Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

ABSTRACTReview of: Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.The report combines the data from two trials, CANVAS and CANVAS-Renal, which were designed to evaluate the safety and effect of canagliflozin, an SGLT-2 inhibitor, on the appearance of cardiovascular and renal events in patients with type 2 diabetes. Enrollees were patients with type 2 diabetes of at least 30 years of age, with a glycated hemoglobin of > or equal to 7.0% and < or equal to 10.5%. Patients either had to have preexisting cardiovascular disease or to be at elevated risk for cardiovascular disease, and to have an estimated glomerular filtration rate (eGFR) of >30 ml/min. Patients were randomized to canagliflozin at doses of either 100 mg or 300 mg or matching placebo in CANVAS, and to canagliflozin 100 mg with a possible increase to 300 mg, or placebo, in CANVAS-Renal. Physicians were instructed to continue appropriate diabetic management and other therapies in accordance with the best practices in their community. There was a significant 14% reduction in the combined endpoint of cardiovascular events of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in the canagliflozin treated patients. There was also a pattern of improvement in markers of renal disease, including the change in the level and nature of albuminuria, a 40% decrease in the glomerular filtration rate, the need for renal replacement therapy, or death from renal causes. This study expands the scope of SGLT-2 inhibitor therapy to prevent cardiovascular disease in diabetic patients beyond those with preexisting cardiovascular disease studied in the previous empagliflozin study, raising the question as to whether SGLT-2 inhibitor therapy should be considered appropriate for most, if not all, type 2 diabetes patients, not only to control hyperglycemia but also to reduce cardiovascular and renal events.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study

CKD is a common complication in people with diabetes ([1][1]) and contributes to approximately half of all incident cases of ESKD in the developed world ([2][2]). CKD occurs in approximately 40% of people with type 2 diabetes ([3][3]); given the health-related effects of CKD, there is great need for

Choosing the Best Therapy for Your Patients in Today's Diabetes World.

Background and Aims Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have revolutionized the management of chronic kidney disease (CKD). As shown in large randomized clinical trials, they reduce the incidence of atherosclerotic cardiovascular disease and heart failure and they delay CKD progression. There is evidence from pharmacokinetic studies that their effect on surrogate endpoints, such as albuminuria or blood pressure, might be dose dependent. However, the effect of SGLT-2 inhibitor dosage on hard clinical endpoints has not been adequately studied. This analysis investigates whether the effects of canagliflozin on cardiovascular and renal endpoints are dose dependent. Methods The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) randomly assigned 4,330 patients with type 2 diabetes and high cardiovascular risk to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo in a 1:1:1 ratio. Results from this trial were reported together with CANVAS-R in the CANVAS program but have not been published independently [1]. Our post-hoc analysis evaluates the impact of each dose of canagliflozin on cardiovascular and renal outcomes. Our primary endpoint was a composite of non-fatal myocardial infarction, stroke, or cardiovascular death. Secondary endpoints included the individual components of the primary outcome, hospitalization for heart failure, all-cause mortality, a composite renal endpoint (including doubling of serum creatinine, end-stage kidney disease or renal death), sustained 40% reduction in estimated glomerular filtration rate, and albuminuria progression or regression. Safety outcomes included acute kidney injury and serious hyperkalemia. Hazard ratios (HR) were estimated using Cox proportional hazards models. Kaplan-Meier survival curves were compared across groups using the log-rank test. Results The study enrolled 4330 participants with type 2 diabetes and high cardiovascular risk. Median age was 61 years and 66% of patients were males. Baseline characteristics were similar across all treatment groups. Median follow-up was 74 months. In the adjusted analysis for age, sex, and history of cardiovascular disease, canagliflozin at 300 mg significantly reduced the incidence of the composite cardiovascular endpoint, compared with placebo: hazard ratio (HR) of 0.83, 95% confidence interval (CI) of 0.68–1.00 (p = 0.049). In contrast, no difference was identified between canagliflozin 100 mg, compared with placebo, for the composite cardiovascular endpoint: HR 0.96 (95% CI 0.80–1.15, p = 0.64). Both doses of canagliflozin were associated with a significant reduction in the incidence of the composite renal endpoint, compared with placebo: HR 0.50 for canagliflozin 100 mg (95% CI 0.25–0.96, p = 0.039) and HR 0.42 for canagliflozin 300 mg (95% CI 0.21–0.86, p = 0.017). Albuminuria progression to a higher stage (A1 to A2 or A2 to A3) was less common with the 300 mg dose, compared with placebo (HR 0.83, 95% CI 0.73–0.95, p = 0.006), but not with 100 mg dose (HR 0.94, 95% CI 0.83–1.07, p = 0.326). All-cause mortality was significantly lower with the 300 mg dose compared with placebo (HR 0.78, 95% CI 0.63–0.97, p = 0.027). In addition, a trend towards lower mortality rates was seen with the 100 mg dose. The incidence of acute kidney injury was comparable across the three treatment arms. A trend towards fewer severe hyperkalemia episodes was seen with the 300 mg canagliflozin dose. Results for all secondary and safety endpoints are shown in Table. Conclusion This post-hoc analysis of the CANVAS trial demonstrates a dose-dependent effect of canagliflozin on cardiovascular endpoints. However, both doses of canagliflozin seem equally effective for the prevention of hard clinical renal endpoints. In addition, both doses of the drug had a comparable safety profile. Our findings suggest that the higher canagliflozin dose may be considered in all patients with type 2 diabetes at high cardiovascular risk.

Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure (HF) and cardiovascular death overall, in those with and without a baseline history of HF, and in other participant subgroups. The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized HF. Participants with a history of HF at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized HF was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized HF (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized HF alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized HF may be greater in patients with a prior history of HF (HR, 0.61; 95% CI, 0.46-0.80) compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without HF at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of HF ( P=0.03). In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized HF across a broad range of different patient subgroups. Benefits may be greater in those with a history of HF at baseline. URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

To the Editor: In the trials of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (Aug. 17 issue),1 patients who had been assigned to receive canagliflozin had significantly lower rates of the primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) than those assigned to receive placebo (hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97). Beyond statistical significance, however, a treatment difference must be clinically significant.2 On an absolute scale, these results show that more than 200 patients must receive daily canagliflozin for the duration of the trial (mean, 3.6 years; median, 2.4 .

Time to Invest in the Future: Assessing the Cost-Effectiveness of Empagliflozin in Diabetic Kidney Disease

IntroductionIn the EASEL study of patients with type 2 diabetes and high cardiovascular risk, initiation of sodium glucose co‐transporter 2 inhibitors (SGLT2i) was associated with lower risk of cardiovascular events and mortality and higher risk of below‐knee lower extremity (BKLE) amputation versus non‐SGLT2i therapies. This analysis further examined risk of cardiovascular events, cardiovascular and noncardiovascular death and BKLE amputation with the SGLT2i canagliflozin versus non‐SGLT2i.MethodsNew user cohorts were constructed from Department of Defense Military Health System patients initiating canagliflozin or non‐SGLT2i (4/1/2013‐12/31/2016). Propensity score matching (1:1) controlled for imbalances in baseline covariates. Incidence rates, hazard ratios and 95% confidence intervals for time to first composite outcome of all‐cause mortality (ACM) and hospitalization for heart failure (HHF), composite major adverse cardiovascular events (MACE) and individual components were evaluated using conditional Cox models. The National Death Index was used to differentiate cardiovascular from noncardiovascular death. The exploratory safety end‐point was BKLE amputation.ResultsAfter propensity matching, 15 394 patients with well‐balanced baseline covariates were followed for a median of 2.03 years (intent‐to‐treat). Canagliflozin showed significant benefit for ACM and HHF (P < .0001), MACE (P = .0001), cardiovascular death (P < .0001) and noncardiovascular death (P = .0018). No significant difference in risk of BKLE amputation was observed (P = .20), though few events were observed. Results were generally consistent in on‐treatment analyses.ConclusionsIn this high cardiovascular risk cohort studied in routine clinical practice, canagliflozin was associated with lower risk of cardiovascular events, cardiovascular death and all‐cause mortality with no significant increase in BKLE amputation risk versus non‐SGLT2i.

Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose

The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program.

A surprising new study EMPA-REG OUTCOME has shown that empagliflozin, one of sodium-glucose cotransporter 2 (SGLT2) inhibitors, in addition to standard care had beneficial effects on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events. Subgroup analyses of the study revealed a better hazard ratio for the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in Asian than Caucasian and in patients with age ≥65 years, body-mass index <30, glycated hemoglobin <8.5% or higher cardiovascular risk than with the respective counterparts. Patients on diuretics also had the hazard ratio favoring empagliflozin, similar to that of patients not on diuretics. I infer that in poorlycontrolled diabetic patients, pre-existing osmotic diuresis is supposed to be augmented by the administration of SGLT2 inhibitors, possibly leading to an acceleration of their dehydration in spite of amelioration of hyperglycemia. Hypovolemia is inferred to be more likely to occur due to osmotic diuresis without an increase in blood glucose level to retain water. It may be recommended that use of SGLT2 inhibitors should be avoided in diabetic patients with glycated hemoglobin ≥8.5% at high risk for cardiovascular events. Because empagliflozin seems to have had no significant effect on nonfatal myocardial infarction or stroke, its ability to reduce cardiovascular mortality may be mediated through osmotic diuresis. SGLT2 inhibitors could be used as a new oral osmotic diuretic to excrete water with a little sodium into urine for non-diabetic patients with heart failure as well. Such action of SGLT2 inhibitors seems to be rather close to that of tolvaptan to promote water diuresis. Thus, the EMPA-REG OUTCOME study has brought a new insight into use of SGLT2 inhibitors in patients with type 2 diabetes.

Background and Aims People with type 2 diabetes mellitus (T2DM) have a greater risk of cardiovascular (CV) disease and major adverse CV events (MACE) that is more common as renal function declines. The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of MACE (CV death, nonfatal myocardial infarction [MI], and nonfatal stroke) in patients with T2DM and high CV risk or nephropathy in the CANVAS Program and CREDENCE trials, respectively. Method This post hoc analysis included integrated, pooled data from the CANVAS Program and the CREDENCE trial. The effects of canagliflozin compared with placebo on MACE were assessed in subgroups defined by baseline urinary albumin:creatinine ratio (UACR; &amp;lt;30, 30-300, and &amp;gt;300 mg/g). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using stratified (by study) Cox regression models, with subgroup by treatment interaction terms added to test for heterogeneity. Interaction P values were calculated by including the terms of treatment group, baseline UACR, and their interaction in the model. Results A total of 14,543 participants from the CANVAS Program (N = 10,142) and CREDENCE (N = 4,401) were included, with mean estimated glomerular filtration rate of 70.3 mL/min/1.73 m2 and median (interquartile range) UACR of 501.0 (8.4-523.6) mg/g. Among participants with baseline UACR measurements, 7038 (48.8%), 2762 (19.1%), and 4634 (32.1%) participants had baseline UACR &amp;lt;30, 30-300, and &amp;gt;300 mg/g, respectively. Rates of MACE and its components increased as UACR increased (Figure). Canagliflozin reduced the risk of MACE compared with placebo in the overall population (HR, 0.83; 95% CI, 0.75, 0.92), with consistent effects observed across UACR subgroups (interaction P value = 0.42). Canagliflozin also reduced the risk of the individual components of CV death (HR, 0.84; 95% CI, 0.72, 0.97), nonfatal MI (HR, 0.83; 95% CI, 0.70, 0.99), and nonfatal stroke (HR, 0.84; 95% CI, 0.69, 1.03), independent of baseline UACR (interaction P values = 0.40, 0.88, and 0.69, respectively). Canagliflozin was generally well tolerated in the CANVAS Program and the CREDENCE trial, with consistent results on safety outcomes across UACR subgroups. Conclusion Event rates of MACE and its components increased with higher UACR. Canagliflozin reduced the risk of MACE and its components in participants with T2DM and high CV risk or CKD in the CANVAS Program and CREDENCE trial, with consistent benefits observed regardless of baseline UACR.