Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Neuen, Brendon L.; Ohkuma, Toshiaki; Neal, Bruce; Zeeuw, Dick de; Mahaffey, Kenneth W.; Fulcher, Greg; Blais, Jaime D.; Li, Qiang; Jardine, Meg; Perkovic, Vlado; Wheeler, David C.

doi:10.1053/j.ajkd.2020.06.018

Cited by 50 publications

(41 citation statements)

References 35 publications

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“…A trial of 1402 participants with type 1 DM (inTandem3) and a short trial of 1250 people hospitalized with COVID-19 (DARE-19) provided only small numbers of clinical outcomes and so were not included in meta-analyses (Supplemental Methods provide more details/results) [ 17 , 30 ]. Data for the remaining eleven trials were extracted from their primary publications [ [2] , [3] , [4] , [5] , [7] , [8] , [9] , [10] , [11] , [12] , [13] ] and eleven subsidiary peer-reviewed publications [ 14 , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , 31 ]. A total of 77,541 participants were included in meta-analyses: four HF trials randomized 15,684 participants [7] , [8] , [9] , [10] , four type 2 DM high-ASCVD risk trials randomized 42,568 participants [2] , [3] , [4] , [5] , and three CKD trials randomized 19,289 participants [11] , [12] , [13] .…”

Section: Resultsmentioning

confidence: 99%

“…For each included trial, data were extracted after reviewing all the principal [ [2] , [3] , [4] , [5] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , 17 ] and relevant subsidiary peer-reviewed publications [ 14 , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] ]. The main outcomes were: hospitalization for HF or cardiovascular death; major adverse cardiovascular events (i.e.…”

Section: Methodsmentioning

confidence: 99%

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Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Staplin¹,

Roddick²,

Emberson³

et al. 2021

eClinicalMedicine

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Background: The net absolute effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors across different patient groups have not been quantified. Methods: We performed a meta-analysis of published large (>500 participants/arm) placebo-controlled SGLT-2 inhibitor trials after systematically searching MEDLINE and Embase databases from inception to 28th August 2021 (PROSPERO 2021 CRD42021240468). Findings: Four heart failure trials (n=15,684 participants), four trials in type 2 diabetes mellitus at high atherosclerotic cardiovascular risk (n=42,568), and three trials in chronic kidney disease (n=19,289) were included. Relative risks (RRs) for all cardiovascular, renal and safety outcomes were broadly similar across these three patient groups, and between people with or without diabetes. Overall, compared to placebo, allocation to SGLT-2 inhibition reduced risk of hospitalization for heart failure or cardiovascular death by 23% (RR=0.77, 95%CI 0.73-0.80; n=6658), cardiovascular death by 14% (0.86, 0.81-0.92; n=3962), major adverse cardiovascular events by 11% (0.89, 0.84-0.94; n=5703), kidney disease progression by 36% (0.64, 0.59-0.70; n=2275), acute kidney injury by 30% (0.70, 0.62-0.79; n=1013 events) and severe hypoglycaemia by 13% (0.87, 0.79-0.97; n=1484). There was no effect of SGLT-2 inhibition on risk of non-cardiovascular death (0.93, 0.86-1.01; n=2226), but a net 12% reduction in all-cause mortality remained evident (0.88, 0.84-0.93; n=6188). However, the risk of ketoacidosis was 2-times higher among those allocated SGLT-2 inhibitors compared to placebo (2.03, 1.41-2.93; n=159; absolute excess in people with diabetes »0.3/1000 patient years). A small increased risk of urinary tract infection was evident (1.07, 1.02-1.13; n=5384) alongside a known increased risk of mycotic genital infections. Overall, risk of lower limb amputations was increased by 16% (1.16, 1.02-1.31; n=1074), but this risk was largely driven by a single outlying trial (CANVAS). Interpretations: The relative effects of SGLT-2 inhibition on key safety and efficacy outcomes are consistent across the different studied groups of patient. Consequently, absolute benefits and harms are determined by the absolute baseline risk of particular outcomes, with absolute benefits on mortality and on non-fatal serious cardiac/renal outcomes substantially exceeding the risks of amputation and ketoacidosis in the main patient groups studied to date. Funding: MRC-UK & KRUK.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Staplin¹,

