Population Diversity of Cardiovascular Outcome Trials and Real-World Patients with Diabetes in a Chinese Tertiary Hospital
Randomized controlled trials (RCTs) are widely regarded as the gold standard for evaluating the safety and efficacy of medicinal products and supporting clinical decision-making. However, RCTs often employ restrictive eligibility criteria to ensure study precision, quality, and patient safety, which can lead to poor representativeness of real-world populations and limited generalizability. To address these limitations, pragmatic RCT designs with fewer recruitment restrictions have been increasingly adopted to improve population representation and applicability to real-world practice. This approach is particularly relevant in the study and management of non-communicable chronic diseases, such as type 2 diabetes, which is a major risk factor for cardiovascular disease.
Since 2008, the U.S. Food and Drug Administration (FDA) has required that new anti-diabetic agents demonstrate not only glucose-lowering efficacy but also cardiovascular safety through cardiovascular outcome trials (CVOTs). These trials, many of which are pragmatic RCTs, play a critical role in the development of clinical practice guidelines for diabetes. However, recent studies have raised concerns about the representativeness of CVOT populations compared to real-world patient populations. This study aimed to explore the representativeness of the EMPA-REG OUTCOME trial, a landmark CVOT investigating the cardiovascular outcomes and long-term safety of empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, in Chinese real-world patients with diabetes.
The study was conducted at West China Hospital (WCH) of Sichuan University, one of the largest tertiary hospitals in China. The researchers performed a retrospective cross-sectional analysis of data obtained from the electronic medical records (EMRs) of all patients with diabetes treated at WCH from January 1, 2011, to June 30, 2019. The study population included both inpatients and outpatients with diabetes who met specific inclusion criteria. Inpatients were included if they had a discharge diagnosis of diabetes according to the International Classification of Diseases 10th Revision (ICD-10) codes E10–E14, fasting glucose >7.0 mmol/L, 2-hour blood glucose after a 75 g glucose challenge >11.1 mmol/L, random glucose >11.1 mmol/L, or glycated hemoglobin A1c (HbA1c) >6.5%. Outpatients were included if they had a diagnosis of diabetes in the free text or ICD-10 codes E10–E14 in the EMR. Patients with missing key laboratory test data, including HbA1c, serum creatinine, and lipid profiles, were excluded.
The researchers identified patients who would have met the inclusion criteria of the EMPA-REG OUTCOME trial, which required a first HbA1c value of 7.0% to 10.0%, a first estimated glomerular filtration rate (eGFR) value of ≥30 mL/min per 1.73 m², and high cardiovascular risk. Cardiovascular risk factors were defined using the closest matching diagnosis ICD-10 codes available for inpatients and diagnosis, disease description, and pharmaceutical therapy records for outpatients.
The study included 48,257 inpatients and 36,857 outpatients with diabetes, of whom 8,389 (17.4%) inpatients and 2,646 (7.2%) outpatients met the inclusion criteria for the EMPA-REG OUTCOME trial. Compared with the trial population, the real-world inpatients meeting the eligibility criteria had similar age, blood pressure, and lipid profiles but comprised fewer males, metformin users, anti-hypertensive drug users, and aspirin users, and had a lower body mass index (BMI). The group of outpatients meeting the eligibility criteria had fewer males, similar age, fewer metformin users, fewer insulin users, fewer anti-hypertensive drug users, and fewer aspirin users compared with the trial population.
The study found that the trial population in EMPA-REG OUTCOME represents only a small portion of patients with diabetes from the inpatient and outpatient departments of a Chinese tertiary medical center. The baseline characteristics of the patients at the tertiary medical center differed somewhat from those of the trial population, highlighting the need for evidence localization and validation within Chinese clinical practice while interpreting data from CVOTs of diabetes medications and the clinical practice guidelines that refer to these data.
The differences observed between the real-world population and the trial population can be attributed to several factors. First, the EMPA-REG OUTCOME trial focused solely on patients with both type 2 diabetes and cardiovascular disease, which represents a minority in both the outpatient and inpatient settings in Chinese hospitals. Second, ethnic differences between Chinese patients and patients in the global EMPA-REG OUTCOME study may also contribute to the observed differences. For example, mean BMI is lower among Chinese patients with diabetes compared with that in Caucasian patients with type 2 diabetes. Additionally, comorbidities of hypertension and chronic kidney disease were markedly less frequent among outpatients and inpatients with diabetes in the study compared with those in the trial population.
The study’s findings are consistent with previous studies in Catalonia, the U.S., and the U.K., which reported that only a small proportion of patients with diabetes met the eligibility criteria for EMPA-REG OUTCOME. These findings suggest that most clinical decision-making is not based on the direct interpretation of this pragmatic RCT. The study also found that eligible patients with diabetes from inpatient and outpatient departments had a lower risk of cardiovascular events compared with the trial population, further supporting the necessity for evidence localization in different clinical settings.
The study had several strengths, including its large sample size, comprehensive medical information, and reliable data. The researchers developed minimally clinically important differences (MCIDs) to explore how the baseline characteristics of the EMR population were clinically different from those of the trial population, which augmented the reliability and power of the study. However, the study also had some limitations, including its single-centered design, which limits the generalizability of the results. Additionally, the retrospective nature of the study based on EMR data could not completely replicate the eligibility criteria of the EMPA-REG OUTCOME, which may have contributed to a slight overestimation of the proportion of eligible patients.
In conclusion, this study demonstrates that only a small proportion of inpatients and outpatients with diabetes at a Chinese tertiary medical center would have been eligible to enter the EMPA-REG OUTCOME trial and that the baseline characteristics of the patients at the tertiary medical center differed somewhat from those of the trial population. These findings highlight the need for evidence localization and validation within Chinese clinical practice while interpreting data from CVOTs of diabetes medications and the clinical practice guidelines that refer to these data. The study underscores the importance of obtaining evidence from pragmatic RCTs of diabetes treatments in China and validating this evidence in real-world populations using existing patient cohorts before clinical use.
doi.org/10.1097/CM9.0000000000001407
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