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Canagliflozin similar to sulfonylurea for NT-proBNP reduction in HF
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PHILADELPHIA — Among older adults with type 2 diabetes and chronic HF, treatment with the SGLT2 inhibitor canagliflozin was not associated with a reduction in median N-terminal pro-B-type natriuretic peptide levels compared with the sulfonylurea glimepiride, according to data presented at the American Heart Association Scientific Sessions.
In the CANDLE prospective, randomized, open-label, blinded-endpoint trial designed to assess noninferiority of canagliflozin (Invokana, Janssen) compared with glimepiride, researchers also found that treatment with canagliflozin mediated a numerically greater reduction in NT-proBNP and an improvement in NYHA subclass, especially among participants with HF with preserved ejection fraction.
“Recent CV outcomes trials with SGLT2 inhibitors showed consistent benefits for risk reduction in HF-related outcomes; however, only a limited proportion of patients had baseline HF in those CV outcomes trials, and their HF status was not fully phenotyped,” Atsushi Tanaka, MD, PhD, of the department of cardiovascular medicine at Saga University, Japan, said during an abstract presentation here. “More recently, the DAPA-HF trial also demonstrated similar benefits, even in patients with HF with reduced ejection fraction. However, the clinical impacts of SGLT2 inhibitors in patients with type 2 diabetes and general HF are still uncertain.”
For the CANDLE trial, researchers examined the noninferiority of 100 mg daily canagliflozin compared with glimepiride (starting dose, 0.5 mg or 1 mg) on NT-proBNP levels in 233 older Japanese adults type 2 diabetes and chronic HF. The mean age for the cohort was 69 years and 75% were men. Mean LV ejection fraction was 57.6% and mean HbA1c was 6.9%. The primary outcome was percentage change in NT-proBNP from baseline to 24 weeks.
At 24 weeks, the mean percentage changes in NT-proBNP levels were 10.4% for canagliflozin and 21.5% for glimepiride, for a group ratio of change of 0.48 (95% CI, –0.13 to 1.59), Tanaka said.
In a post hoc responder analysis, the researchers found that a greater proportion of participants treated with canagliflozin — in particular, individuals with HFpEF — experienced a 20% reduction in NT-proBNP, Tanaka said. In contrast, fewer participants with HFrEF assigned canagliflozin experienced a 20% or more increase in NT-proBNP. There was no significant difference between the treatment groups.
Overall, a greater reduction in NT-proBNP levels was observed among individuals treated with canagliflozin compared with those assigned glimepiride; however, there was no significant difference between groups, Tanaka said.
“Interestingly, when stratified by baseline NT-proBNP levels, canagliflozin treatment reduced NT-proBNP more in patients with elevated levels of NT-proBNP,” Tanaka said. “Furthermore, in a subgroup analysis of HFrEF and HFpEF patients, a greater reduction in NT-proBNP was observed among HFpEF patients treated with canagliflozin, although it did not reach statistical significance.”
Nine participants taking canagliflozin and 13 taking glimepiride experienced at least one adverse event. One participant assigned canagliflozin and three assigned glimepiride experienced an exacerbation of HF, Tanaka said.
“Overall, a prespecified primary hypothesis — noninferiority of group ratio of percentage change in NT-proBNP — was not achieved in the CANDLE trial,” Tanaka said. “This might partly result from a larger variability of NT-proBNP and greater proportions of patients with HFpEF, in whom the clinical benefits of SGLT2 inhibitors might be smaller vs. HFrEF in the recent substudies from CV outcomes trials. However, canagliflozin mediated a greater reduction in NT-proBNP, and an improvement in NYHA subclass was observed , especially in the HFpEF subgroup.”
Tanaka said ongoing trials assessing SGLT2 inhibitors for HFpEF, such as EMPEROR-Preserved and DELIVER, will help elucidate whether SGLT2 inhibitors have therapeutic potential in HFpEF. – by Regina Schaffer
Reference:
Tanaka A, et al. Abstract 170. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Disclosure: Tanaka reports he has received honoraria or research funding from Boehringer Ingelheim, Daichi Sankyo, Fukuda Denshhi, GlaxoSmithKline, Mitsubishi Tanabe, MSD, Novo Nordisk, Ono, Taisho Toyama, Takeda and Teijin.
Perspective
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Peter Goulden, MD, FRCP, PGCE
This is an exciting time for diabetes management in terms of the newer options we have for people. What is nice about the CANDLE abstract is the researchers wanted to look at the safety side of treatment with SGLT2 inhibitors in type 2 diabetes with HF. That is always useful. We are always keen to have as much cardiac safety data as possible ahead of a new treatment.
Here, the researchers looked at the NT-proBNP levels. When concerned about an acute exacerbation in patients with HF, looking for a rise in NT-proBNP levels is a useful marker. The researchers looked at this against glimepiride, and the question was: Was there going to be any adverse effect with canagliflozin compared with glimepiride? The nice thing about this is, it shows that canagliflozin was noninferior to glimepiride. From that, we can say it is potentially a very good treatment for patients with type 2 diabetes and HF.
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