Diabetes Ther (2018) 9:1021–1036 https://doi.org/10.1007/s13300-018-0410-8 ORIGINAL RESEARCH Clinical Trajectories, Healthcare Resource Use, and Costs of Diabetic Nephropathy Among Patients with Type 2 Diabetes: A Latent Class Analysis . . . . Ruixuan Jiang Ernest Law Zhou Zhou Hongbo Yang Eric Q. Wu Raafat Seifeldin Received: January 31, 2018 / Published online: March 29, 2018 The Author(s) 2018 diagnosis of T2DM and C 2 urine albumin tests ABSTRACT within the Truven MarketScan database (2004–2014), based on T2DM-related compli- Introduction: Patients with type 2 diabetes cations, comorbidities, and therapies. DN mellitus (T2DM) are clinically heterogeneous in severity categories (normoalbuminuria, moder- terms of disease severity, treatment, and ately increased albuminuria, and severely comorbidities, potentially resulting in differen- increased albuminuria) were determined based tial diabetic nephropathy (DN) progression on urine albumin measure. The risks of DN courses. In this exploratory study we used latent progression and reversal (change to a more/less class analysis (LCA) to identify patient groups severe DN category) were compared among all with distinct clinical proﬁles of T2DM severity identiﬁed latent classes using Kaplan–Meier and explored the association between disease analyses and log-rank tests. All-cause and DN- severity, DN progression or reversal, and related costs and HRU were assessed and com- healthcare resource use (HRU) and costs. pared during the study period among the Methods: Latent class analysis was used to identiﬁed latent classes. group adults with C 2 medical claims with a Results: Four clinically distinct proﬁles were identiﬁed among the 23,235 eligible patients: Enhanced content To view enhanced content for this low comorbidity/low treatment (46.5%), low article go to https://doi.org/10.6084/m9.ﬁgshare. comorbidity/high treatment (29.0%), moderate comorbidity/high insulin use (9.7%), and high Electronic supplementary material The online comorbidity/moderate treatment (14.8%). The version of this article (https://doi.org/10.1007/s13300- 018-0410-8) contains supplementary material, which is 5-year DN progression rates for these clinically available to authorized users. distinct proﬁles were 11.8, 18, 16.5, and 27.7%, respectively. Compared with the low comor- R. Jiang E. Law (&) bidity/low treatment group, all other groups Department of Pharmacy Systems, Outcomes, and were associated with an increased risk of DN Policy, College of Pharmacy, University of Illinois at progression (all p \ 0.001). Increasing comor- Chicago, Chicago, IL, USA e-mail: email@example.com bidity was signiﬁcantly associated with higher all-cause and DN-related HRU and costs, pri- Z. Zhou H. Yang E. Q. Wu marily driven by higher pharmacy and inpa- Analysis Group, Inc., Boston, MA, USA tient costs. R. Seifeldin Conclusion: Patients with T2DM who have Formerly of Takeda Development Center Americas, more comorbidities experienced higher rates of Inc., Deerﬁeld, IL, USA 1022 Diabetes Ther (2018) 9:1021–1036 DN progression and HRU and incurred higher Prospective Diabetes Study (UKPDS) examined healthcare costs compared with patients with the progression of DN among 5100 T2DM low comorbidity proﬁles. Future prospective patients followed for over a decade . The studies are needed to conﬁrm the signiﬁcance of UKPDS reported the rates and time to DN pro- these groups on DN progression, HRU, and gression among patients with normoalbumin- costs. uria, moderately increased albuminuria, or Funding: Takeda Development Center Americ- severely increased albuminuria, and found that as, Inc. the more severe the albuminuria, the shorter the time to progression to the next stage of DN . In addition, in T2DM patients, long dura- Keywords: Clinical outcomes; Costs; Diabetic tion and poor control have been associated with nephropathy; Healthcare resource use; Type 2 DN progression , while the treatment of diabetes metabolic syndrome has been shown to be independently associated with lesser progres- INTRODUCTION sion of DN in T2DM . A prospective study of Japanese patients with T2DM examined the frequency of and reasons for DN reversal and Diabetic nephropathy (DN), often referred as diabetic kidney disease, is a common and seri- found that DN duration, DN treatment type, glycated hemoglobin (HbA1c) levels, and heal- ous complication of type 2 diabetes mellitus (T2DM), and presents as albuminuria and/or thy blood pressure were linked to likelihood of reversal . The relationship between factors decreased glomerular ﬁltration rate (GFR) [1–3]. In addition to being a leading cause of end-stage related to treatment type and comorbidity cannot be assumed to lie on a continuum, but renal disease (ESRD), DN greatly increases the risk of all-cause and cardiovascular-related rather may co-vary in different ways in different patients, resulting in distinct clinical patterns. mortality, cardiovascular disease and coronary atherosclerosis, and kidney failure among These patterns, or their relationship to mean- ingful outcomes, have not been explored. patients with diabetes [4, 5]. DN affects up to Understanding the relationships between 40% of patients with T2DM  and had an estimated prevalence of 3.3% (6.9 million DN progression and T2DM comorbidity and severity, as well as which patients are at partic- adults) within the USA during 2005–2008 . The overall prevalence of DN among U.S. adults ular risk of progression or poor outcomes, may help improve patient-centered disease manage- with diabetes did not change signiﬁcantly from 1988 to 2014 . The disease progression of DN ment. The use of real-world patient data from claims databases to characterize T2DM could is