Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials

Perkovic, Vlado; Zeeuw, Dick de; Mahaffey, Kenneth W.; Fulcher, Greg; Erondu, Ngozi; Shaw, Wayne; Barrett, Terrance D.; Weidner‐Wells, Michele A.; Deng, Hsiaowei; Matthews, David R.; Neal, Bruce

doi:10.1016/s2213-8587(18)30141-4

Cited by 538 publications

(556 citation statements)

References 32 publications

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“…The risk of doubling of SCr was reduced by 50% with canagliflozin (HR 0.50, 95% CI 0.30 to 0.84). Annual eGFR decline was slower (slope difference between groups 1.2 ml/min/1.73 m 2 per year, 95% CI 1.0 to 1.4) in the canagliflozin group .…”

Section: Cardiovascular Outcome Trialsmentioning

confidence: 91%

“…In the subgroups of participants with normo‐, micro‐ or macroalbuminuria at baseline, the mean differences in albuminuria in the canagliflozin group compared to the placebo group were 9% (95% CI 7 to 12), 34% (95% CI 29 to 38) and 36% (95% CI 28 to 43), respectively. New‐onset albuminuria (micro‐/macro‐albuminuria) occurred less frequently with canagliflozin compared to placebo (HR 0.80, 95% CI 0.73 to 0.88) .…”

Section: Cardiovascular Outcome Trialsmentioning

confidence: 99%

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Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

et al. 2020

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In 2008, the US Food and Drug Administration provided guidance for the evaluation of the cardiovascular safety of antidiabetes drugs. The newer antidiabetes drugs, approved after 2008, were therefore evaluated in long‐term cardiovascular outcome trials, designed and powered for the assessment of cardiovascular safety. Accordingly, the primary endpoint of these trials was a cardiac composite endpoint. Since 2008, the data from various cardiovascular outcome trials have been reported, including SAVOR‐TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide once‐weekly), SUSTAIN‐6 (injectable semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), PIONEER‐6 (oral semaglutide), EMPA‐REG OUTCOME (empagliflozin), the CANVAS Program (canagliflozin) and DECLARE‐TIMI 53 (dapagliflozin). Some of these trials subsequently also published data on renal outcomes, although these were secondary or exploratory analyses. Dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists had beneficial effects on albuminuria, while sodium‐glucose co‐transporter‐2 inhibitors additionally showed a positive effect on ‘hard’ renal outcomes. In contrast to the cardiovascular outcome trials, the renal outcome trial of canagliflozin, CREDENCE, assessed a hard renal endpoint as its primary endpoint and showed positive effects on these hard renal outcomes. In this review, we aim to highlight the renal outcome data from the cardiovascular outcome trials and the CREDENCE trial and understand the differences between their results. The post CREDENCE era would appear to reinforce the position of sodium‐glucose co‐transporter‐2 inhibitors as drugs providing cardiorenal protection, in addition to their anti‐glycaemic effects.

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Section: Cardiovascular Outcome Trialsmentioning

confidence: 91%

Section: Cardiovascular Outcome Trialsmentioning

confidence: 99%

Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

et al. 2020

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“…In addition, SGLT2 inhibitors enhance natriuresis, cause intravascular volume contraction and alter intra‐renal haemodynamics, which probably contribute to beneficial effects on blood pressure, body weight and albuminuria . These pleiotropic effects have translated into reductions in cardiovascular events and preservation of kidney function in large cardiovascular outcome trials and, as a consequence, this class of agent is now recommended as second‐line therapy after metformin for individuals with T2DM and established cardiovascular disease in the latest North American and European clinical practice guidelines …”

Section: Introductionmentioning

confidence: 99%

Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta‐analysis

Toyama

Neuen

Jun

et al. 2019

Diabetes Obesity Metabolism

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Aim The use of sodium glucose co‐transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta‐analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Materials and methods We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals. Results Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (−0.29%; 95% CI, −0.39 to −0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70‐0.94) and heart failure (RR, 0.61; 95% CI, 0.48‐0.78), without a clear effect on all‐cause mortality (HR, 0.86; 95% CI, 0.73‐1.01). These agents also attenuated the annual decline in eGFR slope (placebo‐subtracted difference of 1.35 mL/1.73 m2/y; 95% CI, 0.78‐1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53‐0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes. Conclusion Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.

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“…These effects have been investigated in multiple clinical trials. The EMPA‐REG OUTCOME trial was the first large clinical trial to demonstrate important diabetic renal protection with SGLT2 inhibitors, and since publication, additional SGLT2 inhibitors have shown similar renal protection benefits (Figure ) . Importantly, in patients with preexisting kidney disease, they continued to demonstrate a significant reduction in CV events.…”

Section: Sglt2 Inhibitors and Diabetic Vascular Complicationsmentioning

confidence: 99%

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

Silva-Cardoso

Sheikh

Nashawi

et al. 2019

Journal of Diabetes

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Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal‐protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.

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Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials

Abstract: Janssen Research & Development.

Cited by 538 publications

References 32 publications

Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE

Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta‐analysis

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

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