Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results From the Randomized CREDENCE Trial
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Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67–0.95]; P =0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49–0.94]) and secondary (HR, 0.85 [95% CI, 0.69–1.06]) prevention groups ( P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61–1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59–1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56–1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups ( P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02065791.
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Based on evidence from the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials, as well as secondary analyses of cardiovascular outcomes trials with SGLT2 inhibitors, cardiovascular and renal events are reduced with SGLT2 inhibitor use in individuals with an eGFR ≥20 mL/min/1.73m2, independent of glucose-lowering effects.
“Based on evidence from the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials, as well as secondary analyses of cardiovascular outcomes trials with SGLT2 inhibitors, cardiovascular and renal events are reduced with SGLT2 inhibitor use in individuals with an eGFR of 20 mL/min/1.73m 2 , independent of glucose-lowering effects (110,113).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [113]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn CREDENCE, there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
“Moreover, in this advanced CKD group, there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (29,110,113).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [113]
The Results section (Cardiovascular Outcomes by Primary and Secondary Prevention; page unavailable) reports that canagliflozin reduced the cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke composite, with consistent effects across prevention groups. The Results section (Numbers Needed to Treat; page unavailable) also reports benefit for cardiovascular death or heart-failure hospitalization. Our copy does not state the claimed 31% and 20% reductions, so it supports the direction and outcomes but not those precise magnitudes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn CREDENCE, there was a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
“there were clear benefits on cardiovascular outcomes demonstrating a 31% reduction in cardiovascular death or heart failure hospitalization and a 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (29,125,126).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [126]
The Results section, “Cardiovascular Outcomes by Primary and Secondary Prevention” (page unavailable), reports reduced major cardiovascular events with canagliflozin, and the Discussion describes cardiovascular benefit in both prevention groups. Our copy does not state the claimed 31% or 20% reductions for the two composites; searches for those percentages and corresponding hazard ratios did not establish them. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCardiovascular and kidney events are reduced with SGLT2 inhibitor use in individuals with severe CKD independent of glucose-lowering effects.
“Cardiovascular and kidney events are reduced with SGLT2 inhibitor use in individuals with severe CKD independent of glucose-lowering effects (126,131).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [126]
The Clinical Implications section reports expected reductions in cardiovascular and renal outcomes with canagliflozin in people with type 2 diabetes and CKD, including those with eGFR of 30–45 mL/min/1.73 m². The paper does not establish that these benefits are independent of glucose-lowering effects; its Discussion lists improved glucose levels among proposed mechanisms and says their relative contributions need further study. The evidence is also specific to canagliflozin in people with type 2 diabetes, rather than all SGLT2 inhibitors or all individuals with severe CKD. No page number was provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn CREDENCE, risk for 3-point major adverse cardiovascular events was significantly reduced with canagliflozin versus placebo overall (HR 0.80; 95% CI 0.67-0.95) and in the primary prevention cohort for atherosclerotic cardiovascular disease (HR 0.68; 95% CI 0.49-0.94), and was numerically similar in the secondary prevention cohort (HR 0.85; 95% CI 0.69-1.06).
“Risk for 3-point MACE was significantly reduced with canagliflozin versus placebo overall (HR, 0.80; 95% CI, 0.67–0.95) and in the primary prevention cohort for ASCVD (HR, 0.68; 95% CI, 0.49–0.94), and was numerically similar in the secondary prevention cohort (HR, 0.85; 95% CI, 0.69–1.06) (Fig. 2).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [49]
In CREDENCE, 3-point major adverse cardiovascular events occurred in 16.1% and 8.3% during a mean of 2.6 years in those with and without established atherosclerotic cardiovascular disease, respectively.
“CREDENCE participants were at high CVD risk, with 3-point MACE occurring in 16.1% and 8.3% during a mean of 2.6 years in those with and without established ASCVD, respectively (49).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [49]
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References 14 · Cited by 291
- Authors
- Mahaffey, K. W., Jardine, M. J., Bompoint, S., Cannon, C. P., Neal, B., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Capuano, G., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Sun, T., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Rosenthal, N., Brenner, B. M., Perkovic, V., & On behalf of the CREDENCE Study Investigators
- Affiliations
- Stanford Medicine (US)
- Concord Repatriation General Hospital (AU)
- George Institute for Global Health, University of New South Wales, Sydney, Australia (M.J.J., S.B., B.N., H.J.L.H., V.P.).
- Brigham and Women's Hospital (US)
- The University of Sydney (AU)
- University Medical Center Groningen (NL)
- NYU Langone Health (US)
- Janssen Research & Development (United States) (US)
- Richard L. Roudebush VA Medical Center (US)
- University of Chicago (US)
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands (H.J.L.H., D.d.Z.).
- University of Utah (US)
- University of British Columbia (CA)
- University College London (GB)
- Peking University First Hospital (CN)
- Mount Sinai Hospital (CA)
- Royal North Shore Hospital (AU)
- Corresponding author
- Mahaffey, Kenneth W.
- ORCID
- Venue
- Circulation
- Published
- 2019-08-27
- Volume
- 140
- Issue
- 9
- Pages
- 739-750
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6727954
- OpenAlex
- W2956532717
- Cited by
- 291
- References
- 14
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 23 · 2023: 33 · 2022: 52 · 2021: 48 · 2020: 92 · 2019: 12 · 2018: 2 · 2017: 1
- FWCI
- 41.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Circulation (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- Minerva Access (University of Melbourne) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Gilead Sciences
- Alnylam Pharmaceuticals
- Celgene
- University of Chicago
- University of Washington
- Regeneron Pharmaceuticals
- Ironwood Pharmaceuticals, Incorporated
- Ablynx
- Amarin Corporation
- Kowa Company
- MyoKardia
- Innovent Biologics
- Verily Life Sciences
- NxStage
- Kidney Foundation of Canada
- Eisai
- Novo Nordisk
- Astellas Pharma
- Servier
- Akebia Therapeutics
- George Institute for Global Health
- National Institutes of Health
- University of California, San Francisco
- Merck Sharp and Dohme
- Medical Research Council
- National Health and Medical Research Council
- Relypsa
- National Institute of Diabetes and Digestive and Kidney Diseases
- Janssen Pharmaceuticals
- Daiichi Sankyo Europe
- Medical Research Future Fund
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- canagliflozin, type 2 diabetes, chronic kidney disease, primary prevention, secondary prevention, cardiovascular events, cardiovascular mortality, myocardial infarction, stroke, heart failure hospitalization, renal failure, SGLT2 inhibitors, CREDENCE trial, renal outcomes, cardiovascular risk reduction, SGLT2 inhibitor safety
- MeSH terms
- Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Humans, Kidney Failure, Chronic, Male, Middle Aged, Risk, Placebo Effect, Proportional Hazards Models, Treatment Outcome, Renal Insufficiency, Chronic, Secondary Prevention
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