classiﬁed by the following stages based on urine albumin levels: normoalbuminuria contribute to this goal, as real-world patients have been shown to be more heterogeneous in (\ 30 mg/24 h or an albumin/creatinine ratio terms of both disease severity and diabetic [ACR] of \ 30 lg/mg), moderately increased treatments received , and claims data are a albuminuria (30–300 mg/24 h or an ACR of large and accessible resource. Latent class anal- 30–300 lg/mg), and severely increased albu- minuria ([ 300 mg/24 h or an ACR [ 300 lg/ ysis (LCA), a statistical method for grouping individuals who share common characteristics mg) . Moderately increased albuminuria pre- cedes severely increased albuminuria, and and thereby allowing distinct ‘‘clusters’’ to be identiﬁed , can integrate the limited disease without treatment, the GFR progressively declines and can ultimately result in ESRD . information available in claims databases. LCA has been previously used to examine hetero- However, the severity of T2DM is clinically heterogeneous among affected patients, which geneity in patient populations, to identify sub- groups at high potential risk of disability or may also result in differential courses of DN adverse effects, or to predict patients who may progression . Several prior studies have identiﬁed risk fac- beneﬁt from particular interventions in various disease areas [18–21]. tors for DN progression. The United Kingdom Diabetes Ther (2018) 9:1021–1036 1023 In the study reported here, we used LCA to with continuous enrollment for C 12 months integrate multiple indicators of T2DM severity prior to and 6 months following the test date; that are readily available in commonly used and (3) without ESRD during the 12 months claims databases to identify patient groups with prior to the test date (Fig. 1). The index date was distinct clinical proﬁles. Differences in the randomly selected among all eligible urine clinical trajectory of DN (i.e., DN progression albumin test dates. and reversal) were then assessed among the identiﬁed latent classes. Additionally, as there is Study Measures and Outcomes limited information regarding the healthcare economic burden among patient groups with Type 2 diabetes mellitus severity indicators (di- distinct clinical proﬁles of T2DM, we assessed abetic comorbidities, complications, and treat- the health resource utilization and healthcare ments) included in the LCA were assessed costs among the patient groups identiﬁed with during the 12-month period prior to the index LCA and identiﬁed the patient subgroup with date. T2DM-related complications and comor- the highest economic burden. bidities included retinopathy, neuropathy, ischemic heart disease, cerebrovascular disease, chronic heart failure, hypertension, chronic METHODS kidney disease (CKD)-related symptoms (hy- perkalemia, high parathyroid hormone level, Data Source and high phosphorus level), and metabolic disorder (lipid disorders and other metabolic This study used data from the Truven Health disorders) (see Appendix A in the Electronic Analytics MarketScan Commercial and Medi- Supplementary Material [ESM]). Diabetic treat- care Supplemental and Lab databases (1 January ments included insulin, metformin, sulphony- 2003 to 31 December 2014), which represent lureas, dipeptidyl peptidase-4 inhibitor, approximately 25 million U.S. employees, glucagon-like peptide-1-based therapy, and dependents, and Medicare-eligible retirees cov- other antidiabetic agents (amylin analogs, ered by over 130 health plans and self-insured amino acid derivatives, meglitinide analogs, employers. A subset of the covered lives (ap- aldose reductase inhibitors, alpha-glucosidase prox. 1 million) have recorded laboratory tests inhibitors, dopamine receptor agonists, insulin (mainly ordered in ofﬁce-based practice) in the sensitizing agents and antidiabetic combina- MarketScan Lab Database. Data were de-iden- tions) (see ESM Appendix B). tiﬁed and comply with the patient conﬁden- tiality requirements of the U.S. Health Baseline Characteristics Insurance Portability and Accountability Act; Baseline characteristics (demographics, disease thus, no institutional review was required. characteristics, and DN-related treatments) were assessed during the 12-month period prior to Study Population and Study Cohorts the index date. Patient demographic informa- tion collected included age, sex, and type of The study sample included adult patients (aged health insurance. The time from the ﬁrst C 18 years) with C 2 distinct medical claims observed T2DM diagnosis to the index date and with a diagnosis of T2DM (International Clas- patients’ DN severity at the index date (nor- siﬁcation of Diseases, 9th revision-Clinical moalbuminuria, moderately increased albu- Modiﬁcation [ICD-9-CM]: 250.x0, 250.x2) and minuria, or severely increased albuminuria) with C 2 urine albumin test results after the ﬁrst were assessed. Normoalbuminuria was deﬁned observed T2DM diagnosis. Patients with at least as urinary albumin excretion of\30 mg/24 h or one eligible urine albumin test who met the an ACR of \ 30 lg/mg; moderately increased following criteria were identiﬁed: (1) with C 1 albuminuria was deﬁned as excretion of additional follow-up urine albumin test; (2) 30–300 mg/24 h or an ACR of 30–300 lg/mg; 1024 Diabetes Ther (2018) 9:1021–1036 Fig. 1 Sample selection. ESRD End-stage renal disease, T2DM type 2 diabetes mellitus Progression or Reversal of DN severely increased albuminuria was deﬁned as excretion of[ 300 mg/24 h or an ACR[ 300 lg/ The time to DN progression and time to DN reversal were assessed from the index date until mg. In addition, for each patient the Charlson Comorbidity Index (CCI) score  and the use inpatient