Effects of Dapagliflozin in Patients in Asia

Background Patients with heart failure (HF) with mildly reduced or preserved ejection fraction in Asia may have different clinical characteristics and outcomes compared with patients from other parts of the world. Objectives The purpose of this study was to investigate the clinical characteristics, safety, and efficacy of dapagliflozin in patients in Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial. Methods In the DELIVER trial, patients with HF and left ventricular ejection fraction >40% were enrolled across 353 sites in 20 countries. The effects of dapagliflozin vs placebo on primary (composite of worsening HF or cardiovascular death) and secondary outcomes were compared in patients from Asia vs outside Asia. Results Among 6,263 participants, 1,226 (19.6%) were enrolled in Asia. Participants from Asia were less likely to have diabetes, hypertension, history of myocardial infarction, or obesity. After adjusting for clinically relevant characteristics, those in Asia had similar risks of primary composite outcome compared with those from outside Asia (HR: 0.97; 95% CI: 0.82-1.15). Those in Asia had a lower risk of all-cause mortality compared with those enrolled outside Asia (HR: 0.54; 95% CI: 0.44-0.66). Enrollment from Asia did not modify the effect of dapagliflozin on the primary outcome (Pinteraction = 0.54). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs outside Asia. Conclusions In the global DELIVER trial, dapagliflozin reduced the risk of CV death or worsening HF events and was well tolerated among participants enrolled in both Asia and other geographic regions.

A sia comprises 60% of the world's population and is both ethnically and socioeconomically diverse.With a rapidly aging population, urbanization, and increased prevalence of comorbidities such as diabetes, obesity, and hypertension, heart failure (HF) has become an urgent public health concern in this region. 1idemiological data suggest that many Asian countries have worse HF outcomes compared with Western countries, but with significant variation among nations.For example, in the INTER-CHF (International Congestive Heart Failure) study, India had the highest 1-year mortality (23%), compared with Southeast Asia (15%) and China (7%). 2 Data from the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry showed the highest mortality in Southeast Asia. 3 Moreover, comorbidities and outcomes vary enormously between and even within Asian countries and ethnicities.Yet despite its large population with high rates of adverse outcomes, Asian countries have been generally underrepresented in global clinical trials until recently.For example, most of the pivotal trials for angiotensin-converting enzyme (ACE) inhibitors and beta blockers did not include any Asian countries at all. 4 The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included a fifth of participants from Asia, 5,6 thus providing a unique opportunity to study the characteristics, outcomes, and response to therapy in a contemporary cohort of patients with HF from Asia.

METHODS
STUDY DESIGN AND PATIENT POPULATION.The design of DELIVER has been previously reported. 5,7Briefly, 6,263 patients were enrolled in the phase III, international, double-blind, randomized-controlled trial.
Patients with chronic HF and left ventricular ejection fraction (LVEF) >40% (including previous LVEF

RESULTS
BASELINE CHARACTERISTICS.There were 1,226 (19.6%) participants enrolled from Asia, all of whom were of Asian ethnicity.Among the participants who were enrolled from outside Asia, most were White (88.1%), with 48 participants of Asian ethnicity (1%).
At baseline, those enrolled in Asia were of similar age as those enrolled outside of Asia but were more likely to be men (Table 1).Those enrolled in Asia had a lower burden of comorbidities, as evidenced by less obesity, dyslipidemia, type 2 diabetes, hypertension, myocardial infarction, stroke, chronic obstructive pulmonary disease, and sleep apnea (Table 1).
Compared with those enrolled from outside Asia, those enrolled in Asia had similar levels of NT-proBNP, higher baseline LVEF, were less likely to have NYHA functional class III/IV symptoms, but were more likely to have a history of HF hospitalization.Participants from Asia were less likely to be on loop diuretics, ACE inhibitors, and beta blockers, but were more likely to be on angiotensin receptor blockers and mineralocorticoid receptor antagonists.1).
OUTCOMES IN ASIA VS OUTSIDE ASIA.Participants enrolled in Asia and outside Asia had a similar incidence of the primary composite outcome and worsening HF outcomes (including HF hospitalization and urgent HF visits) (Table 2).However, those enrolled in Asia had a lower risk of CV death (HR: 0.64; 95% CI: 0.49-0.84;P ¼ 0.001) and all-cause death (HR: 0.61; 95% CI: 0.50-0.73;P < 0.001) (Figure 1) compared with those enrolled outside Asia.These differences persisted after adjusting for age, sex, and baseline LVEF, with adjusted HRs (aHRs) of 0.66 (95% CI: 0.51-0.87)and 0.60 (95% CI: 0.49-0.72)for CV death and allcause death, respectively (Table 2).After adjusting for baseline clinical profiles, those enrolled in Asia still had an almost 50% lower risk of CV death, non-CV death, and all-cause death (Table 2).
IMPACT OF REGION ON TREATMENT EFFECT OF DAPAGLIFLOZIN.Enrollment from Asia did not modify the effect of dapagliflozin on primary outcome (P interaction ¼ 0.54), components of primary outcome, or secondary outcomes (P interaction >0.32 for all outcomes) (Central Illustration, Figure 2).After adjusting for baseline differences, the treatment effects of dapagliflozin remained similar in both participants from Asia and outside Asia (Supplemental Figure 2).4).There was no evidence of region-by-treatment interaction (P interaction >0.50 for total symptom score, clinical summary score, and overall summary score) (Table 4).

