How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area

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.

Population diversity of cardiovascular outcome trials and real-world patients with diabetes in a Chinese tertiary hospital

“…Our findings are in line with those from previous studies in Catalonia, the US, and the UK, which reported that only 8.2%, 4.1%, and 15.7% of patients with diabetes, respectively, met eligibility criteria for EMPA-REG OUTCOME. [ 21 , 37 , 38 ] Previous studies [ 21 , 39 ] found that over 80% and 90% of new users of SGLT-2 inhibitors, respectively, would not have been eligible for the EMPA-REG OUTCOME trial. These findings suggest that most clinical decision-making is not based on the direct interpretation of this pragmatic RCT.…”

Cost-effectiveness analysis of dapagliflozin for the treatment of type 2 diabetes mellitus in Spain: results of the DECLARE-TIMI 58 study

“…A further limitation is related to the patient characteristics used in the model. This analysis assumed that patient profile of the Spanish population with T2DM in clinical practice was similar to that of the patients in the DECLARE-TIMI 58 trial, but published evidence shows that around 38% and 51% of patients treated with dapagliflozin in clinical practice met the inclusion criteria for the DECLARE-TIMI 58 trial [ 19 , 47 ]. However, univariate sensitivity analyses were carried out, in which baseline characteristics (age and eGFR) were modified, and a PSA were also performed to ensure the representativeness of T2DM patients who may be treated with dapagliflozin in real clinical practice.…”

Is HbA1c a valid surrogate for mortality in type 2 diabetes? Evidence from a meta-analysis of randomized trials

“…Eligibility requirements for study participation usually include having a history of cardiovascular disease or high cardiovascular risk in addition to certain age and blood glucose control specifications. According to estimates from population-based data, only 4% to 38% of the real-world population with type 2 diabetes would have qualified for enrollment into renowned CVOTs [ 21 – 23 ]. Moreover, as pointed to by Lipska/Krumholz [ 24 ], CVOTs would probably not be very informative for the present study question, because the study protocols of the CVOTs in general encourage additional glucose control according to the local guidelines.…”