mortality, the end of continuous eli- of DN-related treatments during the 12-month gibility, or the end of data availability, which- period before the index date were recorded. DN- ever came ﬁrst. DN severity was classiﬁed into related treatments included angiotensin con- four disease stages ranging from normal to most verting enzyme inhibitors, angiotensin receptor severe: normoalbuminuria, moderately blockers, diuretics, calcium channel blockers, increased albuminuria, severely increased albu- minuria, and presence of ESRD/dialysis/renal and other antihypertensive agents  (see ESM Appendix B). transplantation procedure (see ESM Appendix C). DN disease progression was deﬁned as the Diabetes Ther (2018) 9:1021–1036 1025 presence of a urine albumin test, diagnosis or Information Criterion and Akaike Information procedure indicating a more severe disease stage Criterion) and interpretability of groups. Once than the index disease stage, while DN disease the model was selected, subjects were assigned reversal was deﬁned as the presence of a urine to the latent class based on their probability of albumin test indicating a less severe disease being in that class. Analyses were conducted in stage than the index disease stage. DN disease SAS version 9.4 software using the PROC LCA reversal was only assessed in patients with procedure . moderately increased albuminuria and severely For baseline characteristics, means and increased albuminuria at the index date. standard deviations (SD) were reported for continuous characteristics; frequencies and percentages were reported for categorical char- Healthcare Resource Use and Costs acteristics. Characteristics were compared Economic outcomes were assessed at the per- between the selected reference latent class ver- patient-per-year (PPPY) level from the index sus other latent classes using Wilcoxon rank- date until 2 years from the index date, the end sum tests for continuous variables and Chi- of continuous eligibility, end of data availabil- square tests for categorical variables. Time to ity, or inpatient mortality, whichever came ﬁrst. disease progression and time to disease reversal Healthcare resource use (HRU) information was were evaluated for each latent class using collected for all-cause and DN-related medical Kaplan–Meier methods and compared between visits, including inpatient, emergency room the reference latent class versus other classes (ER), outpatient, and other medical visits. DN- using log-rank tests. The incidence rates of each related HRU was deﬁned as medical services type of healthcare visit PPPY and the annual associated with a diagnosis of DN or kidney healthcare costs were described for each latent disease, or a procedure for dialysis/hemodialysis class and compared between the reference or renal transplantation. latent class versus other classes using Wilcoxon All-cause and nephropathy-related health- rank-sum tests. A p value of B 0.05 was consid- care costs were calculated from a U.S. payer’s ered to be statistically signiﬁcant. perspective and inﬂated to 2016 U.S. dollars All procedures followed were in accordance using the annual medical care component of with the ethical standards of the responsible the Consumer Price Index . Cost compo- committee on human experimentation (insti- nents included medical costs (inpatient, ER, tutional and national) and with the Helsinki outpatient, and other medical services costs) Declaration of 1964, as revised in 2013. Only and pharmacy costs. DN-related costs were de-identiﬁed data was used in this study, thus deﬁned as costs associated with a diagnosis code no institutional review was required. This article of diabetic nephropathy or costs associated with is based on previously conducted studies and a procedure for dialysis/hemodialysis or renal does not contain any studies with human par- transplantation. ticipants or animals performed by any of the authors. Statistical Analysis Latent class analysis was used to identify groups RESULTS of patients with clinically distinct T2DM sever- ity proﬁles. Class membership was determined Latent Class Analysis based on the T2DM disease severity and treat- ment indicators, and individual patients could A total of 23,235 patients with T2DM fulﬁlled belong to only one group. Models with a vary- all study criteria and were included in the ing number of classes were estimated, and the analysis, including 18,409 patients with nor- best-ﬁtting model was chosen. Model selection moalbuminuria, 3863 with moderately was based on the consideration of several cri- increased albuminuria, and 963 with severely teria, including model ﬁt statistics (Bayesian increased albuminuria (Fig. 1). In the LCA, a 1026 Diabetes Ther (2018) 9:1021–1036 four-class model yielded the best ﬁt, and four low comorbidity/low treatment group (all clinically distinct T2DM patient proﬁles were p \ 0.05) (Table 2). Compared with the low identiﬁed based on distributions of complica- comorbidity/low treatment group, all other tions/comorbidities (e.g., microvascular and groups had signiﬁcantly longer mean time since cardiovascular disease, CKD-related symptoms, ﬁrst observed T2DM diagnosis (low comorbid- and metabolic disorder) and use of diabetic ity/low treatment: 32.9 [SD 25.1] months; low treatment (e.g., insulin, metformin, etc.) comorbidity/high treatment: 42.0 [26.8] (Table 1). The four clinically distinct proﬁles months; moderate comorbidity/high insulin were deﬁned as: (1) Latent Class 1 (46.5% of the use: 42.6 [26.9] months; high comorbid- sample [N = 10,812]; reference latent class), low ity/moderate treatment: 46.6 [29.6] months; all comorbidity/low treatment; (2) Latent Class 2 p \ 0.01). Patients in the high comorbid- (29.0% [N = 6728]), low comorbidity/high ity/moderate treatment group had the highest treatment; (3) Latent Class 3 (9.7% [N = 2255]), mean CCI (mean 2.9 [SD 1.6]), followed by the moderate comorbidity and high insulin use; (4) moderate comorbidity/high insulin group (1.7 Latent Class 4 (14.8% [N = 3440]), high [1.1]), the low comorbidity/high treatment comorbidity and moderate treatment. group (1.6 [1.0]), and the low comorbidity/low Retinopathy was more common among Latent treatment group (1.4 [1.0]). All other groups had Classes 3 (26.8%) and 4 (24.4%) compared with signiﬁcantly higher mean CCI compared with Latent Classes 1 (2.6%) and 2 (13.3%), and the low comorbidity/low treatment group (all Latent Class 4 had a higher incidence of all p \ 0.05). other comorbidities in comparison with the other three latent classes. Time to DN Disease Progression Baseline Demographics and Disease The median years of follow-up for DN progres- Characteristics sion among the low comorbidity/low treat- ment, low comorbidity/high treatment, The baseline demographics and disease charac- moderate comorbidity/high insulin use, and teristics of the four latent classes are described high comorbidity/moderate treatment groups in Table 2; multiple signiﬁcant differences were 2.1, 1.9, 2.1, and 1.6 years, respectively. existed between the characteristics of the latent The respective 1-, 3-, and 5-year DN progression classes. For example, patients with moderate rates were 9.3, 20.8, and 27.7% for the high comorbidity/high insulin use were younger comorbidity/moderate treatment group; 5.9, (mean [SD] 49.1 [13.3] years) than those in the 13.3, and 16.5% for the moderate comorbidity/ low comorbidity/low treatment group (54.5 high insulin group; 5.6, 13.9, and 18.0% for the [9.2] years), and patients with high comorbid- low comorbidity/high treatment group; and ity/moderate treatment were older (58.2 [8.7] 4.0, 9.6, and 11.8% for the low comorbidity/low years) and more likely to be male than those in treatment group (Fig. 2). Compared to the low the low comorbidity/low treatment group (male comorbidity/low treatment group, all other 57 vs. 54%, respectively; all p \ 0.05). Patients groups were associated with a signiﬁcantly from the southern USA were over-represented in increased risk of progression to a more severe every class (range 38–44%). Preferred provider stage of DN (all p \ 0.01). The high comorbid- organization was the most common type of ity/moderate treatment group was associated health plan among all classes (range 72–76%). with the highest risk of disease progression The majority of patients in all groups were among all latent groups. classiﬁed with normoalbuminuria at the index date (range 68–84%); however, higher propor- Time to DN Disease Reversal tions of patients were classiﬁed with moderately increased albuminuria or severely increased The median years of follow-up for DN reversal albuminuria in other groups compared with the among the low comorbidity/low treatment, low Diabetes Ther (2018) 9:1021–1036 1027 Table 1 Item–response probabilities for the four-class model: probability of each patient in a given latent class Item Latent class (%) Latent Class 1 (low Latent Class 2 (low Latent Class 3 Latent Class 4 (high comorbidity/low comorbidity/high (moderate comorbidity/moderate treatment group) treatment group) comorbidity/high treatment group) insulin use group) Comorbidity Microvascular disease Retinopathy 2.6 13.1 26.8 24.4 disease Neuropathy 5.2 13.3 16.4 31.7 disease Cardiovascular disease Ischemic heart 6.8 6.2 4.7 40.7 disease Cerebrovascular 2.4 1.3 2.0 19.0 disease Chronic heart 0.6 0.1 1.6 11.0 failure Hypertension 58.2 64.0 32.8 94.7 CKD-related 0.5 0.9 1.0 5.3 disease Metabolic 64.1 72.1 43.3 92.8 disorder Use of diabetic treatment Metformin 59.8 88.2 18.3 56.3 Sulphonylureas 13.5 48.3 3.5 25.9 Insulin 0.0 21.9 87.7 44.1 DPP4 inhibitor 4.6 19.3 0.7 12.8 GLP1-based 1.5 15.2 3.1 9.5 therapy Other antidiabetic 7.6 35.5 31.3 26.5 agents Item–response probabilities were calculated among all patients, given the probability of each patient being in that latent class CKD Chronic kidney disease, DPP4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1 CKD-related disease included hyperkalemia, high parathyroid hormone level, and high phosphorus level Metabolic disorder included lipid disorders and other metabolic disorders Other antidiabetic agents included amylin analogs, amino acid derivatives, meglitinide analogs, aldose reductase inhibitors, alpha-glucosidase inhibitors, dopamine receptor agonists, insulin sensitizing agents, and antidiabetic combinations 1028 Diabetes Ther (2018) 9:1021–1036 Table 2 Patient baseline demographics and disease characteristics according to latent class Patient baseline demographics Latent Class Latent Latent Latent p value and disease characteristics 1 Class 2 Class 3 Class 4  vs.  vs.  vs. (N = 10,812) (N = 6728) (N = 2255) (N = 3440)    Age at index date (years) 54.5 ± 9.2 54.4 ± 8.6 49.1 ± 13.3 58.2 ± 8.7 \ 0.01 \ 0.001 Male 5795 (54%) 3789 (56%) 1199 (53%) 1965 (57%) \ 0.05 \ 0.001 U.S. region Northeast 2016 (19%) 1196 (18%) 394 (17%) 837 (24%) \ 0.001 North-Central 2826 (26%) 1629 (24%) 722 (32%) 828 (24%) \ 0.05 \ 0.01 \ 0.001 South 4533 (42%) 2976 (44%) 855 (38%) 1367 (40%) \ 0.05 \ 0.01 \ 0.001 West 1434 (13%) 927 (14%) 283 (13%) 408 (12%) \ 0.001 Insurance plan type Preferred provider organization 8094 (75%) 5145 (76%) 1678 (74%) 2483 (72%) \ 0.05 \ 0.001 Non-capitated point-of-service 781 (7%) 538 (8%) 166 (7%) 225 (7%) Exclusive provider organization 501 (5%) 343 (5%) 82 (4%) 228 (7%) \ 0.01 \ 0.001 Comprehensive 1025 (9%) 502 (7%) 198 (9%) 442 (13%) \ 0.05 \ 0.001 Consumer-driven health plan 314 (3%) 