Generalizability of Cardiovascular Safety Trials on SGLT2 Inhibitors to the Real World: Implications for Clinical Practice
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Following the US Food and Drug Administration (FDA) guidance on the evaluation of novel agents for the treatment of type 2 diabetes mellitus (T2DM), a number of cardiovascular outcomes safety trials (CVOTs) on sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been conducted. These trials show similarities in study design and definition of primary endpoints, but differ in their eligibility criteria. The aim of the present study was to investigate the generalizability of CVOTs on SGLT2i to Italian adults with T2DM; we estimated the proportions of this patient population who would be eligible for enrollment in EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS-CV (ertugliflozin) studies.
This observational, cross-sectional study was conducted in 222 Italian diabetes clinics. Data on 455,662 adult patients with T2DM seen during 2016 were analyzed against the published patient eligibility criteria for the four CVOTs. The current use of SGLT2i in potentially eligible patients was assessed.
Among the population identified, the proportion of patients meeting major eligibility criteria was 11.7% for EMPA-REG OUTCOME, 29.4% for CANVAS, 55.9% for DECLARE-TIMI 58, and 12.8% for VERTIS-CV. Of the patients eligible for these CVOTs, only a minority (range 4.4–6.8%) was actually prescribed an SGLT2i. Compared with patients in the CVOTs, eligible patients in the real world showed older age and longer diabetes duration, lower BMI and HbA1c levels, lower prevalence of established cardiovascular and cerebrovascular disease, and higher rates of microvascular complications and peripheral arterial disease.
The percentage of patients potentially eligible for treatment with SGLT2i varies as a reflection of different eligibility criteria applied in the trials. A large number of patients that could benefit from SGLT2i in terms of not only cardiovascular protection but also renal protection do not receive the treatment.
KeywordsCardiovascular outcomes safety trials Electronic medical records Eligibility criteria Endocrinology Quality of care Real-world data Sodium-glucose cotransporter-2 inhibitors Type 2 diabetes
We thank the AMD Annals network of diabetes centers, AMD executive committee, AMD Foundation, the whole staff of CORESEARCH involved in the regulatory/data management/statistical analysis/medical writing activities of the project, and the METEDA company (San Benedetto del Tronto (AP), Italy) for the development and management of anonymous data extraction procedure from electronic medical records.
The study and Rapid Service Fee were supported by an unrestricted grant by AstraZeneca, Italy. The sponsor had no role in the study design, data collection, analysis, interpretation and in writing the paper.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis
Valeria Manicardi: educational activities for AstraZeneca, Eli Lilly, MSD; Riccardo Candido: scientific consultant and educational activities for Eli Lilly, Sanofi Aventis, Takeda, MSD, Astra Zeneca, Novo Nordisk, Roche Diabetes Care, Boehringer Ingelheim, Abbott, Mundipharma Pharmaceuticals; Domenico Cucinotta: educational activities for Eli Lilly, Sanofi Aventis; Antonio Nicolucci: received research funding by AlfaSigma, AstraZeneca, Bruno Farmaceutici, Eli Lilly, Medtronic, Novo Nordisk, Pikdare, Roche, Sanofi, Shionogi, Theras; Maria Chiara Rossi: received research funding by AlfaSigma, AstraZeneca, Bruno Farmaceutici, Eli Lilly, Medtronic, Novo Nordisk, Pikdare, Roche, Sanofi, Shionogi, Theras; Alberto Rocca: educational activities for Mundipharma Pharmaceuticals; Franco Tuccinardi: educational activities for AstraZeneca, Novo Nordisk, Eli Lilly, MDS, Novartis, Sanofi Aventis. Giusi Graziano has nothing to disclose.
Compliance with Ethics Guidelines
The AMD Annals initiative has been approved by the ethics committees of all participating centers (Supplementary Table 2). On the basis of Italian regulations, the written informed consent from participants was not required, being extracted data anonymous. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
All data generated or analyzed during the current study are available from the study sponsor (AMD scientific society) on reasonable request.
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