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Highlights
• The cardiorenal benefit of SGLT2 inhibitor enavogliflozin has yet to be investigated.
• The ENVELOP trial is a large, ongoing trial investigating cardiorenal outcomes.
• The ENVELOP trial will clarify cardiorenal effects of enavogliflozin in T2D patients.
• Cardiorenal outcomes of enavogliflozin will be compared with other SGLT2 inhibitors.
INTRODUCTION
According to the International Diabetes Federation, over 530 million people worldwide will have diabetes mellitus in 2021, with a projected increase to approximately 783 million by 2045, marking a substantial rise [1]. Diabetes mellitus is a significant contributor to global mortality, accounting for 11.3% of all deaths worldwide. Nearly half of these occurrences observed in individuals under the age of 60 years, emphasizing its pivotal role as a leading cause of premature mortality [2]. In South Korea, diabetes mellitus has a prevalence of 15.9% among men and 11.8% among women aged 30 years and older, aligning the worldwide increase in diabetic population [3].
Sodium-glucose cotransporter-2 (SGLT2) inhibitors work through the inhibition of SGLT2 in the renal proximal tubule, resulting in urinary glucose excretion and natriuresis [4]. Randomized controlled trials have consistently demonstrated that SGLT2 inhibitors extend their efficacy beyond glycemic control, encompassing risk reduction for major cardiovascular events, heart failure outcomes, and kidney-related events [5]. Given their well-established cardioprotective and renoprotective effects, SGLT2 inhibitors are recommended as the primary therapeutic approach for patients with type 2 diabetes mellitus (T2DM) and concomitant atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease [6,7].
Enavogliflozin (DWP-16001), a novel SGLT2 inhibitor developed by Daewoong Pharmaceutical Co. Ltd. (Seoul, Korea), has been investigated as an effective therapeutic agent for T2DM. In a comprehensive pharmacokinetic-pharmacodynamic study, enavogliflozin displayed potent inhibitory activity against SGLT2, characterized by a low half-maximal inhibitory concentration and exceptional selectivity (1,015-fold) for SGLT2 over SGLT1 [8]. In phase 3 clinical trials, enavogliflozin was shown to be effective in reducing glycosylated hemoglobin (HbA1c) levels without a significant increase in serious adverse events (AEs) [9-11]. It exhibited comparable efficacy in HbA1c reduction while achieving higher urinary glucose excretion than dapagliflozin. Additionally, enavogliflozin significantly reduced body weight, systolic blood pressure, and albuminuria, similar to dapagliflozin. However, most of these trials were of relatively short duration, typically less than 24 weeks, necessitating further investigations to establish the long-term cardiorenal protective potential of the drug.
Accordingly, the primary objective of this randomized controlled trial is to assess the effect of enavogliflozin on cardiovascular and renal outcomes in direct comparison with other SGLT2 inhibitors that have demonstrated cardiorenal outcome benefits, particularly in patients diagnosed with T2DM and concurrent cardiovascular risk factors.
METHODS
Study design and overview
The Enavogliflozin to evaluate cardiorenal outcomes in patients with type 2 diabetes (ENVELOP) study is an investigator-initiated, multicenter, randomized, pragmatic, open-label, active-controlled, non-inferiority trial. The study objective is to demonstrate the non-inferiority of enavogliflozin to other SGLT2 inhibitors with proven cardiorenal benefits, dapagliflozin or empagliflozin, in addition to the standard of care, for major adverse cardiovascular and kidney outcomes in patients with T2DM at increased risk of or with cardiovascular disease. The overall scheme of this study is illustrated in Fig. 1. The ENVELOP study was designed as a pragmatic clinical trial, which demonstrates the real-world effectiveness of the intervention in broad patient groups [12].
The study protocol was approved by the Institutional Review Boards of Yonsei University Health System Severance Hospital (IRB number 4-2023-1334) and each participating center. The study protocol complies with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice. The trial was registered at the Clinical Research Information Service (http://cris.nih.go.kr; identifier: KCT0009243).
Study population
Participants will be recruited from 60 secondary or tertiary medical centers in South Korea. Eligible participants are adults (aged ≥19 years) with T2DM who have a history of or are at risk of cardiovascular disease. The detailed inclusion and exclusion criteria are provided in Table 1. Definition of items in the inclusion criteria is described in the Supplementary Table 1 [13].