141 (2%) 99 (4%) 43 (1%) \ 0.05 \ 0.01 \ 0.001 High-deductible health plan 97 (1%) 59 (1%) 32 (1%) 19 (1%) \ 0.01 \ 0.001 Time from ﬁrst observed T2DM 32.9 ± 25.1 42.0 ± 26.8 42.6 ± 26.9 46.6 ± 29.6 \ 0.05 \ 0.01 \ 0.001 diagnosis in the database to the index date (months) Diabetic nephropathy disease status at the index date Normal 9083 (84%) 5249 (78%) 1728 (77%) 2349 (68%) \ 0.05 \ 0.01 \ 0.001 Moderately increased 1483 (14%) 1208 (18%) 400 (18%) 772 (22%) \ 0.05 \ 0.01 \ 0.001 albuminuria Severely increased albuminuria 246 (2%) 271 (4%) 127 (6%) 319 (9%) \ 0.05 \ 0.01 \ 0.001 Charlson Comorbidity Index 1.4 ± 1.0 1.6 ± 1.0 1.7 ± 1.1 2.9 ± 1.6 \ 0.05 \ 0.01 \ 0.001 Nephropathy-related treatments 6892 (64%) 5369 (80%) 1352 (60%) 2975 (86%) \ 0.05 \ 0.01 \ 0.001 ACE inhibitor 3045 (28%) 2823 (42%) 782 (35%) 1524 (44%) \ 0.05 \ 0.01 \ 0.001 Diuretic 1646 (15%) 1291 (19%) 327 (15%) 1201 (35%) \ 0.05 \ 0.001 Calcium channel blocker 1339 (12%) 1017 (15%) 225 (10%) 856 (25%) \ 0.05 \ 0.01 \ 0.001 ARB 1208 (11%) 981 (15%) 262 (12%) 704 (20%) \ 0.05 \ 0.001 Diabetes Ther (2018) 9:1021–1036 1029 Table 2 continued Patient baseline demographics Latent Class Latent Latent Latent p value and disease characteristics 1 Class 2 Class 3 Class 4  vs.  vs.  vs. (N = 10,812) (N = 6728) (N = 2255) (N = 3440)    Other antihypertensive agent 2716 (25%) 1978 (29%) 360 (16%) 1108 (32%) \ 0.05 \ 0.01 \ 0.001 Data in table are presented as the mean ± standard deviation (SD) or as an absolute number with the percentage in parenthesis The four latent classes are described in Table 1 and in section ‘‘Latent Class Analysis’’ T2DM Type 2 diabetes mellitus,ACE angiotensin converting enzyme, ARB angiotensin receptor blockers Latent Classes 2–4 were compared to Latent Class 1, respectively Other antihypertensive agents included direct renin inhibitors, antiadrenergic antihypertensives, selective aldosterone receptor antagonists, agents for pheochromocytoma, vasodilators, monoamine oxidase inhibitors, and antihypertensive combinations comorbidity/high treatment, moderate comor- associated with a signiﬁcantly higher rate of bidity/high insulin use, and high comorbid- disease reversal compared to the low comor- ity/moderate treatment groups were 2.1, 2.0, bidity/low treatment patients (all p \ 0.05). 2.2, and 1.7 years, respectively. The respective 1-, 3-, 5-year DN reversal rates were 7.1, 12.0, All-Cause and DN-Related HRU and 13.9% for the high comorbidity/moderate treatment group; 5.0, 8.9, and 8.9% for the Increasing comorbidity was associated with moderate comorbidity/high insulin group; 6.1, signiﬁcant increases in the annual frequency of 9.9, and 10.5% for the low comorbidity/high all-cause healthcare visits, with a consistent treatment group; and 4.5, 7.9, and 8.9% for the trend across inpatient, outpatient, ER, and low comorbidity/low treatment group (Fig. 3). other medical services visits (p \ 0.01 in all The low comorbidity/high treatment and high pairwise comparisons vs. low comorbidity/low comorbidity/moderate treatment groups were treatment group) (Table 3). The high Fig. 2 Time to progression to a more severe diabetic nephropathy (DN) disease stage. The respective 1-, 3-, Fig. 3 Time to reversal to a less severe DN disease stage. 5-year DN progression rates were 9.27, 20.79, and 27.70% The respective 1-, 3-, 5-year DN reversal rates were 7.09, for the high comorbidity/moderate treatment group 11.99, and 13.92% for the high comorbidity/moderate (purple); 5.86, 13.26, and 16.46% for the moderate treatment group (purple); 5.00, 8.91, and 8.91% for the comorbidity/high insulin group (green); 5.60, 13.93, and moderate comorbidity/high insulin group (green); 6.11, 17.97% for the low comorbidity/high treatment group 9.90, and 10.54% for the low comorbidity/high treatment (red); and 3.95, 9.54, and 11.78% for the low comorbidity/ group (red); and 4.51, 7.88, and 8.89% for the low low treatment group (blue) comorbidity/low treatment group (blue) 1030 Diabetes Ther (2018) 9:1021–1036 Table 3 All-cause and diabetic nephropathy-related healthcare resource use and healthcare costs Per patient per year HRU and Latent Class 1 Latent Class 2 Latent Class 3 Latent Class 4 p value costs, mean – SD (N = 10,812) (N = 6728) (N = 2255) (N = 3440)  vs.  vs.  vs.    All-cause HRU Inpatient admissions 0.09 ± 0.29 0.11 ± 0.36 0.14 ± 0.48 0.26 ± 0.62 \ 0.05 \ 0.01 \ 0.001 Inpatient days 0.44 ± 2.23 0.62 ± 3.18 0.83 ± 3.75 1.71 ± 6.30 \ 0.05 \ 0.01 \ 0.001 Emergency room services 0.39 ± 1.12 0.42 ± 1.04 0.58 ± 2.83 0.80 ± 2.12 \ 0.05 \ 0.01 \ 0.001 Outpatient services 12.96 ± 11.26 13.94 ± 11.66 14.87 ± 13.11 21.07 ± 16.71 \ 0.05 \ 0.01 \ 0.001 Other 1.65 ± 3.56 2.13 ± 3.55 4.22 ± 4.93 4.60 ± 7.57 \ 0.05 \ 0.01 \ 0.001 DN-related HRU Inpatient admissions 0.00 ± 0.06 0.01 ± 0.12 0.02 ± 0.17 0.05 ± 0.28 \ 0.05 \ 0.01 \ 0.001 Inpatient days 0.03 ± 0.55 0.11 ± 1.80 0.15 ± 1.47 0.53 ± 4.35 \ 0.05 \ 0.01 \ 0.001 Emergency room services 0.00 ± 0.07 0.00 ± 0.09 0.01 ± 0.15 0.03 ± 0.25 \ 0.01 \ 0.001 Outpatient services 0.22 ± 1.63 0.35 ± 1.49 0.60 ± 3.49 1.46 ± 8.17 \ 0.05 \ 0.01 \ 0.001 Other 0.01 ± 0.59 0.02 ± 0.49 0.05 ± 0.63 0.20 ± 3.67 \ 0.05 \ 0.01 \ 0.001 All-cause healthcare costs (2016 USD) Total healthcare costs 10,172 ± 19,518 13,836 ± 23,696 17,411 ± 25,149 24,564 ± 36,317 \ 0.05 \ 0.01 \ 0.001 Total medical costs 7,383 ± 18,161 8,709 ± 22,059 11,314 ± 23,555 17,812 ± 34,637 \ 0.05 \ 0.01 \ 0.001 Inpatient admission costs 2300 ± 11,886 3107 ± 16,511 3521 ± 14,939 7616 ± 27,065 \ 0.05 \ 0.01 \ 0.001 Emergency room service costs 645 ± 2760 703 ± 3329 997 ± 9189 1581 ± 6625 \ 0.05 \ 0.01 \ 0.001 Outpatient service costs 3973 ± 9413 4252 ± 8327 4520 ± 9125 6745 ± 10984 \ 0.05 \ 0.01 \ 