The association of long-acting insulin analogue use versus neutral protamine Hagedorn insulin use and the risk of major adverse cardiovascular events among individuals with type 2 diabetes: A population-based cohort study.

AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom.

BACKGROUND: Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. METHODS: We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. RESULTS: Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). CONCLUSION: Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.

Initiation of four basal insulins and subsequent treatment modification in people treated for type 2 diabetes in the United Kingdom: Changes over the period 2003-2018.

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.

SGLT-2 inhibitors and the risk of hospitalization for community-acquired pneumonia: A population-based cohort study.

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 (SD: 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.

Decreasing Surgical Site Infections in Plastic Surgery: A Systematic Review and Meta-analysis of Level 1 Evidence.

BACKGROUND: Although many interventions are implemented to prevent surgical site infections (SSIs) in plastic surgery, their supporting evidence is inconsistent. OBJECTIVES: The goal of this study was to assess the efficacy of methods for decreasing SSIs in plastic surgery. METHODS: A systematic review and meta-analysis were performed to compare the effects of SSI prevention methods. All the studies were assessed for quality of evidence according to the GRADE assessment. RESULTS: Fifty Level 1 randomized controlled trials were included. The most common interventions for preventing SSIs were antibiotic prophylaxis, showering, prepping, draping, and the use of dressings. Current evidence suggests that antibiotic prophylaxis is largely unnecessary and overused in many plastic surgical procedures, with the exception of head and neck oncologic, oral craniofacial, and traumatic hand surgeries. CONCLUSIONS: Efficacy of antibiotic prophylaxis in plastic surgery is dependent on surgery type. There is a lack evidence that showering and prepping with chlorohexidine and povidone reduces SSIs.

Predicting serum vitamin D concentrations based on self-reported lifestyle factors and personal attributes.

Evidence supports the role of vitamin D in various conditions of development and ageing. Serum 25-hydroxyvitamin D (25(OH)D) is the best indicator for current vitamin D status. However, the cost of its measurement can be prohibitive in epidemiological research. We developed and validated multivariable regression models that quantified the relationships between vitamin D determinants, measured through an in-person interview, and serum 25(OH)D concentrations. A total of 200 controls participating in a population-based case-control study in Montreal, Canada, provided a blood specimen and completed an in-person interview on socio-demographic, reproductive, medical and lifestyle characteristics and personal attributes. Serum 25(OH)D concentrations were quantified by liquid chromatography-tandem MS. Multivariable least squares regression was used to build models that predict 25(OH)D concentrations from interview responses. We assessed high-order effects, performed sensitivity analysis using the lasso method and conducted cross-validation of the prediction models. Prediction models were built for users and non-users of vitamin D supplements separately. Among users, alcohol intake, outdoor time, sun protection, dose of supplement use, menopausal status and recent vacation were predictive of 25(OH)D concentrations. Among non-users, BMI, sun sensitivity, season and recent vacation were predictive of 25(OH)D concentrations. In cross-validation, 46-47 % of the variation in 25(OH)D concentrations were explained by these predictors. In the absence of 25(OH)D measures, our study supports that predicted 25(OH)D scores may be used to assign exposure in epidemiological studies that examine vitamin D exposure.

Comparative effectiveness of Denosumab vs alendronate among postmenopausal women with osteoporosis.

Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab versus alendronate in reducing fracture risk among women with postmenopausal osteoporosis (PMO) in the US. Women with PMO ≥ 66 years of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk.