Roddick²,

Emberson³

et al. 2021

eClinicalMedicine

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show abstract

“…In post hoc analyses of trials, the relative benefits of SGLT2 inhibitors were similar across KDIGO categories while the absolute benefit for major cardiovascular events was greater in higher risk categories. 7 , 34 When considering poor outcomes in heart failure patients and rapidly rising global prevalence of end-stage kidney disease, 35 guidelines and a risk matrix are urgently needed to identify the candidates who are most likely to have a net benefit from SGLT2 inhibitor treatment.…”

Section: Discussionmentioning

confidence: 99%

SGLT2 Inhibitors and Kidney and Cardiac Outcomes According to Estimated GFR and Albuminuria Levels: A Meta-analysis of Randomized Controlled Trials

Chun

Jung

2021

Kidney Medicine

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…This finding is biologically plausible [7], and has been supported by the observation that, in cardiovascular safety studies in type 2 diabetes enriched with patients with CKD, the incidence of HF hospitalization exceeds that of ACVD [19]. In a secondary analysis of the CANVAS [26] study, there was also an increase in the prevalence of HF and in the incidence rate of hospitalization for HF in the successive KDIGO risk categories, with the beneficial effect of canagliflozin being more marked in absolute terms in the highest risk categories. Given the association between HF and CKD, the KDIGO guidelines recommend developing strategies to diagnose and treat both conditions at an early stage [27].…”

Section: Discussionmentioning

confidence: 72%

Association of the KDIGO Risk Classification with the Prevalence of Heart Failure in Patients with Type 2 Diabetes

Gimeno-Orna

Rodríguez‐Padial

Anguita‐Sánchez

et al. 2021

JCM

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The objectives of this study were to determine the main characteristics associated with the presence of heart failure (HF) in patients with type 2 diabetes (T2DM), and specifically to assess the association of the risk classification proposed by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines with HF. The DIABET-IC study is a multicentre, observational, prospective and analytical study in T2DM patients recruited in Spanish hospitals. This work, which features a cross-sectional design, has been conducted with the data obtained at the inclusion visit. The main dependent variable analysed was the presence of HF. The predictive variables evaluated were the demography, clinic, laboratory testing (including natriuretic peptides) and echocardiography. Patients were classified according to the number of vascular territories with atherosclerotic involvement and the KDIGO risk category. Multivariate logistic regression models were performed to determine the risk posed by the various baseline variables to present HF at the time of study inclusion. The study included 1517 patients from 58 hospitals, with a mean age of 67.3 (standard deviation (SD): 10) years, out of which 33% were women. The mean DM duration was 14 (SD: 11) years. The prevalence of HF was 37%. In a multivariate analysis, the independent predictors of HF were increased age (odds ratio (OR) per 1 year = 1.02; p = 0.006), decreased systolic blood pressure (OR per 1 mmHg = 0.98; p <0.001), decreased haemoglobin (OR per 1 g/dL = 0.86; p <0.001), the presence of obstructive sleep apnoea (OR = 1.61; p = 0.006), the absence of hepatic steatosis (OR = 0.59; p = 0.016), the severity of atherosclerotic involvement (OR 1 territory = 1.38 and OR >1 territory = 2.39; p = 0.02 and p<0.001 respectively) and the KDIGO risk classification (high-risk OR = 2.46 and very high-risk OR = 3.39; p <0.001 for both). The KDIGO risk classification is useful to screen for the presence of HF in T2DM patients. Therefore, we believe that it is necessary to carry out a systematic screening for HF in the high- and very high-risk KDIGO categories.

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Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program

Cited by 50 publications

References 35 publications

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

SGLT2 Inhibitors and Kidney and Cardiac Outcomes According to Estimated GFR and Albuminuria Levels: A Meta-analysis of Randomized Controlled Trials

Association of the KDIGO Risk Classification with the Prevalence of Heart Failure in Patients with Type 2 Diabetes

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