531737
research-article2014
AOPXXX10.1177/1060028014531737Annals of PharmacotherapySwindle et al
Research Report
Colesevelam, Ezetimibe, and Patients With Type 2 Diabetes Mellitus: Characteristics and Clinical Outcomes From a Health Care Database
Annals of Pharmacotherapy 2014, Vol. 48(7) 847–855 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014531737 aop.sagepub.com
Jason P. Swindle, PhD, MPH1, Xin Ye, MS, PhD2, Rajiv Mallick, PhD3, Rui Song, PhD1, Thomas Horstman, BS1, and Harold E. Bays, MD, FTOS, FNLA, FACE4
Abstract Background: Despite the prevalence of therapies available to patients at highest coronary heart disease risk, only a minority of type 2 diabetes mellitus (T2DM) patients reach desired cholesterol treatment levels, with limited data regarding their outcomes. Objective: To examine “real-world” effectiveness of initiating treatment with either colesevelam or ezetimibe among individuals with evidence of T2DM and hypercholesterolemia (HCh). Key outcomes included treatment patterns and cardiovascular (CV) events. Methods: This retrospective administrative claims-based study utilized medical, pharmacy, and enrollment data linked to laboratory results information from a large United States health plan (January 1, 2006, to March 31, 2011) and included individuals with recorded evidence of T2DM and HCh. The index date was the date of first pharmacy claim for colesevelam or ezetimibe, with cohort assignment based on index medication. Assessments included baseline characteristics, follow-up treatment patterns, and composite CV event, with propensity score matching to correct for sample selection bias. Results: In total, 4231 individuals were identified with evidence of HCh and T2DM (ezetimibe n = 3384; colesevelam n = 847). After matching, the baseline characteristics between cohorts were rendered to be similar. Mean days of persistent medication use was lower with colesevelam compared with ezetimibe (P < 0.001). Compared with ezetimibe, a smaller percentage of individuals in the colesevelam cohort experienced a follow-up composite CV event, and adjusted Cox model results suggested decreased risk (hazard ratio = 0.58; P = 0.004) of a follow-up composite CV event. Conclusion: In this health care database analysis among patients with HCh and T2DM, colesevelam was associated with decreased risk of a composite CV event compared with ezetimibe, despite lower persistence. Keywords diabetes, colesevelam, ezetimibe, adherence, persistence, cardiovascular
Background High blood cholesterol (hypercholesterolemia; HCh) is a leading risk factor in the development of atherosclerotic coronary heart disease (CHD), one of the primary causes of death in the United States.1 Both elevated low-density lipoprotein cholesterol (LDL-C) levels and presence of diabetes mellitus (DM) are major CHD risk factors. In 2010, an estimated 31% of the US population older than 20 years had LDL-C levels ≥130 mg/dL, and 12% had either diagnosed or undiagnosed DM.2 Studies have suggested that controlling high levels of LDL-C levels can substantially reduce cardiovascular (CV) morbidity and mortality.1 The predominant treatment for elevated LDL-C is statin therapy, with current estimates suggesting that 1 in 4 Americans 45 years and older is taking a statin.3 As reported by the American Diabetes Association, cardiovascular disease (CVD) is a major cause of morbidity
and mortality in those with DM, emphasizing that hypertension and dyslipidemia, commonly associated with type 2 DM (T2DM), are risk factors for CVD.4 A more recent set of guidelines by the American College of Cardiology and the American Heart Association prioritize the use of moderate- or high-intensity statin therapy for patients with T2DM who are 40 to 75 years of age.5 However, not all patients are able or willing to take statins. This emphasizes the need for
1
Optum, Inc, Eden Prairie, MN, USA Daiichi Sankyo, Inc, Parsippany, NJ, USA 3 Formerly of Daiichi Sankyo, Inc, Parsippany, NJ, USA 4 L-Marc Research Center, Louisville, KY, USA 2
Corresponding Author: Jason P. Swindle, Optum, Inc, 200 W Madison St, Suite 2000, Chicago, IL 60606, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Harvard Libraries on April 20, 2015
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Annals of Pharmacotherapy 48(7)