0.001 Other medical service costs 466 ± 2036 646 ± 2048 2275 ± 4455 1870 ± 5730 \ 0.05 \ 0.01 \ 0.001 Total pharmaceutical costs 2788 ± 4920 5127 ± 5828 6097 ± 6003 6753 ± 8028 \ 0.05 \ 0.01 \ 0.001 DN-related healthcare costs (2016 USD) Total healthcare costs 378 ± 2088 475 ± 2088 700 ± 5015 1687 ± 11,386 \ 0.05 \ 0.001 Total medical costs 113 ± 2017 166 ± 2000 474 ± 4977 1292 ± 11,369 \ 0.05 \ 0.01 \ 0.001 Inpatient admission costs 58 ± 1500 90 ± 1589 299 ± 3800 701 ± 5867 \ 0.05 \ 0.01 \ 0.001 Emergency room service costs 4 ± 127 6 ± 137 9 ± 206 28 ± 326 \ 0.01 \ 0.001 Outpatient service costs 49 ± 1191 68 ± 744 141 ± 1746 458 ± 6318 \ 0.05 \ 0.01 \ 0.001 Other medical service costs 2 ± 90 3 ± 84 25 ± 366 105 ± 2251 \ 0.05 \ 0.01 \ 0.001 Total pharmaceutical costs 265 ± 514 309 ± 530 226 ± 444 395 ± 624 \ 0.05 \ 0.01 \ 0.001 Data in table are presented as the mean ± SD The four latent classes are described in Table 1 DN Diabetic neuropathy, HRU health resource utilization, USD U.S. dollars Latent Classes 2–4 were compared to Latent Class 1, respectively Other medical services included durable medical equipment, home care, skilled nursing facility care, and dental or vision care comorbidity/moderate treatment group experi- had 13.0 (SD 11.3) visits (p \ 0.001). In addi- enced a mean of 0.3 (SD 0.6) inpatient admis- tion, the high comorbidity/moderate treatment sions annually, with a mean length of stay of group had increased all-cause HRU compared 1.7 (SD 6.3) days, while the low comorbidity/ with the low comorbidity/high treatment or low treatment group experienced 0.1 (SD 0.3) moderate comorbidity/high insulin use groups admissions with a mean stay of 0.4 (SD 2.2) days in each HRU category. (p \ 0.001). For outpatient services, the high A similar trend was observed regarding DN- comorbidity/moderate treatment group experi- related HRU; patients with high comorbid- enced a mean of 21.1 (SD 16.7) visits annually, ity/moderate treatment had a notably high while the low comorbidity/low treatment group incidence of nephropathy-related inpatient, ER, Diabetes Ther (2018) 9:1021–1036 1031 outpatient, and other medical services visits in Regarding the components that were the largest comparison with the other groups (all p \ 0.05). contributors to total healthcare costs, a similar For example, the high comorbidity/moderate trend was observed in DN-related costs as with all- treatment group had a mean of 1.5 (SD:8.2) DN- cause costs, with pharmacy costs contributing the related outpatient visits annually, compared to majority of the cost difference between the low 0.22 (SD 1.36) visits for the low comorbidity/ comorbidity/low treatment and low comorbid- low treatment group (p \ 0.001). ity/high treatment groups. Higher inpatient admission costs and outpatient costs drove the increase in DN-related healthcare costs among All-Cause and DN-Related Healthcare patients with increasing comorbidity (i.e., low Costs comorbidity/low treatment group vs. the moder- ate comorbidity/high insulin group and the high Following from the observed trend of higher HRU comorbidity/moderate treatment group). associated with higher comorbidity burden, In this study, we did not adjust for baseline higher comorbidity was also associated with sig- characteristics in the outcome comparisons. niﬁcantly higher all-cause healthcare costs The reason for this decision is that latent (Table 3). The incremental differences in total all- patient groups, as the main effect in the model, cause healthcare costs PPPY between the low were identiﬁed by LCA using complications, comorbidity/low treatment group and the low comorbidity, and therapies for T2DM during comorbidity/high treatment, moderate comor- the baseline period. Therefore, these character- bidity/high insulin use, and high comorbid- istics should not be adjusted for when outcomes ity/moderate treatment groups were US$3664, are compared across latent patient groups. In US$7239, and US$14,392, respectively (all addition, baseline demographics are in general p\ 0.05). Pharmaceutical cost differences comparable across groups. (US$2339) accounted for approximately 60% of the all-cause cost differences between the low comorbidity/high treatment and low comorbid- DISCUSSION ity/low treatment groups (the next largest com- ponent was inpatient admission costs [22%; cost A large proportion of patients with diabetes difference US$807]). Similarly, pharmaceutical develop DN, leading to progressive increases in cost differences (US$3309) accounted for approx- albuminuria, declining GFR, and risk of ESRD imately50% of thedifferencebetween themod- . Thus, an important step towards improving erate comorbidity/high insulin use and low the management, treatment, and clinical out- comorbidity/low treatment groups (the next lar- comes of patients with T2DM is to identify gest components were other medical services patients at high risk of DN progression. To the [25%; cost difference US$1809] and inpatient best of our knowledge, this is the ﬁrst study that admission [17%; US$1221] costs). Conversely, the has utilized LCA to identify subgroups of T2DM majority of the cost differences between high patients based on their diabetes comorbidity comorbidity/moderate treatment and low comor- and treatment proﬁle within a claims database, bidity/low treatment groups was due to differences and that has compared the clinical trajectories in inpatient admission costs (37%; cost difference of DN, HRU, and costs among the identiﬁed US$5316), followed by pharmaceutical (28%; subgroups. Patients with larger burdens of US$3965) and outpatient (19%; US$2772) costs. comorbidity had signiﬁcantly increased risk of The incremental differences in total DN-re- progression