Osteoporosis-related fractures can have a significant impact on the health and quality of life of women with postmenopausal osteoporosis (PMO), as well as pose a significant burden to society. Although clinical trials have shown that denosumab is more effective at increasing bone mineral density compared to alendronate, there is a lack of evidence evaluating the fracture risk between these two commonly used osteoporosis therapies. In this study using Medicare claims data for almost 500 000 women with PMO with no prior history of osteoporosis medication use, we compared the risk of fracture, an important outcome to patients and health care providers, between denosumab and alendronate. Advanced analytic methods were implemented to ensure the study results were valid and were not unduly influenced by biases common in observational studies. We observed clinically meaningful reductions (from 30% up to 50%) in the risk of hip, nonvertebral, non-hip nonvertebral, hospitalized vertebral, and major osteoporotic fractures for patients treated with denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk than those who remained on alendronate.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50 years initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardised mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95% confidence interval (CI) between treatment and NCO was estimated using Cox models. Presence of residual confounding was evaluated with two approaches1: >5% of NCOs with 95% CI excluding 1,2 >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2-11% imbalance remaining after weighting, matching or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Treatment groups in clinical practice may not be comparable as patient characteristics differ according to the need for the prescribed medication, known as confounding. We assessed comparability of two common osteoporosis treatments, denosumab and oral bisphosphonate, in 280 288 postmenopausal women using electronic health records from UK Clinical Practice Research Datalink (CPRD) and Danish National Registries (DNR). We evaluated comparability of recorded patient characteristics with three propensity score (PS) methods, matching, stratification, and weighting. We assessed residual confounding from unrecorded patient characteristics via negative control outcomes (NCO), events known not to be associated with treatment such as delirium. We found that achieving comparability of osteoporosis treatment groups depended on the study population, PS method, and definition of residual confounding. Weighting and stratification performed the best in DNR and CPRD, respectively. Using a stricter threshold based on statistical significance for the NCO suggested the treatment groups were not comparable, except for PS stratification in DNR. Applying clinically significant thresholds of treatment effect size showed comparability using weighting in CPRD and all PS methods in DNR. Studies should consider more than one PS method to test robustness and identify the largest number of NCO to give the greatest flexibility in detecting residual confounding.

Efficacy and Safety of Aflibercept Therapy for Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

Purpose: To assess the real-world efficacy and safety of aflibercept for the treatment of diabetic macular edema (DME). Methods: A systematic search was conducted across multiple databases. Articles were included if participants had DME and received aflibercept treatment for a minimum of 52 ± 4 weeks. Primary outcomes included changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). A risk of bias assessment of studies was completed, pooled estimates were obtained, and a meta-regression was performed. Information on adverse events was collected. Results: The search yielded 2112 articles, of which 30 were included. Aflibercept was more effective than laser photocoagulation functionally (12-month BCVA-weighted mean difference [WMD] = 10.77 letters, P < 0.001; 24 months = 8.12 letters, P < 0.001) and anatomically (12-month CMT WMD = -114.12 µm, P < 0.001; 24 months = -90.4 µm, P = 0.004). Compared to bevacizumab, aflibercept was noninferior at improving BCVA at 12 months (WMD = 1.71 letters, P = 0.34) and 24 months (WMD = 1.58 letters, P = 0.083). One study found that aflibercept was more effective than bevacizumab anatomically at 1 and 2 years (P < 0.001 at 12 and 24 months). Compared to ranibizumab, aflibercept rendered a greater improvement in BCVA at 1 year (WMD = 1.76 letters, P = 0.001), but not 2 years (WMD = 1.66 letters, P = 0.072). CMT was not significantly different between both therapies at 12 months (WMD = -14.30 µm, P = 0.282) and 24 months (P = 0.08). One study reported greater functional improvement with aflibercept compared with dexamethasone (P = 0.004), but inferiority in reducing CMT (P < 0.001). Meta-regression analysis demonstrated that dosing schedule was found to impact outcomes at 12 and 24 months, while study design and sample size did not impact outcomes at 12 months. There were minimal safety concerns using aflibercept therapy. Conclusions: Aflibercept is a safe and effective therapy option for DME in the clinical setting, performing superiorly to laser photocoagulation. Evidence regarding comparisons with bevacizumab, ranibizumab, and dexamethasone is mixed and limited.

