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Aim . - We assessed the risk of all-cause hospitalization and all-cause death associated with the use of Sodium Glucose Cotransporter-2 inhibitors (SGLT2i). Methods . - Population-based propensity scores-matched cohort study of new users of metformin who subsequently initiated SGLT2i compared to those who initiated dipeptidyl peptidase-4 inhibitors (DPP4i) (primary comparison), sulfonylureas, thiazolidinediones, GLP1-Receptors agonists, and insulin, respectively. Alberta (Canada) health administrative data and United Kingdom Clinical Practice Research Datalink (CPRD) data were used to assess the study outcomes. Conditional Cox regressions were performed to assess the risk of each outcome, separately for each dataset and then results were combined using random-effects meta-analysis. Results . - For SGLT2i versus DPP4i, 7531 and 1647 SGLT2i-DPP4i matched pairs were analyzed in Alberta and CPRD data respectively. The mean age of patients was 56 and 57 years, and 39 % and 43% were females, respectively in Alberta and CPRD cohorts. Compared with DPP-4-i, SGLT2i use was associated with a significant lower risk of all-cause hospitalization (combined hazard ratio (HR): 0.84, 95% confidence interval (95%CI): 0.75-0.95), and all-cause death (0.56, 0.38-0.83). SGLT2i use was also associated with a significant lower risk of all-cause hospitalization and all-cause death when compared to sulfonylureas (HRs: 0.80, 95%CI: 0.71-0.90 and 0.56, 95%CI: 0.38-0.82, respectively) and insulin (HRs: 0.55, 95%CI: 0.41-0.74, and 0.33, 95%CI: 0.24-0.46, respectively). Conclusions . - SGLT2i initiation was associated with a decreased risk of all-cause hospitalization and all-cause death when compared to DPP4i, sulfonylureas, and insulin.

Background It is vigorously debated whether pneumococcal polysaccharide vaccination (PPV) reduces risk of acute coronary syndrome (ACS) events in patients with community-acquired pneumonia (CAP). Methods Clinical data were prospectively collected on a population-based cohort of adults presenting with CAP in Edmonton (Alberta, Canada). Multivariable Cox models and propensity matching were used to examine the association between PPV status and ACS events within 90 days of pneumonia. Sensitivity analyses related to PPV administration (before pneumonia vs after) and duration of benefit (90 days vs 1 year) were conducted to rule out confounding. Results Overall, 6171 patients were included; mean age 59 (SD 21) years, 53% male subjects, 18% had ischaemic heart disease and 2738 (44%) were hospitalised. Within 90 days of pneumonia, ACS events occurred in 175 (3%) patients and most were non-fatal (162 (93%)). In multivariable analyses, PPV exposure was associated with a 58% reduction in ACS events (12 vs 16 events per 100 patient-years, adjusted HR (aHR) 0.42 (0.27 to 0.66)) and results were nearly identical with propensity matching (aHR 0.46 (0.28 to 0.73)). However, indepth sensitivity analyses, with some with large assumptions, could not refute the existence of a small protective benefit of PPV. Conclusion Even after extensive adjustment using clinical data, the authors observed that PPV exposure was associated with a 60% reduction in ACS events among patients with pneumonia. Sensitivity analyses demonstrated that these findings, at least in part, were probably a result of confounding, most likely the ‘healthy-vaccinee’ effect. Previous observational studies using administrative data suggesting a very large protective benefit of PPV on ACS events may have been heavily confounded.

