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The American Journal of Managed Care May 2015
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Changing Trends in Type 2 Diabetes Mellitus Treatment Intensification, 2002-2010
Rozalina G. McCoy, MD; Yuanhui Zhang, PhD; Jeph Herrin, PhD; Brian T. Denton, PhD; Jennifer E. Mason, PhD; Victor M. Montori, MD; Steven A. Smith, MD; Nilay D. Shah, PhD
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Changing Trends in Type 2 Diabetes Mellitus Treatment Intensification, 2002-2010

Rozalina G. McCoy, MD; Yuanhui Zhang, PhD; Jeph Herrin, PhD; Brian T. Denton, PhD; Jennifer E. Mason, PhD; Victor M. Montori, MD; Steven A. Smith, MD; Nilay D. Shah, PhD
Glycemic control can lower the risk of diabetes-related complications, and delayed treatment intensification can impede optimal diabetes care.This study examines trends in hyperglycemia treatment intensification between 2002 and 2010.

Objectives: Glycemic control can lower the risk of diabetes-related complications, and delayed treatment intensification can impede optimal diabetes care.This study examines trends in hyperglycemia treatment intensification between 2002 and 2010.

Study Design: Retrospective secondary data analysis of a large national administrative data set of privately insured individuals across the United States.

Methods: Adults 18 years or older with diabetes, initiated on metformin monotherapy between 2002 and 2007, were studied, stratified by date of first metformin prescription (2002-2003, 2004-2005, 2006-2007).Time to treatment intensification between 2002 and 2010, defined by the addition of ≥1 agents to metformin, was estimated using Kaplan-Meier and Cox proportional hazards regression analysis.

Results: There were 75,069 treatment-naïve adults with diabetes first initiated on metformin between 2002 and 2007; mean age was 60 years (SD = 11.5), 49.7% were women, and 63.1% were non-Hispanic white. Diabetes therapy was intensified in 26,169 individuals (34.6%).Treatment intensification became increasingly more likely with time for the 2004-2005 cohort (hazard ratio [HR], 1.07; 95% CI, 1.04-1.10) and for the 2006-2007 cohort (HR, 1.11; 95% CI, 1.07-1.14) compared with the 2002-2003 cohort (P <.001), after adjustment for significant confounders including sex, income level, education level, and comorbidity burden. Sulfonylureas were the most commonly used agents, though their use declined over time; thiazolidinedione use decreased; and incretin use increased (all P <.001).

Conclusions: There was a significant increase in diabetes treatment intensification between 2002 and 2010. Choice of secondline agents changed as well, with decreasing prevalence of thiazolidinedione and sulfonylurea use and rising prevalence of incretin use.
Take-Away Points

This study examines trends in treatment intensification among privately insured adults of all ages in the era of greater focus on quality improvement and performance measurement for diabetes.
  • In a geographically and demographically diverse population, time to treatment intensification decreased consistently between 2002 and 2010.
  • This study specifically addresses the selection of second-line agents as add-on therapy to metformin in routine clinical practice. The use of incretin agents and insulin increased significantly over the past decade, while the use of thiazolidinediones has decreased.
  • Sulfonylureas remained the most commonly prescribed class of second-line agents used to treat type 2 diabetes mellitus.
Diabetes is one of the most prevalent and costly chronic diseases; it affects more than 12% of the US adult population1 and accounts for nearly 13% of total healthcare expenditures.2 Poor glycemic control is associated with worse quality of life and increased risk of diabetes-related complications.3-9 Because of the high burden of illness—in addition to rising costs to individuals, society, and healthcare systems2 — improving the quality of diabetes care has emerged as a priority for patients, healthcare providers, payers, and government organizations.

Individuals with hyperglycemia not adequately controlled by lifestyle modifications alone are generally started on metformin, the first-line agent in the management of type 2 diabetes mellitus (T2DM).10,11 Due to the progressive course of diabetes, most patients ultimately require the addition of other glucose-lowering medications,12 and failure to intensify treatment in a timely manner has been linked to poor glycemic control and greater risk of diabetes-related complications.13-15 Treatment intensification may be delayed due to a variety of patient-related factors, such as concern for polypharmacy, burden of treatment, nonadherence, and financial challenges. Similarly, provider-related factors may stem from competing clinical demands, lack of awareness or education, and inadequate encounter times. Such clinical inertia is common and contributes to poor glycemic control.13-17 Recently, the percent of diabetes patients in the United States who meet glycemic targets has improved,18 potentially as a result of increased focus on public reporting of diabetes performance metrics and prioritization of glycemic control.19

Public availability of performance data and performance-based reimbursement may have affected provider practice and led to increased rates of treatment intensification.19 Two seminal studies, published in 200320 and 2006,21 revealing the inadequacies of diabetes care and delayed treatment intensification also may have led clinicians to increase their focus on achieving and maintaining glycemic targets. However, little is known about recent trends in treatment intensification in clinical practice. Moreover, the choice of second-line agents used to intensify diabetes therapy probably changed as a result of greater availability and marketing of new pharmacotherapies. Several recent studies showed changing trends in the use of glucose-lowering therapies,22,23 but they were not designed to assess treatment intensification practices, as they did not distinguish between monotherapy and combination therapy, or specify whether certain drugs were used as first-, second-, or third-line therapies.

We used data from a large nationally representative data set of privately insured individuals to identify and characterize the temporal changes in treatment intensification rates, and medications used as second-line therapies, between 2002 and 2010.


