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Associated Trial(s):- NCT01032629 - A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus
- NCT02065791 - A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 Diabetes Mellitus and Diabetic Nephropathy
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Status: OngoingResearch Proposal
Project Title: Meta-analysis on the effectiveness of canagliflozin in heart failure in elderly patients
Scientific Abstract:
Background: Canagliflozin is an innovative sodium-glucose co-transporter 2 (SGLT2) inhibitor used in the management of type 2 diabetes. Despite its widespread use, comprehensive data synthesizing its efficacy and safety is limited, compared to other SGLT2 inhibitors.
Objective: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the overall impact of canagliflozin on cardiovascular outcomes and adverse events in elderly patients (>75yo).
Study Design: This will be a systematic review and meta-analysis of RCTs comparing canagliflozin with placebo or other antidiabetic agents. The study will follow PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and eventually will be registered with PROSPERO.
Participants: Elderly (>75 years old) patients with type 2 diabetes mellitus from included RCTs, regardless of disease duration, comorbidities, or previous antidiabetic treatments.
Primary and Secondary Outcome Measure(s): The primary outcome will be the incidence of cardiovascular events, and reported adverse events.
Statistical Analysis: Data will be pooled using a random-effects model to calculate weighted mean differences for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals. Heterogeneity will be assessed using the I2 statistic, and publication bias will be evaluated through funnel plot analysis and Egger's test.
Brief Project Background and Statement of Project Significance:
Project Background: Elderly patients show very high rates of cardiovascular events, compared to the overall population. Canagliflozin, as part of the SGLT2 inhibitor class, has emerged as a pivotal treatment option for type 2 diabetes mellitus (T2DM), offering benefits beyond glycemic control, such as weight loss and cardiovascular risk reduction. However, individual studies have provided varying results regarding its efficacy and safety, and actually there is no meta-analysis regarding the effect of canagliflozin on the cardiovascular risk in elderly patients, leading to uncertainties in clinical decision-making.
Statement of Project Significance: This meta-analysis aims to consolidate existing data from randomized controlled trials to provide a more definitive understanding of canagliflozin's therapeutic profile. By integrating findings from multiple studies, we expect to offer clearer guidance on its use in diverse patient populations, potentially influencing treatment guidelines and patient care strategies.
The anticipated outcomes of this project will not only enhance scientific knowledge in the field of diabetes management but also have practical implications for public health by informing safer and more effective use of canagliflozin in T2DM patients.
Specific Aims of the Project:
Specific Aims of the Project:
Aim 1: To examine the incidence of cardiovascular events in elderly patients treated with canagliflozin compared to controls.
Hypothesis 1: Canagliflozin significantly reduces the risk of major cardiovascular events compared to placebo or other treatments il elderly patients.
Aim 2: To analyze the safety profile of canagliflozin in elderly patients, with particular attention to adverse events reported across different studies.
Hypothesis 2: Canagliflozin has a comparable or better safety profile than other antidiabetic agents, with an adverse event rate not exceeding that observed with other treatments.
These aims are intended to provide a deeper understanding of the impact of canagliflozin on the clinical conditions of patients with type 2 diabetes, thereby contributing to improved treatment strategies and quality of care.
Study Design: Meta-analysis (analysis of multiple trials together)
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations New research question to examine treatment safety Confirm or validate previously conducted research on treatment effectiveness Confirm or validate previously conducted research on treatment safety Participant-level data meta-analysis Meta-analysis using only data from the YODA Project Develop or refine statistical methods Research on comparison group Research on clinical prediction or risk prediction
Software Used: RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Upon approval, we will access participant-level data sets through the YODA Project's secure data sharing platform. All data analyses will be conducted using the high security users identification standards (in the provided platform) in order to maintain data security and confidentiality. We will utilize the most common analytical tools, including RStudio.
Exclusion criteria: None.
Inclusion criteria: all patients of the studies will be included in the analysis.
Analytic Approach: For Aim 1, we will perform a meta-analysis of cardiovascular events reported in the two selected studies. For Aim 2, we will calculate risk ratios for cardiovascular events. For Aim 3, we will conduct a safety profile analysis, focusing on adverse event frequencies.
Conceptual Models and Causal Relationships: We will construct a conceptual framework based on the hypothesized effects of canagliflozin on glycemic control and cardiovascular outcomes, considering potential mediators and moderators, identifying potential confounders using multivariable regression models to adjust for the confounders. Subgroup analyses will be conducted based on patient characteristics like age and comorbidity.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary Outcome Measure(s): The primary outcome measure will be the incidence of cardiovascular events (heart attack, stroke, and cardiovascular death.) in patients treated with canagliflozin compared to controls.
Secondary Outcome Measure(s): Secondary outcome measures include: Fasting Plasma Glucose (FPG): Measured in milligrams per deciliter (mg/dL), indicating the blood sugar level after an overnight fast.
Body Weight: Recorded in kilograms (kg), assessing the impact of canagliflozin on weight management.
Blood Pressure: Systolic and diastolic blood pressure measured in millimeters of mercury (mmHg), evaluating the cardiovascular effects of the medication.
Cardiovascular Events: Incidence of major adverse cardiovascular events (MACE), including heart attack, stroke, and cardiovascular death.
Adverse Events: Frequency and severity of any adverse events reported during the study, categorized according to the Common Terminology Criteria for Adverse Events (CTCAE).
