Patients with Type 2 Diabetes Initiating Exenatide Twice Daily or Insulin in Clinical Practice: CHOICE Study

Introduction Changes to Treatment and Outcomes in Patients with Type 2 Diabetes Initiating Injectable Therapy (CHOICE) is a European prospective, observational cohort study assessing time to, and factors associated with, a significant change in therapy after type 2 diabetes patients initiate their first injectable glucose-lowering therapy, and these patients’ clinical outcomes over 24 months. The authors report baseline data and factors associated with the injectable treatment regimen. Methods Demographic, clinical, and healthcare resource-use data were collected at initiation of injectable therapy and analyzed using univariate tests between cohorts and multivariate logistic regression analysis for treatment. Results Overall, 1,177 patients initiated exenatide twice daily (b.i.d.) and 1,315 initiated insulin. Most patients were recruited by secondary-care physicians. Univariate analyses revealed statistically significant differences between the characteristics of patients who initiated exenatide b.i.d. and patients who initiated insulin. On multivariate analysis, higher body mass index [BMI; 5 kg/m2 higher: odds ratio (OR) 2.10, 95% confidence intervals (CI) 1.84–2.40], lower glycated hemoglobin (HbA1c; 1% higher: OR 0.77, 95% CI 0.69–0.86), and lower age (5 years older: OR 0.82, 95% CI 0.76–0.88) were the variables most strongly associated with increased probability of receiving exenatide b.i.d. (P < 0.0001). Patients initiating exenatide b.i.d. had a mean BMI of 35.3 ± 6.5 kg/m2, HbA1c of 8.4 ± 1.4%, and age of 58 ± 10 years, compared with 29.7 ± 5.4 kg/m2, 9.2 ± 1.9%, and 64 ± 11 years, respectively, in patients initiating insulin (P < 0.0001). Other characteristics significantly associated with exenatide b.i.d. initiation were “disinhibited eating” (Diabetes Health Profile-18), lower random blood glucose, less blood glucose self-monitoring, lower low-density lipoprotein cholesterol, and receipt of diet/exercise advice. Conclusions Patients who initiated exenatide b.i.d. were on average younger and more obese with lower HbA1c than those initiating insulin.

and as adjuvant therapy with basal insulin, with or without metformin and/or pioglitazone, in patients who had not achieved adequate glycemic control with these agents (in 2012). In head-to-head phase 3 clinical trials, exenatide b.i.d. and insulin (glargine and biphasic insulin aspart) provided similar glycemic control in patients whose diabetes was not controlled with oral antidiabetic medications (OADs). Exenatide b.i.d. treatment was associated with weight loss, while patients randomized to insulin typically gained weight [1][2][3]. Metabolic improvements with exenatide b.i.d. were maintained in a subset of patients treated for 3.5 years [4].
While randomized, controlled trials are the reference standard for assessing the efficacy and safety of therapy, large, observational studies are necessary to determine how glucose-lowering medications are used in clinical practice and to evaluate their effectiveness and safety in this setting [5,6]  The following strategy was used to achieve the required number of patients in each cohort without intervening in treatment decisions made during normal clinical practice: once a cohort within a participating country was filled, investigating physicians were asked to stop enrollment into that cohort and to continue enrolling patients only into the other treatment cohort, as and when they initiate patients on that treatment according to their usual practice.

