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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
Eligibility Varies Among the 4 Sodium-Glucose Contransporter-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
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Generalizability of Glucagon-Like Peptide-1 Receptor Agonist Cardiovascular Outcome Trials Enrollment Criteria to the US Type 2 Diabetes 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
Real World Evidence in Type 2 Diabetes: Focus on SGLT2 Inhibitors and GLP-1 Receptor Agonist Participating Faculty

Generalizability of Glucagon-Like Peptide-1 Receptor Agonist Cardiovascular Outcome Trials Enrollment Criteria to the US Type 2 Diabetes 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: Cardiovascular outcomes trials (CVOTs) for evaluating the safety of novel antidiabetic agents are required by the FDA. CVOTs vary in their design and inclusion criteria, making it difficult to evaluate their applicability to the general population. This study examined the proportion of adults eligible for 7 ongoing or completed glucagon-like peptide-1 receptor agonist (GLP-1 RA) CVOTs.
Study Design: This cross-sectional, retrospective, cohort study compared data from the National Health and Nutrition Examination Survey (NHANES) with published eligibility criteria from GLP-1 RA CVOTs.
Methods: Patient information on T2D status and other relevant characteristics were extracted from the 2009 to 2010 and the 2011 to 2012 NHANES. Weighted analyses of these data were used to calculate the numbers of adults with T2D in the US population who would have met eligibility criteria for enrollment in the following published or ongoing CVOTs: ELIXA (lixisenatide; NCT01147250), EXSCEL (Exenatide Study of Cardiovascular Event Lowering) (exenatide once weekly; NCT01144338), FREEDOM-CVO (exenatide via ITCA 650 miniature osmotic pump; NCT01455896), HARMONY Outcomes (albiglutide; NCT02465515), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) (liraglutide; NCT01179048), REWIND (Researching Cardiovascular Events With a Weekly INcretin in Diabetes) (dulaglutide; NCT01394952), and SUSTAIN-6 (semaglutide; NCT01720446).
Results: The proportion of adults with T2D eligible for enrollment varied substantially among CVOTs (6.4%-47.2%); EXSCEL, which had a pragmatic study design, had the most generalizable inclusion criteria. More than 60% of patients with T2D would have qualified for enrollment into at least 1 GLP-1 RA CVOT.
Conclusions: Most adults with T2D in the United States would have qualified for enrollment into at least 1 of the GLP-1 RA CVOTs evaluated. EXSCEL had the most generalizable eligibility criteria of these trials and ELIXA the least.
Am J Manag Care. 2018;24:-S0
Poor glycemic control has been associated with increased risks of death, microvascular complications, and cardiovascular disease (CVD),1,2 with intensive control of blood glucose in type 2 diabetes (T2D) shown to reduce the risks of microvascular complications.1,3 However, certain antihyperglycemic medications used for T2D, such as thiazolidinediones, were found to be associated with an increased risk of cardiovascular (CV) events such as congestive heart failure (CHF).4-7 In 2008, the FDA  initiated guidance that the CV safety of all new agents for T2D should be evaluated, primarily in randomized, controlled cardiovascular outcomes trials (CVOTs). These trials should examine the agent’s safety with respect to major adverse cardiac events (MACE), including CV death, stroke, and nonfatal myocardial infarction (MI).4,8,9

A number of subcutaneously administered glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including albiglutide,10,11 dulaglutide,12,13 exenatide once weekly,14,15 liraglutide,16,17 lixisenatide,18,19 and semaglutide,20,21 have been approved in the United States for use in T2D in recent years or are in late-stage clinical development (eg, the ITCA 650 exenatide continuous delivery system22). GLP-1 RAs lower glucose levels in patients with T2D by activating receptors for the incretin glucagon-like peptide-1, resulting in enhanced insulin release and inhibiting glucagon secretion in response to elevated blood glucose.23,24 They also slow gastric emptying and increase the sensation of satiety.23,24 In addition to their beneficial activity in controlling blood glucose, GLP-1 RAs in T2D have also been associated with reductions in body weight,10,12,14,16,18,20,22 and improvements in other CV risk factors.25-27

To meet the requirements of the FDA drug approval process, and those of other nations, the CV effects of these GLP-1 RAs have been or are currently being evaluated in multiple CVOTs.13,15,17,19,21,28-32 The inclusion criteria for these GLP-1 RA CVOTs, however, vary with different requirements for their baseline glycated hemoglobin (A1C) levels, prior CVD or CV risk factors, renal function, and concomitant use of other T2D treatments.13,15,17,21,28-32 Such differences present a challenge when trying to compare the statistical power and outcomes of each study, attempting to uniformly extrapolate findings to the likely CV impact of GLP-1 RA therapy in a real-world T2D population, and trying to compare the CV impact of the different GLP-1 RA agents. In addition to these differences, the results of studies with highly specific inclusion criteria may apply to a minority of patients, whereas the results of studies with broader criteria may be relevant to the majority of patients. Assessment of the generalizability of inclusion criteria requires information on the real-world population affected by diabetes, which can be obtained from national patient registries. This analysis was conducted to assess applicability of all planned or completed GLP-1 RA CVOTs to the US T2D patient population.

Study Design

A cross-sectional, retrospective, cohort study was conducted using data on T2D prevalence and other patient characteristics in the United States obtained from the National Health and Nutrition Examination Survey (NHANES),33 compared with patient eligibility criteria from publications describing the design, baseline data, and outcomes of the GLP-1 RA CVOTs.13,15,17,21,28-30,32

Methods

The primary outcomes of this analysis were the estimated total number and percentage of US adults with T2D eligible for inclusion in all, any, or none of these GLP-1 RA CVOTs, based upon analysis of NHANES data.