nonstatin cholesterol-lowering agents, preferably ones with atherosclerotic CVD outcomes data. The Centers for Disease Control and Prevention notes that controlling hypertension, hyperglycemia, and dyslipidemia are key to preventing DM-related complications, including CHD.6 Individuals with T2DM may also be at increased risk for other health complications; therefore, T2DM therapy regimens should aim to address the multiple facets of this disease.7 Although some cases of T2DM can be managed through healthy eating and regular exercise, several medications and treatments are available to help patients reduce glucose and lipid levels.8 Despite the prevalence of glucose- and lipid-lowering agents available to patients at highest CHD risk, a minority of T2DM patients achieve desired glucose and lipid levels.9,10 The available lipid-lowering agents include statin medications (3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitors), which are commonly used to lower lipid levels in patients when diet and exercise are not sufficient. Alternately, ezetimibe is a lipid-lowering medication commonly prescribed to those with HCh and may be used either alone or in conjunction with a statin. In addition, colesevelam HCl is a bile acid sequestrant that also reduces cholesterol levels11-13 and an agent that has an indication to lower glucose levels in individuals with T2DM.7,14-16 Although it is important to investigate the comparative effectiveness of cholesterol-targeted agents in terms of clinical outcomes in actual, real-world use,17,18 data regarding the comparative use and potential benefits of ezetimibe and colesevelam oral therapies are scarce. Accordingly, this health care database study was conducted to characterize the real-world use of these 2 agents as well as the effectiveness of colesevelam HCl compared with ezetimibe as a treatment option for patients with T2DM, in terms of longterm clinical outcomes. In addition to comparing composite CV events, including myocardial infarction (MI), nonhemorrhagic stroke, and arterial revascularization procedures, a secondary objective was to characterize demographics, clinical characteristics, and treatment patterns (ie, time to discontinuation and proportion of days supplied with medication) in patients with T2DM receiving colesevelam versus ezetimibe.
Methods Study Design and Data Source This retrospective observational study was conducted using medical and pharmacy claims data for the period from July 1, 2005, to March 31, 2012, within a large US managed care health plan affiliated with Optum, Inc. Member coverage was geographically diverse, with coverage across all US census regions. Because individual identities or medical records were not disclosed and data were accessed using
methods consistent with the Health Insurance Portability and Accountability Act, institutional review board approval was not required for this study.
Study Sample The study included commercial health plan members with ≥1 pharmacy claim (ie, ≥1 filled prescription) for colesevelam or ezetimibe between January 1, 2006, and March 31, 2011 (defined as the subject identification period). The date of the first evidence of colesevelam or ezetimibe therapy was defined as the index date. The 6-month period prior to the index date was defined as the baseline period. Starting on the index date, individuals were followed for a minimum of 12 months after (and including) the index date until the earlier of disenrollment or March 31, 2012 (defined as the follow-up period). Individuals were required to meet the following inclusion criteria: ≥1 medical claim with a diagnosis code for pure HCh (ICD-9-CM 272.0; any placement) during the baseline period; ≥18 years of age on the index date; and continuous enrollment with pharmacy and medical benefits in both baseline and follow-up periods. Individuals with a pharmacy claim for colesevelam on the index date were assigned to the colesevelam cohort, whereas individuals with a pharmacy claim for ezetimibe on the index date were assigned to the ezetimibe cohort. In addition, none of the following criteria could be met: any pharmacy claims for colesevelam, ezetimibe, or fixeddose combination simvastatin/ezetimibe during the baseline period; any pharmacy claims for both colesevelam and ezetimibe during the follow-up period; any pharmacy claims for cholestyramine or colestipol during the baseline period or follow-up period; or among individuals in the colesevelam cohort, any pharmacy claims for fixed-dose combination simvastatin/ezetimibe during the follow-up period. Finally, individuals with any medical claims with a diagnosis code for hypertriglyceridemia, mixed hyperlipidemia, or hyperchylomicronemia (ICD-9-CM 272.1, 272.2, 272.3; any placement) during the baseline period were excluded. Those meeting the selection criteria above were then screened for DM via a stepwise algorithm using baseline pharmacy and medical claims data, as follows: (1) identify all individuals with diagnosis code for DM (ICD-9-CM 250.xx; any placement); (2) after step 1, individuals without evidence of insulin therapy are classified as type 2; (3) among unclassified after step 2, individuals with evidence of insulin pump therapy are classified as type 1; (4) among unclassified after step 3, individuals are classified as type 1 or type 2 if all diagnosis codes for DM suggest either type 1 (ICD-9-CM 250.x1, 250.x3) or type 2 (ICD-9-CM 250.x0, 250.x2). Only individuals classified as type 2 were retained in the final study sample.