Design and Data Set

We conducted a retrospective secondary data analysis of adults 18 years and older with T2DM included in Optum Labs Data Warehouse, an administrative claim database of enrollees from commercial US health plans. This database includes medical and pharmacy benefit coverage for more than 96 million individuals in all 50 states and of all ages and ethnic/racial groups. Medical claims include diagnosis and procedure codes, site of service codes, provider specialty codes, and health plan and patient costs. Pharmacy claims include information on medications dispensed, prescription quantity, and date of issue. Study data were accessed using techniques compliant with the Health Insurance Portability and Accountability Act of 1996. Because this study involved analysis of preexisting, de-identified data, it was exempt from institutional review board approval.

Study Population

Individuals with T2DM were identified on the basis of Healthcare Effectiveness Data and Information Set criteria.24 In order to restrict data analysis to treatment-naïve individuals newly initiated on metformin monotherapy, we included only those people who had a period of 6 or more months preceding enrollment without a claim for any diabetes medications. Patients who received a prescription for another antihyperglycemic agent within 30 days following the first metformin prescription were excluded, as they were likely started a priori on combination therapy rather than metformin monotherapy. Cohort entry point was defined by the issue date of the first metformin prescription, and patients were allocated to 1 of 3 cohorts based on the years when this occurred (2002-2003, 2004-2005, and 2006-2007).

Assessment of Treatment Intensification

Our primary outcome was the number of days to treatment intensification after first initiation of metformin monotherapy. Treatment intensification was defined as a new prescription for ≥1 antihyperglycemic agent(s) in addition to metformin, or replacement of metformin by insulin (insulin prescription filled within 90 days of the preceding metformin coverage date). Second-line agents were grouped into 1 of 5 categories (eAppendix, available at, and combination tablets and insulins were considered as consisting of both classes.

Censoring occurred when patients were disenrolled from the health plan (defined as no pharmacy claims for ≥6 months), when they discontinued metformin (unless replaced by insulin), or on December 31, 2010. Medication discontinuation was identified by a lack of refills 90 days beyond the last day covered by the preceding fill. There was no difference in the relative proportion of patients censored due to metformin discontinuation, metformin replacement by another non-insulin hypoglycemic agent, or health plan disenrollment between the 3 cohorts. Based on all available information, we assumed that censoring was non-informative.

Independent Variables

Diagnoses were determined using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Administrative claims were used to derive the Charlson comorbidity (CC) index and count for 1 calendar year prior to initiation of metformin. The CC index is a widely used measure of disease burden that weighs comorbid conditions by the strength of their association with 1-year mortality,25 and it has been previously validated for use in diabetes.26,27 Socioeconomic characteristics included age, gender, race/ethnicity, highest education level achieved, and median household income at the census block level based on the residence of the individual.

Statistical Analysis

Patient characteristics were compared among cohorts using χ2 tests for categorical variables, and ANOVA for continuous variables (age).

We graphed the Kaplan-Meier curves for the 3 cohorts, and used a log-rank test to test for differences in unadjusted time to intensification curves for the 3 cohorts.28 Proportional hazards assumptions were checked by testing a nonzero slope in a generalized linear regression of the scaled Schoenfeld residuals on functions of time for the cohort variable.28,29 Preliminary analysis rejected the assumption that hazards were proportional across the 3 cohorts, so we assessed a range of parametric specifications for time-to-event models according to model performance, selecting a Gompertz model30 as most appropriate.

We then estimated a single model to determine the association between cohort and the risk of future treatment intensification while adjusting for patients’ age at the time of metformin initiation, gender, race/ethnicity, income level, education level, CC count, and concomitant statin treatment. Patient's age at the time of metformin initiation was modeled as a continuous variable; other covariates were modeled as categorical variables. Missing data were imputed using ordered and multiple logit models that included age, sex, CC count, statin use, and cohort.31 We report coefficients as hazard ratios, and the P values for the hypothesis that the hazard ratio was different from zero. For categorical covariates, we also report the Wald test P value for the hypothesis that the set of hazard ratios for that covariate were jointly equal to zero.

To assess patterns of second-line treatments according to year of metformin initiation, we summarized the frequency of use of each drug class for each study cohort. We used χ2 tests to test for differences in rates of each agent across cohorts, and report the P values.

All analyses were conducted using SAS 9.3 (SAS Institute, Cary, North Carolina) and Stata 13.1 (Stata Corp, College Station, Texas). Probability values <.05 were considered to be statistically significant.


Patient Characteristics

Between 2002 and 2007, 75,069 treatment-naïve adults with T2DM were initiated on metformin monotherapy; their baseline demographic and comorbidity characteristics are summarized in Table 1. Median duration of follow-up until treatment intensification or censoring was comparable between the 3 cohorts: 1.7 years (interquartile range [IQR], 0.8, 3.3), 1.7 years (IQR, 0.8, 3.2), and 1.6 years (IQR, 0.8, 2.8) for the 2002-2003, 2004-2005, and 2006-2007 cohorts, respectively. Average age at the time of metformin initiation was 60.0 (SD = 11.5) years, and there was a significant trend toward younger age at metformin initiation over time (P <.001). Nearly a third of patients had 1 or more chronic medical illnesses in addition to diabetes, with an overall mean CC index of 1.5 (SD = 1.4) (Table 1). Chronic disease burden increased over time, with mean CC index rising from 1.4 (SD = 1.3) in the 2002-2003 cohort to 1.5 (SD = 1.4) in the 2004-2005 cohort, and 1.6 (SD = 1.5) in the 2006-2007 cohort (P <.001). The number of patients with no chronic illness aside from diabetes declined from 70.1% in the 2002-2003 cohort, to 65.7% in the 2004-2005 cohort, to 62.7% in the 2006-2007 cohort (P <.001). The prevalence of concomitant statin therapy was 42% across all years, and increased in successive cohorts: 34.2% in the 2002-2003 cohort, 40.3% in the 2004-2005 cohort, and 46.8% in the 2006- 2007 cohort (P <.001).

Choice of Second-Line Therapy

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