to a more severe stage of DN, as well lated costs PPPY between the low comorbidity/ as higher all-cause and DN-related HRU and low treatment group and the low comorbidity/ healthcare costs. In particular, patients with high treatment, moderate comorbidity/high high comorbidity and moderate treatment use insulin use, and high comorbidity/moderate had the highest 5-year DN progression rate, treatment groups were $US97 (p\ 0.05), US$322, HRU, and costs compared to all of the other and US$1309 (p \ 0.001), respectively (Table 3). groups. The current results demonstrate the 1032 Diabetes Ther (2018) 9:1021–1036 feasibility of using LCA to identify clinical sub- therapy . These prior ﬁndings may help groups using many aspects of diabetes severity, explain why group of patients in the current and the validity of the identiﬁed subgroups was study with moderate comorbidity/high insulin supported by the differential DN progression, use had lower rates of DN progression (5-year resource use, and costs observed across the rate 16.5%) than the group with low comor- subgroups. bidity/high treatment use (5-year rate 18.0%). Previous research has helped establish the A small number of studies have previously association between DN progression and dia- examined the relationship between T2DM betes complications or anti-diabetic treatments. severity and healthcare costs, reporting ﬁndings Hypertension, a common complication of dia- similar to the present results. A 2013 systematic betes, plays a major role in the onset and pro- literature review by Banerji et al. synthesized gression of DN, and anti-hypertensive studies reporting the impact of glycemic control treatment can reduce albuminuria and slow the and treatment adherence, which are important progression of DN [26, 27]. Remission of very contributors to DN and other diabetes compli- advanced DN has been observed among type 1 cations, on the healthcare costs of T2DM diabetes mellitus (T1DM) and T2DM patients patients . These authors observed that the undergoing aggressive anti-hypertensive treat- healthcare resource utilization and costs asso- ment [28–31]. In the present study, the high ciated with T2DM management were reduced comorbidity/moderate treatment group had the when glycemic levels and comorbidity were highest prevalence of hypertension (94.7%) and better controlled, although comorbid condi- the highest rates of DN progression (5-year rate tions were still prevalent and anti-diabetic 27.7%) among all groups. The low comorbidity/ medication adherence was largely suboptimal high treatment group had the next highest [37–40]. A retrospective study in 2010 by Men- prevalence of hypertension (64%), as well as the zin et al. reported that the hospitalization rate next highest rate of DN progression (5-year rate and healthcare costs were signiﬁcantly higher 18.0%). A previous retrospective analysis for T1DM and T2DM patients with poorly con- reported that the concomitant presence of trolled versus well-controlled blood glucose retinopathy was signiﬁcantly associated with ([ 10 vs. \ 7% HbA1c) . Furthermore, DN progression in patients with T2DM , patients with severe complications or comor- perhaps due to similar underlying contributing bidities related to T2DM have been shown to pathology. In the present study, the low incur healthcare costs that are threefold higher comorbidity/low treatment group had a much than those of matched patients without lower prevalence of retinopathy (2.6%) than did comorbidities , similar to the present the other groups (range 13.1–26.8%), as well as results. Our results emphasize the magnitude of the lowest rate of DN progression (5-year rate this cost difference and may present opportu- 11.8% vs. [range] 16.5–27.7%). nities to identify patients at risk of higher In addition, several studies have shown that healthcare expenditures. DN progression can be slowed with intensive The results of this study have potential glycemic control [33–35]. The randomized trial implications for the management of T2DM and ACCORD reported that therapy targeting DN as well as for the further application of this HbA1c to levels of \ 6.0 vs. 7.0–7.9% delayed method to identify high-risk patients based on the onset of severely increased albuminuria and claims data. The heterogeneous nature of T2DM some microvascular complications, but complicates clinical management, and the cur- increased risk mortality and other complica- rent results indicate that some patients (e.g., the tions (e.g., hypoglycemia) . A similar, high comorbidity/moderate treatment group) prospective study reported that anti-diabetic may have received suboptimal anti-diabetic therapy targeting HbA1c to levels of \ 6.5% treatment or suboptimal blood pressure control, resulted in delayed onset of DN, retinopathy, which led to a high risk of DN progression. and neuropathy in comparison to conventional However, although patients with the highest Diabetes Ther (2018) 9:1021–1036 1033 comorbidity were at the highest risk of DN Diabetes Complication Severity Index (DCSI), a progression, the 5-year rates of DN reversal 13-point scale for scoring patients’ diagnostic, among both the low comorbidity/high treat- pharmacy, and laboratory data, has also been ment group (10.5%) and the high comorbid- used to assess healthcare costs and comorbidity ity/moderate treatment group (13.9%) were management [45–47]. However, deriving the higher than those of the low comorbidity/low DSCI from claims data is again restrained by the treatment and moderate comorbidity/high availability of laboratory information in claims insulin use groups (both 8.9%). This result databases. In the present study, we derived dif- suggests that anti-diabetic