RACIAL DIFFERENCES IN ORAL ANTIDIABETIC MEDICATION ADHERENCE, HEALTHCARE UTILIZATION AND COSTS ASSOCIATED WITH TYPE 2 DIABETES IN MEDICAID ENROLLEES

Transcription

1 RACIAL DIFFERENCES IN ORAL ANTIDIABETIC MEDICATION ADHERENCE, HEALTHCARE UTILIZATION AND COSTS ASSOCIATED WITH TYPE 2 DIABETES IN MEDICAID ENROLLEES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Rahul A. Shenolikar, M.S. * * * * * The Ohio State University 2006 Dissertation Committee: Approved by: Professor Rajesh Balkrishnan, Advisor Professor Roger T. Anderson Professor Milap C. Nahata Advisor Graduate Program in Pharmacy Professor Sharon Schweikhart

2 Copyright by Rahul Avinash Shenolikar 2006

3 ABSTRACT The prevalence of diabetes is higher in Non-Hispanic Blacks, and Hispanics as compared to non-hispanic Whites. Adherence to medications is required in achieving glycemic control as it has a well established relationship with improved treatment outcomes and is associated with decreased utilization of medical resources. This study examined the racial differences in medication adherence and associated healthcare costs and utilization. A modified version of Health Belief Model and Aday-Andersen model for healthcare utilization was used as the theoretical model. This retrospective cohort study which used North Carolina Medicaid database compared 1517 African Americans, 1115 Whites and 505 patients of other races newly starting metformin, sulfonylureas or thiazolidiendiones. The patients were followed for one year after the start of medication to gather the data on medication utilization, healthcare costs, hospitalization and emergency room visits. Demographic, clinical and medication related information was extracted from the database. Multiple log-linear regression analysis was employed to model medication adherence and healthcare costs, while multiple logistic regression analysis was utilized for hospitalization, and emergency room visits. ii

4 Adherence levels of this population were considerably lower than the generally accepted level of eighty percent. The study found that there were racial differences in medication adherence, healthcare costs, likelihood of hospitalizations and emergency room visits. Being an African American was associated with decreased medication adherence, increased healthcare costs, increased likelihood of hospitalization and emergency room visit as compared to Whites. Factors such as age, comorbidities, and number of medications consumed were also significant predictors of outcomes. Medication adherence was mainly associated with hospitalization and ER visit, which reinforces the importance of adherence in avoiding complications in diabetes patients. The predictive power of the models explaining adherence was moderate, while models explained variance in healthcare costs considerably well. Third-party payers such as Medicaid need to target at-risk patients based on the above mentioned factors. Disease management programs remain the most important tool to target at-risk patients, consider their clinical profile and medication management issues for optimal utilization of healthcare resources. iii

5 Dedicated to my parents iv

6 ACKNOWLEDGMENTS I would like to thank number of individuals for making this effort possible. First of all, I would like to thank my major advisor, Dr.Rajesh Balkrishnan, Merrell Dow Professor, for his research expertise and guidance. The completion of this project would not have been possible without him. I would like to thank him for infinite opportunities he has given to me during my doctoral curriculum. Besides dissertation, I would like to thank him for the knowledge I have gained, and fundamentals of research that I learned from him. His work and his personality will always be an inspiration for me. Further, I would like to thank for numerous enriching discussions that I enjoyed in last three years with him and George. I would also to thank Dr. Roger Anderson for allowing me to work on research projects and providing an insight on each of them. I appreciate his assistance and guidance in this and number of other projects. I would like to thank Dr. Milap Nahata for being a wonderful Chair, providing feedback regularly, and encouraging me in my endeavors. I would like to thank Dr.Timothy Whitmire for providing the data, and finally Dr. Sharon Schweikhart for agreeing to be a part of my committee and facilitating the process. Dr.Lu Ann Aday, and Dr.Luisa Franzini at The University of Texas School of Public Health need to be thanked for being excellent tutors and for teaching two of the best courses I learned in my Ph.D. Fabian Camacho who has been a wonderful help not v

7 only in my dissertation but also throughout my Ph.D. This dissertation would not have been completed at such pace without his assistance. I will always be grateful to Kathy Brooks and Sara Turner for facilitating graduate student activities. Last but not the least; I cannot thank enough the most important people in my life. I would like to thank my mother, Mrs. Shilpa Shenolikar, without whom this degree would not have been possible and my father, Dr. Avinash Shenolikar, for always having faith in me. I would like to thank my sisters, Sonali and Rashmi, for their immense love and emotional support, and my brothers-in-law, Amit and Akshay, for their advice and support whenever needed. Finally, I would also like to thank Monali for having trust and belief in me. This is for our future together. vi

