Diabetes is an illness that affects an estimated. Outcomes and Medication Use in a Longitudinal Cohort of Type 2 Diabetes Patients, 2006 to 2012

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1 Original Research Outcomes and Medication Use in a Longitudinal Cohort of Type 2 Diabetes Patients, 2006 to 2012 Julienne K. Kirk, PharmD, Stephen W. Davis, MA, Kathryn Lawrence, MD, Carol A. Hildebrandt, BA, and Richard W. Lord Jr, MD, MA Abstract Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice. Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and A total of 891 patients were identified who made followup visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes. Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m 2 to 34.1 kg/m 2 ), while mean LDL cholesterol significantly decreased from 109 mg/dl in 2006 to 98.8 mg/dl in The number of patients achieving a goal LDL < 100 mg/dl increased from 43.5 % in 2006 to 58.6% in The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients. Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin. Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3 5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dl, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9]. In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin From the Wake Forest School of Medicine, Winston-Salem, NC. Vol. 21, No. 1 January 2014 JCOM 9

2 Diabetes Table 1. Baseline Characteristics of Type 2 Diabetes Cohort (n = 891) Characteristic Value Mean age, yr Male, n (%) 373 (41.9) Race/ethnicity, n (%) White 441 (49.5) African American 429 (48.1) Other 21 (2.4) Smoker, n (%) 146 (16.4) BMI, n (%) Normal or underweight 100 (11.3) Overweight 207 (23.2) Obese 400 (44.9) Extreme 184 (20.6) Insurance, n (%) None 4 (0.4) Medicare 289 (32.4) Medicaid 62 (7) Medicare & Medicaid 105 (11.8) Private 431 (48.4) is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decisionmaking [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time. Methods Setting Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice. Data Collection A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years. The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year. The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine. Statistical Analysis Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL including patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and Results The longitudinal cohort population consisted of 891 patients, 49.5% white and 48.1% African American, with a mean age of 57.9 years (Table 1). The cohort represented 63.7% (891/1398) of the baseline population of patients with diabetes in Over half of the patients were female and the majority of the sample was overweight or obese. At baseline, almost the entire cohort had some type of insurance including private, Medicare, Medicaid, or a combination. The number of visits per patient was 5.9 in 2006 and 5.3 in A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dl in 2006 to 98.8 ± 40.4 mg/dl in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from ± 14.2 to ± 16.1 mm Hg with diastolic BP remaining constant. 10 JCOM January 2014 Vol. 21, No. 1

3 Original Research Table 2. Diabetes Outcomes, 2006 vs Outcome Year Mean ± SD Median Achieved Goal, %* A1C, % n = ± (< 7%), 58.2 (< 7.5%), 68.4 (< 8%) ± (< 7%), 53.4 (< 7.5%), 64.8 (< 8%) LDL, mg/dl n = ± ± Systolic BP, mm Hg n = ± ± Diastolic BP, mm Hg n = ± ± BMI, kg/m ± ± BMI = body mass index; BP = blood pressure; LDL = low density lipoprotein. *McNemar test. P < The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dl) increased from 43.5% in 2006 to 58.6% in The most common therapeutic regimen was combination therapy with insulin and oral medications, taken by 37% (n = 277) of the cohort (Table 3). Approximately onethird of the study population was taking oral combination therapy using metformin. There were 149 (16.7%) patients who did not have A1C measurements available in both years. The largest group by medication regimen with controlled A1C (< 7 %) were those taking metformin with a combination drug (ie, sulfonylurea, DPP-4 inhibitor, glitazone, or an injectable GLP-agonist). There were 71 patients on no medication, and 86% were at A1C goal. Table 3 shows number of patients at LDL goal of < 100 mg/dl by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92). Table 3 shows achievement of BP < 130/80 by antihypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninetythree percent of the cohort had data for evaluation in both years. The numbers of medications needed to achieve control for glycemia, hypertension, and LDL are shown in Table 4. The mean number of glucose medications increased from 1.2 to 2.2 between 2006 and For BP and LDL management, the mean number of medications nearly doubled over the 6-year period. The highest number of medications was needed to reach BP goals, with 2.7 medications needed for systolic BP and 3.3 medications necessary for diastolic control. Results were similar for number of required medications for patients achieving a goal A1C of < 7% or a relaxed goal of < 8% in this cohort. Discussion Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular Vol. 21, No. 1 January 2014 JCOM 11

4 Diabetes Table 3. Patients at Goal by Medication Regimen Controlled n Not Controlled n A1C (n = 742) No medications Metformin Metformin combination* Insulin only Insulin + metformin 7 27 Insulin + metformin combination* LDL (n = 588) No medications Statin only Statin + other lipid-lowering drug BP (n = 891) No medications ACEI or ARB only ACEI or ARB + diuretic (no CCB) ACEI or ARB + CCB (no diuretic) ACEI or ARB + diuretic + CCB Diuretic or CCB (no ACEI or ARB) ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker. *Metformin with sulfonlyurea, dipepetidyl peptidase 4-inhibitor, glitazone, or GLP-agonist. Niacin, fibrates, colesevelam, fish oil, ezetibime. complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dl [8]. Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004 [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications. Table 4. Mean Number of Medications Taken for Disease Control Hypoglycemics if A1C < 7% Hypoglycemics if A1C < 8% Lipid lowering if LDL < 100 mg/dl Antihypertensives if SBP < 130 mm Hg Antihypertensives if DBP < 80 mm Hg Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively. For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes. The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) 12 JCOM January 2014 Vol. 21, No. 1

5 Original Research group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer. In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers. These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19]. The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug. Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review. Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC , jkirk@wakehealth.edu. Financial disclosures: None. Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH. References 1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290: McWilliams JM, Meara E, Zaslavsky AM, Ayanian JZ. Differences in control of cardiovascular disease and diabetes by race, ethnicity, and education: U.S. trends from 1999 to 2006 and effects of Medicare coverage. Ann Intern Med 2009;150: Vouri SM, Shaw RF, Waterbury NV, et al. Prevalence of achievement of A1c, blood pressure, and cholesterol (ABC) goal in veterans with diabetes. Manag Care Pharm 2011;17: Kirk JK, Bell RA, Bertoni AG, et al. Ethnic disparities: control of glycemia, blood pressure, and LDL cholesterol among US adults with type 2 diabetes. Ann Pharmacother 2005;39: American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2006;29(Suppl 1):S4 S American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2012;35(Suppl 1):S11 S Casagrande SS, Fradkin JE, Saydah SH, et al. 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6 Diabetes control improving in US adults? Diabetes Care 2008;31: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35: Kirk JK, Strachan E, Martin CL, et al. Patient characteristics and process of care measures as predictors of glycemic control. J Clin Outcomes Manag 2010;17: Chopra I, Kamal KM, Candrilli SD. Variations in blood pressure and lipid goal attainment in primary care. Curr Med Res Opin 2013;29: Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359: Grossman E. Blood pressure: the lower, the better. The con side. Diabetes Care 2011;34:S Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362: Appiah B, Hong Y, Ory MG, et al. Challenges and opportunities for implementing diabetes self-management guidelines. J Am Board Fam Med 2013;26: Best JD, Drury PL, Davis TME, et al. Glycemic control over 4 years in 4,900 people with type 2 diabetes. Diabetes Care 2012;35: Copyright 2014 by Turner White Communications Inc., Wayne, PA. All rights reserved. 14 JCOM January 2014 Vol. 21, No. 1