Canagliflozin Effects on NT-proBNP and Heart Failure

Which subgroup of patients with type 2 diabetes and heart failure is more beneficial from treatment with canagliflozin?

Patients with type 2 diabetes are at risk for many cardiovascular diseases, including heart failure. In a cohort study published by Nichols et al., patients with type 2 diabetes are more likely to develop congestive heart failure than patients without diabetes (incidence rate 30.9 versus 12.4 cases per 1,000 person-years, RR 2.5, 95% CI 2.3 to 2.7). Previous clinical trials and meta-analyses showed that patients with type 2 diabetes benefit from sodium-glucose co-transporter-2 (SGLT-2) inhibitors, especially in reducing the risk of hospitalization for heart failure. The N-terminal pro-brain natriuretic peptide (NT-proBNP) level is a marker in the prognosis for patients with heart failure. In the CANDLE trial, the author tried to assess the effect of canagliflozin, an SGLT-2 inhibitor, versus glimepiride on the NT-proBNP levels in patients with type 2 diabetes and chronic heart failure. The trial did not show a significant difference in the change in NT-proBNP levels between the two groups; however, showed that there was a greater reduction in NT-proBNP levels in patients with preserved ejection fraction than patients with reduced ejection fraction.

CANDLE trial was a single nation, multicenter, randomized, prospective, open-label, blinded endpoint trial that was conducted in Japan and had a total of 133 patients who underwent randomization. The study in this discussion is a post hoc analysis of the CANDLE trial hypothesizing that the effect on NT-proBNP might be depending on the baseline of cardiac function. In this post hoc analysis, the primary endpoint was a comparison between canagliflozin and glimepiride regarding the changes of NT-proBNP levels from baseline after 24 weeks, stratified according to baseline ventricular diastolic function (measured by echocardiography and presented by the septal annular velocity, SEP). 

Consistently with the findings in the CANDLE trial, the change in NT-proBNP levels is nonsignificant at week 24 (canagliflozin group: 0.98 pg/mL, 95% CI 0.89 to 1.08; glimepiride group: 1.07 pg/mL, 95% CI 0.97 to 1.18) with a ratio of change of 0.93 (95% CI 0.82 to 1.05).  In the first tertile of SEP-e’ values (<4.7 cm/s), the ratio of change with canagliflozin/glimepiride was 0.83 (95% CI 0.66 to 1.03). The ratios of change were 1.02 (95% CI 0.81 to 1.28) in the second SEP-e’ tertile (4.7 to 6.4 cm/s) and 1.00 (95% CI 0.78 to 1.28) in the third SEP-e’ tertile (≥6.4 cm/s). The ratios of changes were 0.95 (95% CI 0.74 to 1.22), 0.98 (95% CI 0.75 to 1.26), and 0.92 (95% CI 0.76 to 1.12) for the first (<10.2 cm/s), second (10.2 to 13.9 cm/s), and third (≥13.9 cm/s) tertile of E/SEP-e’ values, respectively. Even though the differences were not significant, the use of canagliflozin was associated with a lower NT-proBNP to a greater extent than with glimepiride in patients with diastolic dysfunction (decreased e’ and elevated E E/e’).

The author emphasized that this is the first study that proposed the vital role of baseline diastolic function in the efficacy of SGLT-2 inhibitors. However, the effectiveness of SGLT-2 inhibitors on NT-proBNP remains inclusive with the data from the CANDLE trial. More valid subtypes and further investigation are needed to properly identify the subgroup that would benefit most from SGLT-2 inhibitors, especially in the setting where multiple mechanisms for cardiovascular benefit from SGLT-2 have been proposed.

Practical Pearls:

• The benefits of canagliflozin for patients with type 2 diabetes can differ in the subtypes of heart failure.
• The effect of SGLT-2 inhibitors, specifically canagliflozin, on NT-proBNP is inconclusive, and more data is needed to identify the subgroup that would benefit from SGLT-2 inhibitors.
• The benefit of canagliflozin for cardiovascular benefit remains; this study only focused on the association between canagliflozin and NT-proBNP levels.

References:

Kusunose, Kenya et al. “Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial.” Cardiovascular diabetology vol. 20,1 186. 14 Sep. 2021,

Nichols, Gregory A et al. “The incidence of congestive heart failure in type 2 diabetes: an update.” Diabetes care vol. 27,8 (2004): 1879-84.

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy