TARGET-EU: Dapagliflozin and major adverse cardiovascular events in type 2 diabetes

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (A10BK01) dapagliflozin

  dapagliflozin

  (A10BH) Dipeptidyl peptidase 4 (DPP-4) inhibitors

  Dipeptidyl peptidase 4 (DPP-4) inhibitors
• Medical condition to be studied:
  Type 2 diabetes mellitus

Population studied

• Short description of the study population:
  This study will be conducted using routinely collected electronic health records from 2012 to 2024. It will be set primarily in primary care and will draw on longitudinal data from general practices, with linkage to hospital and mortality records. ; ; The study population will consist of adults with type 2 diabetes mellitus (T2D) who initiate treatment with either dapagliflozin or a dipeptidyl peptidase-4 (DPP-4) inhibitor during the study period. Cohort entry (index date) will be defined as the date of the first prescription of either treatment.; ; To be eligible, individuals must have a recorded diagnosis of T2D prior to the index date and be aged 40 years or older at cohort entry. In addition, individuals must have either established atherosclerotic cardiovascular disease (ACVD) or be at high risk of ACVD. Established ACVD will be defined as a history or diagnosis, at any time prior to the index date, of ischemic heart disease, ischemic cerebrovascular disease, or peripheral arterial disease. High cardiovascular risk will be defined among individuals without established ACVD as those meeting age-specific thresholds (≥55 years for men and ≥60 years for women) and having at least one additional cardiovascular risk factor. These risk factors include a history of dyslipidaemia, current use of lipid-lowering therapy, a history of hypertension, current use of antihypertensive medication, or current or recent tobacco use (within the previous year).; ; Several exclusion criteria will be applied to ensure appropriate cohort definition. Individuals must have at least one year of recorded medical history prior to the index date to allow adequate assessment of baseline characteristics. To implement a new-user design, individuals with any use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) or DPP-4 inhibitors in the year prior to cohort entry will be excluded. Individuals with a documented acute cardiovascular event in the year prior to the index date will also be excluded to ensure that outcomes observed during follow-up are incident events. In addition, patients with a history of type 1 diabetes at any time prior to cohort entry will be excluded.; ; Overall, the final study population will comprise adults aged 40 years or older with type 2 diabetes and either established or high risk of atherosclerotic cardiovascular disease, who newly initiate dapagliflozin or a DPP-4 inhibitor between 2012 and 2024 and meet all inclusion and exclusion criteria.
• Age groups:
  • Adults (46 to < 65 years)
  • Elderly (≥ 65 years)

    • Adults (65 to < 75 years)
    • Adults (75 to < 85 years)
    • Adults (85 years and over)

Study design details

• Study design:
  This study will emulate a hypothetical target trial using a retrospective, active-comparator, new-user cohort design based on routinely collected electronic health records.
• Main study objective:
  The overall aim is to assess whether dapagliflozin reduces the time to first major adverse cardiovascular event compared to DPP-4 inhibitors in patients with type 2 diabetes and established cardiovascular disease or at least two cardiovascular risk factors.
• Setting:
  This study is conducted using routinely collected electronic health records from 2012 to 2024, reflecting the period of dapagliflozin use in routine clinical practice. The study is set primarily in primary care, drawing on longitudinal data from general practices with linkage to hospital data. Data are sourced from two European countries, the United Kingdom (Clinical Practice Research Datalink [CPRD]) and Spain (Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria [BIFAP]), providing population-based and representative coverage of real-world clinical care.
• Comparators:
  The comparator group consists of patients who initiate any oral DPP-4 inhibitor, at any dose, formulation, or regimen. This includes individuals receiving DPP-4 inhibitors as part of a combination therapy used as first-line treatment, as monotherapy for first-line treatment, or as a switch to or add-on therapy to any existing antihyperglycemic treatment. The intervention period for DPP-4 inhibitors may also last for up to five years.; The use of an active comparator is the most appropriate approach because it aligns with real-world clinical practice and helps to address confounding by indication. It allows for the safety and effectiveness of dapagliflozin to be benchmarked against another medication that is commonly prescribed to treat patients with type 2 diabetes. DPP-4 inhibitors are frequently used as an alternative to SGLT2 inhibitors in routine care. Furthermore, DPP-4 inhibitors are considered to have a neutral effect on cardiovascular outcomes, making them a suitable comparator for evaluating cardiovascular safety and effectiveness.;
• Outcomes:
  The primary endpoint will be time to the first occurrence of major adverse cardiovascular events (MACE). For this study a modified version of the MACE endpoint will be considered. MACE is a composite endpoint that includes myocardial infarction, ischemic stroke or cardiovascular death. In this study we will include all-cause death as part of the endpoint in order to implement a composite strategy to handle both cardiovascular and non-cardiovascular death. Components of MACE represent serious, life-threatening events that directly reflect the cardiovascular health of a patient. All-cause mortality is considered here, but death is expected to be mainly related to cerebrovascular, cardiovascular causes among those with type 2 diabetes
• Data analysis plan:
  The analyses are conducted within a target trial emulation framework to estimate the effect of dapagliflozin compared with DPP-4 inhibitors on the risk of major adverse cardiovascular events (MACE). ; For Estimand 1, the main estimand supporting decision making, the primary causal effect summary measure is the hazard ratio for time to first MACE, estimated using an inverse probability of treatment weighted (IPTW) Cox proportional hazards model. The Cox model will be fitted separately within each data source (CPRD and BIFAP), and the resulting hazard ratios will be combined using a random-effects meta-analysis; potential sources of heterogeneity will be described qualitatively, including structural differences (e.g., coding systems, population coverage) and measurement differences (e.g., recording practices) and their implications (e.g., residual confounding or misclassification). ; ; Sensitivity analyses will assess robustness of the primary findings to key assumptions, including inverse probability of censoring weighting (IPCW), tipping point analysis, and probabilistic bias analysis for non-differential exposure misclassification. ; ; Two supplemental estimands are also defined: Estimand 2, applying a while-on-treatment strategy for intercurrent events, and Estimand 3, estimating treatment effects using restricted mean survival time (RMST) derived from an IPTW-weighted Weibull accelerated failure time (AFT) model. In addition, supplemental analyses (e.g., crude and IPTW-adjusted Kaplan–Meier curves, crude Cox models, event counts and incidence rates, propensity score and weight distributions, covariate balance before and after weighting, censoring and intercurrent event patterns, proportional hazards diagnostics, positivity checks, and multiple-imputation diagnostics) will be conducted to support interpretation of the main analysis.;
• Summary results:
  Not yet available