8 VITA March 17, 1978 Born- Mumbai, India 2003 M.S. Pharmacy Administration, The University of Toledo 1999.Bachelor of Pharmaceutical Sciences, Mumbai University Research Publication PUBLICATIONS 1. Shenolikar RA, Balkrishnan R, Camacho FT, Whitmire JT, Anderson RT. Race and medication adherence in Medicaid enrollees with type-2 diabetes.j Natl Med Assoc Jul;98(7): Balkrishnan R, Anderson R, Shenolikar R, Rajagopalan R. Outcomes associated with introduction of thiazolidinedione therapy in medicaid enrolled patients with type 2 diabetes mellitus: a retrospective data analysis with additional data. Current Medical Research and Opinion 2006; 22(3): Rasu RS, Shenolikar R, Balkrishnan R. Physician Prescribing of Sleep Disorder Medications in United States Outpatient Settings: Factors affecting prescription of high abuse potential and costly medications. Clinical Therapeutics 2005; 27(12): Rasu R, Balkrishnan R, Shenolikar R, Nahata MC. Outcomes associated with the treatment of insomnia in outpatient settings: A review and update. Expert Review of Pharmacoeconomics and Outcomes Research 2005; 5(6): Balkrishnan R, Jurgensmeyer JC, Shenolikar R, Fleischer AB, Feldman SR. Prescribing Patterns for Topical Retinoids within NAMCS Data. Journal of Drugs in Dermatology 2005; 4(2): Bhosle M, Shenolikar R, Kulkarni A, Balkrishnan R. Outcomes associated with inhaled corticosteroid use in asthma and COPD: an update. Expert Review of Pharmacoeconomics and Outcomes Research 2004; 4(6): vii

9 7. Shenolikar RA, Balkrishnan R, Hall MA. How patient-physician encounters in critical medical situations affect trust: results of a national survey. BMC Health Services Research 2004; 4(1): Balkrishnan R, Rajagopalan R, Shenolikar RA, Camacho FT, Whitmire JT, Anderson RT. Healthcare costs and prescription adherence with introduction of thiazolidinedione therapy in Medicaid type 2 diabetic patients: a retrospective data analysis. Current Medical Research and Opinion 2004; 20(10): Greisinger AJ, Balkrishnan R, Shenolikar RA, Wehmanen OA, Muhammad S, Champion PK. Diabetes care management participation in a primary care setting and subsequent hospitalization risk. Disease Management 2004; 7(4): Major Field: Pharmacy FIELDS OF STUDY viii

10 TABLE OF CONTENTS Page Abstract...ii Dedication....iv Acknowledgements......v Vita...vii List of Tables...xii List of Figures....xiv List of Abbreviations...xv Chapters: 1. Introduction Rationale and Significance of the study Specific objectives and hypotheses 7 2. Literature review Diabetes and its economic burden Oral antidiabetic agents in treatment of type 2 diabetes Insulin secretagogues Alpha-glucosidase inhibitors Insulin sensitizers Racial disparities: Healthy People ix

11 2.4 Racial disparities in diabetes Factors associated with medication use and medication adherence in diabetes patients Methods of measuring medication adherence Methods Theoretical framework Health Belief Model The Aday-Andersen model for healthcare utilization Proposition of theoretical framework Study Design Study population Study perspective Patient selection, treatment cohorts, and time frame Study variables Working definition of medication adherence Measurement of study variables Statistics and Hypothesis testing Regression diagnostics Results Data management and analysis Descriptive statistics Hypothesis testing Regression diagnostics x

12 4.5 Sensitivity analysis Discussion Discussion of descriptive findings Discussion of multivariable regression findings Test of theoretical model Limitations of study Implications for medical care policy Conclusions Future research..109 List of references APPENDICES A. Approval for data access B.NDC codes of medications xi

13 LIST OF TABLES Table Page 3.1 Selected records retrieved from the Medicaid database Selected variables in the main dataset ICD-9 codes of conditions included in Charlson Comorbidity Index Distribution of race in study population Distribution of type of therapy Means of patient characteristics Distribution of patient characteristics Comparison of adherence rate to each therapy among races Comparison of medication adherence between races using multiple regression analysis Comparison of healthcare costs between races using multiple regression analysis Comparison of likelihood of hospitalization between races Comparison of likelihood of emergency room visit between races Comparison of medication adherence between races using multiple regression analysis in three therapy groups Comparison of total healthcare costs between races using multiple regression analysis in three therapy groups.. 78 xii

14 4.12 Comparison of likelihood of hospitalization between races using logistic regression analysis in three therapy groups Comparison of likelihood of emergency room visit between races using logistic regression analysis in three therapy groups Examination of association between medication adherence and healthcare costs using multiple regression analysis Examination of association between medication adherence and likelihood of hospitalization using logistic regression analysis Examination of association between medication adherence and likelihood of emergency room visit using logistic regression analysis Sensitivity analysis showing analysis using logged and unlogged version of Medication Possession Ratio Sensitivity analysis showing analysis using logged and unlogged version of total annual healthcare costs...96 xiii

15 LIST OF FIGURES Figure Page 3.1 Original Health Belief Model developed by Rosenstock Modification of Health Belief Model by Becker and Maiman The Aday-Andersen Model for determinants of healthcare utilization Theoretical model proposed for the study based on modification of Health Belief Model by Becker and Maiman, and Aday-Andersen Steps involved in creation of the analytical dataset for the study xiv