Enrollment and randomization
When the investigator enrolls subjects considered to be eligible by reviewing the inclusion and exclusion criteria, a randomization number will be automatically assigned in the electronic data capture system. Once a randomization number is assigned to a subject, it cannot be reassigned to another subject. The subjects will be assigned to the study or control groups at a ratio of 1:1, based on the randomization number. The randomization number will be used for subject identification until the end of the study. For a randomization table, a statistician independent of the study will issue randomization numbers using statistical software (SAS, latest version, SAS Institute Inc., Cary, NC, USA) prior to start of the study. The stratification factor includes cardiovascular risk classification (with prior atherosclerotic cardiovascular disease, without prior atherosclerotic cardiovascular disease) at screening. Because this is an open-label trial, blinding or masking will not be implemented.
Study procedure
The visit schedule for this study consists of visit 1 (screening and baseline visit), visit 2 (6 months, follow-up visit), visit 3 (12 months, follow-up visit), visit 4 (24 months, follow-up visit), visit 5 (36 months, follow-up visit), and visit 6 (48 months, end of study visit). The overall study procedures are presented in Table 2.
The efficacy assessment will include cardiorenal composite outcome events and changes in biomarkers until the end of the study. Cardiorenal composite outcome events for the efficacy assessment will be collected based on in-person visits, telephone visits, and medical records. The safety assessment will include AEs, AEs of special interest, laboratory tests, vital signs, and electrocardiography. At each visit during the treatment phase, the following variables will be collected: body weight, vital signs, drug use and laboratory test results (HbA1c, blood chemistry, blood lipid profile, and urine analysis) (Table 3).
The end of the study for each participant will be discussed by an Event Adjudication Committee annually, and the continuation and early termination of the overall study will be determined by the Data and Safety Monitoring Board.
Outcomes
The primary endpoint is the time to the first occurrence of a composite of major adverse cardiovascular or renal events. Major adverse cardiovascular events include non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, coronary or peripheral revascularization, and death from any cause. Renal events include a sustained decline in estimated glomerular filtration rate (eGFR) calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation of ≥40% from baseline to <60 mL/min/1.73 m2, onset of end-stage kidney disease (dialysis for ≥28 days, kidney transplantation, or an eGFR of <15 mL/min/1.73 m2), development of macroalbuminuria, and death from renal causes.
The key secondary endpoints include the time to first event of a composite of key major adverse cardiovascular events (non-fatal MI, non-fatal stroke, and death from cardiovascular causes), time to death from any cause, time to death from cardiovascular causes, time to first event of hospitalization for unstable angina, time to first event of hospitalization for heart failure, time to first event of a composite of major kidney events, and time to development of macroalbuminuria.
Details of endpoint and event definition are described in the Supplementary Methods [14]. The Event Adjudication Committee will consist of endocrinologist, cardiologists and nephrologists who have no conflicts of interest with the study and will independently assess the cardiorenal composite outcome events of each subject in a blinded manner using the data collected from the subject. The detailed operation instructions will be established separately.
Safety
AEs will be collected and recorded at every visit, and symptoms or signs identified at the screening and baseline visit (visit 1) that worsen in severity after study drug administration will be considered treatment-emergent AEs. When AEs occur, the symptoms, duration, severity, and causal relationships will be carefully documented in the case report form. All AEs will be classified by system organ class and the preferred term in the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
An AE is defined as any untoward medical occurrence (any unfavorable and unintended sign, symptom, or disease) in a study participant. The AEs of special interest are urinary tract infections, genital infections, ketoacidosis, hypoglycemia, and diabetic foot ulcers.
At each visit during the study period, any AEs will be recorded by the investigators. The intensity of AEs will be judged as mild, moderate, or severe according to the frequency, duration, and tolerability of the signs or symptoms. The standard for the grading of AE severity is as follows: (1) mild (The AE does not significantly impair normal daily activities [function] to the extent that the subject is hardly aware of it. Most cases do not require treatment); (2) moderate (The AE causes discomfort and may impair normal daily activities [function]. The subject can continue participating in the study, but treatment may be necessary); and (3) severe (The AE causes extreme discomfort, rendering normal daily activities [function] impossible, and may prevent continued participation in the study). Treatment or hospitalization may be required. Medical judgement will also be used to determine this relationship by considering all relevant factors.
