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1 Hemoglobin A 1c Outcomes and Health Care Resource Use In Type 2 Diabetes Mellitus Patients Treated With Combination Oral Antidiabetic Drugs Through Step Therapy And Loose-Dose and Fixed-Dose Combinations Setareh A. Williams, PhD, director, economics and outcomes research, AstraZeneca LP; Erin K. Buysman, MS, associate director, and Erin M. Hulbert, MS, senior research analyst in health economics and outcomes research, OptumInsight; Joette Gdovin Bergeson, PhD, associate director of health economics and outcomes research, Bristol-Myers Squibb Co.; Bin Zhang, MD, associate director of health economics and outcomes research, Bristol Myers-Squibb Co.; John Graham, PharmD, executive director of health services, Bristol Myers-Squibb Co. Importance of the study: This study verifies, as defined by current guidelines, that initial treatment with fixed dose combinations (FDC) is associated with a better likelihood of HbA 1c goal attainment and lower health care resource use and costs. Abstract Purpose: To compare outcomes of type 2 diabetes mellitus (T2DM) patients initiating therapy with FDC those with loose-dose combination (LDC) or step therapy (ST) in a managed care population. Design: A retrospective claims database analysis. Methodology: Treatment-naïve T2DM patients who were continuously enrolled in a health plan during were studied. Eligible patients were assigned to FDC, LDC, or ST cohorts. Glycated hemoglobin goal attainment (HbA 1c <7%) was assessed using the American Diabetes Association (ADA) treatment guidelines. Health care resources use and costs, including inpatient, emergency room (ER), and ambulatory visits, were measured during the 12 months after therapy initiation. All-cause and diabetes-related use and costs were assessed. Principal findings: 21,048 patients met study criteria (FDC n=8,416, ST Disclosure The authors report that they have no financial, commercial, or industrial relationships to disclose regarding this article. Funding was provided by AstraZeneca and Bristol-Myers Squibb. n=8,407, LDC n=4,225), and 1,926 of these patients had HbA 1c results. FDC patients had lower rates of postindex all-cause inpatient stays and ER visits compared with the other cohorts. FDC patients had lower average counts of diabetes-related ambulatory visits (2.7) compared with ST (3.7; p<0.001) and LDC (3.2; p<0.001) and significantly lower average postindex all-cause and diabetes-related costs compared with the other cohorts, with average all-cause costs for Author correspondence Setareh A. Williams, PhD Director, health economics and outcomes research AstraZeneca LP 1800 Concord Pike Wilmington, DE Telephone: Fax: setareh.williams@astrazeneca.com Erin K. Buysman, MS Associate director, health economics and outcomes research OptumInsight Technology Drive Eden Prairie, MN Telephone: Fax: erin.buysman@innovus.com Erin M. Hulbert, MS Senior research analyst, health economics and outcomes research OptumInsight Technology Drive Eden Prairie, MN Telephone: Fax: erin.hulbert@innovus.com FDC, ST, and LDC of $8,445, $10,515, and $9,688, respectively, and diabetes-related costs of $1,641, $2,099, and $1,900, respectively. FDC patients had higher rates of achieving HbA 1c goal (61%) compared to ST (48%; p<0.001) or LDC (52%; p=0.015). Differences in outcomes remained following multivariate analyses. Conclusion: Treatment with FDC was associated with lower health care resources use and costs and better likelihood of HbA 1c goal attainment. Joette Gdovin Bergeson, PhD Associate director, health economics and outcomes research Bristol-Myers Squibb Co. Tampa, FL Telephone: or joette.gdovin@bms.com Bin Zhang, MD Associate director, health economics and outcomes research Bristol Myers-Squibb 777 Scudders Mill Road Plainsboro, NJ Telephone: Fax: bin.zhang2@bms.com John Graham, PharmD Executive director, health services Bristol Myers-Squibb 777 Scudders Mill Road Plainsboro, NJ Telephone: Fax: john.graham@bms.com 40 MANAGED CARE / JULY 2012

