Effect of Dapagliflozin on Electrocardiographic Parameters in Type 2 Diabetes Patients: DAPA - ECG Study

Phase 4

Completed

• Conditions: Arrhythmias, Cardiac; Diabetes Mellitus
• Interventions: Drug: Dapagliflozin (DAPA)

• Registration Number: NCT06721442
• Lead Sponsor: Beneficência Portuguesa de São Paulo

Brief Summary

The goal of this clinical trial is to evaluate whether dapagliflozin can reduce ventricular electrical remodeling, as measured by electrocardiographic parameters, in patients with type 2 diabetes (T2D). The study focuses on understanding how dapagliflozin affects the risk of potentially malignant ventricular arrhythmias and sudden cardiac death in this population.

The main questions it aims to answer are:

* Does dapagliflozin reduce the TpTe interval in patients with T2D?

* Does dapagliflozin impact other electrocardiographic parameters such as QT and QTc intervals, TpTe/QT ratio, and QT dispersion?

Researchers will compare patients treated with dapagliflozin plus optimized medical therapy (OMT) o those receiving OMT without SGLT2 inhibitors to assess whether there is a significant difference in the electrocardiographic parameters and ventricular electrical remodeling.

Participants will:

Be randomized into two groups: one treated with dapagliflozin and the other with optimized medical therapy.

Undergo clinical, electrocardiographic, laboratory, and echocardiographic evaluations at baseline and after three months.

This randomized, prospective, multicenter, open-label study seeks to clarify the cardioprotective mechanisms of dapagliflozin, particularly its impact on ventricular electrical remodeling in patients with type 2 diabetes.

Detailed Description

Background: In patients with type 2 diabetes (T2D), hyperglycemia and glycemic variability lead to prolongation and greater heterogeneity of ventricular repolarization, manifested on the electrocardiogram through an increase in QT, QTc, TpeakTend (TpTe) intervals and the TpTe/QT ratio, increasing the risk of potentially malignant arrhythmias. Dapagliflozin has demonstrated efficacy in reducing cardiovascular events in diabetic patients at high cardiovascular risk and in the risk of serious ventricular arrhythmias and sudden cardiac death. However, the exact mechanisms by which dapagliflozin confers this protection have not yet been fully elucidated.

Objective: The main objective of the study was to evaluate the impact of dapagliflozin on the TpTe interval of patients with T2D, and secondarily, it examined its impact on various electrocardiographic parameters such as the QT and QTc intervals, the TpTe/QT ratio, QT dispersion, J-T peak interval, QRS-T angle and heart rate.

Methods: This randomized, prospective, multicenter and open-label study involved 174 patients with T2D, divided into two groups: one treated with dapagliflozin and the other with optimized medical therapy without iSGLT2. Clinical, electrocardiographic, laboratory and echocardiographic evaluations were carried out at the beginning and after three months. The statistical analysis included means, standard deviations, quartiles, and frequencies, with 95% confidence intervals, using Chi-square (or Fisher) and t-Test (or Mann-Whitney) for initial differences, and a linear mixed-effects model to evaluate the results, adopting a significance level of 0.05.

Study Timeline

• Study Start: 2023-01-10
• Primary Completion: 2023-12-10
• Study Completion: 2024-07-10
• Study First Submitted: 2024-11-27
• Status Verified: 2024-12
• Study First Submitted QC: 2024-12-05
• Last Update Submitted: 2024-12-05
• Study First Posted: 2024-12-06
• Last Update Posted: 2024-12-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 174

Inclusion Criteria

• Adult patients (≥18 years old);
• Resting 12-lead electrocardiogram in sinus rhythm;
• Type 2 diabetes;
• Body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, of 45 or less;
• Estimated glomerular filtration rate (eGFR) of at least 30 ml per minute per 1.73 m² of body surface area, according to CKD-EPI criteria;
• Agreed to participate in the study and signed the informed consent form (ICF).

Exclusion Criteria

• Patients with a QRS interval > 120 ms;
• Insulin use;
• Atrial fibrillation rhythm;
• Cardiac pacemaker rhythm;
• Planned cardiac surgery or angioplasty within 3 months;
• Glycemic control issues (glucose > 240 mg/dL) after an overnight fast of 8 hours in both groups;
• Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 times the upper limit of normal during the baseline phase;
• Medicinal treatment for weight loss within 3 months of the study start;
• Pregnant women, women with delayed menstruation, or those breastfeeding.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapafliflozin	Dapagliflozin (DAPA)	A total of 174 individuals were assessed for eligibility, of whom 87 were randomized to receive dapagliflozin in combination with optimized medical treatment for type 2 diabetes.

Primary Outcome Measures

Name	Time	Method
Effect of Dapagliflozin on the TpeakTend Interval	90 days	In the intervention group (dapagliflozin), 12-lead electrocardiograms (ECGs) were performed during designated outpatient visits, with the initial baseline recording conducted at visit 1 (day 0) and the subsequent recording at the final visit, approximately 90 days after the study began.; The ECGs were obtained using Micromed electronic equipment, configured with a paper speed of 25 mm/s and an amplitude of 10 mm/mV, ensuring standardized measurements. The ECG intervals were manually measured using Wincardio software (version 11.1.0.0).; The primary outcome, the interval between the peak of the T wave and the end of the T wave (TpTe), was assessed to evaluate the effect of dapagliflozin. This assessment compared the two time points (baseline and follow-up), with all ECGs analyzed by an independent external examiner to ensure objectivity and reliability of the study results.

