Given the growing prevalence of type 2 diabetes (T2D) and its contribution to cardiovascular disease, cardiovascular outcomes trials should aim to be more representative of the average patient with T2D.
In 2008, the FDA issued Guidance for Industry in Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention.1 The Guidance recommends that all new medications for the treatment of type 2 diabetes (T2D) be tested to ensure that they do not lead to an “unacceptable increase in cardiovascular risk” by including multiple cardiovascular (CV) endpoints in new trials or evaluating the frequency of CV events in ongoing or completed trials. The American Diabetes and American Heart Associations have also weighed in, issuing new guidelines on the prevention of CV disease (CVD) among patients with diabetes.2 Following the FDA recommendations, sponsors of all dipeptidyl-peptidase-4 inhibitors (DPP-4is) available in the United States designed at least 1 randomized controlled trial to evaluate the CV safety of these medications: saxagliptin (SAVOR),3,4 alogliptin (EXAMINE),5,6 sitagliptin (TECOS),7 and linagliptin (CAROLINA and CARMELINA).8-13 Some of these CV outcomes trials (CVOTs) are complete (SAVOR, EXAMINE, and TECOS), while others are ongoing (CAROLINA and CARMELINA).
The 5 CVOTs evaluated in this analysis differed considerably with respect to region, study size, primary outcomes, length of follow-up, and inclusion/exclusion criteria. Specific to enrollment criteria, the representativeness of a study, or the external validity, is the extent to which the results of the study apply to other and, or, larger populations.14 This analysis provides a quantitative assessment of the representativeness of the DPP-4i CVOTs populations, as a whole, and differences among the 5 trials. In this analysis, we used the National Health and Nutrition Examination Survey (NHANES) to determine the extent to which each CVOT is representative of the population of adults with T2D in the United States. We used 2 recent waves of NHANES data, 2009 to 2010 and 2011 to 2012, to estimate the proportion of Americans with T2D who would be eligible for enrollment in each of the 5 CVOTs.
Research Design and Methods
Study Population and Inclusion Criteria
This analysis used NHANES, a nationally representative survey designed to measure objective health data from the noninstitutionalized US population, combined with field surveys about health and health behavior. Within the “diabetes” component of the questionnaire, individuals are asked if they have been diagnosed with diabetes, whether they are on insulin, or whether they are “taking diabetic pills to lower blood sugar.” The NHANES prescribed medicine data is based on a combination of patient self-reports and examination of pill bottles. Patients also undergo a physical examination and complete a broad range of laboratory tests.
The target population of this analysis is adults (older than 18 years of age) with a diagnosis of T2D. We attempted to distinguish individuals with T2D from both pregnant women with gestational diabetes and individuals with type 1 diabetes (T1D).
Patients fulfilling all of the following criteria were included in the analysis: (i) Patients at least 18 years of age (ii) Patients with diagnosis of diabetes.
Patients fulfilling the following criteria were excluded from the analysis to limit the analysis to the target population of adults with T2D: (i) Patients younger than 18 years (ii) Patients who were pregnant (iii) Patients diagnosed with diabetes before age 30 years (iv) Patients currently on insulin and those who initiated insulin use within 1 year of diagnosis, indicating T1D.15 (v) Patients were excluded from the analysis if they had missing information on: a. Age b. Gender c. Other demographics d. Diabetes status e. Age of diagnosis and/or medication use f. Glycated hemoglobin (A1C) g. Body mass index (BMI) h. Smoking status i. Other CVOT inclusion/exclusion criteria variables.
Sample Size and Patient Characteristics
From the pooled NHANES data for 2009-2010 and 2011-2012, we had a sample with non-missing data on all the variables required to determine eligibility in each of the 5 CVOTs for 3439 individuals aged 18 years and older. Overall, 654 of these patients reported having a diagnosis of diabetes. We identified 17 of these patients as having T1D, leaving 637 patients with T2D.
Using the NHANES sample we identified adults with diagnosed T2D. Next, based on the enrollment criteria for each CVOT, we identified individuals within the adult T2D sample who were eligible for each of the CVOTs based on published descriptions of the study designs.4,6,11,13,16 The CVOT inclusion and exclusion criteria were based on patient’s A1C, age, cardiovascular event history, smoking status, renal function, blood pressure, blood cholesterol, body weight, liver function, and prescription medication use. From these counts, ie, the number of patients with T2D and the number of patients with T2D meeting the enrollment criteria for each CVOT, we estimated the share of all adults with T2D each CVOT represents.