2 Introduction As of 2010, approximately 23 million people in the United States are diagnosed with T2DM (ADA 2010). In the United States, 12.0 million men and 11.5 million women aged 20 years or older have diabetes. According to the American Diabetes Association (ADA), 1.6 million new cases of diabetes are diagnosed annually. Diabetes was the seventh leading cause of death in the United States in 2006 (ADA 2010). The estimated total cost of diabetes in the United States was $174 billion in 2007, making diabetes a tremendous burden on the nation s health care system (ADA 2010). The goal of diabetes treatment is to maintain blood glucose at normal levels to reduce the risk of complications (UKPDS 1998). The majority of patients presenting with T2DM are overweight or obese at the time of diagnosis and are unable to achieve or sustain normal glycemic levels without pharmacological treatment. Treatment options for T2DM include lifestyle modifications, weight loss, insulin therapy, glucagon-like peptide-1 analogs, and oral antidiabetic agents (OADs). Classes of OADs include sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 (DPP-IV) inhibitors. In 2009 and 2011, the ADA published updated guidelines for the Standard of Medical Care in Diabetes, recommending initial treatment with metformin and lifestyle interventions. If metformin alone does not reduce HbA 1c levels to less than 7%, another glucose-lowering agent, which may include insulin, may be added. The majority of individuals require combination therapy to effectively control their diabetes (ADA 2009/2011). Because monotherapy is unlikely to be successful in patients with HbA 1c levels of %, the American Association of Clinical Endocrinologist/American College of Endocrinology (AACE/ACE) states that patients with higher baseline HbA 1c levels should be initiated on dual therapy to reach an HbA 1C target level of 6.5% (ADA 2010). Real-world evidence evaluating the outcomes associated with earlier initiation of dual therapy in T2DM is limited. Previous studies have focused on the impact of FDC and LDC on adherence. Previous studies have shown improved adherence in patients treated with FDC therapy patients treated with loose dose combination of the same agents, regardless of whether patients initiated with FDC or switched to FDC from LDC of the same treatments. In one study, 7,570 FDC users had 1.8% higher medication possession ratios (MPR) in the post-index period compared with 14,762 patients on LDC (Cheong 2008). In another study, within a managed care organization, previously treated patients receiving monotherapy with an oral antidiabetic medication who required additional therapy exhibited significantly greater adherence when they were switched to FDC therapy compared with LDC therapy. Patients receiving LDC therapy who were switched to FDC therapy exhibited significantly greater adherence after the switch (Melikiun 2002). The impact of earlier initiation of dual combination therapy in T2DM and the benefits of FDC on health outcomes independent of adherence are not known. The purpose of this study was to compare health outcomes among patients who initiated with FDC LDC and ST in a population naïve to diabetes treatment. Methods Study design This was a retrospective database analysis of health care claims data of patients enrolled in a large, geographically diverse, managed health care plan in the United States. The claims database contained eligibility information, pharmacy claims, and medical claims for approximately 18 million patients enrolled in the plan during the study period. Personal identifiers were removed before data analyses, and data were accessed in a manner that was compliant with the HIPAA Privacy Rule of Institutional Review Board approval was not needed. Data sources Medical claims, pharmacy claims, and laboratory test results were identified for commercially insured health plan members with prescription fills for oral antidiabetic (OAD) agents between Jan. 1, 2007 through Oct. 31, The date of the first qualifying OAD prescription fill was defined as the index date. The 6-month period prior to the index date were the pre-index period and the 12-month period following the index date was the post-index period. Subject identification Inclusion criteria included: age 18 as of the index year; 2 filled prescriptions for an OAD during the post-index period (including the index fill); no filled prescriptions for OADs during the pre-index period; no filled prescriptions for non-oad medications (GLP-1 analogs, pramlintide, or insulin) during the preindex period or on the index date; evidence of medical claims for T2DM (ICD-9-CM diagnosis codes 250.x0 or 250.x2) during the pre-index or post-index periods; and continuous enrollment in a commercial health plan with pharmacy and medical benefits during the pre-index and post-index periods. Additional inclusion criteria for the analysis of HbA 1c outcomes included: 1 HbA 1c laboratory value during (index date: 182 days) through index date; and 1 HbA 1c laboratory value during (index JULY 2012 / MANAGED CARE 41