Sample size calculation
Based on the study hypotheses, the number of participants was determined using a non-inferiority margin. The non-inferiority margin for cardiorenal outcome events used to determine the number of subjects was based on the U.S. Food and Drug Administration Guideline for the evaluation of cardiovascular risk of new antidiabetic medications in patients with T2DM. The guideline indicates that a new antidiabetic drug with the upper limit of the two-sided 95% confidence interval of cardiovascular risk ratio to a control group (e.g., placebo control and active drug control) exceeding 1.8 is considered inappropriate and one between 1.3 and 1.8 is considered comprehensively evaluable. Thus, as this is an active-controlled study, a non-inferiority margin of 1.5 was established, considering that the incidence rates of the two groups would be similar.
The event incidence rate was determined by referring to the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [15], Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) [16], and Canagliflozin Cardiovascular Assessment Study (CANVAS) trials [17], which are cardiovascular outcome trials (CVOTs) of SGLT2 inhibitors with a design similar to that of the present study, and was estimated based on the CANVAS trial. Considering that this study includes participants with a generally lower cardiovascular risk than those in previous CVOTs of SGLT2 inhibitors, the event incidence rate was conservatively estimated. Therefore, by referring to the weighted mean of endpoints in CANVAS trial of 12.2% and considering the more expanded endpoints of the ENVELOP study than the CANVAS trial, the expected incidence of primary endpoints was established at 13%.
Based on the assumed PASS version 20.0.10 (NCSS LLC., Kaysville, UT, USA) calculation results, 1,216 subjects were calculated to be needed to reach 95% power, with non-inferiority margin of 1.5, and group-specific event incidence rate of 13% at a one-sided significance level of 2.5%. Considering a 15% dropout rate, a total 2,862 subjects are required.
Statistical methods and analysis
Efficacy assessment will be performed primarily in the full analysis set and secondly in the per protocol set. The statistician will prepare a statistical analysis plan (SAP) to define the analysis variables, methods, and standards for tables, figures, and listings that will be generated. The SAP should be finalized prior to the database lock, and the justification for all changes to the planned statistical analysis in the SAP will be described in the clinical study report.
In principle, all statistical analyses will use statistical software (SAS version 9.4 or higher version), and all statistical tests will be performed with a two-sided test at a significance level of 5%, unless otherwise specified. Continuous variables will be summarized using the number of subjects, mean, standard deviation, median, minimum, and maximum, and categorical variables will be presented using frequency tables (number and percentage of subjects).
In this study, missing data will not be imputed separately, and the available dataset will be used as it is for the analyses. Time variables for withdrawals or missing data points will be censored. The demographic data and baseline information of the participants will be summarized using descriptive statistics by group.
For the primary endpoint, a Kaplan-Meier curve of time from study drug administration relative to randomization to the first onset of cardiorenal composite outcome events up to the end of study will be presented, and the incidence, median time, and 95% confidence interval will be presented by group. A log-rank test will be performed to compare differences between groups. Also, a one-sided 97.5% confidence interval for the hazard ratio (HR) of study group versus control group will be presented. If the upper limit of the confidence interval is less than the clinical non-inferiority margin of 1.5, the study group will be determined to be non-inferior to the control group. Additionally, the HR and 95% confidence interval will be provided using a Cox proportional hazards model with baseline information (sex, age, smoking status, and concomitant antidiabetic drugs) as covariates.
For the secondary efficacy endpoints corresponding to the cardiorenal composite outcome events, the Kaplan-Meier curve of time from the study drug administration relative to randomization to the first onset of major cardiovascular events up to the end of study will be presented, and the incidence, median time, and 95% confidence interval will be presented by group. A log-rank test will be performed to compare differences between groups. The number and proportion of patients who require hospitalization due to heart failure from study drug administration on the randomization day up to the end of study and 95% confidence interval will be presented. Then, a Pearson’s chi-square test will be performed to compare the differences between the groups.