16 LIST OF ABBREVIATIONS US Hba1c OHA HMO UKPDS TZD LDL BMI United States Glysolated hemoglobin Oral hypoglycemic therapy Health Maintenance Organization United Kingdom Prospective Diabetes Study Thiazolidinediones Low density lipid Body Mass Index NHANES National Health and Nutrition Examination Survey MPR ICD-9 NDC FDA ER ANOVA OLS ESS VIF CI Medication Possession Ratio International Classification of Diseases, 9 th revision, Clinical Modification National Drug Code Food and Drug Administration Emergency room visit Analysis of variance Ordinary least squares Explained sum of squares Variance Inflation Factor Confidence Interval xv

17 LR Likelihood Ratio xvi

18 CHAPTER 1 INTRODUCTION 1.1 Rationale and significance of the study Currently, around 20.8 million people in the United States (US) have diabetes, out of which an estimated 14.6 million people have been diagnosed with it, while 6.2 million people are unaware that they have diabetes. 1 Diagnosis of diabetes can be categorized as Type 1, Type 2 diabetes or gestational diabetes. Type 1 diabetes results because of body s failure to produce insulin, the hormone that is responsible for regulation of glucose levels in blood. Type 2 diabetes results from insulin resistance, a condition in which body fails to properly use insulin. Most Americans are diagnosed with type 2 diabetes. Type 2 diabetes, previously called as non-insulin dependent diabetes, accounts for 90-95% of all diagnosed cases of diabetes. 2 The prevalence of type 2 diabetes is more common in older people, especially in people who are overweight, and its occurrence varies across different ethnicities. 3 Those aged 45 and above are at higher risk of developing type 2 diabetes than the younger age groups. Type 2 diabetes is more common in African Americans, Latinos, Native Americans, and Asian Americans/Pacific Islanders. 4,5 Its prevalence is at least 2 to 4 times higher among non-hispanic Black, Hispanic/Latino American, American Indian, and Asian/Pacific Islander women than among non-hispanic White women. Among all 1

19 the non-hispanic whites, 8.7% of all aged 20 years or older have diabetes, while 13-14% of all non-hispanic blacks aged 20 years or older have diabetes. After adjusting for population age differences, non-hispanic blacks are 1.8 times as likely to have diabetes as non-hispanic whites while Mexican Americans, the largest Hispanic/Latino subgroup, are 1.7 times as likely to have diabetes as non-hispanic whites. 4,5 Diabetes is associated with an increased risk for a number of serious, sometimes life-threatening complications. The complications arise due to high glucose levels. Inadequate control of glucose levels has been associated with development of complications in diabetes patients. Studies in the United States and abroad have found that improved glycemic control benefits people with both type 1 or type 2 diabetes. Every percentage point drop in glysolated hemoglobin (Hba1c) blood test results (e.g., from 8.0% to 7.0%) reduces the risk of microvascular complications (eye, kidney, and nerve diseases) by 40%. 6 Therefore, the main aim of diabetes treatment is to bring glucose levels to as close as to normal range. There are numerous strategies to reduce blood sugar levels. Initial treatment for type 2 diabetes often begins with meal planning, weight loss, and exercising. However, in most of the diabetes patients, blood sugar cannot be reduced near the normal range without using antidiabetic medications. Therefore, the next step is taking medications as they have the ability to lower blood glucose levels near the normal range. Although numerous strategies exist to improve glycemic control levels, administration of medications on a continual basis is the cornerstone of diabetes treatment. There are two basic types of medications, 1) insulin secretagogues: these increase insulin secretion, 2) insulin sensitizers: these insulin sensitivity, and alpha-glucosidase inhibitors. 2

20 In the past it has been shown that consuming medications improves glycemic control levels and therefore helps in reducing the risk of complications. Importance of measuring medication adherence Medication use is generally measured as medication adherence or medication persistence to a particular therapy. Medication adherence can be defined as the extent to which a person s medication taking behavior coincides with medical advice. 7 Medication adherence is one of the important factors in achieving glycemic control. Adherence to diabetes medications improves glycemic control. Some studies demonstrated that selfreported medication adherence was associated with improved glycemic control. In some studies, improved medication adherence was associated with reduction in Hba1c levels after adjusting for all other factors. 8,9 Adherence to medications is also important due to its association with healthcare services utilization. It has a well established relationship with treatment outcomes. Increased adherence has shown to be associated with decreased utilization of medical resources. A study by Hepke et al conducted in a non-managed care setting showed that increased pharmaceutical adherence was associated with decreased use of emergency department and inpatient visits. Another longitudinal study by Balkrishnan et al, conducted using a data from Medicare Health Maintenance Organization (HMO), found that increased adherence was the strongest predictor of decreased total annual health care costs (8.6% to 28.9% decrease in annual costs with every 10% increase in medication possession ratio). These findings have been reinforced in other studies conducted in different settings. 10, 11, 12 Nonadherence to oral hypoglycemics is also associated with increased risk of hospitalization. 13 3