Individual trials included enrollment criteria regarding the timing of prior CV events, which was not directly available in NHANES. The timing of these events was imputed based on patient responses to questions about their health history and laboratory files. To identify patients in NHANES who had a myocardial infarction (MI) or a hospitalization for unstable angina in the 15 to 90 days prior to completing their survey, we used information from the physical functioning questionnaire in the 2007-2008 NHANES survey—a recent wave of NHANES to ask patients how many days they have experienced specific health problems, including heart and stroke problems, and imputed the number of days a recent MI or stroke survivor with T2D had a heart or stroke problem as a function of age, gender, race, and other comorbidities using multivariate regression analysis. We then used these estimated parameters to predict the duration of heart and stroke problems among patients with T2D who reported an MI or stroke in the previous year in the 2009-2010 and 2011-2012 NHANES samples, which were used in the primary analysis.
Patients in the NHANES sample who met the criteria for at least 1 of the 5 CVOTs were older (P <.0001), more likely to be in Medicare (P <.0001), and had more numerous comorbidities (eg, hypertension (P = .0010), high cholesterol (P = .0225), heart failure (P = .0345), and stroke (P = .0097), compared with the overall NHANES population with T2D (TABLE 1).
Overall, 28% of the T2D population met the enrollment criteria for at least 1 of the 5 CVOTs (FIGURE 1). Among DPP-4i CVOTs, the proportion of adult Americans with T2D who would have met enrollment criteria varied substantially. Approximately 21.4%, 9.0%, 5.3%, 4.3%, and 0.2% of patients with T2D met the criteria for SAVOR, CARMELINA, CAROLINA, TECOS, and EXAMINE, respectively (FIGURE 2). Due to large differences in the enrollment criteria, particularly with the most representative study, SAVOR, most patients (60%) who met enrollment criteria for a DPP-4i CVOT met the enrollment criteria for just 1 trial and no patients met the criteria for all 5 trials. Nearly 40% of patients with T2D eligible for any DPP-4i CVOT were eligible for SAVOR alone, whereas 12% were eligible for CARMELINA only, and 17% were eligible for SAVOR and CARMELINA, the 2 CVOTs with the greatest overlap in eligibility (TABLE 2).
FDA requires CVOTs in the interest of patient safety, but provides little guidance on the design of such studies. Different study designs ask and answer different questions, and the enrollment criteria component of the design greatly influences the external validity of a study. On the whole, the representativeness of a study, or the external validity, is the extent to which the results of the study apply to other and/or larger populations.14 In the case of T2D CVOTs, a trial design will have greater external validity if the trial participants are representative of the T2D population, as a whole, something stakeholders may want to consider in the decision-making process. The less generalizable each CVOT design, the more dissimilar the participants of each study may be, and the less comparable their results. This analysis provides a quantitative assessment of these differences.
All 5 CVOTs in this analysis were large randomized trials with excellent internal validity, but each CVOT faced tradeoffs between trial efficiency and external validity. The enrollment criteria among the 5 trials used different age, CVD risk, glycemic control (as measured by A1C), medication history, and renal impairment requirements. Collectively, the enrollment criteria of DPP-4i CVOTs also differ substantially from those used in the Glycemia Reduction Approaches in Diabetes comparative effectiveness study (GRADE), which aims to compare the efficacy and CV safety of 4 different classes of antidiabetic medications over a 4- to 7-year follow-up period, but excluded patients with recent CV events and those with diabetes for 5 or more years.17 Some studies focused on the adult population, while others focused on middle-aged and older populations. The allowable A1C ranges also varied substantially among the 5 CVOTs. CARMELINA, TECOS, and SAVOR excluded patients with renal impairment or chronic kidney disease (CKD), but each study used a different threshold and/or different biomarkers to define renal impairment. The CV risk factors also varied considerably among the 5 CVOTs; SAVOR and CAROLINA enrolled patients with established CVD, as well as broad, but differing definitions of CV risk factors related to age, sex, hypertension, or current smoking. The remaining trials exclusively enrolled patients with established CVD and the EXAMINE study restricted enrollment solely to patients 15- to 90-days post ACS.