Downloaded from aop.sagepub.com at Harvard Libraries on April 20, 2015
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Swindle et al
Study Variables Study variables were created using medical and pharmacy claims data, enrollment information, and linked laboratory results. Information was collected for the following demographics during the baseline period: age, gender, and geographic location. In addition, several baseline clinical characteristics were examined between the 2 treatment cohorts. Quan-Charlson comorbidity score was calculated based on the presence of baseline ICD-9-CM diagnosis codes. Baseline hemoglobin A1c (HbA1c) and LDL-C results were examined for those individuals with available test results. Finally, baseline medications, including dyslipidemia medications, oral antihyperglycemic agents, or nonDM agents, were also examined using medical claims and pharmacy claims. Treatment patterns, including dosage form, discontinuation, persistence, and proportion of days covered (PDC) were all examined during the follow-up period. Because colesevelam is available in both suspension and tablet form, dosage form was captured on the index date for individuals in the colesevelam cohort. Discontinuation of index therapy was defined as a gap of ≥60 days. Persistence was measured as the number of days to discontinuation of index therapy; among individuals without discontinuation, persistence was equal to length of follow-up. PDC served as a proxy for adherence and was defined as the total number of days of therapy divided by the number of days of follow-up. PDC calculations were corrected for inpatient stays under the assumption that inpatient medications are supplied by the facility. PDC values were categorized as good (≥0.80) or suboptimal (
research-article2014
AOPXXX10.1177/1060028014531737Annals of PharmacotherapySwindle et al
Research Report
Colesevelam, Ezetimibe, and Patients With Type 2 Diabetes Mellitus: Characteristics and Clinical Outcomes From a Health Care Database
Annals of Pharmacotherapy 2014, Vol. 48(7) 847–855 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014531737 aop.sagepub.com
Jason P. Swindle, PhD, MPH1, Xin Ye, MS, PhD2, Rajiv Mallick, PhD3, Rui Song, PhD1, Thomas Horstman, BS1, and Harold E. Bays, MD, FTOS, FNLA, FACE4
Abstract Background: Despite the prevalence of therapies available to patients at highest coronary heart disease risk, only a minority of type 2 diabetes mellitus (T2DM) patients reach desired cholesterol treatment levels, with limited data regarding their outcomes. Objective: To examine “real-world” effectiveness of initiating treatment with either colesevelam or ezetimibe among individuals with evidence of T2DM and hypercholesterolemia (HCh). Key outcomes included treatment patterns and cardiovascular (CV) events. Methods: This retrospective administrative claims-based study utilized medical, pharmacy, and enrollment data linked to laboratory results information from a large United States health plan (January 1, 2006, to March 31, 2011) and included individuals with recorded evidence of T2DM and HCh. The index date was the date of first pharmacy claim for colesevelam or ezetimibe, with cohort assignment based on index medication. Assessments included baseline characteristics, follow-up treatment patterns, and composite CV event, with propensity score matching to correct for sample selection bias. Results: In total, 4231 individuals were identified with evidence of HCh and T2DM (ezetimibe n = 3384; colesevelam n = 847). After matching, the baseline characteristics between cohorts were rendered to be similar. Mean days of persistent medication use was lower with colesevelam compared with ezetimibe (P < 0.001). Compared with ezetimibe, a smaller percentage of individuals in the colesevelam cohort experienced a follow-up composite CV event, and adjusted Cox model results suggested decreased risk (hazard ratio = 0.58; P = 0.004) of a follow-up composite CV event. Conclusion: In this health care database analysis among patients with HCh and T2DM, colesevelam was associated with decreased risk of a composite CV event compared with ezetimibe, despite lower persistence. Keywords diabetes, colesevelam, ezetimibe, adherence, persistence, cardiovascular