3 date + 91 days) through (index date days). Patients were assigned to study cohorts based on the OADs filled during the post-index period. Patients with fills for triple therapy (either FDC + third agent or 3 agents in loose-dose form) or with fills for GLP-1 or insulin on the index date were excluded, as were patients with evidence of gestational diabetes (ICD-9-CM diagnosis codes 648.8x or HCPCS S9214) during the pre-index or postindex periods. Cohorts The FDC cohort included patients with 2 or more prescription fills for an FDC therapy. Examples of FDC therapy include Metaglip (metformin plus glipizide) or Actoplus MET (metformin plus pioglitizide), which are available in one pill. The ST cohort included patients with prescription fills for one of the (non-fdc) medications on the index date who augmented therapy with a second OAD or GLP-1 analog and had at least two distinct 15-day overlaps of the 2 medications included in the ST regimen. GLP-1 was the only injectable allowed for ST inclusion. The LDC cohort (LDC) included patients with fills for 2 non-fdc OAD classes on the index date who had at least two distinct 15-day overlaps in the 2 medications included in the LDC therapy regimen. Examples of ST or LDC therapy include metformin with Amaryl (glimipiride) or metformin with Onglyza (saxagliptin), which are taken as 2 separate pills. It should be noted that medications that are available in fixeddose form may also be taken as LDC or ST therapy if the 2 medications are taken as 2 separate pills, whereas FDC therapy is available for limited number of combinations. Patients with evidence of monotherapy throughout the post-index period and FDC patients with evidence of previous OAD prescription fills were initially identified and considered for the analyses. The monotherapy group was excluded from the final study sample because they had better HbA 1c control at index, appeared to be less progressed in their diabetes, and were more likely to reach goal during follow-up. Non-naïve FDC patients were excluded from the study because the use of OADs in the baseline period resulted in better HbA 1c control at index. Therefore, the nonnaïve patients were not comparable to patients in other treatment-naïve cohorts. Study measures Outcomes The HbA 1c outcomes were evaluated only for the subset of patients with HbA 1c values available in the laboratory data. HbA 1c outcomes were measured from index date + 91 days through the end of the 12-month follow-up period (index date days). For the subset of patients whose HbA 1c levels were above 7% at index, an indicator variable was created to identify whether the patient achieved HbA 1c goal at any time during the follow-up period (from index date + 91 days through index date days). For patients with multiple HbA 1c laboratory values in the post-index period, any laboratory value that met the defined goal was sufficient to qualify as goal attainment. The 2011 ADA Clinical Practice Recommendations (ADA 2010) set a goal of 7%. The time from the index date to HbA 1c goal attainment was measured. For patients who did not attain goal, this variable was set to 365 days. All health care resources usage and cost outcomes were measured in the overall sample in the post-index period, inclusive of the index date. All-cause and diabetes-related health care resource usage included ambulatory visits (office and outpatient), ER visits, and inpatient admissions. The number of ambulatory visits was also calculated for each patient. Usage was defined as attributable to diabetes if the claim had a primary diagnosis code for T2DM (ICD-9-CM 250.x0 or 250.x2). All-cause and diabetes-related health care costs were computed as the combined health plan and patient paid amounts in the post-index period. Costs were calculated as total, medical, and pharmacy costs. Costs were adjusted using the annual medical care component of the consumer price index (CPI) to reflect inflation between 2006 and 2009 (CPI 2009). Costs were defined as attributable to diabetes if the claim had a primary diagnosis code of T2DM or was a pharmacy claim for OADs, GLP-1 analogs, pramlintide, or insulin. Demographic characteristics Age was defined as of the index year, and gender was determined based on information from enrollment files. Patients were assigned to either the or 65 age group. The geographic region in which the study subject was enrolled in a health plan was identified as Northeast, Midwest, South, or West. Clinical characteristics The index diabetes treatment regimen was identified as sulfonylureas (SU), metformin (MET), thiazolidinediones (TZD), DPP-IV inhibitors (DPP-IV), α-glucosidase inhibitors (AGI), meglitinide derivatives, and/or GLP-1 (GLP-1 for ST only). For patients in the FDC and LDC cohorts, both OADs filled as part of the fixed- or loose-dose combination on the index date were identified; for patients in the ST cohort, both agents filled as part of the ST regimen were identified. The Charlson-Quan comorbidity score was calculated for each patient based on the presence of diagnosis codes on medical claims in the pre-index period (Quan 2005). 42 MANAGED CARE / JULY 2012

