Showing papers by "Pierre Ernst published in 2020"
TL;DR: SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect; prior receipt of insulin appeared to decrease the risk.
Abstract: Background Sodium-glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA). Objective To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes. Design Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221). Setting Electronic health care databases from 7 Canadian provinces and the United Kingdom. Patients 208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors. Measurements Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin. Results Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk. Limitations There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites. Conclusion SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect. Primary funding source Canadian Institutes of Health Research.
74 citations
TL;DR: The short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors, and similar benefits for MACE were observed with canagliflozin.
Abstract: Objective To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. Design Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. Setting Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. Population 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. Main outcome measures The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. Results Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). Conclusions In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. Trial registration ClinicalTrials.gov NCT03939624.
57 citations
TL;DR: In this paper, the authors compared the effectiveness and safety of triple therapy with a LAMA-LABA combination in a real-world clinical practice setting, and found that the triple combination of LAMA, LABA, and ICS inhalers is generally as effective as combining LAMA and LABA inhalers in preventing COPD exacerbations.
43 citations
Jewish General Hospital1, University of Toronto2, Sunnybrook Health Sciences Centre3, International Council for the Exploration of the Sea4, McGill University5, Saskatchewan Health6, University of Manitoba7, University of British Columbia8, Memorial University of Newfoundland9, University of Calgary10
TL;DR: 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, and studies with a longer duration of follow-up are needed to assess potential long-term effects.
Abstract: 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.
21 citations
TL;DR: Inhaled corticosteroid use is not associated with a reduction in lung cancer incidence in patients with COPD, and the proposition of a randomised trial warrants some caution.
Abstract: Background Inhaled corticosteroids (ICS) are suggested for potential chemoprevention of lung cancer. Several observational studies in patients with chronic obstructive pulmonary disease (COPD) reported inconsistent results, either significant reductions in lung cancer incidence with ICS use or no effect. We assessed this association, using an approach that avoided biases affecting some of the studies. Methods A cohort of patients with COPD, new users of long-acting bronchodilators over 2000–2014, was formed using the Quebec healthcare databases, and followed until 2015 for a first diagnosis of lung cancer. A 1-year delay after cohort entry was used to avoid protopathic bias and a 1-year latency period was included after the initiation of ICS use. A time-dependent Cox regression model was used to estimate the hazard ratio (HR) of lung cancer associated with ICS exposure, adjusted for covariates. Results The cohort involved 63 276 subjects, including 63% receiving ICS, with 3743 lung cancers occurring during a mean follow-up of 5 years. The adjusted HR of lung cancer associated with any ICS exposure was 1.01 (95% CI 0.94–1.08), relative to no ICS use. The HR with longer time (>4 years) since ICS initiation was 0.92 (95% CI 0.83–1.03), while with higher mean daily ICS dose (>1000 μg fluticasone equivalents) was 1.36 (95% CI 1.03–1.81). Conclusions Inhaled corticosteroid use is not associated with a reduction in lung cancer incidence in patients with COPD. Observational studies reporting such reduction may have been affected by time-related biases and the inclusion of patients with asthma. The proposition of a randomised trial warrants some caution.
17 citations
TL;DR: Fluentquinolones are associated with improved clinical outcomes among women with uncomplicated UTIs and must be weighed against risk of fluoroquinolone resistance and rare but serious fluoroquetolone side effects when selecting first line treatment for these patients.
16 citations
TL;DR: The apparent association of β2 agonists with a decreased risk of Parkinson's disease is likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD.
Abstract: A recent study found a decreased risk of Parkinson disease (PD) associated with the β2 adrenergic agonist (β2-agonist) salbutamol. However, other mechanisms might explain this apparent association. Using the UK Clinical Practice Research Datalink, we formed a cohort of 2,430,884 patients aged 50 years or older between 1995 and 2016. During follow-up, 8,604 cases of PD were identified and matched to 86,040 controls on sex, age, date of cohort entry, and duration of follow-up, after applying a 1-year latency time window. Incidence rate ratios of PD associated with use of β2-agonists were estimated using conditional logistic regression. Ever-use of β2-agonists was associated with a 17% decreased rate of PD (rate ratio = 0.83, 95% confidence interval: 0.75, 0.91) compared with no use. However, this association was limited to early short-term use and was no longer observed after more than 2 years of cumulative duration of use (rate ratio = 0.97, 95% confidence interval: 0.80, 1.17). A similar pattern was observed when stratifying by time since first β2-agonist prescription and by duration of follow-up. The apparent association of β2-agonists with a decreased risk of PD is likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD.
11 citations
TL;DR: In this large multi-site study, an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting was not observed.
Abstract: Aim: To compare urosepsis rates in patients with type 2 diabetes treated using sodium-glucose co-transporter-2 inhibitors (SGLT2i) with dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world setting.
Methods: We conducted a matched cohort study using a prevalent new-user design with time-conditional propensity scores. New users of SGLT2i from seven Canadian provinces and the UK were matched to DPP4i users. The primary outcome was hospitalization with a diagnosis of urosepsis and the secondary outcome was Fournier's gangrene. Site-specific hazard ratios for urosepsis comparing SGLT2i with DPP4i were estimated using Cox proportional hazards models and pooled using a random effects meta-analysis.
Results: We included 208 244 users of SGLT2i and 208 244 users of DPP4i. Among SGLT2i users, 42% initiated canagliflozin, 31% dapagliflozin and 27% empagliflozin. During a mean follow-up of 0.9 years, patients initiating SGLT2i had a lower rate of urosepsis compared with those receiving DPP4i. The pooled adjusted hazard ratio was 0.58 (95% confidence interval [CI]: 0.42-0.80). The incidence rates of Fournier's gangrene were numerically similar in SGLT2i (0.08 per 1000 person-years; 95% CI: 0.05-0.13) and DPP4i users (0.14; 95% CI: 0.09-0.21).
Conclusions: In this large, multi-site study, we did not observe an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting.
9 citations
TL;DR: The method of data analysis used in the study of the association between inhaled corticosteroids and lung cancer incidence in COPD used the proper analysis that avoided immortal time bias, though the wide discrepancy in results with other studies remains; further studies are needed.
Abstract: Raymakers and colleagues used the proper analysis that avoided immortal time bias, though the wide discrepancy in results with other studies remains; further studies are neededhttp://bit.ly/2Oobgqb
5 citations