Generalizability of Glucagon-Like Peptide-1 Receptor Agonist Cardiovascular Outcome Trials Enrollment Criteria to the US Type 2 Diabetes Population

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.

Am J Manag Care. 2018;24:-S0

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.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 guidelines^36-38 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.

Among the 7 GLP-1 RA CVOTs, the proportion of US adults with T2D who would have met enrollment criteria varied substantially. EXSCEL had the most inclusive eligibility criteria of the 7 trials, as these would have been met by 47.2% of the US T2D population (Table 3). By contrast, eligibility was just 6.4% in the case of ELIXA (Table 1).^19,28 Overall, more than 60% of US adults with T2D would have qualified for enrollment into at least 1 of the GLP-1 RA CVOTs; however, when the EXSCEL study was excluded from this calculation, this figure decreased to less than half of this population (42.4%). Furthermore, just 1.0% of this population would have been eligible to participate in all 7 of the CVOTs evaluated.

Discussion

This retrospective study sought to explore the extent to which US patients would be eligible for enrollment into trials of CV safety of GLP-1 RAs for T2D. In this analysis, data on the prevalence of T2D in the United States were derived from the NHANES. The figure of 9.4% prevalence obtained in the present analysis is in agreement with the findings of the CDC, which estimated that in 2015, 9.3% (23 million) of US adults were diagnosed with diabetes.³⁹

Considerable variation was observed in the extent to which the eligibility criteria, and hence the results of these CVOTs, could be generalized and applied to a broad real-world patient population. Although most of the potential US adult T2D population would have been eligible to participate in at least 1 of the CVOT trials, only 1 of the studies (EXSCEL) had criteria that would have included more than 45% of this population, compared with less than 23% being eligible for each of the other 6 studies. The generalizability of the eligibility criteria for most of these studies was limited by the inclusion of highly specific T2D patient populations, such that they focused primarily on older patients with a prior history of CVD or those with high risk for CVD, as shown in Table 4.

The ELIXA study had the lowest percentage of inclusivity, largely as a result of it being designed to explore MACE outcomes in patients with an ACS event within the previous 180 days.²⁸ Most participants in ELIXA had an MI as their qualifying event and the remainder were hospitalized due to unstable angina.²⁸ SUSTAIN-6 included 2 subgroups, one of patients aged at least 50 years with established CVD and the other of patients aged at least 60 years with indicators of subclinical CVD.²¹ Of these, 83% had established CVD without CKD, and 11% had CKD without other CVD. The remaining patients in the study were included in the subclinical CVD subgroup.²¹ LEADER also included patients aged at least 50 years with concomitant CV or renal disease, and a subgroup of patients aged at least 60 years who had risk factors for CVD.¹⁷ Most of those included had established CVD and the remainder had CKD of stage 3 or higher, or both CVD and CKD.¹⁷ The REWIND trial included patients with established CVD (aged ≥50 years), with subclinical vascular disease (aged ≥55 years), or at least 2 CVD risk factors (aged ≥60 years).¹³ Approximately one-third of participants in the REWIND study had a history of CVD and almost all were diagnosed with hypertension.¹³ At the time of publication no data have been published on the baseline characteristics of patients in the FREEDOM-CVO or HARMONY Outcomes studies. FREEDOM-CVO included slightly younger patients (aged ≥40 years) with a history of CVD,³⁰ and HARMONY Outcomes included patients with established CVD, but with a slightly older age range than ELIXA (aged ≥40 years vs ≥30 years, respectively).³²

