Objective: To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.Design: We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).Intervention: SGLT2 inhibitors, compared with placebo or active comparators.Primary outcomes: Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.Results: We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I²=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I²=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I²=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I²=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I²=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.Conclusions: Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.PROSPERO registration number: CRD42016038715.

Background. Patients with hypoxemia (blood oxygen saturation <90%) are usually hospitalized, although validated criteria (eg, the Pneumonia Severity Index [PSI]) suggest outpatient treatment is safe. We sought evidence to support or refute the practice. Methods. All patients in Edmonton, Alberta, Canada with pneumonia assessed at any of 7 emergency departments (EDs) and then discharged were enrolled in a population-based cohort study. The independent variable of interest was oxygen saturation; the outcome was the composite endpoint of 30-day mortality or hospitalization. Results. The study evaluated 2923 individuals with pneumonia who were treated as outpatients at any of 7 EDs. The patients’ mean age (standard deviation [SD])was 52 (20) years; 47% were women; 74% were low risk (PSI Class I–II). The mean blood oxygen saturation (SD) was 95% (3%); 126 patients (4%) had blood oxygen saturations <90%, and 201 patients (7%) had blood oxygen saturations of 90%–92%. Over 30 days, 39 patients (1%) died and 252 (9%) reached the composite endpoint. Compared with patients with higher blood oxygen saturations, those discharged with saturations <90% had significantly (P < .001) higher rates of 30-day mortality (7 [6%] vs 32 [1%]), hospitalization (23 [18%] vs 201 [7%]), and composite endpoints (27 [21%] vs 225 [8%]). Blood oxygen saturation <90% was independently associated with 30-day mortality or hospitalization (adjusted odds ratio (OR), 1.7; 95% confidence interval (CI) 1.1–2.8; P = .032). If the saturation threshold for hospitalization was 92%, then there was no association with adverse events (adjusted OR 1.1, 95% CI 0.8–1.7, P = .48). Raising the admission threshold to 92% entails 1 additional hospitalization for every 14 patients discharged. Conclusions. Among outpatients with pneumonia, oxygen saturations <90% were associated with increased morbidity and mortality. Our results indicate a hospital admission threshold of <92% would be safer and clinically better justified.

Background—: Access to medical care differs between urban and rural residents, but the magnitude of these differences and whether they affect outcomes are unknown. We aimed to determine whether outcomes differ for patients with incident heart failure (HF) by urban-rural status. Methods and Results—: This cohort study used administrative data from Alberta, Canada. Patients with incident HF were identified from April 1, 1999, to December 31, 2005, and followed for 1-year. Multivariable logistic regression was used to assess differences in 1-year outcomes after initial HF diagnosis in patients living in rural versus urban settings. We identified 72 043 patients with incident HF (mean age, 72±14; male sex, 50%) of whom 12 173 (17%) died and 29 074 (39%) were hospitalized within 1 year. Although crude all-cause 1-year mortality rates were higher in urban than in rural residents (17.3% versus 15.6%, P <0.001), after adjustment for comorbidities, no significant differences were observed (adjusted odds ratio [aOR], 0.95; 95% CI, 0.90 to 1.00). However, sex-specific analyses indicated that urban men had a significantly lower risk of mortality than rural men (aOR, 0.89; 95% CI, 0.83 to 0.96). In contrast, no difference was observed between urban and rural women (aOR, 1.02; 95% CI, 0.94 to 1.10). Urban patients were more likely to have office-based physician visits in the first year after HF diagnosis (aOR, 1.09; 95% CI, 1.02 to 1.17) and exhibited lower rates of hospitalization (aOR, 0.71; 95% CI, 0.68 to 0.74) and emergency department visits (aOR, 0.62; 95% CI, 0.60 to 0.65) than rural patients. Conclusions—: Even within a universal healthcare system, there are differences in outcomes after HF diagnosis based on location of residence. Urban patients with HF are more likely to receive outpatient care and less likely to be hospitalized or present to the emergency department in the first year after diagnosis than rural patients with HF.

Objective: To quantify the association between diabetes and the risk of incident infections by conducting a systematic review and meta-analysis. Research design and methods: Two reviewers independently screened articles identified from PubMed, EMBASE, Cochrane Library, IPA, and Web of Science databases. Cohort studies (CS) or case–control studies (CCS) evaluating the incidence of infections in adults with diabetes were included. Infections were classified as: skin and soft tissue, respiratory, blood, genitourinary, head and neck, gastrointestinal, bone, viral, and non-specified infections. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Summary crude and adjusted OR with 95% CIs were calculated using random effects models, stratified by study design. Heterogeneity was measured using the I²statistic and explored using subgroup analyses. Results: A total of 345 (243 CS and 102 CCS) studies were included. Combining adjusted results from all CS, diabetes was associated with an increased incidence of skin (OR 1.94, 95% CI 1.78 to 2.12), respiratory (OR 1.35, 95% CI 1.28 to 1.43), blood (OR 1.72, 95% CI 1.48 to 2.00), genitourinary (OR 1.61, 95% CI 1.42 to 1.82), head and neck (OR 1.17, 95% CI 1.13 to 1.22), gastrointestinal (OR 1.48, 95% CI 1.40 to 1.57), viral (OR 1.29, 95% CI 1.13 to 1.46), and non-specified (OR 1.84, 95% CI 1.66 to 2.04) infections. A stronger association was observed among CCS: skin (OR 2.64, 95% CI 2.20 to 3.17), respiratory (OR 1.62, 95% CI 1.37 to 1.92), blood (OR 2.40, 95% CI 1.68 to 3.42), genitourinary (OR 2.59, 95% CI 1.60 to 4.17), gastrointestinal (OR 3.61, 95% CI 2.94 to 4.43), and non-specified (OR 3.53, 95% CI 2.62 to 4.75). Conclusion: Diabetes is associated with an increased risk of multiple types of infections. A high degree of heterogeneity was observed; however, subgroup analysis decreased the amount of heterogeneity within most groups. Results were generally consistent across types of infections.

People with diabetes may be at higher risk for acquiring infections through both glucose-dependent and biologic pathways independent of glycemic control. Our aim was to estimate the association between diabetes and infections occurring in primary care. Using the Newfoundland and Labrador Sentinel of the Canadian Primary Care Sentinel Surveillance Network, patients with diabetes ≥18 years between 1 January 2008 and 31 March 2013 were included with at least 1-year of follow-up. We randomly matched each patient with diabetes on the date of study entry with up to 8 controls without diabetes. Primary outcome was the occurrence of ≥1 primary care physician visits for any infectious disease. Secondary outcomes included primary visits for head & neck, respiratory, gastrointestinal, genitourinary, skin and soft tissue, musculoskeletal, and viral infections. Using multivariable conditional logistic regression analysis, we measured the independent association between diabetes and the occurrence of infections. We identified 1779 patients with diabetes who were matched to 11,066 patients without diabetes. Patients with diabetes were older, had a higher prevalence of comorbidities, and were more often referred to specialists. After adjusting for potential confounders, patients with diabetes had an increased risk of any infection compared to patients without diabetes (adjusted odds ratio = 1.21, 95% confidence interval 1.07–1.37). Skin and soft tissue infections had the strongest association, followed by genitourinary, gastrointestinal, and respiratory infections. Diabetes was not associated with head and neck, musculoskeletal, or viral infections. Patients with diabetes appear to have an increased risk of certain infections compared to patients without diabetes.