Background High blood cholesterol (hypercholesterolemia; HCh) is a leading risk factor in the development of atherosclerotic coronary heart disease (CHD), one of the primary causes of death in the United States.1 Both elevated low-density lipoprotein cholesterol (LDL-C) levels and presence of diabetes mellitus (DM) are major CHD risk factors. In 2010, an estimated 31% of the US population older than 20 years had LDL-C levels ≥130 mg/dL, and 12% had either diagnosed or undiagnosed DM.2 Studies have suggested that controlling high levels of LDL-C levels can substantially reduce cardiovascular (CV) morbidity and mortality.1 The predominant treatment for elevated LDL-C is statin therapy, with current estimates suggesting that 1 in 4 Americans 45 years and older is taking a statin.3 As reported by the American Diabetes Association, cardiovascular disease (CVD) is a major cause of morbidity
and mortality in those with DM, emphasizing that hypertension and dyslipidemia, commonly associated with type 2 DM (T2DM), are risk factors for CVD.4 A more recent set of guidelines by the American College of Cardiology and the American Heart Association prioritize the use of moderate- or high-intensity statin therapy for patients with T2DM who are 40 to 75 years of age.5 However, not all patients are able or willing to take statins. This emphasizes the need for
1
Optum, Inc, Eden Prairie, MN, USA Daiichi Sankyo, Inc, Parsippany, NJ, USA 3 Formerly of Daiichi Sankyo, Inc, Parsippany, NJ, USA 4 L-Marc Research Center, Louisville, KY, USA 2
Corresponding Author: Jason P. Swindle, Optum, Inc, 200 W Madison St, Suite 2000, Chicago, IL 60606, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Harvard Libraries on April 20, 2015
848
Annals of Pharmacotherapy 48(7)
nonstatin cholesterol-lowering agents, preferably ones with atherosclerotic CVD outcomes data. The Centers for Disease Control and Prevention notes that controlling hypertension, hyperglycemia, and dyslipidemia are key to preventing DM-related complications, including CHD.6 Individuals with T2DM may also be at increased risk for other health complications; therefore, T2DM therapy regimens should aim to address the multiple facets of this disease.7 Although some cases of T2DM can be managed through healthy eating and regular exercise, several medications and treatments are available to help patients reduce glucose and lipid levels.8 Despite the prevalence of glucose- and lipid-lowering agents available to patients at highest CHD risk, a minority of T2DM patients achieve desired glucose and lipid levels.9,10 The available lipid-lowering agents include statin medications (3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitors), which are commonly used to lower lipid levels in patients when diet and exercise are not sufficient. Alternately, ezetimibe is a lipid-lowering medication commonly prescribed to those with HCh and may be used either alone or in conjunction with a statin. In addition, colesevelam HCl is a bile acid sequestrant that also reduces cholesterol levels11-13 and an agent that has an indication to lower glucose levels in individuals with T2DM.7,14-16 Although it is important to investigate the comparative effectiveness of cholesterol-targeted agents in terms of clinical outcomes in actual, real-world use,17,18 data regarding the comparative use and potential benefits of ezetimibe and colesevelam oral therapies are scarce. Accordingly, this health care database study was conducted to characterize the real-world use of these 2 agents as well as the effectiveness of colesevelam HCl compared with ezetimibe as a treatment option for patients with T2DM, in terms of longterm clinical outcomes. In addition to comparing composite CV events, including myocardial infarction (MI), nonhemorrhagic stroke, and arterial revascularization procedures, a secondary objective was to characterize demographics, clinical characteristics, and treatment patterns (ie, time to discontinuation and proportion of days supplied with medication) in patients with T2DM receiving colesevelam versus ezetimibe.