4 General comorbid conditions were defined using the Clinical Classification software managed by the Agency for Healthcare Research and Quality (2009). This measure generates indicator variables for specific disease conditions based on ICD-9-CM diagnoses. Comorbidities of interest as confounders included hypertension, disorders of the lipid metabolism, cancers and neoplasms, and conditions affecting mental health status. A count of non-diabetesrelated medications filled in the preindex period was calculated. Flags for in-patient stays and ER visits and a count of ambulatory visits, both all-cause, and diabetes related, were calculated in the pre-index period. CPI-adjusted, pre-index, all-cause and diabetes-related health care costs were computed as the combined health plan and patient paid amounts in the pre-index period. An MPR was calculated based on the MPR for each OAD filled during the post-index period, weighted by the length of time that the patient was supposed to be taking the medication. In addition, pre-index HbA 1c values during (index date: 182) days through the index date were determined in the subset of patients with available HbA 1c results. Analysis Data extraction and statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, N.C.) and Stata version 10.0 (Stata- Corp, College Station, Texas). All patient characteristics and study outcomes were compared descriptively between the FDC cohort and the ST and LDC cohorts using t-tests or chisquared tests. Outcomes analyzed using multivariate methods included: HbA 1c goal attainment, post-index all-cause inpatient/er visits, post- index count of diabetes-related ambulatory visits, post-index all-cause total costs, and post-index diabetes-related total costs. HbA 1c goal attainment Figure 1. Sample selection and attrition Total number of commercial enrollees (n = 17,762,402) Patients identified with 1 claim for an OAD (n = 580,681) Treatment naïve FDC, step, or LDC cohorts (n = 78,359) Met continuous enrollment criteria (n = 23,024) Patients for analysis of cost and utilization outcomes (n = 21,048) FDC = 8,416 step = 8,407 LDC = 4,225 Did not meet T2DM and gestational diabetes criteria (n = 1,976) Available pre- and post-index HbA 1C results (n = 1,926) and occurrence of all-cause post-index inpatient or ER visit were modeled using logistic regression models; counts of diabetes-related ambulatory visits were modeled using a negative binomial regression with a log link; and cost measures were modeled using generalized linear models with a gamma distribution and a log link, which avoids potential difficulties introduced by transformation and retransformation of the dependent variable (Manning 1998). For ease of interpretation, the average predicted number of diabetesrelated ambulatory visits and allcause and diabetes-related costs were calculated for each cohort. In addition to cohort, each model included age, gender, health plan geographic region, pre-index Charlson-Quan comorbidity score, flags for hypertension, disorders of lipid metabolism, cancers and neoplasms, conditions affecting mental health status, preindex count of medications, preindex total all-cause costs (in 1,000s of dollars), pre-index inpatient stays, pre-index ER visits, pre-index count of diabetes-related ambulatory visits, and weighted MPR. In addition, the pre-index HbA 1c value was included in the model of HbA 1c goal attainment, but was not included in the other models for which laboratory data were not available for all patients. Results Sample identification Figure 1 outlines the sample selection process. Nearly 17.8 million patients were enrolled in this commercial health plan between Jan. 1, 2007 and Oct. 31, Of these, 580,681 patients had evidence of OAD use, and nearly all of these patients were 18 or older; 78,359 patients met criteria to be included in the FDC, ST, or LDC cohorts JULY 2012 / MANAGED CARE 43