Type 2 diabetes mellitus and risk of community-acquired pneumonia: a systematic review and meta-analysis of observational studies.

BACKGROUND: People with type 2 diabetes are at greater risk for infections than those without type 2 diabetes. Our objective was to examine the association between type 2 diabetes and the risk of community-acquired pneumonia (CAP). METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, CINAHL, ProQuest theses and dissertations, Global Health, the Global Index Medicus of the World Health Organization, and Google Scholar. We included observational studies published in English or French between Jan. 1, 1946 (start of MEDLINE) and July 18, 2020. Two independent reviewers extracted data and assessed quality using the ROBINS-I tool. DerSimonian-Laird random-effects models were used to pool estimates of the association between type 2 diabetes and CAP. RESULTS: Our systematic review included 15 articles, reporting on 13 cohort studies and 4 case-control studies (14 538 968 patients). All studies reported an increased risk of pneumonia among patients with type 2 diabetes, and all were at serious risk of bias. When estimates were pooled across studies, the pooled relative risk was 1.64 (95% confidence interval [CI] 1.55-1.73); although there was a substantial amount of relative heterogeneity (I 2 94.2), the amount of absolute heterogeneity was more modest (T2 0.008). The relative risk was 1.70 (95% CI 1.63-1.77, I 2 85.2%, T2 0.002) among cohort studies (n = 13), and the odds ratio was 1.54 (95% CI 1.14-2.09, I 2 92.7%, T2 0.07) among case-control studies (n = 4). INTERPRETATION: Type 2 diabetes may be associated with an increased risk of CAP; however, the available evidence is from studies at serious risk of bias, and additional, high-quality studies are needed to confirm these findings. PROSPERO REGISTRATION: CRD42018116409.

Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: The cardiovascular safety of testosterone replacement therapy (TRT) is controversial. While several studies have investigated the association between TRT and the risk of arterial thrombosis, limited information is available regarding its risk of venous thromboembolism (VTE). We aimed to compare the risk of VTE in men randomized to TRT versus placebo or active-comparator in a systematic review. METHODS: We searched Medline, EMBASE, CINAHL, CENTRAL, and clinical trial registries to identify randomized controlled trials (RCTs) comparing TRT to placebo in men aged ≥18 years. We assessed study quality using the Cochrane Risk of Bias assessment tool and the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were pooled across RCTs using random-effects models. RESULTS: A total of 13 RCTs (n = 5050) were included in our meta-analysis. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and TRT duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49-2.14; I2: 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes. CONCLUSIONS: Our systematic review suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.

Efficacy and Safety of Metformin for Obesity: A Systematic Review.

CONTEXT: The efficacy and safety of metformin for obesity in children and adolescents remains unclear. OBJECTIVE: To assess the efficacy and safety of metformin via systematic review. DATA SOURCES: Data sources included PubMed, Embase, the Cochrane Library, Scopus, and ClincalTrials.gov (inception to November 2019). STUDY SELECTION: We selected randomized controlled trials (RCTs) in which researchers assessed the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity. DATA EXTRACTION: Two researchers independently extracted data and assessed quality. The primary outcomes were mean changes from baseline in BMI, BMI z score, homeostatic model assessment of insulin resistance, and gastrointestinal adverse effects. RESULTS: Twenty-four RCTs (1623 patients; range: 16 to 151) were included. Ages ranged from 4 to 19 years, and follow-up ranged from 2 months to 2 years. Metformin resulted in a modest decrease in BMI (range of mean values: -2.70 to 1.30 vs -1.12 to 1.90), BMI z score (range of mean values: -0.37 to -0.03 vs -0.22 to 0.15), and homeostatic model assessment of insulin resistance (range of mean values: -3.74 to 1.00 vs -1.40 to 2.66). Metformin resulted in a higher frequency of gastrointestinal adverse effects (range: 2% to 74% vs 0% to 42%). LIMITATIONS: The available evidence is of varying quality, with high heterogeneity between trials, suggesting some uncertainty in the benefits of metformin in this population. CONCLUSIONS: With this systematic review of RCTs, we suggest that metformin has modest but favorable effects on weight and insulin resistance and a tolerable safety profile among children and adolescents with obesity.