Methods Study Design and Data Source This retrospective observational study was conducted using medical and pharmacy claims data for the period from July 1, 2005, to March 31, 2012, within a large US managed care health plan affiliated with Optum, Inc. Member coverage was geographically diverse, with coverage across all US census regions. Because individual identities or medical records were not disclosed and data were accessed using
methods consistent with the Health Insurance Portability and Accountability Act, institutional review board approval was not required for this study.
Study Sample The study included commercial health plan members with ≥1 pharmacy claim (ie, ≥1 filled prescription) for colesevelam or ezetimibe between January 1, 2006, and March 31, 2011 (defined as the subject identification period). The date of the first evidence of colesevelam or ezetimibe therapy was defined as the index date. The 6-month period prior to the index date was defined as the baseline period. Starting on the index date, individuals were followed for a minimum of 12 months after (and including) the index date until the earlier of disenrollment or March 31, 2012 (defined as the follow-up period). Individuals were required to meet the following inclusion criteria: ≥1 medical claim with a diagnosis code for pure HCh (ICD-9-CM 272.0; any placement) during the baseline period; ≥18 years of age on the index date; and continuous enrollment with pharmacy and medical benefits in both baseline and follow-up periods. Individuals with a pharmacy claim for colesevelam on the index date were assigned to the colesevelam cohort, whereas individuals with a pharmacy claim for ezetimibe on the index date were assigned to the ezetimibe cohort. In addition, none of the following criteria could be met: any pharmacy claims for colesevelam, ezetimibe, or fixeddose combination simvastatin/ezetimibe during the baseline period; any pharmacy claims for both colesevelam and ezetimibe during the follow-up period; any pharmacy claims for cholestyramine or colestipol during the baseline period or follow-up period; or among individuals in the colesevelam cohort, any pharmacy claims for fixed-dose combination simvastatin/ezetimibe during the follow-up period. Finally, individuals with any medical claims with a diagnosis code for hypertriglyceridemia, mixed hyperlipidemia, or hyperchylomicronemia (ICD-9-CM 272.1, 272.2, 272.3; any placement) during the baseline period were excluded. Those meeting the selection criteria above were then screened for DM via a stepwise algorithm using baseline pharmacy and medical claims data, as follows: (1) identify all individuals with diagnosis code for DM (ICD-9-CM 250.xx; any placement); (2) after step 1, individuals without evidence of insulin therapy are classified as type 2; (3) among unclassified after step 2, individuals with evidence of insulin pump therapy are classified as type 1; (4) among unclassified after step 3, individuals are classified as type 1 or type 2 if all diagnosis codes for DM suggest either type 1 (ICD-9-CM 250.x1, 250.x3) or type 2 (ICD-9-CM 250.x0, 250.x2). Only individuals classified as type 2 were retained in the final study sample.
Downloaded from aop.sagepub.com at Harvard Libraries on April 20, 2015
849
Swindle et al
Study Variables Study variables were created using medical and pharmacy claims data, enrollment information, and linked laboratory results. Information was collected for the following demographics during the baseline period: age, gender, and geographic location. In addition, several baseline clinical characteristics were examined between the 2 treatment cohorts. Quan-Charlson comorbidity score was calculated based on the presence of baseline ICD-9-CM diagnosis codes. Baseline hemoglobin A1c (HbA1c) and LDL-C results were examined for those individuals with available test results. Finally, baseline medications, including dyslipidemia medications, oral antihyperglycemic agents, or nonDM agents, were also examined using medical claims and pharmacy claims. Treatment patterns, including dosage form, discontinuation, persistence, and proportion of days covered (PDC) were all examined during the follow-up period. Because colesevelam is available in both suspension and tablet form, dosage form was captured on the index date for individuals in the colesevelam cohort. Discontinuation of index therapy was defined as a gap of ≥60 days. Persistence was measured as the number of days to discontinuation of index therapy; among individuals without discontinuation, persistence was equal to length of follow-up. PDC served as a proxy for adherence and was defined as the total number of days of therapy divided by the number of days of follow-up. PDC calculations were corrected for inpatient stays under the assumption that inpatient medications are supplied by the facility. PDC values were categorized as good (≥0.80) or suboptimal (
