Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis

Abstract

BackgroundA pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterise the CV profile of dapagliflozin. This showed no increase in CV risk with dapagliflozin compared with control (placebo or comparator treatment) with or without background glucose-lowering therapies. The analysis reported here aimed to characterise the CV profile of dapagliflozin in subgroups of patients in these 21 studies grouped by degree of CV risk, based on both baseline and in-study risk factors (including hypoglycaemic events), with a focus on major adverse CV events (MACE).MethodsPatients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analysed. A further analysis compared CV risk in patients who experienced a hypoglycaemic event prior to MACE and those who did not. Analyses were based on time to first event using a Cox proportional hazards model stratified by study comparing dapagliflozin versus control.ResultsIn total, 9339 patients were included in this meta-analysis; 5936 patients received dapagliflozin 2.5–10 mg (6668 patient–years) and 3403 received control (3882 patient–years). Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population [Hazard Ratio (HR) 0.77; 95 % CI (0.54, 1.10) for MACE] and in those with a history of CVD [HR 0.80 (0.53, 1.22)]. These findings were consistent in patients with varying degrees of CV risk, including age, number and type of CVD events in medical history and number of CV risk factors present. Furthermore, there was no increased risk of MACE in patients who experienced a hypoglycaemic event compared with those who did not.ConclusionsThere was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated. In addition, the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium–glucose cotransporter-2 (SGLT2) inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0356-y) contains supplementary material, which is available to authorized users.

Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?

“…Furthermore, use of dapagliflozin seemed to have a neutral effect on the risk for stroke (HR 0.999; 95% CI 0.536 to 1.864) 31. However, meta-analytic data of CV events from phase II and III trials of canagliflozin were reported in the European Medicines Agency assessment report, and among other CV outcomes examined, a slight trend for a higher stroke risk was noted among patients on canagliflozin treatment (HR1.47; 95% CI 0.83 to 2.59).…”

The impact of dapagliflozin on cardiovascular system in the course of type 2 diabetes mellitus

“…The beneficial effect of dapagliflozin on cardiovascular risk reduction has also been demonstrated in another meta-analysis by Sonesson et al [23]. The incidence of MACE and unstable IHD in the dapagliflozintreated group in relations to control group matched for age, BMI, duration of diabetes, smoking, eGFR, LDL cholesterol and blood pressure were analysed.…”

“…The incidence of MACE and unstable IHD in the dapagliflozintreated group in relations to control group matched for age, BMI, duration of diabetes, smoking, eGFR, LDL cholesterol and blood pressure were analysed. After about four years of treatment, dapagliflozin has been shown to reduce the risk of MACE and/or unstable angina in all groups of patients, even in those with a history of cardiovascular events and hypertension [23].…”

A consensus statement for the clinical use of the renal sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes mellitus

“…Due to its rapid effects on kidney, dapagliflozin rapidly reduces also glucose toxicity. Several registrative trials confirmed that the insulin-independent fast glucose-lowering effect of dapagliflozin does not generate specific metabolic or apparent CV harm [8]. A possible direct effect on the alpha cell leading to increase glucagon secretion has been claimed [9].…”

“…A simulated projection by using the Archimedes model showed that adding dapagliflozin to other antidiabetic agents further decreases CV and microvascular complications associated with T2DM over a 20-year period [62]. Thus, dapagliflozin has the potential for a beneficial effect both in the overall population and in those with a history of CV disease [8].…”