Positive Cardiac Biomarker Changes Seen With Canagliflozin in T2D

Marlene Busko

August 08, 2017

In a post hoc analysis of a study of the sodium-glucose cotransporter 2 (SGLT-2) inhibitor canagliflozin (Invokana, Janssen) in older patients with type 2 diabetes and a moderate risk of cardiovascular disease (CVD), canagliflozin blunted the increase in serum levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin I (hsTnI) over a 2-year period.

Levels of soluble ST2 (sST2) remained the same, but there was a transient increase in levels of galectin-3 in patients who received canagliflozin vs placebo.

"These cardiac biomarker data provide support for the beneficial cardiovascular effect" of SGLT2 inhibitors in type 2 diabetes, James L Januzzi Jr, MD, from Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues summarize in an article published in the August 8 issue of the Journal of the American College of Cardiology.

Following the unexpected beneficial CV effects seen with empagliflozin in the EMPA-REG OUTCOME trial and canagliflozin in the CANVAS trials, the changes in these biomarkers in the current trial "suggest that SGLT2 inhibitors may prevent or delay the development of CV disease, particularly the development of heart failure," Nikolaus Marx, MD, from University Hospital Aachen and Aachen University, in Germany, echoes, in an accompanying editorial.

However, the findings may not be generalizable to "the higher-risk populations in EMPA-REG OUTCOME and the integrated CANVAS program," Dr Marx cautions, since the current study was restricted to older patients with type 2 diabetes and a moderately increased CV risk, whereas patients in EMPA-REG OUTCOME all had prevalent CVD and patients in CANVAS had a high CV risk (including 65% with a history of CVD).

Nevertheless, the study "may certainly pave the way for future research" into preventing CVD and heart failure in diabetes and explaining the CV outcomes seen in the EMPA-REG OUTCOME and CANVAS trials.

Canagliflozin and Cardiac Biomarkers

Levels of NT-proBNP can help diagnose heart failure, whereas levels of hsTnI are an indication of cardiomyocyte injury and levels of sST2 and galectin-3 are a measure of cardiovascular stress and tissue fibrosis, Dr Januzzi and colleagues note.

However, there are few prior data about how SGLT2 inhibitors might change the levels of these cardiovascular biomarkers.

To investigate this, the researchers measured the concentrations of NT-proBNP, hsTnI, sST2, and galectin-3 at baseline, 6 months, 1 year, and 2 years in frozen serum samples from 666 patients in the Safety and Efficacy Study of Canagliflozin in Older Patients with Type 2 Diabetes Mellitus trial.

The patients had at least one sample at baseline and one at a later time. They were 55 to 80 years old (mean age, 64) and had a mean HbA1c of 7.8%.

They had been randomized to receive 100-mg canagliflozin, 300-mg canagliflozin, or placebo, but since there was no dose response, results for the two canagliflozin doses were combined in the current study.

Canagliflozin prevented a rise in NT-proBNP and hsTnI.

Median NT-proBNP levels remained the same over time in the patients who received canagliflozin, but they increased in the patients who received placebo. The between-group difference was 15%, 16%, and 27% at 6 months, 1 year, and 2 years, respectively (all < .05).

Similarly, median hsTNI levels remained the same over time in the patients who received canagliflozin, but they increased in the patients who received placebo. The between-group difference was 8%, 12%, and 10% at 6 months, 1 year, and 2 years, respectively (all < .05).

These effects were perhaps not surprising, since SGLT2 inhibitors are associated with naturesis, diuresis, blood-pressure lowering, loss of body weight, long-term preservation of renal function, and improvement in myocardial remodeling, among other effects, the researchers note.

Galectin-3 levels increased modestly with canagliflozin, with significant differences from placebo at 6 months and 1 year but not at 2 years — possibly through a transient reduction in estimated glomerular filtration rate (eGFR).

"Further studies are needed to understand the mechanisms by which SGLT2 inhibitors ameliorate myocardial stress and prevent necrosis in patients with type 2 diabetes and to clarify how biomarkers can be optimally utilized to guide therapy," Dr Januzzi and colleagues urge.

The study was sponsored by Janssen. Dr Januzzi has received research support from Janssen, Boehringer Ingelheim, Novartis, Roche Diagnostics, Siemens, Prevencio, Singulex, and Amgen; has served as a consultant for Janssen, Abbott, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Philips; and has served on clinical-end-points adjudication committees for AbbVie and Pfizer. Disclosures for the coauthors are listed in the paper. Dr Marx has received support for clinical trial leadership from Boehringer Ingelheim; has served as a consultant to Boehringer Ingelheim, Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Novo Nordisk, and Bayer; has received grant support from Boehringer Ingelheim; and has served as a speaker for Boehringer Ingelheim Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Novo Nordisk, and Bayer.

J Am Coll Cardiol. 2017;70:704–712. ArticleEditorial

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