ADVERSE EVENTS IN ASIA VS OUTSIDE ASIA.
Data on serious adverse events, adverse events that led to discontinuation of dapagliflozin or placebo, and select other adverse events were collected.Overall, patients enrolled in Asia vs outside Asia had similar rates of adverse events (Supplemental Table 1), with a few exceptions.In the overall patient group (regardless of treatment assignment), those enrolled in Asia had lower rates of adverse events (14.5% outside Asia vs 7.6% in Asia, P < 0.001), amputation (0.9% outside Asia vs 0.1% in Asia), and myocardial infarction (2.5% outside Asia vs 1.0% in Asia).In both groups, those randomized to dapagliflozin did not have a higher rate of adverse events compared with those randomized to placebo (Supplemental Table 1).Further, there was no evidence of effect modification by region (P interaction $ 0.07 for all adverse event outcomes) (Supplemental Table 1).

DISCUSSION
In this subgroup analysis of the DELIVER trial, participants enrolled in Asia had a lower burden of comorbidities, had similar incidence of HF events, but were less likely to experience CV death or allcause death.Despite these differences, dapagliflozin was well tolerated in both patients in Asia and outside Asia.Further, enrollment from Asia did not modify the effect of dapagliflozin on primary and secondary outcomes.
The differences in baseline characteristics in patients from Asia compared with those from outside Asia were overall consistent with previous studies, with some notable exceptions.In the ASIAN-HF reg-  Wang et al Although prior studies suggested worse outcomes in certain patients with HF in Asia, 2,10 our analyses demonstrated a lower risk of CV death and all-cause death in patients with chronic HF and LVEF >40%.
The lower risk of CV death and all-cause death was observed despite a similar risk of HF events.One possible explanation for this observation is the eligibility criteria used in DELIVER, such as the requirement for elevated NT-proBNP, to standardize risk of worsening HF events.In contrast, there were no specific eligibility criteria for other cardiac and noncardiac comorbidities, which may have accounted for the differences in risks of CV death and all-cause death.Regardless, there are notable differences within countries of Asia.Compared with Japan, those from China and Taiwan experienced a higher risk of worsening HF events, CV death, and all-cause death.
Those from Vietnam had markedly higher risk of allcause death, but similar rates of HF events.However, it is worth noting that the overall event rates in patients from Vietnam were low, and thus these cross-country comparisons may be underpowered.
Nevertheless, these notable differences reflect the diverse ethnic and sociodemographic backgrounds of Cox regression models were used to compare outcomes in those enrolled in Asia vs outside Asia.Unadjusted hazard ratios with participants outside Asia are displayed.The primary outcome was a composite of worsening heart failure (HF) or cardiovascular (CV) death.The cumulative incidence of (A) the primary outcome, (B) cardiovascular death, (C) heart failure events, and (D) all-cause death were estimated with the use of the Kaplan-Meier method in patients enrolled in Asia and outside Asia.Compared with participants outside Asia, those from Asia had lower incidence of CV death and all-cause death, but similar incidence of primary outcome and HF events.
people in Asia.For example, patients from Japan are known to have one of the longest life expectancies in the world, and the overall better outcomes are likely a reflection of its socioeconomics and health care infrastructure. 11In comparison, even though patients from Vietnam were younger and had lower comorbidity burden compared with other regions in Asia, they still had markedly higher mortality rates.This is consistent with the observations in the ASIAN-HF registry, where Southeast Asians with HFpEF had the highest rates of death or HF hospitalization. 9en after adjusting for baseline comorbidities and demographic factors, Southeast Asians in the ASIAN-HF registry had a 2.7-fold risk of death of HF hospitalizations compared with Northeast Asians, and an almost 4-fold risk of all-cause death. 9This higher risk of adverse outcomes warrants further research to understand the underlying social and biological factors driving this risk.
Patients in DELIVER and enrolled from Asia derived similar benefits from dapagliflozin compared with those outside Asia.This is consistent with previously reported analyses in DAPA-HF, which evaluated the effect of dapagliflozin in patients with heart failure with reduced ejection fraction. 12In DAPA-HF, 1,096 (23.1%) were enrolled in Asia, with similar event rate of primary composite endpoint compared with those enrolled outside Asia (13.9 per 100 personyears vs 13.4 per 100 person-years).Those enrolled in Asia vs outside Asia also had similar rates of worsening HF events, CV death, all-cause death, and total HF hospitalization and CV death. 12In DAPA-HF, dapagliflozin had a consistent effect in reducing the primary endpoint in patients enrolled in Asia vs outside Asia, and was well tolerated in both populations.In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with a Reduced Ejection Fraction), patients with  14 However, there was no evidence of treatment-by-region interaction for the primary outcome (P interaction ¼ 0.10). 14Taken together, these data suggest that enrollment from Asia does not modify the efficacy of SGLT2 inhibitors in patients with HF.[17] Our study highlighted the importance of including Asian patients in clinical trials.Earlier HF trials included few or no Asians. 4For example, early HF trials of ACE inhibitors and beta blockers did not enroll any patients from Asia. 4   Wang et al