Meta-Analysis of Transcatheter Versus Surgical Aortic Valve Replacement in Low Surgical Risk Patients.

Current guidelines recommend transcatheter aortic valve implantation (TAVI) for patients with severe aortic stenosis at elevated surgical risk, but not for patients at low surgical risk. Our objective is to compare major clinical outcomes and procedural complications with TAVI versus surgical aortic valve replacement in patients with severe aortic stenosis at low surgical risk. We conducted a systematic review and meta-analysis of randomized controlled trials, identified through a systematic search of the MEDLINE, Embase, and Cochrane databases. Count data were pooled across trials using random-effects models with inverse variance weighting to obtain relative risks (RRs) and corresponding 95% confidence intervals (CIs). Three randomized controlled trials (n = 2,629) were included. At 30 days, TAVI was associated with a substantial reduction in all-cause mortality (RR: 0.45, 95%CI: 0.20 to 0.99), atrial fibrillation (RR: 0.27, 95%CI: 0.17 to 0.41), life threatening/disabling bleeding (RR: 0.29, 95%CI: 0.12 to 0.69), and acute kidney injury (RR: 0.28, 95%CI: 0.14 to 0.57). The reduction in atrial fibrillation persisted at 12 months (RR: 0.32, 95%CI: 0.21 to 0.49). However, TAVI patients had an increased risk of permanent pacemaker implantation at both 30 days (RR: 3.13, 95%CI: 1.36 to 7.21) and 12 months (RR: 2.99, 95%CI: 1.19 to 7.51). Due to the low absolute numbers of events, results were inconclusive at 30 days and 12 months for cardiovascular mortality, stroke, transient ischemic attack, and myocardial infarction. In conclusion, while some outcomes remained inconclusive, these data suggest that TAVI should be considered as a first-line therapy for the treatment of severe aortic stenosis in low surgical risk patients.

Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study.

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.

Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.

INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. METHODS: Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY® iPLEX® Gold SNP Genotyping assay. RESULTS: PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. CONCLUSION: Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals.

Screen and nonscreen sedentary behavior and sleep in adolescents.

OBJECTIVE: This study examined the associations between screen (computer, videogame, TV) and nonscreen (talking on the phone, doing homework, reading) sedentary time, and sleep in adolescents. PARTICIPANTS: Data were drawn from AdoQuest, a prospective investigation of 1843 grade 5 students aged 10-12 years at inception in the greater Montreal (Canada) area. METHODS: Data for this cross-sectional analysis on screen and nonscreen sedentary time, sleep duration, and daytime sleepiness were collected in 2008-2009 from 1233 participants (67% of 1843) aged 14-16 years. RESULTS: Computer and videogame use >2 hours per day was associated with 17 and 11 fewer minutes of sleep per night, respectively. Computer use and talking on the phone were both associated with being a short sleeper (<8 hour per night) (odds ratio =2.2 [1.4-3.4] and 3.0 [1.5-6.2], respectively), whereas TV time was protective (odds ratio=0.5 [0.3-0.8]). Participants who reported >2 hours of computer use or talking on the phone per day had higher daytime sleepiness scores (11.9 and 13.9, respectively) than participants who reported d2 hours per day (9.7 and 10.3, respectively). CONCLUSIONS: Computer use and time spent talking on the phone are associated with short sleep and more daytime sleepiness in adolescents. Videogame time is also associated with less sleep. Clinicians, parents, and adolescents should be made aware that sedentary behavior and especially screen-related sedentary behavior may affect sleep duration negatively and is possibly associated with daytime sleepiness.