To the Editor: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are recognized as one of the essential drugs for the treatment of heart failure (HF). Recent randomized controlled trials (RCTs) have shown that the SGLT-2 inhibitors significantly reduced the occurrence of HF hospitalizations or cardiovascular mortality in HF patients.[1–3] In addition, a comprehensive meta-analysis confirmed that SGLT-2 inhibitors improve the prognosis of patients with HF regardless of left ventricular ejection fraction.[4] However, the analysis by race is not highlighted in this meta-analysis. Since some studies have suggested a poorer prognosis for HF patients in Asia compared to those in Western countries,[5–7] we hypothesized that SGLT-2 inhibitors would have different efficacy in Asians compared to Western HF patients. Therefore, we performed a meta-analysis to elucidate the effectiveness of SGLT-2 inhibitors for Asian HF patients.

We analyzed three large-scale RCTs (>1000 patients), having data of sub-analysis stratified by race (Asian, white and black).[1–3] A total of 13,857 patients with HF, including 2612 (19%) Asian, 10,504 (76%) white, and 741 (5%) black patients, were analyzed. Two studies used empagliflozin,[1,3] and one used dapagliflozin.[2] The hazard ratio (HR) for the primary endpoint (composite of cardiovascular death and hospitalization for HF) was pooled using the random-model generic inverse variance method after logarithm conversion (RevMan ver 5.4. Cochrane Collaboration, London, UK). Figure 1 demonstrates the comparison of HR for the primary endpoint. Treatment with SGLT-2 inhibitors resulted in a significant reduction in the primary endpoint in Asian (HR: 0.62, 95% confidence interval [CI]: 0.51–0.74, P <0.001, I2 = 0, P for heterogeneity = 0.83), White (HR: 0.82, 95% CI: 0.75–0.90, P <0.001, I2 = 0, P for heterogeneity = 0.56), and Black (HR: 0.58, 95% CI: 0.43–0.78, P <0.001, I2 = 0, P for heterogeneity = 0.44). The effect of the SGLT-2 inhibitor was higher in Asian HF patients than in white HF patients (P = 0.006) and similar to black HF patients (P = 0.74) [Figure 1].

Figure 1:

The HR of composite cardiac events across the races (Asian, white and black). CI: Confidence interval; HF: Heart failure; HR: Hazard ratio; SE: Standard error; SGLT-2: Sodium-glucose cotransporter 2.

Approximately 60% of the world's population lives in Asian countries, but the information is limited regarding the characteristics and outcomes of Asian HF patients. Several studies indicated the difference in prognosis between Asian and Western countries. Dewan et al[5] examined the prognosis of 13,174 patients with HF with reduced ejection fraction and have shown the differences in the characteristics of HF patients in Asian and Western countries. For example, Asian HF patients are younger, have lower BMI, and have a lower prevalence of hypertension and diabetes. The low prevalence of chronic obstructive pulmonary disease, kidney disease, and atrial fibrillation is also intriguing. In addition, there was a generally low trend for complications of ischemic heart disease, although there was regional variation. In Asia, the use of diuretics and devices decreased while the use of digoxin increased. Most notably, there were differences in prognosis, with Asia having a higher incidence of cardiovascular death/HF hospitalization than Western countries (China 14.9; Western Europe 10.4; North America 12.8 per 100 patient-years).[5] The ATTEND Registry[8] (registry from Japan) revealed that the in-hospital mortality rate of HF patients was 6.4%, which was slightly higher than that reported in the ADHERE (4.0%)[9] and OPTIMIZE-HF (3.8%)[10] (both registries from the USA). The causal relationship between these differences in background factors and prognosis is unclear. In light of this, we hypothesized that the prognostic efficacy of SGLT-2 inhibitors may differ in Asian populations versus Western populations. In our analysis, we have shown that the favorable effects of SGLT-2 inhibitors are significantly higher in Asian HF patients than in white HF patients. This finding may provide hope for improving the prognosis of Asian HF patients, who have a higher risk of death than HF patients in Western countries. Future RCTs focusing on the Asian population were required to confirm the efficacy of SGLT-2 inhibitors.

Funding

The study was supported by a grant from the Research Grant, Japan Society for the Promotion of Science: Grant-in-Aid for Early-Career Scientists(C).

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