Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data

Abstract

BackgroundTreatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors.MethodsAnalyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports.ResultsAt week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (−0.95 and −1.07%) versus no history of CV disease (−0.71 and −0.90%), history of hypertension (−0.72 and −0.89%) versus no history of hypertension (−0.73 and −0.95%), baseline statin use (−0.77 and −0.99%) versus no statin use (−0.69 and −0.85%), and 0–1 CV risk factor (−0.72 and −0.87%) versus ≥2 CV risk factors (−0.74 and −1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.ConclusionsThe efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors. Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0517-7) contains supplementary material, which is available to authorized users.

Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice

“…Furthermore, many studies demonstrated that SGLT2is decrease body weight, blood pressure, and TG. These results support the hypothesis that SGLT2is have specific cardioprotective effects 16,17) . Further studies are needed to understand the cardioprotective effects of SGLT2is.…”

“…Recent randomized placebo-control studies found that sodium-dependent glucose transport 2 inhibitors (SGLT2is) (e.g., canagliflozin) reduced cardiovascular events in addition to their effect as antidiabetic drugs [11][12][13][14] . Previous studies demonstrated that SGLT2is reduce blood glucose levels, blood pressure, and body weight in T2DM patients, all of which play roles in atherogenesis 11,[15][16][17] . However, the mechanisms by which SGLT2is prevent cardiovascular events are not completely understood and need to be explored to achieve better treatment in T2DM patients with risk of cardiovascular events.…”

“…By contrast, recent studies demonstrated that SGLT2i, including canagliflozin, reduced cardiovascular events in diabetic patients 11,12) . Several studies demonstrated that canagliflozin reduced albuminuria, plasma lipid levels, blood pressure, and body weight, in addition to its effect as an antidiabetic drug, thus suggesting that these metabolic actions of canagliflozin contribute to cardiovascular protection 11,[15][16][17] . However, the mechanisms by which SGLT2is reduce cardiovascular events are not well established.…”

Effect of SGLT2 inhibitors on body composition, fluid status and renin–angiotensin–aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy

“…In contrast to our study cohort, patients with heart failure are at risk for fluid overload and extracellular water accumulation, leading to hydropic decompensation and hospitalization [47]. Treatment with SGLT2 inhibitors has been shown to reduce this risk [12] and was found to be safe and efficient in patients with type 2 diabetes and different stages of cardiovascular disease [48]. SGLT2 inhibition could lead to a sustained correction of fluid accumulation in patients starting with an elevated level of overhydration and extracellular water.…”

A safety update on sodium glucose co‐transporter 2 inhibitors

“…In a pooled data analysis of four clinical trials with canagliflozin, both 100 and 300 mg doses were associated with an increased frequency of osmotic diuresis symptoms (eg, increased urine volume and frequency) yet symptoms related to a reduction of vascular volume (eg, orthostatic and postural hypotension) were not increased by either dose. In an analysis of several trials with empagliflozin, events related to volume depletion were infrequent (1.8%) yet significantly increased in older patients over aged 75 years…”