These differences likely contributed to our finding that, of those patients who met the criteria for any of the 5 CVOTs, most patients met the enrollment criteria for only 1 and none met the criteria for all 5 CVOTs. Patients who met the enrollment criteria for at least 1 of the CVOTs tended to be older, more likely to have experienced a CV event, and had more numerous comorbid conditions. In light of these findings, caution in extrapolating from the results of a CVOT—which may be representative of the health characteristics of patients referred to clinical trials by physicians—to the general population with T2D and comparisons between CVOTs is warranted.
One strength of this analysis is that NHANES is nationally representative and the individuals with T2D in NHANES are generally representative of the adult population with T2D in the United States. In addition, NHANES contains nearly all of the information needed to apply the CVOT enrollment criteria, making NHANES better suited to this analysis than other survey or claims databases, which have far less granular information on patient health characteristics and behaviors.
While NHANES, overall, may be representative of the US population and patients with T2D, within the subsample eligible for a particular CVOT we may have relatively few observations to estimate sample means, and across-group comparisons may not be representative of the whole T2D population. In addition, diagnosis of T2D is self-reported in NHANES, and there is a small chance that diagnosis is misreported. Since respondents are surveyed in their homes, NHANES may not be entirely representative of an inpatient population like that targeted in EXAMINE, either. Another limitation of the analysis is that the timing of the ACS event is imputed in our sample based on data from the 2007-2008 NHANES. We cannot completely separate T1D and T2D, as patients are not asked to distinguish between the 2 types in NHANES. Also, NHANES data do not contain information on bariatric surgery, and thus, we cannot exclude patients with T2D who have undergone bariatric surgery as done in the CARMELINA trial. However, bariatric survey is relatively uncommon, even among individuals with T2D (only 0.4% of T2D patients in the 2009-2011 Medical Expenditure Panel Survey reported having an “other gastric operation”). Also, the date of the T2D diagnosis cannot be determined with certainty; we can only identify the year of T2D diagnosis. Lastly, TECOS excluded patients with 2 or more hypoglycemic events requiring third-party assistance in the preceding 12 months.18 However, NHANES does not contain any information that allowed us to identify these patients. This criterion would only exclude more patients, so to that extent, our estimate of the proportion of patients with T2D that would meet the enrollment criteria for TECOS is an upper bound.
The results of the DPP-4i CVOTs speak to the mid-term (1.5 to 3 years) CV safety of DPP-4is among a subset of adult patients with T2D at increased CV risk. They do not establish the potential long-term macrovascular effects of DPP-4is—positive or negative—among the majority of patients with T2D. Manufacturers should consider and balance the pros (increased representativeness) and cons (expense and duration) of enrolling lower-risk patients. Similarly, clinicians should consider these enrollment criteria when interpreting the applicability of the results of these trials to their patients and consider differences in the enrollment criteria when comparing the results of individual DPP-4i CVOTs. Duality of Interest: JPM is and employee, JVO is a past employee, and AM and ALP are consultants at Precision Health Economics, which was compensated by AstraZeneca to perform the study. ALP has consulted for Amgen, AstraZeneca, Abbott Diabetes Care, Boehringer Ingelheim, Becton Dickinson, Janssen, Merck, Novo Nordisk, Lilly, Biodel, Lexicon, Sanofi and Takeda. She has received research funding from Medtronic and Janssen. Precision Health Economics provides consulting and other research services to pharmaceutical, device, governmental, and non-governmental organizations. JS and IK are past employees of AstraZeneca.
Author Information: Joanna P MacEwan, PhD, is a research economist at Precision Health Economics, LLC (PHE). John J Sheehan, PhD, RPh, was employed with AstraZeneca at the time of the research. Anne Peters, MD, is a professor of Medicine at the Keck School of Medicine at the University of Southern California. Jacqueline Vanderpuye-Orgle, PhD, was employed with PHE at the time of the research. Iftekhar Kalsekar, PhD, was employed with AstraZeneca at the time of the research; Anup Malani, PhD, JD, is professor of Law at the University of Chicago School of Law. Funding: AstraZeneca supported this study.
Corresponding author: Joanna P. MacEwan, PhD, 11100 Santa Monica Blvd, Suite 500, Los Angeles, CA 90025. Joanna.MacEwan@PHEconomics.com. References
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