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Supplements Real-World Evidence in Type 2 Diabetes: Focus on SGLT2 inhibitors and GLP-1 Receptor Agonists
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
Objectives: Guidance to industry from the FDA requires studies to evaluate the cardiovascular safety of novel type 2 diabetes (T2D) medications. Although the objectives of such cardiovascular outcomes trials (CVOTs) are similar, differences in features such as enrollment criteria present a challenge when trying to assess the applicability of these studies to real-world T2D populations. This study evaluated the proportions of US adults with T2D who met the eligibility criteria for each of the 4 sodium-glucose cotransporter-2 (SGLT2) inhibitor CVOTs.
Study Design: A cross-sectional retrospective study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) and published patient eligibility criteria for completed or ongoing SGLT2 inhibitor CVOTs.
Methods: Data on T2D diagnosis and other relevant clinical and demographic characteristics were extracted from the NHANES (2009-2010 and 2011-2012). Weighted analysis of these data was used to estimate the percentage of US adults with T2D who met the eligibility criteria for the CANVAS program (CANagliflozin cardioVascular Assessment Study) (canagliflozin; NCT01032629, NCT01989754), and the DECLARE-TIMI 58 (dapagliflozin; NCT01730534), EMPA-REG OUTCOME (empagliflozin; NCT01131676), and VERTIS-CV (ertugliflozin; NCT01986881) trials.
Results: The weighted analysis identified a population of 23,941,512 US adults from data on key inclusion criteria and information indicating a diagnosis of T2D. Of these, 4.1% met the criteria for EMPA-REG OUTCOME, 4.8% for VERTIS-CV, 8.8% for the CANVAS program, and 39.8% for the DECLARE-TIMI 58 trial.
Conclusions: There were considerable differences in the proportions of US adults with T2D who met the eligibility criteria for these studies.
The DECLARE-TIMI 58 trial criteria were the most generalizable to the US T2D population.
Am J Manag Care. 2018;24:-S0
In 2015, more than 23 million adults in the United States had a diagnosis of diabetes, with an estimated 95% of cases being type 2 diabetes (T2D).1 Patients with T2D are at increased risk of cardiovascular disease (CVD),2 and therefore, improvement of cardiovascular (CV) outcomes is a goal of diabetes management.3,4 Good glycemic control in T2D has been associated with a reduced risk of microvascular complications,5,6 but its effects on the risk of CVD are less clear.7-9 However, findings from a number of studies have shown that the use of certain classes of antihyperglycemic agents and some intensive glucose-lowering treatment regimens were associated with an increased risk of CV events or death.10-13 As a result of such reports, the FDA issued guidance in 2008 on the evaluation of novel agents for the treatment of T2D with respect to major adverse cardiac events.14,15 Studies of newer T2D therapies, such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors, for example, have shown a reduction in the risk of CV events in certain patient groups.16-21

SGLT2 inhibitors lower blood glucose by preventing reabsorption of glucose from the proximal renal tubule in the kidney, with the consequent excretion of excess glucose in the urine having additional beneficial effects on body weight and blood pressure,22 as demonstrated in clinical trials of canagliflozin,23 dapagliflozin,24-26 and empagliflozin.27 SGLT2 inhibitors do not act on insulin or related pathways and could therefore be used in combination with agents such as glucagon-like peptide-1 receptor agonists in patients who require additional glycemic control.28 As with other novel antihyperglycemic medications, the CV safety of SGLT2 inhibitors has been evaluated in randomized, controlled CV outcomes trials (CVOTs), as in the case of empagliflozin,16,29 and canagliflozin,20,21,30 or such studies are ongoing, as they are for dapagliflozin31,32 and ertugliflozin.33 Although the FDA has provided some guidance on the design, primary outcomes, and patient populations for CVOTs of T2D medications,15,34 there are some differences in these 4 randomized, controlled studies. For example, such differences include the number of patients to be recruited, and inclusion and exclusion criteria, such as patients’ ages at enrollment, glycated hemoglobin (A1C) values at baseline, and histories of CVD and presence of CVD risk factors.16,29-31,33 These differences in study populations, assessments of SGLT2 inhibitors to placebo rather than active therapies, and potential issues with statistical power may prevent meaningful comparisons between their findings and present a barrier to uniform extrapolation of outcomes when assessing the potential CV safety of a particular treatment in a real-world T2D population.

An understanding of the generalizability of the eligibility criteria of a particular CVOT can aid clinicians when evaluating the applicability of its findings to their patients. It is likely that the less generalizable the study design, the less similar the study participants to patients encountered in clinical practice and, therefore, the less applicable the study results. To investigate the generalizability of the eligibility criteria for these 4 SGLT2 inhibitor CVOTs to US adults with T2D, an analysis was undertaken to estimate the proportions of this patient population who would be eligible for enrollment in each of these studies.

