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A Retrospective Real-World Study of Dapagliflozin Versus Other Oral Antidiabetic Drugs Added to Metformin in Patients with Type 2 Diabetes
Huan Huang, PhD; Kelly F. Bell, PharmD, MSPhr; Ray Gani, PhD; Cathy W. Tugwell, RN, BSN; James M. Eudicone, MS, MBA; and Michelle R. Krukas-Hampel, MA
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Eligibility Varies Among the 4 Sodium-Glucose Cotransporter-2 Inhibitor Cardiovascular Trials: Implications for the General Type 2 Diabetes US Population
Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Kelly F. Bell, PharmD, MSPhr; Devin M. Enhoffer, PharmD; Keith Latham, PharmD; and Jennifer B. Green, MD
Comparison of Low-Dose Liraglutide Use Versus Other GLP-1 Receptor Agonists in Patients Without Type 2 Diabetes
Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Sepehr Farahbakhshian, MS; and Carrie McAdam-Marx, PhD, MSCI, RPh
Real World Evidence in Type 2 Diabetes: Focus on SGLT2 Inhibitors and GLP-1 Receptor Agonist Participating Faculty

Eligibility Varies Among the 4 Sodium-Glucose Cotransporter-2 Inhibitor Cardiovascular Trials: Implications for the General Type 2 Diabetes US Population

Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Kelly F. Bell, PharmD, MSPhr; Devin M. Enhoffer, PharmD; Keith Latham, PharmD; and Jennifer B. Green, MD

This retrospective study assessed the extent to which the results of completed or ongoing (at the time of the analysis) studies of CV safety for the SGLT2 inhibitor class of antihyperglycemic medications could be generalized to adults in the United States with T2D. Data for this study were derived from the NHANES, which is a nationally representative survey of health in the United States.32 The calculated prevalence of T2D of 11.8% was similar to that reported by the CDC for 2015 (9.4% of US adults with diagnosed diabetes, with virtually all of these having T2D).1 The slight disparity in prevalence observed could be due to various factors, such as the requirement for data on key eligibility criteria for those patients included in the denominator population in the present study.

This study found substantial differences in the extent to which the eligibility criteria, and hence the CV findings, of these CVOTs could be generalized to a real-world adult T2D patient population. Approximately 40% of the US adult T2D population identified via the weighted analysis of the NHANES data would have been eligible to participate in at least 1 of these 4 studies, but only the DECLARE-TIMI 58 study of dapagliflozin31,41 had eligibility criteria that would have included more than 10% of this population.

The 2008 FDA Guidance for Industry recommends that CV safety studies of novel T2D therapies include patients who are representative of those likely to receive the agent being investigated.14 It is recommended that participants include those at higher risk of CV events, including the elderly, and those with relatively advanced T2D or with some level of renal impairment.14 This is important, as patients with T2D are at a disproportionately high risk of death from CVD, with more than two-thirds of those at least 65 years of age dying from heart disease and approximately 15% from stroke,2,42 and they are also more likely than the general population to have risk factors for CVD, such as hypertension, dyslipidemia, or chronic kidney disease, in addition to diabetes.43 However, when CVOTs in T2D are planned, ideally the inclusion criteria should not be so restrictive as to jeopardize the applicability of findings from the study to patient populations that are encountered in real-world clinical practice.

As estimated by analyses of the NHANES data, the inclusion criteria in 3 of the studies were applicable to less than 10% of the US adult T2D population. All 3 of these CVOTs focused on patients who had a history of prior CVD or were considered to be at high risk of CV events (Table 1).29,30,33 The original CANVAS study included 2 subgroups of patients, one  in those at least 30 years of age with a history of symptomatic atherosclerotic vascular disease and one in those at least 50 years of age without a history of known CVD, but with 2 or more prespecified risk factors in addition to T2D.30 More than 10,000 adults (mean age, 63 years) were included in the combined CANVAS and CANVAS-R analysis,31 of whom 66% had a history of macrovascular atherosclerotic disease before the study.32 Adults aged at least 18 years could participate in the EMPA-REG OUTCOME trial, but only if they were at a high risk of CV events, which were defined by various criteria (including a history of myocardial infarction, and the presence of multivessel coronary artery disease [CAD] or of single-vessel CAD plus evidence, for example, of prior unstable angina, stroke, or peripheral artery disease).29 The study included more than 7000 patients at high risk of CV events with a mean age of 63 years.16,29 The VERTIS-CV Study included patients with T2D at least 40 years of age, but again with specific CVD-related criteria, which specified a history of coronary, cerebral, or peripheral atherosclerotic disease;33,37 data for the recruited patient population were not available at the time of writing this paper. By contrast, DECLARE-TIMI 58 included 2 subgroups, 1 of patients at least 40 years of age with a high risk of CV events because of a history of heart disease or stroke, and a broader subgroup group of women at least 60 years of age and men at least 55 years of age without a known history of CVD, but with at least 1 risk factor (dyslipidemia, hypertension, or tobacco smoking) in addition to T2D.31,40 More than 17,000 patients (mean age, 64 years) were randomized for this study; of these, almost 7000 (41%) had established CVD prior to enrollment, and the remainder had multiple CV risk factors.40 In DECLARE-TIMI 58, the definition of a T2D diagnosis was also broader than that in the other 3 studies (see Table 1). Patients were required to have been told by a physician that they had T2D and an A1C level of 6.5% to 12.0%.32 However, participation in the EMPA-REG OUTCOME trial required patients to have an A1C level of 7.0% to 9.0% if T2D-treatment–naïve or 7.0% to 10.0% if they were already taking antihyperglycemic medication,16 and for both CANVAS and VERTIS-CV, an A1C value of  7.0% to 10.5% was stipulated (Table 1).20,37 Therefore, the DECLARE-TIMI 58 study population comprised a broad population of middle-aged and older adults with T2D, including patients with established CVD or CVD risk factors.