Categorization and Definition: Each outcome measure will be clearly defined according to standard clinical criteria.For example, cardiovascular events will be categorized as 'major' or 'minor'.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
Main Predictor/Independent Variable: The main independent variable in this study is the treatment with canagliflozin. This variable will be categorized based on the dosage and duration of the treatment as follows:
Dosage: The amount of canagliflozin administered to the participants, measured in milligrams (mg). This will be categorized into standard dosing groups (e.g., 100 mg, 300 mg) as per the dosing regimens used in the clinical trials included in the meta-analysis.
Duration: The length of time that participants received the treatment, measured in weeks or months.
Categorization and Definition: The categorization of the treatment variable will allow for the analysis of dose-response relationships and the assessment of the efficacy and safety of canagliflozin over different treatment durations. It will also enable comparisons across studies and with the final analysis reported in any publication resulting from this research.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
Other Variables of Interest:
In addition to the primary independent variable of canagliflozin treatment, the following variables will be included in the analysis:
Age: Categorized into clinically relevant age groups (e.g., <40, 40-59, >=60 years) to assess the efficacy and safety across different life stages.
Gender: Recorded as male, female, or other, to investigate any gender-specific responses to canagliflozin.
Baseline HbA1c Levels: Categorized into ranges (e.g., 8%) to evaluate the treatment effect relative to baseline glycemic control.
Duration of Diabetes: Defined as the time since diagnosis and categorized into ranges (e.g., 10 years) to explore the impact of disease chronicity on treatment outcomes.
Comorbidities: Presence of additional conditions such as hypertension or dyslipidemia, which will be defined according to standard clinical criteria and categorized as present or absent.
Concomitant Medications: Types of other antidiabetic or cardiovascular medications taken alongside canagliflozin, categorized by drug class.
Categorization and Definition: Each variable will be clearly categorized to facilitate multivariable risk adjustment.
Statistical Analysis Plan:
Statistical Analysis Plan:
Descriptive Analysis: Initially, we will conduct a descriptive analysis to summarize the characteristics of the study population. This will include measures of central tendency and dispersion for continuous variables (mean, standard deviation) and frequency distributions for categorical variables.
Bivariate Analysis: Bivariate analyses will be performed to examine the relationship between canagliflozin treatment (independent variable) and each outcome measure. For continuous outcomes, we will use t-tests or ANOVA, and for categorical outcomes, chi-square tests will be employed.
Multivariable Analysis: We will use multivariable regression models to adjust for potential confounders identified a priori. For continuous outcomes, linear regression will be used, and for dichotomous outcomes, logistic regression will be employed. The models will include terms for the main effects of the treatment and other covariates.
Advanced Analyses:
Propensity Score Methods: To account for treatment selection bias, we will use propensity score matching or weighting to create a balanced cohort for comparison.
Kaplan-Meier and Cox Modeling: For time-to-event data, such as the occurrence of cardiovascular events, Kaplan-Meier survival curves will be generated, and Cox proportional hazards models will be used to estimate hazard ratios.
Non-Parametric Testing: If the data do not meet the assumptions of parametric tests, non-parametric methods such as the Mann-Whitney U test will be used for analysis.
Model Diagnostics: We will perform diagnostics for each statistical model, including checks for multicollinearity, interaction terms, and the proportional hazards assumption for Cox models.
Sensitivity Analysis: To assess the robustness of our findings, sensitivity analyses will be conducted by varying the inclusion criteria and the definition of outcomes.
Narrative Summary:
Dear YODA Project Team,
I am planning a study that will look at data from previous researches on a drug called canagliflozin. This drug is used to treat conditions like diabetes, but it might be particularly helpful for elderly people who have heart failure.
In this study the collected data from two previous studies on canagliflozin will be analyzed to see how effective and safe the drug is for different groups of patients: the main focus will be on elderly patients with heart failure.
This research is important because it could help us find new ways to treat heart failure in elderly patients. It could also give us more information about the safety of canagliflozin in elderly patient.
Project Timeline:
Project start date: 12/08/2024
analysis completion date: 12/03/2025
date manuscript drafted 03/06/2025
first submitted for publication 05/08/2025
date results reported back to the YODA Project: 2025, May 12th
Dissemination Plan:
Anticipated Products:
- A comprehensive meta-analysis report detailing the efficacy and safety of canagliflozin across various studies.
- An executive summary highlighting key findings and implications for clinical practice.
- Infographics and visual aids to succinctly present the data for broader audiences.
Target Audiences:
- Healthcare professionals, including endocrinologists, cardiologists, and nephrologists, who are directly involved in the management of diabetes and its complications.
- Researchers and academicians in the field of diabetes research and pharmacology.
- Policy makers and healthcare organizations that influence drug approval and clinical guidelines.
Expectation for Study Manuscript(s):
- The primary manuscript will be prepared in accordance with the PRISMA guidelines for reporting systematic reviews and meta-analyses.
- A draft manuscript will be circulated among co-authors for review and feedback.
- The final manuscript will be submitted for publication within six months of completing the meta-analysis.
Potentially Suitable Journals for Submission:
- Cardiovascular Diabetology
- Frontiers in Pharmacology
- Diabetes Therapy
Bibliography:
-S Albalushi, R N Rashid Nadeem, Meta-analysis on the effectiveness of SGLT2 inhibitors in heart failure, European Heart Journal. Acute Cardiovascular Care, Volume 12, Issue Supplement_1, May 2023, zuad036.173, https://doi.org/10.1093/ehjacc/zuad036.173
-Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X. Epub 2018 Nov 10. Erratum in: Lancet. 2019 Jan 5;393(10166):30. PMID: 30424892.