Cardiorenal Risk Estimates in T2D Mediated by Common Biomarker Response to Canagliflozin

Elevated levels of 4 common serum biomarkers in persons with type 2 diabetes (T2D) and albuminuria were found strongly predictive for the development of cardiovascular and renal disease in an analysis of data from the landmark CREDENCE clinical trial.¹

The study found that increased concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTn), growth differentiation factor-15 (GDF-15), and insulin-like growth factor binding protein 7 (IGFBP7) measured during the CREDENCE trial were associated with a 4-fold increase in risk of the composite outcome and that treatment with canagliflozin reduced concentrations of biomarkers as well as the primary composite outcome, suggesting that each of the 4 biomarkers may serve as surrogate measures of cardiorenal risk.¹

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“High levels of certain biomarkers are indicators of heart and kidney complications and may help predict future risk of disease progression,” said lead author James Januzzi, MD, a cardiologist at Massachusetts General Hospital and director of heart failure and biomarker trials at the Baim Institute for Clinical Research in Boston, in an American Heart Association statement.² 

“Treatment with canagliflozin, a sodium-glucose cotransporter-2 inhibitor lowered biomarker levels and reduced the risk of hospitalization for heart failure and other heart complications in people at the highest risk.”

CREDENCE, new analysis

In the CREDENCE trial, investigators evaluated the safety and efficacy of canagliflozin on a background of standard care for the prevention of chronic kidney disease and CVD vs placebo in 4401 participants with T2D, estimated glomerular filtration rate of 30 to 90 mL/min/1.73 m² and urinary albumin-to-creatinine ratio of 300 to 5000 mg/g. The primary outcome specifically was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 mL/min/1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.

For the current study, Januzzi and colleagues analyzed the effect of canagliflozin on levels of the 4 biomarkers among the 2627 CREDENCE trial participants for whom there were baseline values.

FINDINGS

The team reported that compared with reference populations, median baseline concentrations of each biomarker were elevated:

• NT-proBNP at 180 ng/L (82-442 ng/L)
• hs-cTn at 19 ng/L (12-29 ng/L)
• GDF-15 at 2595 ng/L (1852-3775 ng/L)
• IGFBP7 at 121.8 ng/mL (105.4-141.5 ng/mL)

At 1 year following initiation of canagliflozin or placebo, serum levels of all 4 markers were increased, in the placebo army by 6% to 29% compared with 3% to 10% elevation among those in the canagliflozin arm, according to the published findings (all P<.01).

Januzzi et al reported that the recorded baseline concentration of each biomarker had significant prognostic value for cardiac and renal outcomes seen in CREDENCE. Further, when investigators assessed concentrations using a multimarker panel, participants with high-risk scores (hazard ratio [HR], 4.01; 95% CI, 2.52–6.35) and moderate risk scores (HR, 2.39; 95% CI, 1.48–3.87) were at a greater risk of the primary outcome relative to participants with lower scores.

Additional analysis found that a 50% increase in each biomarker was associated with greater risk of the primary composite outcome at 1 year:

• NT-proBNP (HR, 1.11; 95% CI, 1.08–1.15)
• hs-cTn (HR, 1.86; 95% CI, 1.64–2.10)
• GDF-15 (HR, 1.45; 95% CI, 1.24–1.70)
• IGFBP7 (HR, 3.76; 95% CI, 2.54–5.56)

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications. Future studies are needed to better understand how type 2 diabetes in conjunction with kidney disease develops and progresses so that we may initiate life-saving therapies earlier, before symptoms of heart and kidney disease have occurred,” said Januzzi.

He added that blah blah blah all recommend biomarker measurement to augment risk assessment in persons with T2D which suggests their current findings may “considerably extend the reach of biomarker-based testing, refining accuracy even further.”

References:

1. Januzzi JL, Mohebi R, Liu Y, et al. Cardiorenal biomarkers, canagliflozin, and outcomes in diabetic kidney disease: the CREDENCE Trial. Circulation. 2023;148(8):651-660. doi:10.1161/CIRCULATIONAHA.123.065251

2. Simple blood test may predict future heart, kidney risk for people with type 2 diabetes. American Heart Association. August 21, 2023. Accessed August 24, 2023. https://newsroom.heart.org/news/simple-blood-test-may-predict-future-heart-kidney-risk-for-people-with-type-2-diabetes