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Evidence-Based Diabetes Management September 2016
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Representativeness of Dipeptidyl-Peptidase-4 Inhibitor Cardiovascular Outcomes Trials
Joanna P MacEwan, PhD; John J Sheehan, PhD; Anne Peters, MD; Jacqueline Vanderpuye-Orgle, PhD; Iftekhar Kalsekar, PhD; and Anup Malani, PhD
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Representativeness of Dipeptidyl-Peptidase-4 Inhibitor Cardiovascular Outcomes Trials

Joanna P MacEwan, PhD; John J Sheehan, PhD; Anne Peters, MD; Jacqueline Vanderpuye-Orgle, PhD; Iftekhar Kalsekar, PhD; and Anup Malani, PhD
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.

Analysis Methods

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.

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