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Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.
The research, norvasc in gravidanza published online today in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.
Examining biomarker levels in more than 2600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.
Combining all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than those with the lowest levels.
As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.
Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, Massachusetts, believes that further study will help refine the predictive value of the panel.
“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.
Speaking to Medscape Medical News, Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”
He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”
Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.”
“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.
However, this will require determining the relative importance of each biomarker and weighting them in the final model.
Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Januzzi said.
By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”
Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”
The authors note that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other.
Individuals with type 2 diabetes and CKD albuminuria, they add, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
Several Biomarkers Associated With Myocardial Stress and Necrosis
The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.
Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.
The current analysis involved 2627 participants who had baseline plasma samples available for analysis of four circulating biomarkers:
N-terminal pro-B-type natriuretic peptide (NT-proBNP)
High-sensitivity cardiac troponin T (hs-cTnT)
Growth differentiation factor-15 (GDF-15)
IGFBP7
Among those, 2385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.
The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.
Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.
For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).
For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).
Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).
For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).
The researchers also report that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.
“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” commented Januzzi.
The CREDENCE trial and the current analysis were funded by Janssen Research & Development, LLC. NT-pro-BNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Januzzi is funded in part by the Hutter Family Professorship.
Januzzi declares relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.
Circulation. Published online August 21, 2023. Abstract
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