Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study

Abstract

ObjectiveTo evaluate the cardiovascular safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice.DesignPopulation based retrospective cohort study.SettingNationwide sample of patients with type 2 diabetes from a large de-identified US commercial healthcare database (Optum Clinformatics Datamart).ParticipantsThree pairwise 1:1 propensity score matched cohorts of patients with type 2 diabetes 18 years and older who initiated canagliflozin or a comparator non-gliflozin antidiabetic agent (ie, a DPP-4i, a GLP-1RA, or a sulfonylurea) between April 2013 and September 2015.Main outcome measuresThe primary outcomes were heart failure admission to hospital and a composite cardiovascular endpoint (comprised of being admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke). Hazard ratios and 95% confidence intervals were estimated in each propensity score matched cohort controlling for more than 100 baseline characteristics.ResultsDuring a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354 ). The hazard ratio for the composite cardiovascular endpoint associated with canagliflozin was 0.89 (0.68 to 1.17) versus a DPP-4i, 1.03 (0.79 to 1.35) versus a GLP-1RA, and 0.86 (0.65 to 1.13) versus a sulfonylurea. Results were similar in sensitivity analyses further adjusting for baseline hemoglobin A1c levels and in subgroups of patients with and without prior cardiovascular disease or heart failure.ConclusionsIn this large cohort study, canagliflozin was associated with a lower risk of heart failure admission to hospital and with a similar risk of myocardial infarction or stroke in direct comparisons with three different classes of non-gliflozin diabetes treatment alternatives as used in routine care.

Cardiovascular outcomes of sodium glucose cotransporter‐2 inhibitors in patients with type 2 diabetes

“…To address this in our study, we employed an incident new‐user design and we censored follow‐up when patients switched from one drug to another. Two other recent analyses of real‐world data reported findings similar to those of our study …”

“…Several observational studies have recently evaluated the cardiovascular safety of SGLT2 inhibitors among patients with type 2 diabetes . One population‐based study, which used data from the Health Improvement Network database, found that, compared to use of other glucose‐lowering agents, the use of empagliflozin was associated with lower risk of all‐cause mortality, irrespective of baseline CVD .…”

“…Similarly, the first analysis from the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT‐2 Inhibitors (CVD‐REAL) study and two follow‐up analyses of the same study showed a lower risk of death and hospitalization as the result of heart failure with use of SGLT2 inhibitors compared to other glucose‐lowering medications (eg, sulfonylureas, thiazolidinediones [TZDs]) but showed no difference in incidence of non‐fatal MI and non‐fatal stroke . In contrast, the most recent analyses of the CVD‐REAL study and two other observational studies, which primarily focused on canagliflozin, reported a lower risk of non‐fatal MI and non‐fatal stroke but a higher risk of lower extremity amputation with the use of SGLT2 inhibitors compared to other glucose‐lowering medications …”

Comparative risk of genital infections associated with sodium‐glucose co‐transporter‐2 inhibitors

“…Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors—a newer class of antidiabetic medications—reduce plasma glucose in an insulin‐independent manner by inhibiting glucose reabsorption in the proximal tubule . In addition to reducing serum glucose concentration, SGLT2 inhibitors also exert additional beneficial effects on cardiovascular markers including blood pressure and body weight, cardiovascular endpoints and all‐cause mortality …”

Eligibility of patients with type 2 diabetes for sodium‐glucose co‐transporter‐2 inhibitor cardiovascular outcomes trials: An assessment using the Diabetes Collaborative Registry

“…However, patients with T2D and a broad CV risk profile enrolled in DECLARE experienced significant reductions in the composite of CV death or heart failure hospitalizations when treated with dapagliflozin compared with placebo . Further supporting these findings from CVOTs, the CVD‐REAL 1 and 2 studies, as well as other real‐world studies, also found a significantly lower risk of CV events associated with initiation of an SGLT‐2i (vs other glucose‐lowering agents). Although large pharmacoepidemiologic studies such as CVD‐REAL have potential limitations (including a possibility of residual confounding), their findings are important and complementary to randomized controlled trials, as they include a population of patients with T2D that is much more representative of that seen in routine clinical practice, with a much broader CV risk profile (13‐25% of patients had prior CVD in CVD‐REAL) …”