As noted elsewhere, the findings of a study designed to enroll a high CV risk patient population may not apply to patients who are at lower risk of CVD,¹⁷ and the impact of GLP-1 RAs on CVD risk in such T2D patients remains unknown. However, some authors have suggested that inclusion of patients with high CVD risk profiles means that study participants then reflect the typical middle-aged T2D patient population (eg, REWIND trial).¹³ Indeed, the FDA Guidance for Industry specifies that studies should include patients at higher risk of CV events.⁹ The EXSCEL study was unique among these 7 GLP-1 RA CVOTs in that it permitted enrollment of patients at least 18 years of age with or without additional CV risk factors or prior CV events,^29,31 although only 1.4% of the patients included were less than 40 years of age (1.5% from North American centers). Of those included, most had prior CV complications (primarily coronary artery disease) and those participants without prior CVD tended to be slightly younger (median age 59 years vs 63 years).³¹ The broad criteria used in the EXSCEL trial could enhance the generalizability and applicability of the study to the real-world setting. The EXSCEL trial was unique in its design compared with the other studies in that it had a pragmatic trial design,⁴⁰ chosen specifically to enable evaluation in a routine clinical practice setting and thus maximize the generalizability of the study.⁴¹ This design permitted a wide range of background T2D medications and did not require a treatment run-in period, which may bias studies to include those most adherent to their medication regimen.³¹

Limitations

There could have been inaccurate estimation of T2D prevalence in the NHANES due to a selection bias of patients who volunteered to participate in the survey, and they may not be representative of the general US patient population. In addition, information about the presence of T2D was ascertained by self-reports rather than being provided or confirmed by treating physicians, and application of the trial definitions of T2D may have been imprecise. Patients who were pregnant, and therefore who may have had current gestational diabetes, were excluded from this analysis; however, our analysis did not exclude patients who previously had an episode of gestational diabetes. Exclusion from this analysis of patients diagnosed with diabetes at less than 18 years of age was used to ensure that patients with type 1 disease were largely excluded from the analysis, although a few patients with T2D might have been excluded as a result. Data for CHF were extracted from the NHANES for analysis, as this can be an indicator of CVD; however, CHF from other causes may also have been captured, which would inflate the generalizability equally across all trials. Data on some of the study eligibility criteria were not available from the NHANES, including CV procedures (PCI, CABG surgery, stress test, and cardiac imaging), peripheral vascular disease, episodes of hyperglycemia and hypoglycemia, and diabetic ketoacidosis. Thus, criteria for resolving such issues were included in the analysis protocol (Appendix 2). However, omission or estimation of certain eligibility criteria based upon data from other sources is expected only to approximate the number of patients who meet those criteria. This approach likely would have disproportionately affected estimates of the numbers of patients meeting key CV eligibility criteria, including established CV complications and prior CV procedures. Inability to ascertain and apply prior history of conditions such as pancreatitis or medullary thyroid cancer, or use of effective contraceptive measures, likely resulted in a very slight degree of overestimation of eligible patient numbers. However, because all trials considered these criteria, the absence of this information was not expected to impact the generalizability of any individual CVOT. Finally, this analysis did not consider differences between the 7 CVOT studies in size, duration, or design.

Conclusions

This analysis showed that the proportion of US adults who would meet the enrollment criteria for CVOTs of GLP-1 RAs for T2D varied considerably among trials. The eligibility criteria for the EXSCEL study of once-weekly exenatide were the most inclusive of those evaluated, with others restricted (eg, ELIXA study) by inclusion of patients with specific histories of CVD. Although most patients in this analysis would have been eligible to participate in at least 1 of the GLP-1 RA studies, narrow eligibility criteria could restrict the applicability of the trial findings for a particular agent to a small percentage of patients with T2D, and also not provide data on CV outcomes that are relevant to those who are not at high risk of a CV event or who do not have a history of prior CVD. In addition, differences in inclusion criteria between CVOTs reduce the ability to make meaningful comparisons when trying to evaluate the relative CV impacts of different GLP-1 RA agents in real-world populations.Acknowledgements

Medical writing and editorial support was provided by Annie Rowe, Prime, UK, in accordance with Good Publication Practice guidelines (available at http://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3) and supported by AstraZeneca. 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); statistical analysis (JME); obtaining funding (KFB); administrative, technical, or logistic support (KL, ETW); supervision (ETW).

Address correspondence to: eric.wittbrodt@astrazeneca.com

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