At the time of this study, details of eligibility criteria were available for 7 ongoing or completed GLP-1 RA CVOTs in patients with T2D (Table 1). These were ELIXA (lixisenatide; NCT01147250),19,28 EXSCEL (Exenatide Study of Cardiovascular Event Lowering) (exenatide once weekly; NCT01144338),15,29,31 FREEDOM-CVO (exenatide via ITCA 650 miniature osmotic pump; NCT01455896),30  HARMONY Outcomes (albiglutide; NCT02465515),32 LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results)  (liraglutide; NCT01179048),17 REWIND (Researching Cardiovascular Events With a Weekly INcretin in Diabetes) (dulaglutide; NCT01394952),13 and SUSTAIN-6 (semaglutide; NCT01720446).21

For the present study, the 2 most recent waves of the NHANES that included data related to the CVOT eligibility criteria were used (2009 to 2010 and 2011 to 2012). The NHANES is a nationally representative survey of US individuals, designed to measure objective health data from patients combined with field surveys about health and health behavior.34 It includes data on patient characteristics, medical conditions, medications, examinations, and laboratory test results.33 The NHANES questionnaire contains a wide variety of survey questions, including self-reports of a previous diagnosis of a range of diseases and conditions. Information on history of hypertension, stroke, MI, coronary heart disease, angina, and CHF was collected as indicators of CVD. In at least 2 trials (LEADER and SUSTAIN-6), CHF was also included as it was considered indicative of CVD.17,21 The NHANES prescription medication data are based on a combination of patient self-reports and examination of pill bottles. Details of the NHANES files used to extract data for the present analysis are shown in Appendix 1.

For the present study, data were extracted from the NHANES for adults at least 18 years of age who had information on their T2D diagnosis. In line with the CVOTs being evaluated, patients were excluded if they were pregnant, based on a response of “yes” when asked if they were pregnant at the time of questioning. For the purposes of this analysis, a diagnosis of T2D was based on patients responding to survey questions that asked if they had been diagnosed with diabetes, were taking insulin, or “taking diabetic pills to lower blood sugar,” or a recorded fasting plasma glucose of at least 126 mg/dL or an A1C level of greater than 6.5%. If patients responded to the questionnaire that they had received a diabetes diagnosis when they were younger than 18 years old, they were considered likely to have type 1 diabetes and so were excluded from the present analysis. The CVOTs had different inclusion criteria and therefore different requirements in terms of what data were necessary for the NHANES-derived T2D population (denominator population) to analyze for potential eligibility in each CVOT (see Table 1 “Key Inclusion Criteria”). This resulted in some differences in the sizes of the denominator populations used for each CVOT.

For each analysis, patients were required to have non-missing data for the key trial criteria (eg, CV status, body mass index [BMI]). When information on a specific inclusion or exclusion criterion for a CVOT was not available from the NHANES, investigators agreed on a procedure to apply in each case (Appendix 2). For example, information pertaining to patient history of medullary thyroid cancer or pancreatitis was not available in the NHANES. In such circumstances, the inclusion/exclusion criteria could not be applied to the population of patients with T2D. Where certain data were not collected as part of the NHANES, other data were applied to identify particular patient types (eg, in the case of waist-to-hip ratio data, BMI was substituted (Appendix 2). Data on coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) could not be obtained from the NHANES and, excepting the ELIXA trial, revascularization procedures were not a trial inclusion/exclusion criterion. In ELIXA, for patients who underwent CABG surgery or PCI  following acute coronary syndrome (ACS), the percentages of such patients in the T2D population were estimated from the findings of the  Platelet Inhibition and Patient Outcomes diabetes substudy.35 Weighted analyses of the dataset derived from the NHANES were conducted according to the NHANES estimation and weighting procedures and analytic guidelines36-38 to estimate the proportions of US patients with T2D who would have met the eligibility criteria for each CVOT.

Results

Data were obtained from the NHANES for 2009 through 2010 and 2011 through 2012 for a total of 20,142 adults who had information regarding their T2D diagnosis. Of these, 1889 had a diagnosis of T2D based on the data extracted from the NHANES and also had non-missing data for the key inclusion criteria of each trial as listed in Table 1 (under “Key Inclusion Criteria”; eg, non-missing data for A1C levels and age), giving a T2D prevalence in this sample of 9.4%.  These patients had a mean age of 59.6 years, and approximately half were male (Table 2). The mean BMI suggested that these patients were generally overweight or obese. Although most did not have a history of CVD or chronic kidney disease (CKD), about two-thirds had hypertension and a similar proportion had hypercholesterolemia.

Each of the 7 CVOTs were multisite, multinational studies, which included patients from 10 (FREEDOM-CVO) to 49 countries (ELIXA).13,15,17,21,28-32 A number of the studies or the subgroup analyses within them specified that patients had a history of certain CVDs and/or risk factors for CVD. The detailed criteria are shown in Table 1

The numbers of identifiable individuals in the United States who had evaluable (non-missing) data for all key inclusion criteria available from the NHANES for all, any, and none of the CVOTs, as calculated using the NHANES-weighted criteria, are shown in Table 3. The numbers and percentages of  individuals who would therefore meet the specific criteria for each individual CVOT are also listed.

 
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