over threefold increase in all-cause mortality, mainly attributed to increased cardiovascular deaths, but found no increased risk of cancer mortality. The Australian Diabetes, Obesity and Lifestyle Study (AusDiab) (3) of over 10,000 individuals reported a little over twofold increase in the risk of all-cause mortality, with the majority due to cardiovascular causes. The Emerging Risk Factors Collaboration (ERFC) study (6), involving over 800,000 individuals, reported a little under twofold increase in the risk of all-cause mortality associated with diabetes. It also found that diabetes was associated with an increased risk of death from cancer (hazard ratio [HR] 1.25 [95% CI 1.19–1.31]), from vascular disease (HR 2.32 [95% CI 2.11–2.56]), and from nonvascular and noncancer etiologies (HR 1.73 [95% CI 1.62–1.85]). More recently, a study using the Swedish National Diabetes Register (5) on over 400,000 patients with type 2 diabetes matched to more than 2 million subjects …