DELIVER Trial in Asia
Prospective Comparison of with ARB Global Outcomes in HF with Preserved Ejection Fraction) enrolled 18% and 16% of patients from Asia, respectively. 5,18DELIVER has a high proportion of participants from Asia (20%), making it uniquely suited to evaluate the clinical characteristics and outcomes in a contemporary HFpEF population. 5UDY LIMITATIONS.First, the analyses presented here were post hoc subgroup analyses of a large, randomized trial, and the results should be interpreted as hypothesis generating.Second, although DELIVER enrolled 20% of participants from Asia, the distribution of these participants was not representative of the overall diverse ethnic and sociodemographic background of patients in Asia.For example, DELIVER did not include any patients from India, which has one of the largest populations in the world with a distinct risk profile and outcomes as reported by other studies.
Third, as is the case with many subgroup analyses, we have a lower number of participants and events in the Asian subgroup, limiting the statistical power to assess the treatment effect of dapagliflozin in this   DELIVER Trial in Asia

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40%) were randomized to receive dapagliflozin 10 mg daily or a matching placebo.In addition to LVEF, other key inclusion criteria included NYHA functional class II-IV HF, evidence of structural heart disease on echocardiography (left atrial enlargement or left ventricular hypertrophy), and elevated natriuretic peptides (NT-proBNP [N-terminal pro-B-type natriuretic peptides] $300 pg/mL for those without atrial fibrillation/flutter, or $600 pg/ mL for those in atrial fibrillation/flutter).Patients were followed for a median of 2.3 years.The trial protocol for DELIVER were approved by institutional review boards at each trial center and trial participants gave informed consent.DEFINITION OF REGIONS AND ETHNICITIES.In the DELIVER trial, the prespecified geo-Continuous variables were analyzed using Student's t-test and reported as mean AE SD.Non-normally distributed variables were analyzed using Wilcoxon rank-sum test.For comparisons between Asian countries, analysis of variance and Kruskal-Wallis A B B R E V I A T I O N S A N D A C R O N Y M S ACE = angiotensin-converting enzyme aHR = adjusted HR BMI = body mass index CV = cardiovascular HF = heart failure HFpEF = heart failure with preserved ejection fraction KCCQ = Kansas City Cardiomyopathy Questionnaire LVEF = left ventricular ejection fraction NT-proBNP = N-terminal pro-B-type natriuretic peptide SGLT2 = sodium glucose co-transporter 2 Cordoba, Argentina; n Department of Cardiology, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri, USA; o Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA; and the p Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.Andrea Salzano, MD, PhD, served as Guest Associate Editor for this paper.Toru Suzuki, MD, PhD, served as Guest Editor-in-Chief for this paper.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.Manuscript received July 7, 2023; revised manuscript received October 2, 2023, accepted October 6, 2023.