treatments can be ferent indicators of T2DM disease severity from effective in slowing or reversing DN even in the claims database, which is also subject to the patients with more severe T2DM. Additionally, limitations introduced by the data source. First, the LCA results highlight that there may be DN severity may be misclassiﬁed due to the use interactions between comorbid conditions, of the results of a single urine albumin test to T2DM treatment, and patient characteristics as deﬁne moderately increased and severely there are no clear indicators of group member- increased albuminuria. To maximize availability ship, i.e., group membership as a proxy for data to assess DN progression or reversal and diabetes severity is not clearly deﬁned by num- because the urine albumin test data were lim- ber or type of T2DM medications or number of ited, we did not require a conﬁrmatory urine co-morbidities, as would be the case in tradi- albumin test. Second, patients with T2DM were tional claims database studies. Future research is identiﬁed by ICD-9-CM codes in medical ser- warranted to identify any unmet treatment vices claims; diagnoses or procedures related to needs in this patient population, to characterize ESRD, transplantation, or dialysis were also patients with high risk of DN progression, and identiﬁed using diagnostic or procedural codes to identify groups with the largest economic in the claims database. However, such diagnoses burden related to T2DM and DN. In addition, and procedures may be over- or under-reported the current study demonstrates the potential for in the data. Similarly, rates of DN progression LCA to be used to identify classes of patients may have been underestimated, as the data do with clinically distinct T2DM proﬁles using not contain complete information regarding information available in commercial claims laboratory values. Finally, only patients with a data. This is an important contribution, as urine albumin test were included in the study, claims databases represent large and readily which may not capture all patients with DN accessible sources of healthcare information but disease status since alternative laboratory tests, may lack data typically used to indicate prog- such as proteinuria and estimated GFR decline, nosis (e.g., HbA1c). Future research using LCA may also indicate DN . Although the data- could further contribute to understanding and base is geographically representative of the USA, reducing the risk of DN progression and the data include only commercially insured improving clinical outcomes for patients with patients and those who have commercial T2DM. insurance in supplement to their Medicare insurance. Thus, the current results may not be generalizable across different study populations Limitations that may be relevant, such as various socioeco- nomic groups or the uninsured. Estimating T2DM disease severity using data from claims databases can be challenging due to the limited amount and types of clinical infor- CONCLUSIONS mation they contain. Laboratory measures, such as HbA1c levels, are useful indicators of This exploratory study demonstrated the feasi- diabetes severity [43, 44], although claims bility of using LCA to identify patient groups databases contain limited proportions of with distinct clinical proﬁles of T2DM severity patients with HbA1c lab values available. The and explored the association between T2DM 1034 Diabetes Ther (2018) 9:1021–1036 disease severity, DN progression or reversal, and consulting fees from Takeda Pharmaceuticals. economic outcomes. Increasing levels of At the time of analysis, Raafat Seifeld was an comorbidity were generally associated with employee of Takeda, and held Takeda stock or higher HRU, healthcare costs, and risk of DN stock options. progression, while anti-diabetic treatment Compliance with Ethics Guidelines. All appeared to slow DN progression. procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and ACKNOWLEDGEMENTS national) and with the Helsinki Declaration of 1964, as revised in 2013. Only de-identiﬁed data was used in this study, thus no institutional Funding. Sponsorship for this study and review was required. This article is based on article processing charges were funded by previously conducted studies and does not con- Takeda Development Center Americas, Inc. All tain any studies with human participants or authors had full access to all of the data in this animals performed by any of the authors. study and take complete responsibility for the integrity of the data and accuracy of the data Data Availability. The datasets generated analysis. during and/or analyzed during the current study are not publicly available due to conﬁ- Medical Writing and Editorial Assis- dentiality agreement. tance. Editorial assistance in the preparation of this manuscript was provided by Dr. Shelley Open Access. This article is distributed Batts of Analysis Group, Inc. The authors would under the terms of the Creative Commons like to thank Jing Zhao from Analysis Group for Attribution-NonCommercial 4.0 International signiﬁcant contribution towards medical writ- License (http://creativecommons.org/licenses/ ing and analytical support. The authors would by-nc/4.0/), which permits any non- also like to thank Melvin Munsaka for his sup- commercial use, distribution, and reproduction port in data analysis. This support was funded in any medium, provided you give appropriate by Takeda Development Center Americans, Inc. credit to the original author(s) and the source, provide a link to the Creative Commons license, Authorship. All named authors meet the and indicate if changes were made. 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Published: Mar 29, 2018