5 23,024 of these patients (29%) met the continuous enrollment criteria and another 1,976 patients were excluded because they did not meet T2DM criteria or they had gestational diabetes. This resulted in a final sample of 21,048 patients for the analysis of cost and health care usage outcomes (8,416 [40%] FDC, 8,407 [40%] ST, and 4,225 [20%] LDC). Of these, preand post-index HbA 1c results were available for 1,926 patients. Patients with evidence of OAD monotherapy (44,940) and patients not naïve to OADs who switched to FDC therapy (10,690) were also considered for the study, but it was determined, through the course of the analysis, that these patients were not comparable to the other groups because they had lower baseline HbA 1c values and were thought to have less severe diabetes compared with patients in the other cohorts. Therefore, our analysis focused on the remaining 3 cohorts. Table 1 presents the demographics of the final study sample. FDC patients were significantly younger (mean age: 53.3 years) than LDC or ST patients (ST: 55.8; LDC: 55.0; p<0.001 in all cohorts). FDC patients had a higher proportion of males (59%) compared with ST (54%; p<0.001), but a similar proportion compared to LDC patients (58%; p=0.498). The health plan region distribution was significantly different among the cohorts, although a majority of patients in all cohorts were from the South. FDC (1.13) and LDC patients (1.15) had similar average Charlson-Quan comorbidity scores (p=0.451), whereas ST (1.21) patients had a significantly higher score (p<0.001). Table 1 presents the clinical characteristics of the final study sample. Metformin was the most commonly prescribed OAD in the index regimen for all cohorts but was more common in FDC (95%) patients, compared with ST (86%) and LDC (87%) patients. This is probably due to the fact that metformin is included as part of nearly all available FDC products, whereas LDC and ST can combine any two agents, regardless of their availability in FDC form. Sulfonylureas were prescribed more frequently as part of ST or LDC therapy compared with FDC, whereas TZDs and DPP-IVs were more often prescribed as part of an FDC regimen. AGIs and meglitinide derivatives were not available in an FDC and were rarely prescribed in the other cohorts. GLP-1 analogs were only considered as part of ST and were filled by 7% of patients. FDC patients filled, on average, 3.4 non-diabetes medications during the pre-index period, while ST patients filled 3.2 Table 1. Patient demographics and clinical characteristics 1. FDC treatment (N=8,416) 2. Step therapy (N=8,407) 3. LDC (N=4,225) Cohort 2 Cohort 3 Mean age (SD) (10.86) (11.72) (11.39) <0.001 <0.001 Male gender N (%) 4,971 (59) 4,559 (54) 2,469 (58) < Geographic region N (%) Northeast 526 (6) 467 (6) 202 (5) <0.001 Midwest 1,137 (14) 1,515 (18) 709 (17) <0.001 <0.001 South 6,201 (74) 5,630 (67) 2,901 (69) <0.001 <0.001 West 552 (7) 795 (9) 413 (10) <0.001 <0.001 Mean Charlson-Quan Comorbidity Score (SD) 1.13 (1.03) 1.21 (1.20) 1.15 (1.13) < Index treatment regimen n (%) Metformin 7,967 (95) 7,202 (86) 3,656 (87) <0.001 <0.001 Sulfonylurea 3,660 (43) 5,308 (63) 3,114 (74) <0.001 <0.001 Thiazolidinediones 3,607 (43) 2,257 (27) 1,263 (30) <0.001 <0.001 DPP-IV inhibitors 1,598 (19) 1,195 (14) 320 (8) <0.001 <0.001 α-glucosidase inhibitors 0 (0) 39 (0) 15 (0) <0.001 <0.001 Meglitinide derivatives 0 (0) 207 (2) 82 (2) <0.001 <0.001 GLP-1 0 (0) 606 (7) 0 (0) <0.001 Mean count of pre-index 3.41 (3.65) 3.22 (3.91) 2.28 (3.11) <0.001 non-diabetes medications (SD) Mean count of pre-index non-diabetes medication dispensing (SD) 6.99 (9.65) 6.71 (10.41) 4.45 (7.91) <0.001 Pre-index medications: Medications, not including antidiabetic medications, filled in the pre-index period; Pre-index medication dispensing: Dispensing for all medications, not including antidiabetic medications, filled in the pre-index period; GLP-1: GLP-1 was the only injectable allowed for step therapy inclusion 44 MANAGED CARE / JULY 2012

6 Table 2. Pre-index health care usage and costs All-cause usage 1. FDC treatment (N=8,416) 2. Step therapy (N=8,407) 3. LDC (N=4,225) Cohort 2 Cohort 3 Inpatient stays n (%) 393 (5) 585 (7) 413 (10) <0.001 <0.001 ER visits n (%) 1,173 (14) 1,338 (16) 716 (17) <0.001 <0.001 Mean ambulatory visit count (SD) 6.05 (7.00) 7.10 (8.12) 5.62 (6.88) <0.001 <0.001 Diabetes-related usage Inpatient stays n (%) 71 (1) 119 (1) 154 (4) <0.001 <0.001 ER visits n (%) 64 (1) 73 (1) 63 (1) <0.001 Mean ambulatory visit count (SD) 1.01 (1.29) 0.92 (1.29) 0.84 (1.17) <0.001 <0.001 All-cause costs Mean total costs (SD) 2,804 (8,131) 3,556 (14,532) 3,633 (12,455) <0.001 <0.001 Mean medical costs (SD) 2,314 (7,881) 3,094 (14,323) 3,321 (12,138) <0.001 <0.001 Mean pharmacy costs (SD) 491 (1,199) 463 (1,207) 312 (1,167) <0.001 Diabetes-related costs Mean total costs (SD) 269 (3,121) 418 (7,919) 794 (7,321) <0.001 Mean medical costs (SD) 269 (3,121) 418 (7,919) 794 (7,321) <0.001 Mean pharmacy costs (SD) 0 (0) 0 (0) 0 (0) Table 3. Post-index usage and costs such medications (p=0.001) and LDC patients filled 2.3 (p<0.001). Table 2 presents the pre-index usage by the final study sample. Patients with FDC regimens had significantly lower rates of all-cause inpatient or ER visits compared with patients in the other cohorts. Diabetes-related inpatient visits were low in general, with approximately 0.8% of FDC patients, 1.4% of ST (p<0.001), and 3.6% of LDC (p<0.001) patients having inpatient stays. In addition, FDC patients had a significantly lower rate of diabetesrelated ER visits compared with LDC patients. The count of pre-index diabetes-related ambulatory visits was significantly different between FDC and the other cohorts, although the actual mean number of visits was similar: FDC (1.0); ST (0.9); and LDC (0.8). Table 2 also presents the pre-index total costs of the final study sample. Preindex all-cause total costs were $2,804, All-cause usage 1. FDC treatment (N=8,416) 2. Step therapy (N=8,407) 3. LDC (N=4,225) Cohort 2 Cohort 3 Inpatient stays n (%) 757 (9) 1,065 (13) 491 (12) <0.001 <0.001 ER visits n (%) 1,839 (22) 2,207 (26) 1,037 (25) <0.001 <0.001 Mean ambulatory visit count (SD) (13.72) (15.45) (14.48) <0.001 <0.001 Diabetes-related usage Inpatient stays n (%) 141 (2) 230 (3) 111 (3) <0.001 <0.001 ER visits n (%) 117 (1) 167 (2) 72 (2) Mean ambulatory visit count (SD) 2.73 (2.93) 3.68 (2.99) 3.16 (3.02) <0.001 <0.001 All-cause costs Mean total costs (SD) 8,445 (18,211) 10,515 (22,096) 9,688 (24,494) < Mean medical costs (SD) 5,708 (17,488) 7,293 (20,894) 6,879 (23,333) < Mean pharmacy costs (SD) 2,737 (2,898) 3,222 (3,525) 2,810 (3,601) < Diabetes-related costs Mean total costs (SD) 1,641 (5,737) 2,099 (8,287) 1,900 (5,288) < Mean medical costs (SD) 663 (5,658) 1,087 (8,218) 936 (5,115) < Mean pharmacy costs (SD) 979(856) 1,013 (1,010) 964 (1,292) JULY 2012 / MANAGED CARE 45

7 Table 4. Pre- and post-index HbA 1c results 1. FDC treatment (N=873) 2. Step therapy (N=712) 3. LDC (N=341) Cohort 2 Cohort 3 Mean pre-index HbA 1c result (SD) 8.74 (2.36) 8.68 (2.24) 8.88 (2.53) Mean post-index HbA 1c result (SD) 7.10 (1.60) 7.32 (1.55) 7.38 (1.70) Mean change in HbA 1c from pre-index to post-index (SD) (2.33) (2.23) (2.66) Pre-index HbA 1c result 7.0%; n (%) 615 (70) 520 (73) 241 (71) Post-index HbA 1c goal attainment (< 7.0%); n (%) 375 (61) 247 (48) 125 (52) < Mean time to post-index HbA 1c goal attainment (SD) (103.40) (95.80) (103.98) < $3,556, and $3,633 for FDC, ST, and LDC patients, respectively (p<0.001 between FDC ST and LDC). Average diabetes-related pre-index costs were similar between FDC and ST patients ($269 $418, p=0.109), but were significantly lower in FDC patients compared with LDC patients ($269 $794, p<0.001). The last pre-index HbA 1c result of the final study sample with HbA 1c results (N=1,926) were similar with average results of 8.74, 8.68, and 8.88 among FDC, ST, and LDC patients, respectively. Outcomes Table 3 presents the post-index usage and cost outcomes of the final study sample. Patients in the FDC cohort had lower rates of all-cause inpatient or ER visits compared with patients in the other cohorts. Diabetes-related inpatient and ER visits were low in general with 1.7%, 2.7%, and 2.6% of FDC, ST, and LDC patients having diabetes-related inpatient visits and 1.4%, 2%, and 1.7% of FDC, ST, and LDC patients having diabetes-related ER visits. ST and LDC patients had a significantly higher rate of diabetes-related inpatient stays, and ST patients had a significantly higher rate and count of diabetes-related ER visits compared with FDC. The mean count [SD] of diabetes-related ambulatory visits was higher for ST (3.7 [2.99]; p<0.001) and LDC (3.2 [3.02]; p<0.001) compared with FDC (2.7, [2.93]). After adjustment for confounders in a logistic regression model, ST and LDC patients had significantly higher odds of post-index all-cause inpatient or ER visits compared with FDC patients: ST, odds ratio(or), 1.37; confidence interval (CI), ; LDC, OR 1.26; CI, Similarly, in a Table 5. Logistic regression model of HbA 1c goal attainment Covariate Odds ratio 95% CI Step therapy FDC therapy 0.44 (0.34,0.57) <0.001 LDC therapy FDC therapy 0.73 (0.53,1.00) Age 1.00 (0.99,1.02) Male gender 1.11 (0.88,1.41) U.S. census region Northeast West 0.50 (0.27,0.94) U.S. census region Midwest West 0.52 (0.28,0.96) U.S. census region South West 0.51 (0.32,0.79) Pre-index Charlson-Quan Comorbidity Score 0.82 (0.72,0.93) Comorbidity hypertension 0.67 (0.52,0.86) Comorbidity disorders of lipid metabolism 0.83 (0.65,1.07) Comorbidity cancers and neoplasms 1.45 (0.99,2.11) Comorbidity conditions affecting mental health status 1.01 (0.70,1.46) Pre-index medication count 1.10 (1.06,1.14) <0.001 Pre-index total cost (in $1000s) 1.05 (1.01,1.09) Pre-index Inpatient stay 0.72 (0.30,1.75) Pre-index ER visit 0.78 (0.54,1.13) Pre-index count of ambulatory visits 0.98 (0.96,1.00) Weighted MPR (medication possession ratio) 6.13 (3.68,10.20) <0.001 Last pre-index HbA 1c value 0.91 (0.86,0.96) MANAGED CARE / JULY 2012

8 negative binomial model of post-index count of diabetes-related ambulatory visits, the adjusted count of visits was significantly lower among FDC patients (2.8) compared with ST (3.6; p<0.001) and LDC patients (3.2; p<0.001). Postindex all-cause total costs were $8,445, $10,515, and $9,688 for FDC, ST, and LDC patients, and costs were significantly lower in FDC patients compared to ST (p<0.001) and LDC (p=0.004). Average diabetes-related post-index costs were significantly higher in ST ($2,099; p<0.001) and LDC ($1,900; p=0.012) patients compared to FDC ($1,641). After controlling for confounders, mean adjusted all-cause post-index costs were significantly lower among FDC patients ($8,745) compared to ST ($10,352; p<0.001) and LDC patients ($10,294; p<0.001). Similarly, mean adjusted diabetes-related costs were lower in FDC patients ($1,713) compared to ST ($2,005; p=0.001) and FDC patients ($1,925; p=0.050). Pre- and post-index HbA 1c outcomes in the final study sample, with HbA 1c results in both the pre-index and post-index periods are shown in Table 4. On average, every cohort had a drop in HbA 1c following the index date, with average changes in HbA 1c of 1.65, 1.36, and 1.51 for FDC, ST, and LDC patients, respectively. The decrease in FDC patients was significantly larger than the HbA 1c decrease observed in ST patients (p=0.013). The rate of goal attainment was significantly higher in FDC patients compared to ST and LDC patients (Table 5). Estimated odds ratios, 95% CI, and s from a logistic regression model of postindex HbA 1c goal attainment also are provided in Table 5. After controlling for confounders, patients in the ST cohort had 56% lower odds of achieving HbA 1c goal (OR: 0.44; CI: ) and patients in the LDC cohort had 27% lower odds (non-significant) of achieving HbA 1c goal (OR: 0.73; CI: ) in the post-index period compared with those in the FDC cohort. Discussion This analysis of treatment-naïve T2DM patients demonstrated that FDC treatment was associated with better likelihood of HbA 1c goal attainment than was LDC or ST. In brief, FDC patients had lower rates of post-index all-cause inpatient stays and ER visits compared with other cohorts and a lower average count of all-cause and diabetes-related ambulatory visits compared with ST and LDC. This cohort also had a lower rate of post-index diabetesrelated inpatient stays compared with the other cohorts. FDC patients also had lower average post-index all-cause and diabetes-related total costs compared with ST and LDC patients. FDC patients also had a larger average drop in HbA 1c and a higher rate of achieving a <7% HbA 1c goal. HbA 1c goal attainment sensitivity analysis was conducted using 6.5% AACE/ACE guidelines, with similar results (Rodbard 2009). Other studies have shown benefits of intensive glucose control using FDC therapy in patients with T2DM (Chalmers 2006, 2007). In this study, a larger difference was observed for FDC therapy ST, which suggests that there are benefits to earlier initiation of dual therapy per AACE/ACE guidance. Many physicians fail to implement the recommended guidelines regarding frequent followup monitoring and dosing titration in the T2DM population (Maclean 2009). Physicians may be slow in advancing therapy, relative to either dosages of medications or switching to a more efficacious therapeutic regimen in a timely manner (Maclean 2009). One of the most important suggestions of the AACE/ACE guidelines is the recommendation to monitor therapy every 2 to 3 months and to augment therapy until the goal for HbA 1c has been achieved (Rodbard 2009). Studies have shown the benefits of glucose monitoring, improving glucose control, and reducing the rate of severe hypoglycemic episodes (Leinung 2010). Dual therapy should begin once a patient naïve to treatment has been identified