The present analysis included available data for key study criteria from a representative sample of the US population. The results demonstrated that broader patient selection criteria allow enrollment of a study population that is more generalizable to a substantial proportion of US adults with T2D.

Study Limitations

As a retrospective database analysis, this study had a number of limitations. A selection bias of patients who volunteered to participate in the survey, who may not be representative of the general US patient population, could have resulted in inaccurate estimation of T2D prevalence in this analysis of the NHANES data. Although the present analysis excluded patients who were pregnant, and therefore those who could have currently had gestational diabetes, it did not exclude patients who might have had gestational diabetes during a previous pregnancy. Data on CHF were extracted from the present analysis as it can be indicative of CVD; however, this could have also captured CHF unrelated to CVD, although this would have probably impacted findings on generalizability equally across all 4 trials. Furthermore, diabetes diagnoses were allocated from self-reported data rather than from diagnosis or confirmation by treating physicians, and application of the trial definitions of T2D to the NHANES data may also have been imprecise (eg, where there were differences in the criteria used in each CVOT to define T2D and the data collected for the NHANES).

Data on some study eligibility criteria were not available from the NHANES, and guidelines for resolving issues of missing or differing ways of defining/recording criteria were therefore included in the analysis protocol (Appendix 2). However, in such cases, the omission or estimation of certain criteria using data acquired in other formats or from other survey responses would be expected to give only approximations for the numbers meeting the CVOT criteria in question. It is likely that such an approach would have had disproportionate effects on estimation of those meeting key CV eligibility criteria. Finally, this analysis did not consider differences in CVOT size, duration, or design.


There were considerable differences among the 4 SGLT2 inhibitor CVOTs in the proportions of patients in the US adult T2D population who would have met the eligibility criteria and, therefore, in the generalizability and applicability of these trials. The DECLARE-TIMI 58 trial was by far the most generalizable, with approximately 40% of this population potentially being eligible for inclusion; however, only 12% of US adult T2D patients would have been eligible for inclusion in any of the other trials. This analysis shows that it is important to bear in mind the differences in eligibility criteria when considering the generalizability and applicability of CVOTs for T2D medications to real-world populations.


Medical writing and editorial support was provided by Annie Rowe, Prime, UK, according to Good Publication Practice guidelines (available at and supported by AstraZeneca. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Author affiliations: AstraZeneca, Wilmington, DE (KFB [at time of study], JME, KL, ETW); Rutgers University, Piscataway, NJ (DME); Division of Endocrinology, Duke University Medical Center, Durham, NC (JBG).
Funding source: This study was funded by AstraZeneca.
Author disclosures: Dr Bell reports employment with GlaxoSmithKline. Mr Enhoffer reports no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement. Mr Eudicone, Dr Latham, and Dr Wittbrodt report employment with AstraZeneca; the subject matter of this supplement pertains to an AstraZeneca product. Dr Green reports serving as a consultant for Boehringer Ingelheim Pharmaceuticals, Inc; Daiichi Sankyo Company, Limited; Merck Sharpe & Dohme Corp; and Novo Nordisk Inc, and reports receipt of research grants from AstraZeneca; GlaxoSmithKline plc; and Intarcia Therapeutics, Inc. 
Authorship information: Concept and design (KFB, JME, JBG, KL, ETW); acquisition of data (DME, ETW); analysis and interpretation of data (KFB, DME, JME, JBG, KL, ETW); drafting of the manuscript (DME); critical revision of the manuscript for important intellectual content (KFB, DME, JME, JBG, ETW); obtaining funding (KFB); administrative, technical, or logistic support (KL, ETW); supervision (ETW).
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