21 Although medication adherence is crucial in achieving glycemic control and reducing complications, previous studies have shown that people with diabetes do not use the medications as prescribed. 14, 15, 16, 17 A systematic review of literature showed that diabetes patients have poor adherence rates with treatment, including both oral hypoglycemic agents and insulin. 18 The adherence rates were low irrespective of the method used to measure adherence. The studies which measured adherence using retrospective analyses showed that adherence to oral hypoglycemic therapy (OHA) therapy ranged from 36% to 93% in patients remaining on treatment for 6 24 months. Prospective electronic monitoring studies documented that patients took 67 85% of OHA doses as prescribed. 18 Young patients filled prescriptions for one-third of prescribed insulin doses. Insulin adherence among patients with type 2 diabetes was 62 64%. Another study has also reinforced these findings. 19 Factors associated with medication adherence A number of studies have been conducted examining adherence to diet and physical activities. 20, 21, 22, 23 Factors that are associated with adherence to diet and physical activities include socioeconomic factors, health system related factors, condition related factors, therapy related factors, and patient related factors. 24 Relatively few studies have examined factors associated with medication adherence in type 2 diabetes patients. Some of the factors that affect adherence with treatment significantly include demographic factors such as age, gender, patients knowledge, education, insurance, clinical factors such as complications/comorbidities, and therapy related factors which include number of medications, frequency of dosage 4

22 administration and complexity of the regimen, and medication costs 14,19,24, 25, 26, 27, 28, 29, 30 31, 32, 33, 34 Among all these factors, therapy related factors play a crucial role in medication adherence. However, other factors are as important as therapy related factors in their association with medication adherence. A study showed that for the patients who had no modification of their medication regimen, persistence with sulfonylurea or metformin monotherapy was 65% greater than with polytherapy over a 1-year period. Adherence with sulfonylurea or metformin monotherapy was 45% greater than with polytherapy. 31 Another study showed that simple one drug antihyperglycemic regimens were associated with better adherence and persistence than more complex multiple-drug regimens among patients with type 2 diabetes in the Medi-Cal population. 32 Recent data indicate that reducing the daily administration frequency of oral antihyperglycemic agents improves compliance with treatment and consequently metabolic control. 33 Those with once-a-day dosing have better adherence rates as compared to those who have twice or thrice a day dosing. 24,34,14 Although the association of many factors with medication adherence has been investigated, previous studies have not examined the relationship between race and medication adherence. Medication adherence could differ across different races due to number of reasons. The reasons could be varied clinical background such as number of comorbidities, risk of complications presented by patients with a particular race. For example, elderly African American Medicare beneficiaries are three to four times more likely than white beneficiaries to undergo amputations of lower limbs due to uncontrolled diabetes. 35,36 The difference could also be due to disparity in the exposure to health care 5

23 system issues such as patient counseling, and continuous care that reinforce adherence. Further, different ethnic groups also have different socioeconomic status, education, healthcare access issues, and knowledge about diabetes and its treatment. Racial disparities in access to medication, and insurance are also documented. 37, 38 All these factors can potentially affect medication adherence. The relationship between ethnicity and medication adherence has been studied in other disease areas such as depression, osteoarthritis, and cardiovascular disease. 39, 40, 41 However, none of the previous studies have focused on the association between adherence and ethnicity in type 2 diabetes patients. Therefore, it is essential to understand if there are any differences in medication adherence to antidiabetic therapies across different races and to understand the influence race as well as medication adherence has on healthcare utilization. It is especially important to examine in populations which have access to health insurance, whether race has an independent role in affecting medication adherence and associated outcomes even when access and access related issues such as insurance, co-payments and income level are constant across groups. The effect of access related issues, also called as barriers can be removed by studying population such as Medicaid enrollees. In this population everyone has similar insurance, co-payments, and comparable income level. Therefore, the aim of this study was to explore the association between patients race and their medication adherence to different antidiabetic therapies. It will further examine the association between race and healthcare costs, healthcare services utilization such as inpatient hospitalizations and emergency room visits adjusting for medication adherence, and other demographic and clinical confounders. 6

24 Significance of the study This study provides new insights into the area of differences in medication taking behavior by examining variations in medication adherence and associated outcomes among different ethnic groups with type 2 diabetes. Medication management is the most important part in diabetes treatment. Racial disparities in diabetes treatment have been noted in the literature; however, previous studies have not explored the association of ethnicity with medication taking behavior. Differences in medication adherence by different ethnic groups would mean that further investigation could be required to understand the reasons for differences in medication adherence. Identifying these differences could not only help in designing strategies to improve medication adherence but it will also help in improving patients glycemic control and potentially reduce healthcare costs by avoiding the complications. The issue of costs especially becomes important to low-income disadvantaged populations such as Medicaid enrollees. Understanding the differences could also help in designing disease management strategies for particular sub-populations. 1.2 Specific objectives and hypotheses: 1. To examine the select patient characteristics among different races in Medicaid enrolled type 2 diabetes patients. 2. To examine the difference in medication adherence among different races across different therapies in Medicaid enrolled type 2 diabetes patients. 3. To examine the association between patients race and medication adherence in type 2 diabetes Medicaid patients adjusting for demographic and clinical confounders. 7

