Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review

Kluger, Aaron Y.; Tecson, Kristen M.; Barbin, Clay M.; Lee, Andy Y.; Lerma, Edgar V.; Rosol, Z; Rangaswami, Janani; Lepor, Norman E.; Cobble, Michael; McCullough, Peter A.

doi:10.31083/j.rcm.2018.02.907

Cited by 41 publications

(28 citation statements)

References 34 publications

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“…We described the differences in CV and renal outcomes between the three CVOTs (CANVAS, DECLARE-TIMI 58, EMPA–REG OUTCOME) in a previous review [35]. We argued that the different results of the trials were at least partially attributable to non-standard inclusion criteria, renal filtration function equations, and event definitions rather than inherent differences among the medications.…”

Section: Discussionmentioning

confidence: 99%

Class effects of SGLT2 inhibitors on cardiorenal outcomes

Kluger

Tecson

Lee

et al. 2019

Cardiovasc Diabetol

128

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Background To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA–REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. Results The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m 2 for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA–REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30–300, 11.0% UACR > 300 mg/g). Conclusions Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

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Section: Discussionmentioning

confidence: 99%

Class effects of SGLT2 inhibitors on cardiorenal outcomes

Kluger

Tecson

Lee

et al. 2019

Cardiovasc Diabetol

128

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“…Our findings suggest that empagliflozin may have only a modest effect over a three-year timescale on atherosclerotic mediated outcomes and that alternative mechanisms need to be explored, as others have suggested, that can more directly explain the cardioprotective benefits observed in the trial. [17] [18] [19] [20] [21] [22] The first version of the UKPDS Outcomes Model (UKPDS-OM1) [23] was used previously to demonstrate that virtually all of the risk reduction observed in the prespecified secondary CV outcome of the PROactive trial (a composite endpoint of allcause mortality, non-fatal myocardial infarction or stroke) [24] could be explained by the observed within-trial pioglitazone-induced changes in conventional CV risk factors. [25] The predictive performance of the UKPDS Outcomes Model has also been validated previously in other populations with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Can the cardiovascular risk reductions observed with empagliflozin in the EMPA‐REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?

Coleman

Gray

Broedl

et al. 2020

Diabetes Obesity Metabolism

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Aim:The EMPA-REG OUTCOME trial demonstrated a significant reduction in cardiovascular (CV) outcomes in patients with type 2 diabetes given empagliflozin, a selective sodium-glucose cotransporter-2 inhibitor. We performed post-hoc analyses of this trial examining the degree to which empagliflozin-induced changes in conventional CV risk factors might explain the observed CV benefits. Materials and methods:We estimated three-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL-cholesterol, LDL-cholesterol, systolic blood pressure, HbA1c, heart rate, white cell count, haemoglobin, estimated GFR, and prior histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk-reductions were compared.Results: Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for allcause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). Conclusions:Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and allcause death reductions observed. Alternative risk-reduction mechanisms need to be -2 -explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.

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“…1. Гемодинамическая регуляция в нефроне при сахарном диабете и после приема ингибитора натрий-глюкозного котранспортера 2 (адаптировано [16] [23,24]). *** -p<0,001 NNT -число больных, нуждающихся в лечении изучаемым препаратом в течение обозначенного количества лет, чтобы предотвратить один указанный неблагоприятный исход (показатель тем лучше, чем меньше значение и короче срок); ОР -относительный риск или канаглифлозин, или дапаглифлозин, по сравнению с группой плацебо характеризовались значительно более низким риском возникновения нефропатии или ее ухудшения, что позволяет уверенно отнести ингибиторы SGLT2 к препаратам с нефропротективной активностью (табл.…”

Section: патофизиологическая роль почек и функционирование натрий-глюunclassified

SGLT2 inhibitors and kidneys: mechanisms and main effects in diabetes mellitus patients

et al. 2021

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Type 2 diabetes mellitus (T2DM) is the cause of the development of diabetic nephropathy — a complication that determines the high degree of disability and mortality of such patients. Until recently, approaches to normalizing glucose levels did not have a significant possibility of influencing the outcome of kidney damage in diabetes. Type 2 sodium glucose cotransporter inhibitors (SGLT2) are a new class of glucose-lowering drugs that improve glycemic control due to an insulin-independent mechanism of action associated with increased urinary glucose excretion. The review provides an analysis of the results of studies on the assessment of nephroprotective actions — one of the pleiotropic actions of this drugs group. These materials show the properties of SGLT2 inhibitors to reduce the risk of developing and the progression of albuminuria, to save glomerular filtration rate, to reduce the frequency of end-stage renal disease and the need for renal replacement therapy in patients with T2DM. The article gives and analyzes the currently existing hypotheses of the mechanism of action of these glucose-lowering drugs. The risk of the most common renal complications with the use of SGLT2 inhibitors is considered. The practical aspects of the use of SGLT2 inhibitors in modern algorithms for the care of patients with T2DM are indicated, as well as the prospects for new randomized clinical trials.

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Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review

Abstract: tively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs.

Cited by 41 publications

References 34 publications

Class effects of SGLT2 inhibitors on cardiorenal outcomes

Class effects of SGLT2 inhibitors on cardiorenal outcomes

Can the cardiovascular risk reductions observed with empagliflozin in the EMPA‐REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?

SGLT2 inhibitors and kidneys: mechanisms and main effects in diabetes mellitus patients

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