Study Design

This was a cross-sectional retrospective cohort study. Data on T2D prevalence in the United States were derived from the National Health and Nutrition Examination Survey (NHANES),35,36 and analyzed against the published patient eligibility criteria for CVOTs that were in progress or completed at the time of the study for the SGLT2 inhibitors canagliflozin (the CANVAS program [CANagliflozin cardioVascular Assessment Study]; CANVAS; NCT01032629, CANVAS-R; NCT01989754),20,21,30 dapagliflozin (DECLARE-TIMI 58; NCT01730534),31,32 empagliflozin (EMPA-REG OUTCOME; NCT01131676),16,29 and ertugliflozin (VERTIS-CV; NCT01986881).33,37

Methods

The primary outcomes of the present analysis were an estimate of the number of US adults with T2D, and the numbers and percentages of adults in this US T2D population who would meet the criteria for inclusion in each of the 4 SGLT2 inhibitor CVOTs, and for participation in any, all, or none of these studies. The eligibility criteria for each of the four SGLT2 inhibitor CVOTs are shown in Table 1.16,29-33 Information on the SCORED study of sotagliflozin (NCT03315143) was not available at the time of the present analysis.

The NHANES is a nationally representative health survey of the US population. It incorporates objective health data from patients in combination with field surveys about health and health behaviors.36 The NHANES questionnaire data are obtained through a range of survey questions, including participant self-reports of past diagnoses of a variety of diseases and conditions. If available, it also includes prescription medication data based on patient self-reports and examination of pill bottles. At the time of the present study, the 2 most recent waves of the NHANES with available data relevant to the study objectives were from 2009 to 2010 and 2011 to 2012. These comprised data on patient characteristics, medications, examinations, and laboratory results.35 The NHANES files used to obtain data for this analysis are listed in Appendix 1.

Data were extracted from the NHANES for adults aged at least 18 years who had information available on their T2D status. For the purposes of this analysis, individuals in this group were categorized as having T2D if they responded to survey questions that they had been diagnosed with diabetes or had a recorded fasting plasma glucose (FPG) value of at least 126 mg/dL or an A1C value greater than 6.5%. If a patient’s responses indicated that they had been diagnosed with diabetes at less than 18 years of age, a diagnosis of type 1 diabetes was considered likely and they were excluded from the T2D analysis. Patients were also excluded if they responded “yes” to questions about pregnancy at the time of participation in the NHANES.

To estimate the total number of US adult patients with T2D and the numbers and percentages of this population who would have met the criteria for each study, weighted analyses of the NHANES-derived datasets were undertaken according to the estimation and weighting procedures and analytic guidelines specified by the NHANES.38-40 For the analysis of each CVOT, patients in the NHANES-derived T2D dataset were required to have non-missing data for the various key trial inclusion criteria (eg, age, A1C level, history of and risk factors for CVD; Table 1). Differences among the inclusion criteria for the 4 CVOTs meant that there were different requirements as to what data were available for the NHANES-derived T2D population to evaluate potential eligibility for each CVOT (see Table 1 “Key Inclusion Criteria”).

Where information on certain eligibility for a given CVOT were not collected as part of the NHANES, the investigators agreed on methods to substitute equivalent data that were collected or they adjudged that the analysis could proceed with the data missing (Appendix 2). For example, an FPG value of less than 40 mg/dL recorded in the NHANES was used as an indicator of a severe hypoglycemic episode, while criteria that required data regarding recurrent urinary tract infections or durations of use of certain medications were ignored (Appendix 2). Heart failure data were extracted from the NHANES as it was not only considered to be an indicator of CVD, but also, New York Heart Association class IV heart failure was an exclusion criterion for the CANVAS program and the VERTIS-CV Study.20,21,30,33,37 Data on coronary artery bypass graft surgery or percutaneous coronary interventions could not be obtained from the NHANES.

Results

Information on T2D status was available for 10,537 participants from the NHANES 2009 to 2010 and for 9756 from the NHANES 2011 to 2012. The weighted analysis using these data identified a US population of up to 203,090,000 adults who had non-missing data on the key inclusion criteria of any trial (eg, non-missing data for A1C values, age; Table 1). Of those, 23,941,512 had evidence supporting a diagnosis of T2D, giving a prevalence of T2D of 11.8% in this population. The mean age of these patients was 59.6 years, with a slightly lower proportion of women than men (Table 2). Patients were generally overweight or obese (mean body mass index, 33.3 kg/m2). Approximately three-fourths of the T2D population had no evidence of CVD, although about two-thirds had hypertension and hypercholesterolemia.

The 4 CVOTs evaluated are described in detail elsewhere and summarized in Table 1.16,20,21,29-31,33,41 All CVOTs were multisite, multinational studies. They included patients from 24 to 42 countries, and each included centers in the United States. Table 3 summarizes the baseline characteristics of the 4 CVOTs.38

Table 4 shows the numbers of US adults with T2D, as calculated using the NHANES-weighted criteria, who had evaluable (ie, non-missing) data for all key inclusion criteria. The numbers and percentages of adults with T2D in this population who met the specific criteria for each of the 4 SGLT2 inhibitor CVOTs are shown in the Figure. Among the US adult T2D population identified, 40.8% would have met the eligibility criteria for at least 1 of the 4 CVOTs, but just 1% would have met the criteria for all 4. DECLARE-TIMI 58 had the most inclusive criteria, with 39.8% of this US adult T2D population meeting the inclusion criteria for this study. By contrast, of the other 3 CVOTs, the CANVAS program had the broadest criteria at 8.8% inclusivity and the other 2 studies at less than 5% each.

 
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