as having an HbA 1c level in the range of 7.6% to 9% because no single medication is likely to bring about a goal of <6.5% (Rodbard 2009). This approach may be more beneficial because it leads to a greater likelihood of successful outcomes. Study limitations These findings must be considered within the context of the study limitations. There are several inherent limitations in the use of claims data. First, diagnostic codes may be incorrectly coded or included as rule-out criteria rather than actual disease. However, in this study, the strict diagnostic and medication use criteria used make it unlikely that anyone included did not have T2DM. An additional limitation of the administrative claims data source is the requirement of continuous enrollment in the health plan to ensure complete medication and pharmacy claims data are available for all patients included in the study. The follow-up period was restricted to one year to allow for an adequate sample of patients in the final study population. Laboratory results data were available only for a subset of the overall sample, and results may be incomplete in patients who do have laboratory information. The HbA 1c results available were values obtained from laboratory tests done by physicians or lab technicians during patient visits, and results obtained by patients at home or during a visit that was not processed by a laboratory for which data are submitted were not available in the laboratory results data. Therefore, the HbA 1c outcomes analysis may not be a complete representation of HbA 1c outcomes in patients using OADs. Although claims data are an excellent source for understanding real-world treatment, data on medication use beyond the patterns of fills observed in the claims are scarce. JULY 2012 / MANAGED CARE 47

9 There is limited information available on the reasons physicians choose to prescribe one type of medication over another in a given patient, or on reasons for discontinuing or switching medications. Several factors may have driven physicians to prescribe a FDC or an LDC medication in a given patient, such as physician or patient preference, patient history, ease of use, costs (e.g, generic branded products, one copay for FDC two copayments for LDC), side effect profiles, perceived or real efficacy or safety concerns, or other factors. It is unknown how much each of these factors may have affected a physician s propensity to prescribe one type of medication over another. The data used for this study come from a commercial managed care population and, therefore, the generalizability of the results of this study is limited. Results of this analysis are applicable primarily to the patterns of OAD use in T2DM patients in stable managed care settings. The plans used for analysis, however, are discounted fee-for-service, IPA - network plans rather than capitated or gatekeeper models. These plans also include a wide geographic distribution across the United States, providing the capability for generalization to managed care populations on a national level. Despite the standard limitations, however, administrative claims data continue to be powerful data sources. These data allow for examination of health care usage and expenditure patterns in a real-world setting, away from the controlled environment of clinical trials, and offer the advantage of large sample sizes with diverse medical histories. conclusion Patients initiating OAD therapy with FDC agents may have a better likelihood for HbA 1c goal attainment compared with patients initiating OADs with ST or LDC therapy. Patients initiating FDC therapy may also have lower post-index health care usage and costs (all-cause and diabetes-related) compared with patients treated with ST or LDC therapy, which may be driven by a lower number of ambulatory visits and fewer needs for medication adjustments. In this study, a larger HbA 1c improvement was observed for FDC therapy ST, suggesting that there are benefits to earlier initiation of dual therapy per AACE guidance. This finding is also important for health plan decision makers when they develop and implement their preferred drug lists (PDLs), given the potential clinical and economic benefits associated with FDC therapy. In addition, some plans may have priorauthorization rules or other restrictions on the use of FDC therapy that require the failure of monotherapy or LDC therapy before being allowed to begin FDC therapy, although this study found a benefit to starting FDC medication as first-line therapy. 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