Summary Background For outpatients with pneumonia, guidelines recommend empiric antibiotics and some suggest macrolides are preferred agents. We hypothesized that both guideline-concordant antibiotics and macrolides would be associated with reduced mortality. Methods All outpatients with pneumonia assessed at 7 Emergency Departments in Edmonton, Alberta, Canada were enrolled in a population-based registry that included clinical-radiographic data, Pneumonia Severity Index (PSI) and treatments. Guideline-concordant regimens included macrolides and respiratory fluoroquinolones; other regimens were "discordant". Main outcome was 30-day all-cause mortality. Results The study included 2973 outpatients; mean age 51 years, 47% female, most had mild pneumonia (73% PSI Class I–II). Over 30-days, 38 (1%) patients died, 228 (8%) were hospitalized, and 253 (9%) reached the endpoint of death or hospitalization. Most (2845 [96%]) patients received guideline-concordant antibiotics. Compared to patients receiving discordant antibiotics, those receiving guideline-concordant antibiotics were less likely to die within 30-days (8 [6%] versus 30 [1%], adjusted OR 0.23, 95% CI 0.09–0.59, p = 0.002). Within the guideline-concordant subgroup, compared to the 947 (33%) patients treated with fluoroquinolones, those receiving macrolides [1847 (64%)] were less likely to die (25 [3%] versus 4 [0.2%], adjusted OR 0.28, 95% CI 0.09–0.86, p = 0.03). Conclusions In outpatients with pneumonia, treatment with guideline-concordant antibiotics and macrolides were both associated with mortality reduction.

The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach. Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression. Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.

The study objective was to evaluate the effects of sitagliptin in patients with type 2 diabetes (T2D) and heart failure (HF).There is uncertainty in the literature about whether dipeptidyl peptidase (DPP)-4 inhibitors cause harm in patients with HF and T2D.We analyzed data from a national commercially insured U.S. claims database. Patients with incident HF were identified from individuals with T2D initially treated with metformin or sulfonylurea and followed over time. Subjects subsequently using sitagliptin were compared with those not using sitagliptin in the 90 days before our primary outcome of all-cause hospital admission or death using a nested case-control analysis after adjustment for demographics and clinical and laboratory data. HF-specific hospital admission or death also was assessed.A total of 7,620 patients with diabetes and incident HF met our inclusion criteria. Mean (SD) age was 54 years (9), and 58% (3,180) were male. Overall, 887 patients (12%) were exposed to sitagliptin therapy (521 patient years of exposure) after incident HF. Our primary composite endpoint occurred in 4,137 patients (54%). After adjustment, sitagliptin users were not at an increased risk for the primary endpoint (7.1% vs. 9.2%, adjusted odds ratio [aOR]: 0.84, 95% confidence interval [CI]: 0.69 to 1.03) or each component (hospital admission 7.5% vs. 9.2%, aOR: 0.93, 95% CI: 0.76 to 1.14; death 6.9% vs. 9.3%, aOR: 1.16, 95% CI: 0.68 to 1.97). However, sitagliptin use was associated with an increased risk of HF hospitalizations (12.5% vs. 9.0%, aOR: 1.84, 95% CI: 1.16 to 2.92).Sitagliptin use was not associated with an increased risk of all-cause hospitalizations or death, but was associated with an increased risk of HF-related hospitalizations among patients with T2D with pre-existing HF.

Objective To determine the attributable risk of community acquired pneumonia on incidence of heart failure throughout the age range of affected patients and severity of the infection. Design Cohort study. Setting Six hospitals and seven emergency departments in Edmonton, Alberta, Canada, 2000-02. Participants 4988 adults with community acquired pneumonia and no history of heart failure were prospectively recruited and matched on age, sex, and setting of treatment (inpatient or outpatient) with up to five adults without pneumonia (controls) or prevalent heart failure (n=23 060). Main outcome measures Risk of hospital admission for incident heart failure or a combined endpoint of heart failure or death up to 2012, evaluated using multivariable Cox proportional hazards analyses. Results The average age of participants was 55 years, 2649 (53.1%) were men, and 63.4% were managed as outpatients. Over a median of 9.9 years (interquartile range 5.9-10.6), 11.9% (n=592) of patients with pneumonia had incident heart failure compared with 7.4% (n=1712) of controls (adjusted hazard ratio 1.61, 95% confidence interval 1.44 to 1.81). Patients with pneumonia aged 65 or less had the lowest absolute increase (but greatest relative risk) of heart failure compared with controls (4.8% v 2.2%; adjusted hazard ratio 1.98, 95% confidence interval 1.5 to 2.53), whereas patients with pneumonia aged more than 65 years had the highest absolute increase (but lowest relative risk) of heart failure (24.8% v 18.9%; adjusted hazard ratio 1.55, 1.36 to 1.77). Results were consistent in the short term (90 days) and intermediate term (one year) and whether patients were treated in hospital or as outpatients. Conclusion Our results show that community acquired pneumonia substantially increases the risk of heart failure across the age and severity range of cases. This should be considered when formulating post-discharge care plans and preventive strategies, and assessing downstream episodes of dyspnoea.