25 4. To examine the association between patients race and associated healthcare costs in type 2 diabetes Medicaid patients adjusting for demographic and clinical confounders. 5. To examine the association between patients race and likelihood of healthcare utilization such as hospitalization and emergency room visit in type 2 diabetes Medicaid patients adjusting for demographic and clinical confounders.. 6. To examine the difference between races in medication adherence, healthcare costs, and likelihood of healthcare utilization within each therapy adjusting for demographic and clinical confounders. 7. To examine the association between medication adherence, healthcare costs and likelihood of healthcare utilization in type 2 diabetes Medicaid patients adjusting for demographic and clinical confounders. The specific hypotheses examined for each of the objectives will be as follows: Alternative Hypotheses: 1. There will be difference in the patient characteristics between races in the Medicaidenrolled Type 2 diabetic patients. 2. African Americans and Other race groups will have lower medication adherence in the Medicaid-enrolled Type 2 diabetic patients. 3. African Americans and Other race groups will have lower medication adherence as compared to Whites adjusting for demographic and clinical confounders. 4. African Americans and Other race groups will have higher healthcare costs as compared to Whites after adjusting for demographic and clinical confounders. 8

26 5. African Americans and Other race groups will have higher likelihood of healthcare utilization such as hospitalization and emergency room visits in the Medicaid-enrolled Type 2 diabetic population after adjusting for demographic and clinical confounders. 6. The medication adherence, healthcare costs, and likelihood of hospitalization within each therapy in the Medicaid-enrolled Type 2 diabetic population will differ between races after adjusting for demographic and clinical confounders. 7. The following three hypotheses were tested in this objective: a. Increase in the medication adherence will decrease the healthcare costs in the Medicaid-enrolled Type 2 diabetic population after adjusting for demographic and clinical confounders. b. Increase in the medication adherence will decrease the likelihood of hospitalization in the Medicaid-enrolled Type 2 diabetic population after adjusting for demographic and clinical confounders. c. Increase in the medication adherence will decrease the likelihood of emergency room visit in the Medicaid-enrolled Type 2 diabetic population after adjusting for demographic and clinical confounders. 9

27 CHAPTER 2 LITERATURE REVIEW This chapter will provide an overview of literature related to diabetes, its pharmacotherapeutic treatment options, racial disparities in diabetes, factors associated with medication use or adherence in diabetes patients, and methods for measuring medication adherence. 2.1 Diabetes and its economic burden Diabetes is a debilitating chronic disease. It has a significant impact on the healthcare system. According to a study by American Diabetes Association, diabetes cost the US an estimated $132 billion in 2002 in medical expenditures and lost productivity, of which a total of $92 billion are accounted by direct medical costs. Expenditures for health care events with a primary diagnosis of uncomplicated diabetes and diabetesrelated supplies are estimated to be $23.2 billion for 2002, which accounts for 25% of all health care attributable expenditures. The expenditures associated with oral agents to lower blood glucose, insulin, and insulin-related supplies are estimated to be approximately $12 billion. Although people with diagnosed diabetes comprise only slightly more than 4% of the U.S. population, almost $1 of every $5 spent on health care in the U.S. is for a person with diabetes according to this study. 42 The resulting economic loss to the US economy in 2002 alone is estimated to be $40 billion. Expenditures 10

28 attributable to diabetes are greatest for hospital inpatient stays ($40.3 billion), followed by nursing home care ($13.9 billion) and visits to physician offices ($10 billion).diabetic complications lead to high morbidity as well as mortality, which in turn account for huge economic burden of this disease. Previous studies show that systematic control of glucose levels, blood pressure and cholesterol in diabetic patients can reduce the risk of developing complications as well as result in considerable cost savings Oral antidiabetic agents in treatment of type 2 diabetes The effect of medications in reduction of glycemic control and diabetes related complications are well documented. The United Kingdom Prospective Diabetes Study (UKPDS) study showed that use of medications is associated with reduction of microvascular complications. 43,44 Although, antidiabetic medications have shown to reduce glycemic control, the choice of antidiabetic agents given to patients anytime is based on a clinical, biochemical markers and consideration of safety profile of the drug. Oral antidiabetic agents are usually initiated at low dose and titrated upwards based on glycemic response. 45 Besides, oral antidiabetic agents, insulin is also administered to diabetes patients. It is generally used in patients: (i) who fail to respond adequately to a combination of oral agents (ii) in whom glycemic control worsens despite using adequate combinations of oral drugs (iii) for patients in which insulin becomes a choice such as during pregnancy, or in patients with severe hepatic or renal impairment. According to the National Health Interview Survey, the distribution of insulin and oral medication treatment among U.S. adults aged 20 years or older with diagnosed 11

29 diabetes in is as follows; Fifty-seven percent were treated with only oral medication, 12 percent received insulin and oral medication, 16 percent received only insulin, and 15 percent received neither oral medication nor insulin. 46 Insulin resistance and defective insulin secretion are main features of type 2 diabetes. In practice, the essential step is to judge whether insulin resistance or insulin deficiency is the main effect in the patients. Oral diabetes drugs can be grouped into following categories based on their mode of action with respect to the above two mechanisms. (i) insulin secretagogues: those that increase insulin secretion (ii) α-glucosidase inhibitors: drugs that delay absorption and digestion of carbohydrates (iii) insulin sensitizing agents: drugs that have direct effect on insulin responsive tissues Insulin secretagogues Sulfonylureas: Sulfonylureas are traditional antidiabetic drugs which have been used since 1950s. They lower blood glucose concentration primarily by stimulating insulin secretion from pancreas. Chlorpropamide (brand name Diabinese ) is the only first-generation sulfonylurea. The second generation sulfonylureas are used in smaller doses than the first-generation drugs. There are three second-generation drugs: glipizide (brand names Glucotrol and Glucotrol XL ), glyburide (Micronase, Glynase, and Diabeta ), and glimepiride (Amaryl ). These drugs are generally taken one to two times a day, before meals. All sulfonylurea drugs have similar effects on blood glucose levels. They differ from each other with respect to side effects, how often they are taken, and interactions with other drugs. There were some initial concerns about cardiovascular toxicity associated with sulfonylureas. The UKPDS investigators did not find any increase in risk 12