For the changes in biomarkers, the absolute change, percent change, and proportion will be analyzed, and descriptive statistics of changes over time from study drug administration relative to randomization up to 6, 12, 24, 36, and 48 months, and the end of the study will be presented by group. An independent t-test or Wilcoxon rank-sum test will be performed to compare the differences between the groups depending on the normality of the data, and a paired t-test or Wilcoxon signedrank test will be performed to compare the differences within the groups depending on the normality of the data. For changes from the study drug administration relative to randomization up to 6, 12, 24, 36, and 48 months after administration and at the end of the study, a paired t-test or Wilcoxon signedrank test will be performed depending on data normality. The number and proportion of subjects will be presented at each time point relative to randomization, and Pearson’s chi-square test will be performed to compare the differences between the groups. The percent changes will be summarized with frequency and percentage by comparing the categories at the investigational product administration relative to randomization and at the time point after administration; McNemar’s test will be used for intra-group comparison before and after administration. In addition, a generalized estimating equation will be applied for inter-group comparisons. It will be analyzed at each time point after administration (6, 12, 24, 36, and 48 months and at the end of the study).
DISCUSSION
SGLT2 inhibitors have received considerable attention because of their insulin-independent glucose-lowering action, which is mechanistically different from existing diabetes treatments [18]. The primary mechanism involves promoting urinary glucose excretion by inhibiting SGLT2, which is a novel approach to antidiabetic treatment that targets renal glucose reabsorption [19]. In addition to a moderate blood glucose-lowering effect, these agents have demonstrated metabolic benefits, including a reduction in body weight, waist circumference, and blood pressure, thus promising a potential reduction in cardiovascular disease risk [20]. The EMPA-REG OUTCOME trial was pivotal in establishing the cardiovascular benefits of the SGLT2 inhibitor empagliflozin, initiating a shift towards organ protection in the management of T2DM [15,21]. Subsequent trials, specifically those evaluating kidney and heart failure outcomes with dapagliflozin and empagliflozin, have provided evidence of their efficacy in slowing kidney disease progression and mitigating heart failure exacerbation [22-27].
The pharmacodynamics of SGLT2 inhibitors vary with differences between drugs in SGLT2 binding affinity and selectivity for SGLT2 [28]. In particular, enavogliflozin has demonstrated superior SGLT2 selectivity and renal tissue protein-binding affinity compared with dapagliflozin and ipragliflozin [8]. A 24-week study showed that enavogliflozin 0.3 mg significantly reduced HbA1c levels in patients with T2DM inadequately controlled by diet and exercise, with a placebo-adjusted mean change in HbA1c from baseline of –0.99% [9]. Furthermore, enavogliflozin exhibited comparable glycemic efficacy and safety to dapagliflozin in patients receiving metformin monotherapy or in combination with gemigliptin [10,11]. However, these results do not guarantee that enavogliflozin has cardiorenal benefits similar to those of dapagliflozin or empagliflozin alone.
The ENVELOP study aims to assess cardiorenal outcomes following enavogliflozin administration compared with dapagliflozin or empagliflozin in Korean patients with T2DM, representing the first large-scale SGLT2 inhibitor outcome study targeting this population. While this study may have limitations in generalizing the results across diverse ethnicities, it offers a unique opportunity to evaluate the clinical effects of SGLT2 inhibitors specifically in Asians. Given that East Asian patients typically present with a lower body mass index and cardiovascular risk than their Western counterparts [29], assessing the efficacy of SGLT2 inhibitors in this demographic could provide valuable insights into managing T2DM in less obese populations with lower cardiovascular risk profiles. Additionally, this study sets the primary endpoints as renal and cardiovascular outcomes. Epidemiological studies in various regions have shown that diabetes is the most common cause of chronic kidney disease and end-stage kidney disease [30]. Chronic kidney disease and end-stage kidney disease are representative complications that impose as much of a medical and socioeconomic burden on patients with diabetes as cardiovascular disease [31], and the stage of chronic kidney disease is closely related to the risk of death [32]. Considering that the management of patients with diabetes involves the comprehensive management of various clinical outcomes, setting cardiovascular and renal outcomes as the primary endpoints could be a more comprehensive approach. This study will provide diverse perspectives on the clinical effects of enavogliflozin and SGLT2 inhibitors.
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