For patients hospitalized with pneumonia, guidelines provide empirical antibiotic recommendations and some studies suggest that macrolide/β-lactam combinations are preferable. We hypothesized that guideline-concordant regimens, particularly macrolide/β-lactams, would reduce mortality and ICU admissions. All patients hospitalized with pneumonia in Edmonton, Alberta, Canada, were managed according to a clinical pathway and enrolled in a population-based registry. Clinical data, Pneumonia Severity Index and treatments were collected. Guideline-concordant regimens were macrolides/β-lactams or respiratory fluoroquinolone monotherapy. The main outcome was in-hospital mortality. The study included 3203 patients and most had severe pneumonia (63% PSI Class IV-V). Three hundred and twenty-one (10.0%) patients died, 306 (9.6%) were admitted to the ICU and 570 (17.8%) achieved the composite of death or ICU admission. Most (n = 2506) patients received guideline-concordant antibiotics. Receipt of guideline-concordant antibiotics was not associated with a reduction in mortality alone (231 (9.2%) vs. 90 (12.9%); adjusted odds ratio (aOR), 0.82; 95% CI, 0.61–1.09; p 0.16), but was associated with decreased death or ICU admission (14.7% vs. 29.0%; aOR, 0.44; 95% CI, 0.36–0.54; p

Objective Our goal was to determine the association between random admission hyperglycemia and new diagnosis of diabetes after discharge in patients hospitalized with pneumonia. Methods Clinical data, including the Pneumonia Severity Index, were prospectively collected on all 2124 patients without diabetes admitted with pneumonia to 6 hospitals in Edmonton, Alberta, Canada. Admission glucose was classified as: normal (4.0-6.0 mmol/L, reference group) versus mild (6.1-7.7 mmol/L), moderate (7.8-11.0 mmol/L), and severe (11.1-20.0 mmol/L) stress hyperglycemia. New diagnosis of diabetes over 5 years was ascertained using well-validated criteria within linked administrative databases. Multivariable Cox models were used, and sensitivity, specificity, and likelihood ratios were calculated. Results Mean age was 68 years; 1091 (51%) were male, and 1418 (67%) had stress hyperglycemia. Over 5 years, 194 (14%) with stress hyperglycemia were diagnosed with diabetes. Compared with the 45 of 706 (6%) incidences of diabetes in normal glycemia patients (4.0-6.0 mmol/L), a strong graded increase in risk of new diabetes existed with increasing hyperglycemia: mild (59 of 841 [7%]; adjusted hazard ratio [aHR] 1.09; 95% confidence interval [CI], 0.74-1.61) versus moderate (86 of 473 [18%]; aHR 2.99; 95% CI, 2.07-4.31) versus severe (49 of 104 [47%]; aHR 11.43; 95% CI, 7.50-17.42). Among moderate-to-severe hyperglycemia (≥7.8 mmol/L) patients, the sensitivity, specificity, and positive and negative likelihood ratios for new diabetes were 57%, 77%, 2.1, and 0.6, respectively, with a number-needed-to-evaluate of 5 to detect one new case of diabetes. Conclusion Moderate-to-severe random hyperglycemia in pneumonia patients admitted to the hospital is strongly associated with new diagnosis of diabetes. Opportunistic evaluation for diabetes may be warranted in this group.