30 of myocardial function among patients treated with sulfonylureas compared with patients randomized to insulin as monotherapy. 43 Sulfonylureas are popular choice as first therapy for patients who have not achieved glycemic control through nonpharmacologic actions. It is also preferred in patients who are not overweight as use of sulfoylureas is generally associated with weight gain. Sulfonylureas can be used in combination with other classes of antidiabetic agents, with the exception of insulin secretagogues. One of the most common adverse events associated with sulfonylureas is that they cause hypoglycemia. Severe hypoglycemia is likely with longer-acting sulfonylureas. Other adverse events include cutaneous sensitivity reactions. 47, 48, 49 Meglitinides: Derivatives of meglitinide used for diabetes treatment are repaglinide and nateglinide. They have action similar to sulfonylureas. Therefore, there is no advantage in administering them in addition to sulfonylureas. This class of drugs is more expensive than sulfonylureas. Both, repaglinide and nateglinide may be used as a monotherapy in patients inadequately controlled by nonpharmacological measures. These drugs are suitable for those who have irregular lifestyles in which meals may be missed. They are associated with low risk of hypoglycemia as compared to sulfonylureas and therefore are an attractive option. However, the disadvantage of these drugs is that they are given in multiple daily doses. 47,48, Alpha-glucosidase inhibitors: These drugs help the body to lower blood glucose levels by blocking the breakdown of starches in the intestine. They inhibit the activity of α-glucosidase enzymes which are responsible for breakdown of carbohydrates to glucose and thereby reduce the 13

31 rate of digestion of carbohydrates. Acarbose (brand name Precose ) and meglitol (Glyset ) are the 2 alpha-glucosidase inhibitors on the market. They have limited gastrointestinal tolerability but are relatively expensive. An alpha-glucosidase inhibitor can be used as monotherapy. They target postprandial hyperglycemia and therefore can be useful in those who have slightly raised basal glucose concentration and more marked postprandial hyperglycemia. It is usually ensured that patients are on diet rich in complex carbohydrates when starting this therapy. The most common adverse effect is gastrointestinal discomfort, and therefore this class of drugs is contraindicated in patients with chronic intestinal disease. 47,48, Insulin sensitizers Biguanides: Metformin improves the insulin sensitivity. It lowers blood glucose concentration without causing hypoglycemia. The clinical efficacy of metformin requires presence of insulin as its action does not involve stimulating insulin release. Metformin is one of the cheaper oral antidiabetics. Metformin (brand name Glucophage ) is a biguanide. Biguanides lower blood glucose levels primarily by decreasing the amount of glucose produced by the liver. Metformin also helps to lower blood glucose levels by making muscle tissue more sensitive to insulin so glucose can be absorbed. Metformin is the therapy of choice for over-weight and obese patients with type 2 diabetes. It is also equally effective in normal weight patients. It can be used in combination with any other class of oral antidiabetic agent or insulin. It is contraindicated in patients with renal impairment or with liver disease. The effect of metformin is dependent upon presence of beta-cell function, but is independent of bodyweight, age and duration of diabetes. 14

32 Bodyweight tends to reduce or stabilize during metformin therapy. Small improvements in blood lipid profile may be observed in hyperlipidemic patients consuming metformin. In the UKPDS study, overweight patients who started with metformin showed significant risk reduction in myocardial infarction. 50 The most common adverse effects of metformin are abdominal discomfort and gastrointestinal adverse effects. The most serious but rarely occurring adverse effect is lactic acidosis. Occurrence of lactic acidosis is rare, but is but life-threatening. It occurs mainly in patients with renal impairment. 47,48,49 Thiazolidinediones (TZD) Troglitazone was the first drug of this class introduced in the US in 1997, but was withdrawn in 2000 because of cases of idiosyncratic hepatotoxicity. 51 Two other thiazolidinediones, rosiglitazone and pioglitazone not known to show hepatotoxicity were introduced in the US in Thiazolidinediones improve insulin sensitivity via multiple actions on gene regulation. The effects are due to stimulation of a nuclear receptor PPARγ. This receptor is at highest level in adipose tissue and less in muscle and liver. Many of the genes activated by TZDs are involved in lipid and carbohydrate metabolism. Effects seen in adipose tissue are increased glucose and fatty acid uptake, and increased lipogenesis. In the muscle there is increase in glucose uptake, increased glycolysis, and glucose oxidation. In liver, there is decreased gluconeogenesis, glycongenolysis and increased lipogenesis. TZDs can be used with other antidiabetic drugs as well as insulin. Substituting a TZD with sulfonylurea or metformin is of limited value; rather its combination with either of the drug is preferred. The TZDs can cause fluid retention and decrease in hemoglobin concentration thus causing edema or anemia. The main cotraindications include active liver disease and congestive heart failure or 15

