Beneficial effects were observed for the individual endpoints of MACE (myocardial infarction, ischaemic stroke, and cardiovascular death). 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 Rabbit Polyclonal to GPRC6A with DPP-4 inhibitors, SGLT2 inhibitors (R)-CE3F4 were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 3.5; 0.85, 0.72 to 1 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). (R)-CE3F4 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 “type”:”clinical-trial”,”attrs”:”text”:”NCT03939624″,”term_id”:”NCT03939624″NCT03939624. Introduction Randomised controlled trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the incidence of major adverse cardiovascular events (MACE) among people with type 2 diabetes and previous cardiovascular disease.1 2 In the EMPAgliflozin Removal of Excess of Glucose OUTCOME trial, participants randomised to empagliflozin had decreased rates of MACE (a composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke) (hazard ratio 0.86, 95% confidence interval 0.74 to 0.99) and of hospital admission for heart failure (0.65, 0.50 to 0.85) compared with those randomised to placebo.3 Similar benefits were found in the CANagliflozin cardioVascular Assessment Study of canagliflozin.4 In contrast, the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 trial5 found that dapagliflozin was non-inferior to placebo for MACE (0.93, 0.84 to 1 1.03) and superior for hospital admission due to heart failure (0.73, 0.61 to 0.88).6 Although these randomised controlled trials found that SGLT2 inhibitors are efficacious compared with placebo, the cardiovascular effects of SGLT2 inhibitors compared with other second line to third line antidiabetic treatments remain unknown. Furthermore, the generalisability of data from these randomised (R)-CE3F4 controlled trials to a real world setting is uncertain.7 To date, several observational studies have examined the association between SGLT2 inhibitors and cardiovascular outcomes, with most of these studies showing a reduced risk in comparisons with other antidiabetic drugs. 8 9 10 11 12 13 14 15 A few of these studies, however, had important limitations that make it difficult to interpret the results. (R)-CE3F4 These limitations included the presence of immortal time bias16 17 18 in three studies.8 9 13 In addition, all these studies used new user designs and thus excluded individuals with recent use of the comparator drugs. Given the highly dynamic treatment of type 2 diabetes and the frequent use of other second line or third line treatments before the initiation of SGLT2 inhibitors, such exclusions can greatly affect the generalisability of study results and might even introduce selection bias.19 Furthermore, limited data are available on the cardiovascular effects of individual SGLT2 inhibitors. We compared the risks of MACE, its components, all cause mortality, and heart failure associated with SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors (a class of oral antidiabetic drugs usually prescribed as a second line or third line treatment of type 2 diabetes) among people with type 2 diabetes by applying a prevalent new user design to population based data from eight jurisdictions. This study was conducted by the Canadian Network for Observational Drug Effect Studies (CNODES).20 Methods Data sources We implemented a prevalent new user design in a retrospective multi-database cohort study using administrative healthcare databases from the Canadian provinces of Alberta, British Columbia, Manitoba, (R)-CE3F4 Nova Scotia, Ontario, Quebec, and Saskatchewan, and the United Kingdom Clinical Practice Research Datalink (CPRD). The Canadian databases include population wide data on doctor claims, hospital admission records, and prescription drug claims. Prescription drug data are restricted to those aged 18 years or more in Alberta, those aged 65 years or more in Ontario, and those aged 65 years or more, receiving social assistance, or without access to a private insurance plan in Quebec. Prescription drug data are available for all ages in the other jurisdictions. The CPRD is a primary care database that contains the records of more than 15 million people registered with more than 700 general practices in the UK.21 Importantly, it includes clinical data not.