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Cardiorenal Biomarkers Predict Major Complications in Patients With Type 2 Diabetes and Chronic Kidney Disease

Key findings

  • This analysis of CREDENCE trial data examined how canagliflozin affected four cardiorenal stress biomarkers in patients with type 2 diabetes and albuminuria and how changes in biomarkers associated with cardiovascular and kidney outcomes
  • High concentrations of any four biomarkers—N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, growth differentiation factor–15, and insulin-like growth factor binding protein 7—indicated a high-risk population
  • Treatment with canagliflozin reduced the longitudinal trajectory of rise in each biomarker; the reduction in NT-proBNP was especially notable, with an average reduction of 15% after one year
  • Baseline biomarker values and their change after one year generally predicted cardiorenal outcomes and additive use of all four markers in a simultaneous panel provided a robust ability to sort participants from lower to very high risk for all endpoints
  • The biomarkers studied may reveal varying risk levels in patients with diabetic kidney disease and possibly be used to target treatment more efficiently

Several publications from the CANVAS Program, which evaluated canagliflozin in individuals with type 2 diabetes (T2D) with or without chronic kidney disease (CKD), have shown that biomarkers of myocardial stress, myocardial necrosis, and renal tubular injury predict the progression of CKD and the risk of heart failure events.

Building on those findings, James L. Januzzi, Jr, MD, cardiologist and director of the Dennis and Marilyn Barry Fellowship in Cardiology Research at Massachusetts General Hospital, and colleagues focused on prognostic biomarkers and the effect of sodium–glucose cotransporter-2 (SGLT2) inhibition in an even higher-risk population: patients with both T2D and CKD.

The team reports in Circulation that four cardiorenal biomarkers individually and collectively predicted outcomes in diabetic kidney disease, illustrating the ability of biomarkers to identify individuals who could most benefit from SGLT2 inhibition.


The researchers conducted a post hoc analysis of CREDENCE, a placebo-controlled trial of canagliflozin versus placebo sponsored by Janssen Research and Development. The 4,401 participants with T2D and CKD were considered at high risk of progression.

The current analysis, also sponsored by Janssen, included 2,627 individuals who had plasma available for baseline measurements of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor–15 (GDF-15), and insulin-like growth factor binding protein 7 (IGFBP7).

Effect of Canagliflozin on Biomarker Concentrations

At baseline, concentrations of each biomarker were generally elevated compared with healthy reference populations. Indeed, in many cases, biomarker concentrations were comparable to those previously reported for individuals with heart failure (HF).

In adjusted analyses, treatment with canagliflozin significantly reduced the longitudinal trajectory of rise in each biomarker. The average reduction from baseline to one year was between 2% (for IGFBP7) and 15% (for NT-proBNP).

Biomarker Concentrations and Outcomes

Between baseline and one year, each unit increase in NT-proBNP, hs-cTnT, GDF-15, or IGFBP7 was associated with a significantly greater risk of every outcome studied:

  • Primary composite endpoint of CREDENCE—end-stage kidney disease (dialysis, transplantation, or sustained estimated glomerular filtration rate <15 mL/min/1.73 m2), doubling of the serum creatinine level or renal death or cardiovascular death
  • Renal composite endpoint—end-stage kidney disease, doubling of the serum creatinine level, or renal death
  • HF hospitalization or cardiovascular death
  • HF hospitalization
  • Cardiovascular death
  • All-cause death

Multimarker Approach for Risk Assessment

The research team created a risk panel for the study participants with baseline data for all four biomarkers of interest. The cutpoints were NT-proBNP ≥125 ng/L, hs-cTnT ≥14 ng/L, GDF-15 ≥1800 ng/L, and IGFBP7 ≥122 ng/mL.

In relative terms, canagliflozin was not specifically beneficial based on the risk level, emphasizing the value of broad-based SGLT2 inhibition. However, the absolute reduction in the risk of every outcome studied was larger in those with more abnormal biomarkers.

Clinical Implications

Current practice recommends using SGLT2 inhibitors in all eligible individuals, regardless of biomarker strata. Yet Medicare data published in Circulation: Cardiovascular Quality and Outcomes reveal enormous gaps in adherence to this guidance.

These results show that biomarkers may reveal varying risk levels and possibly be used to target treatment to individuals with proteinuric CKD more efficiently. The findings also support 2022 consensus recommendations of the American Diabetes Association that NT-proBNP or hs-cTnT be measured periodically to identify patients with diabetes who are at risk of HF events.

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For assessing patients with chronic kidney disease, James L. Januzzi, MD, Reza Mohebi, MD, and colleagues have developed a panel of four biomarkers that have different roles in the pathophysiology of cardiovascular disease and may be useful as a unique tool for predicting cardiovascular events.


Cian P. McCarthy, MBBCh, BAO, SM, James L. Januzzi, Jr., MD, and colleagues found in a prospective study that coronary artery disease affected 92% of patients with type 2 myocardial infarction, but despite a large overall burden of coronary plaque, 74% did not have hemodynamically significant focal stenosis.