33 heart failure. Rosiglitazone can cause small rise in total cholesterol concentration which stabilizes in about 3 months. Pioglitazone appears to have little effect on total cholesterol, but has been shown to reduce triglyceride concentrations. Both TZDs reduce portion of smaller more atherogenic low density lipid (LDL) cholesterol. Clinical implications of anti-atherogenic actions or risk factors of cardiovascular disease are important. These effects are being studied in clinical trials with cardiovascular endpoints. 53,47,48, Racial disparities: Healthy People 2010 Racial disparities are one of the most important issues that healthcare policy makers are addressing in recent years. The government has set objectives and goals to eliminate racial disparities. One of the strongest efforts put forth by the government is Healthy People Healthy People 2010 is a comprehensive set of disease prevention and health promotion objectives for the nation to achieve over the first decade of the new century. Created by scientists both inside and outside of Government, it identifies a wide range of public health priorities and specific, measurable objectives, designed to measure progress over time. The first goal of Healthy People 2010 is to help individuals of all ages increase life expectancy and improve their quality of life while the second goal of healthy people 2010 is to eliminate health disparities. According to Healthy People 2010, health disparities are differences that occur by gender, race or ethnicity, education or income, disability, geographic location, or sexual orientation. It has numerous focus areas and diabetes markedly is one of the important areas due to racial health disparities associated with the disease. 54 The varying demographic patterns in the US are expected to increase the number of people who are at risk for diabetes. This increase in the number of cases of diabetes has occurred particularly within certain racial and ethnic groups

34 Gaps exist among racial and ethnic groups in the rate of diabetes and its associated complications in the United States. 55, 56 Certain racial and ethnic communities, including African Americans, Hispanics, American Indians, and certain Pacific Islander and Asian American populations as well as economically disadvantaged or older people, suffer disproportionately compared to white populations. For example, the relative number of persons with diabetes in African American, Hispanic, and American Indian communities is one to five times greater than in white communities. Deaths from diabetes are 2 times higher in the African American population than they are in the white population, and diabetes-associated renal failure is 2.5 times higher in the African American population than it is in the Hispanic population. 57,58 Particularly within certain racial and ethnic groups, there are four potential individual reasons for the greater burden of diabetes: Greater number of cases of diabetes. Due to more common prevalence of diabetes, more amputations, death, and other complications from diabetes would be expected among certain ethnic groups. 59 Greater seriousness of diabetes. A greater diabetes-related disease burden will occur if hyperglycemia or other serious comorbid conditions are present in certain racial and ethnic groups. Many other factors could be involved, including genetics and excess weight. 59 Inadequate access to proper diabetes prevention and control programs. If wellestablished diabetes services, such as self-management training programs or eye-retina examinations, are not a part of routine diabetes care, then effective programs to reduce the burden of diabetes will not be accessed and used. These essential diabetes services often are provided by specialists. Unfortunately, many diabetes at-risk groups reside in 17

35 medically underserved areas or are without adequate insurance and thus do not have access to these types of preventive services. 59 Improper quality of care. If the quality of care in diabetes management services is inadequate, prevention programs would not be effective in reducing the burden of diabetes. 59 Understanding racial disparities in medication adherence, and healthcare utilization is important to understand the gaps between the quality of care received by particular race. Identifying the areas for disparities in diabetes health outcomes is important in tailoring the interventions in areas where disparities exist. It is important to eliminate these disparities due to disproportionate occurrence of diabetes and complications among minority groups. 2.4 Racial disparities in diabetes Racial disparities exist in diabetes control, as well as complications associated with it. African Americans are more likely to have poorly controlled diabetes. Glycemic control is poorer for non-hispanic blacks, and Mexican Americans as compared to non- Hispanic whites. 60 Both African American and Hispanics are significantly more likely to have borderline or poorly controlled hypertension than non-hispanic whites.61 Adams et al found increased Hba1c levels among African-Americans as compared to whites in HMO setting after adjusting for baseline Hba1c, Body Mass Index (BMI), and age, as well as annual measures of type of diabetes medications, diabetes-related hospitalization, time and the number of Hba1c tests, physician visits, and non-diabetes medication. It was seen that among male patients with previously diagnosis of diabetes, African Americans 18