J 4 8 DELIVER
A C C : A S I A , V O L . 4 , N O . 2 , 2 0 2 Wang et al F E B R U A R Y 2 0 2 4 : 1 0 8 -1 1 Trial in Asia tests were used for normally and non-normally distributed continuous variables, respectively.Categorical variables were compared using chi-square test and reported as numbers and percentages.Cox regression models were used to compare outcomes in those enrolled in Asia vs outside Asia.Three models were constructed: 1) unadjusted; 2) with age, sex, and baseline LVEF as covariates; and 3) with body mass index (BMI), NYHA functional class, atrial fibrillation/ flutter, stroke, dyslipidemia, diabetes, myocardial infarction, hypertension, and prior HF hospitalization as covariates in addition to those included in Model 2. Total events analyses were performed using the Lin-Wei-Yang-Ying model.To evaluate the effect of dapagliflozin in participants in Asia vs outside Asia, we constructed Cox proportional hazards models without covariates.To assess the impact of region on the treatment effect of dapagliflozin, we included a region-by-treatment interaction term in the Cox proportional hazards models.Linear regression was used to compare changes in KCCQ scores at 8 months, with baseline KCCQ included in the linear regression model to account for baseline differences.The impact of region was tested by including a region-by-treatment interaction term in the linear regression model.Stata, version 16 (StataCorp) was used for all analyses.The value P < 0.05 was considered statistically significant.No adjustments were made for multiple comparisons.
REGIONAL VARIATIONS IN KCCQ SCORES.At baseline, participants from Asia had a KCCQ total symptom score (KCCQ-TSS) of 81.2 AE 19.7, compared with a KCCQ-TSS score of 67.5 AE 21.9 in those from outside Asia (P < 0.001).Treatment with dapagliflozin resulted in a significant benefit in those enrolled in Asia and outside Asia (Table . Consistent with registry data, patients in DELIVER and enrolled in Asia were less likely to have prior myocardial infarction and had lower BMI, with a mean BMI of 25 (Asia) vs 31 (outside Asia).Despite a significantly lower prevalence of overweight/obesity, almost 40% of participants in Asia had diabetes, with the rate as high as 45% in those enrolled from Taiwan.This is consistent with prior findings in ASIAN-HF, where prevalence of diabetes was high despite a lower BMI, suggesting a key role of metabolic derangement in the development of HFpEF 9 in this patient population.

FIGURE 1
FIGURE 1 Cumulative Incidence of CV Outcomes According to Geographic Region In comparison, PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (The CENTRAL ILLUSTRATION The DELIVER Trial in Asia

FIGURE 2 4 DELIVER
FIGURE 2 Treatment Effect of Dapagliflozin in Participants According to Geographic Region

TABLE 2
Unadjusted and Adjusted Primary and Secondary Outcomes in Patients in Asia vs Outside Asia event refers to HF hospitalization and urgent outpatient HF visits.a Model 1: Unadjusted.b Model 2: Adjusted for age, sex, baseline LVEF.c Model 3: Adjusted for age, sex, baseline LVEF, body mass index, NYHA functional class, atrial fibrillation/flutter, stroke, dyslipidemia, type 2 diabetes mellitus, myocardial infarction, hypertension, prior HF hospitalization.CV ¼ cardiovascular; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; py ¼ person-year; RR ¼ rate ratio. HF

TABLE 3
Unadjusted and Adjusted Primary and Secondary Outcomes in Patients in Countries of Asia Select baseline clinical characteristics and primary composite outcome in participants enrolled from Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial.Map graphics were created with Microsoft Excel with software powered by Bing.

TABLE 4
Changes in Kansas City Cardiomyopathy Questionnaire Scores From Baseline to 8 Months Outside Asia (n ¼ 3430) Asia (n ¼ 981) Values are point changes in Kansas City Cardiomyopathy Questionnaire score (95% CI) unless otherwise indicated.