Secondary Outcome Measures

Name	Time	Method
Effect of Dapagliflozin on the QT and QTc Interval	90 days	In the intervention group (dapagliflozin), 12-lead electrocardiograms (ECGs) were performed during designated outpatient visits, with the initial baseline recording conducted at visit 1 (day 0) and the subsequent recording at the final visit, approximately 90 days after the study began.; The ECGs were obtained using Micromed electronic equipment, configured with a paper speed of 25 mm/s and an amplitude of 10 mm/mV, ensuring standardized measurements. The ECG intervals were manually measured using Wincardio software (version 11.1.0.0).; The secondary outcomes, the QT and corrected QT (QTc) intervals, were assessed to evaluate the effect of dapagliflozin. These intervals were analyzed by comparing the two time points (baseline and follow-up). All ECGs were reviewed by an independent external examiner, ensuring objectivity and reliability in the interpretation of the study data.
Effect of Dapagliflozin on the TpTe/QT ratio	90 days	To evaluate the effect of dapagliflozin on the TpTe/QT ratio, an electrocardiographic marker of arrhythmogenesis that reflects the degree of heterogeneity in myocardial repolarization. The TpTe interval, measured as the time from the peak of the T wave to the end of the T wave, and the TpTe/QT ratio, calculated by dividing the TpTe interval by the QT interval, were assessed at baseline (visit 1, day 0) and follow-up (final visit, approximately 90 days later).; Prolonged TpTe and TpTe/QT intervals are associated with a higher risk of sudden cardiac death (SCD) in various cardiac conditions, including hypertrophic cardiomyopathy and long QT syndrome, making them valuable prognostic markers. In this study, 12-lead ECGs were recorded using Micromed electronic equipment (configured at a paper speed of 25 mm/s and amplitude of 10 mm/mV), and intervals were manually measured with Wincardio software (version 11.1.0.0).
Effect of Dapagliflozin on the J-Tpeak Interval	90 days	The J-Tp interval (JTp), an important marker of delays in the early phase of the action potential, was measured from the J point to the peak of the T wave (Tp) on 12-lead electrocardiograms (ECGs). Baseline ECG recordings were conducted at visit 1 (day 0), while follow-up recordings were obtained approximately 90 days later at the final visit.; All ECGs were recorded using Micromed electronic equipment, standardized with a paper speed of 25 mm/s and an amplitude of 10 mm/mV. Manual measurements of the JTp interval were performed using Wincardio software (version 11.1.0.0). This parameter was assessed to evaluate the effect of dapagliflozin on early ventricular repolarization dynamics, providing valuable insights into potential delays in the initial phase of the cardiac action potential and contributing to the overall understanding of its impact on cardiac electrophysiology.
Effect of Dapagliflozin on the QT interval dispersion (QTd)	90 days	QT interval dispersion (QTd), a marker of spatial heterogeneity in ventricular repolarization, was calculated as the difference between the longest (QTmax) and shortest (QTmin) QT intervals measured on 12-lead electrocardiograms (ECGs). Baseline ECG recordings were taken at visit 1 (day 0), and follow-up recordings were acquired approximately 90 days later at the final visit.; The ECGs were obtained using Micromed electronic equipment, configured with a paper speed of 25 mm/s and an amplitude of 10 mm/mV. All interval measurements were manually conducted using Wincardio software (version 11.1.0.0) to ensure precision and standardization.; This parameter was analyzed to assess the impact of dapagliflozin on reducing ventricular repolarization dispersion, which has been associated with an increased risk of arrhythmias and sudden cardiac death (SCD) in patients with type 2 diabetes.
Effect of Dapagliflozin on The QRS-T angle	90 days	The QRS-T angle, a vectorcardiographic marker of ventricular repolarization heterogeneity and electrical dyssynchrony, was evaluated using data obtained from 12-lead electrocardiograms (ECGs). Baseline ECGs were recorded at visit 1 (day 0), and follow-up recordings were performed approximately 90 days later at the final visit.; The QRS-T angle was calculated by analyzing the electrical axes of the QRS complex and the T wave in the frontal plane leads. These measurements were performed using the MYEKG software, which processed the R and T wave amplitudes in millimeters and calculated the spatial QRS-T angle using a dedicated algorithm available at \[https://pt.my-ekg.com/calculadoras-ecg/calculadora-eixo-eletrico.php\].; The QRS-T angle was categorized into three groups: normal (0 to 105°), borderline (105 to 135°), and abnormal (135 to 180°). This parameter was assessed to determine the impact of dapagliflozin on ventricular electrical heterogeneity
Effect of Dapagliflozin on the Heart rate	90 days	Heart rate was measured from 12-lead electrocardiograms (ECGs) recorded during designated outpatient visits. Baseline ECG recordings were obtained at visit 1 (day 0), and follow-up ECGs were performed approximately 90 days later at the final visit.; The ECGs were recorded using Micromed electronic equipment, standardized with a paper speed of 25 mm/s and an amplitude of 10 mm/mV. Heart rate measurements were automatically calculated by the Wincardio software (version 11.1.0.0) and manually verified when necessary to ensure precision and consistency.; This parameter was evaluated to assess the effect of dapagliflozin on overall cardiac rhythm and rate regulation in patients with type 2 diabetes. Independent external examiners reviewed all ECGs to ensure objectivity and reliability in the study data.

Trial Locations

Locations (2)

Hospital Beneficencia Portuguesa de São Paulo; 🇧🇷 São Paulo, SP, Brazil

Instituto Dante Pazzanese de Cardiologia; 🇧🇷 São Paulo, SP, Brazil