36 had average Hba1c levels that were 0.11 units higher than those for white men. Among women with previously diagnosed diabetes, African Americans had a 0.30 units higher adjusted average Hba1c than whites. Among newly diagnosed men, African American race was associated with a significant 0.49 units greater average Hba1c after covariate adjustment. Among women with newly diagnosed diabetes, although the direction of the effect remained positive, there were no significant differences in Hba1c by race. 62 African Americans and Hispanics also have more diabetes associated neuropathy 63, retinopathy 64, and diabetes-related amputations than non-hispanic whites 65. A study by Konen et al showed that African-Americans have poor blood pressure as well as glycemic control as compared to Whites. African-American females were significantly more likely to experience constipation and hypertension, but less likely to develop peripheral vascular disease. Among male subjects, African-American males are more likely to experience blurred vision and hypertension but less likely to have peripheral atherosclerotic disease. 66 Microvascular complications of the eyes, nerves, kidneys, and lower extremity amputations are more common in African-Americans, Hispanic Americans as compared to non-hispanic Caucasian patients. 67, 68, 69, 70, 71 The reasons for the disparities in complications are not clear. Some of the explanations have included, greater burden of disease among minorities, increased disease severity, lower knowledge, genetic predisposition, inadequate access to diabetes prevention programs, and difference in access and quality of diabetes care. 72 One study which was conducted using the 2000 Behavioral Risk Factor Surveillance System data examined the association between type of health insurance coverage and quality of care provided to individuals with diabetes in the United States. This study demonstrated that 19

37 uninsured diabetic patients were more likely to be African American or Hispanic and those reporting low income. The uninsured were the ones who were less likely to report annual dilated eye exams, foot examinations, or Hba1c tests and less likely to perform glucose monitoring as compared to those with private health insurance. 73 Limited healthcare access causes impaired glycemic control in African Americans with low socioeconomic status. Patients who had difficulty obtaining care had higher Hba1c levels as compared to those who used acute care facilities. Patients who had no usual source of care had significantly higher Hba1c levels as compared to those who sought care at doctor s clinics. 74 Racial differences exist in health insurance coverage for adults with diabetes, although these differences also exist in adults without diabetes. Harris et al analyzed a representative sample of diabetics from the Third National Health and Nutrition Examination Survey (NHANES) and found that among those aged years old, higher proportion of non-hispanic whites and non-hispanic blacks than Mexican- Americans had insurance coverage. Among private insurers, non-hispanic whites (81%) had highest rate of coverage, followed by non-hispanic blacks having an intermediate rate (56%) and Mexican-Americans (45%) having the lowest rate of coverage. 75 Even though the level of care is important in determining patient centered outcomes in diabetes patients, the specialty of provider delivering care such as physicians specialty (endocrinologist/primary care physician), may not have much impact on quality of care. 76 Another study by Harris et al, that used nationally representative sample (NHANES), it found that health care access and utilization rates were high for diabetes patients, however health status and outcomes are unsatisfactory

38 Disparities existing in health care use may be because of literacy levels, knowledge about managing chronic conditions (such as monitoring symptoms and adhering to treatment recommendations), expectations of and trust in health care system. Problems in accessing health care services may be due to the socioeconomic barriers. African Americans may have certain barriers in obtaining care, which include socioeconomic and familial barriers which may reduce their quality of life. The socioeconomic barriers could include money problems, housing problems, family problems, and problems associated with caretaker role and responsibilities. 78 Minority populations also may not access health care services because of inability to pay for those services. Elderly African American beneficiaries are more than twice as likely as white beneficiaries to not fill prescriptions because they cannot afford them. 79 A study which compared prescription use between dually eligible Medicare beneficiaries found that after controlling for presence of chronic conditions, African American beneficiaries had significantly fewer prescriptions filled and lower pharmacy costs in 8 of the 10 states included in the study. 80 One explanation for medication under use among minority population is that they face problems in paying for necessary medications. Patients therefore use different strategies to cope with prescription costs. These strategies could include cutting back on necessities, increasing debts or restricting medication use. A study by Heisler et al investigated patient characteristics associated with patients strategies in coping with high medication costs. It found that nonwhite respondents were more than twice as likely as white respondents to report cutting necessities and increasing debts after adjusting for confounders. 81 Such barriers will exist among insured populations such as Medicaid which provides prescription benefits. 21

39 2.5 Factors associated with medication use and medication adherence in diabetes patients Diabetes is a chronic disease, and requires filling medications on a continual basis. Adherence to treatment regimen is therefore important for beneficial effect of therapy. Due to some reasons; financial, clinical or personal, diabetes patients cannot adhere to the treatment regimen. Many older Americans having drug overage often have to pay copayments of $10 to $30 per prescription. 82 Most of the outpatient prescription costs are paid by insurers but are subject to copayments by patients. This is also true for Medicaid beneficiaries for whom the outpatient costs are paid by the states but the demand for drugs is restricted through copayments (usually $1 3 per refill) or limits on the number of concurrent prescriptions. 83 Many patients with diabetes have comorbid conditions such as hypertension, hyperlipidemia and depression, the treatment of which requires continuous prescription drug use. As a result diabetes patients usually have higher than average monthly out-of-pocket expenses 84, 85, 86 and high out-of-pocket expenses can be a barrier to adherence to prescription drug regimen. 27 Many chronically ill adults cut back on medications due to high prescription cost. Inadequate prescription coverage and out of pocket expenses are one of the strong predictors of their medication adherence problems. 87 It has also been reported that patients use strategies such as cutting back on necessities, underusing medications or increase debt to cope with the high prescription costs. The strategies to manage cost pressure vary across different socioeconomic groups, but the use of all strategies is common among those with low income, poor health, and taking multiple medications. 81 Around 8-22% of the older adults use lesser medication 22