Abstract
Objective Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials' eligibility criteria can be applied to a real-world Mediterranean T2D population. Methods Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain). Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). Results By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70 ± 12 years, 54.9% male, with a mean duration of T2D of 9 ± 6 years, and a mean glycated haemoglobin (HbA1c) of 7.12% ± 1.32 (59% with HbA1c < 7%). Of these, 86,534 (23%) had established CV disease and 28% chronic renal failure (estimated glomerular filtration < 60 ml/min/1.73m2). Among all included patients, only 8.2% would have qualified for enrolment into the EMPA-REG OUTCOME trial, 29.6% into the CANVAS program, and 38% into the DECLARE-TIMI 58 trial. The main limiting factors for inclusion would have been a previous history of CV disease and the baseline HbA1c value. Conclusion The external validity of the analysed CVOTs is clearly limited when applying the same eligibility criteria to a T2D Mediterranean population.
Highlights
Patients with type 2 diabetes (T2D) have an increased risk of renal and cardiovascular disease (CVD) and mortality [1]
Chronic renal failure was a restrictive criterion in DECLARE, while in EMPAREG and CANVAS, only patients with severe renal failure were excluded (4% in SIDIAP). In this population-based study using routine clinical data, we estimated the proportion of patients with T2D that would have been eligible for inclusion in the main CV outcome trials (CVOTs) regarding the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in our environment (Catalonia, Spain)
We found that the DECLARE-TIMI 58 CVOT trial had the highest representativeness, covering 38% of the T2D patients in our general T2D population, which is in line with previously reported studies conducted in Northern Europe and the US
Summary
Patients with type 2 diabetes (T2D) have an increased risk of renal and cardiovascular disease (CVD) and mortality [1]. While tight good glycaemic control in T2D is associated with reduced risk of microvascular disease [2, 3], the benefit regarding macrovascular disease is less clear [4,5,6]. There was no difference in the incidence of CV mortality [7] Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require, for each new antidiabetic therapy to treat T2D, to show a neutral or beneficial effect in CV safety through the conduction of CV outcome trials (CVOTs) [8, 9]
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