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Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering
David M Charytan1, Kenneth W Mahaffey2, Meg J Jardine3
1United States, NYU, New York, New York, USA.
Insights
Sodium glucose co-transporter 2 inhibitors like canagliflozin show preserved kidney and cardiovascular benefits, even when glycemic effects lessen at lower eGFR. Non-glycemic pathways likely drive these protective outcomes.
Area of Science:
- Nephrology
- Cardiology
- Endocrinology
Background:
- The relationship between the glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors (SGLT2i) and their impact on kidney and cardiovascular outcomes remains unclear.
- Understanding these relationships is crucial for optimizing SGLT2i therapy in diabetic patients with kidney disease.
Purpose of the Study:
- To investigate the association between glycemic control achieved with canagliflozin and its effects on kidney and cardiovascular outcomes.
- To determine if the glycemic-lowering effects of canagliflozin are modified by baseline kidney function and if these effects mediate the drug's benefits.
Main Methods:
- Analysis of 4395 participants from The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, randomized to canagliflozin or placebo.
- Assessment of hemoglobin A1c (HbA1c) changes using mixed models and mediation analysis with proportional hazards regression.
- Evaluation of primary composite kidney and cardiovascular outcomes, including kidney death, end-stage kidney disease, and doubling of serum creatinine.
Main Results:
- HbA1c reduction with canagliflozin was attenuated at lower estimated glomerular filtration rates (eGFR).
- Despite reduced glycemic effects at lower eGFR, canagliflozin demonstrated preserved benefits on the primary composite kidney and cardiovascular outcomes.
- Adjusting for achieved HbA1c only marginally attenuated the treatment effects, indicating that non-glycemic mechanisms contribute significantly to the observed benefits.
Conclusions:
- The kidney and cardioprotective benefits of canagliflozin appear to be preserved even when its glycemic-lowering effects are diminished, particularly in patients with reduced eGFR.
- Non-glycemic pathways are likely the primary drivers of the kidney and cardioprotective effects of canagliflozin.
- These findings support the use of canagliflozin for cardiorenal protection in diabetic patients, irrespective of glycemic control levels.
Introduction:
Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.
Research Design And Methods:
We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components.
Results:
HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control.
Conclusions:
The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22.
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