Statistical Analysis
All patients eligible at baseline were included in the analyses. Baseline patient data were reported using descriptive statistics and 95% CI where appropriate. For continuous variables mean, SD, median, minimum, maximum, and quartiles were calculated. Absolute numbers and percentages (including missing values) were given for categorical variables. Percountry analyses were also performed.
Univariate analyses were performed to compare all baseline patient characteristics between the two cohorts (overall population and per country). Continuous variables were analyzed using t tests, analyses of variance (ANOVA), or where necessary the corresponding nonparametric alternatives (e.g., Wilcoxon signed rank test). Categorical variables were analyzed using v 2 tests, Fisher's exact tests, and trend tests. Logistic regression models were then applied to identify factors significantly associated with injectable treatment regimen (differentiation between exenatide b.i.d. and insulin), using forward selection processes and including only those variables that were statistically significant (P\0.1) at the univariate level. For all these analyses missing data were not imputed.
Logistic regression was also used to derive propensity scores from baseline data (0.10 threshold for between-cohort differences).
The propensity score estimates the probability that a patient will be assigned to a treatment group based on baseline characteristics (score range 0-1). Propensity score analysis was used to assess comparability of the treatment cohorts [11]. For this analysis all eligible baseline data were included. Missing data were imputed with the overall mean or median for continuous variables, and most frequent category for categorical variables, in order to give a conservative estimate. Patients were matched 1:1 by country based on the propensity score and optimal matching to identify matched subsets from the two cohorts. All P values are reported without multiplicity adjustments.

Demographic and Clinical Characteristics
Overall, patients had a mean age of 61 ± 10 years, BMI of 32.3 ± 6.6 kg/m 2 and HbA 1c of 8.9 ± 1.7%. Mean duration of diagnosed diabetes was 9 ± 7 years. Univariate analyses revealed statistically significant differences between patients whom clinicians initiated on exenatide b.i.d. and starter insulin regimens (collectively referred to as ''insulin'';     initiation of injectable therapy and this was consistent across countries. There were no significant differences between cohorts in the use of cardiovascular, lipid-lowering, or antiplatelet agents (Table 1). Exenatide b.i.d.
patients were statistically significantly more likely to have used weight-lowering medications than insulin patients (4.6% vs. 1.5%, respectively; P\0.0001).

Resource Use
Overall, 79.4% of patients self-monitored blood glucose, using a mean of 9.6 ± 8.3 test strips/ week. There were no statistically significant differences between the cohorts in the number of contacts with healthcare professionals in the 6 months prior to baseline (Table 1).

Factors Associated with Injectable Treatment Regimen and Propensity Score
A multiple logistic regression analysis (forward selection) identified BMI, age, and HbA 1c as the variables most strongly associated with a propensity for treatment assignment, with higher BMI, lower age, and lower HbA 1c indicating an increased probability of receiving exenatide b.i.d. (  (Table 2).
A propensity score analysis based on baseline demographic and clinical variables underlined the differences between the treatment cohorts. The mean propensity score value for the probability of receiving exenatide b.i.d. was 0.63 ± 0.23, and of receiving insulin was 0.33 ± 0.23 (Table 3)

DISCUSSION
Well-designed, observational (''real-world'') studies are essential to enhancing the evidence upon which the management of T2DM is based [5]. The CHOICE study, a large prospective observational study conducted in six European countries, has provided the first available data on the way exenatide b.i.d. is used in clinical practice across Europe. The present report focuses on the baseline characteristics of patients and it identifies differences between patients who initiate exenatide b.i.d. and those who initiate starter insulin at the discretion of the treating physician. As well as being of intrinsic interest, these data will also have implications for the comparability of clinical outcomes between the CHOICE cohorts in future publications, and perhaps for the comparability between exenatide b.i.d. and insulin data from clinical practice more generally.
were characterized by: younger age; higher body weight, BMI, and waist circumference; higher diastolic blood pressure, lower total and LDL cholesterol levels; shorter time since diabetes diagnosis; and better glycemic control. A lower  The observation (on univariate analysis) of a higher proportion of diagnosed dyslipidemia or hypertension inpatients initiating exenatide b.i.d.
is of unclear significance but may be related to body weight. Similar findings were observed in the aforementioned retrospective database analysis in the United States [16]. In common with CHOICE, this previous analysis also found that patients initiating exenatide b.i.d. had significantly lower rates of macrovascular and microvascular complications than those initiating insulin [16].
Overall, the mean blood pressure values among CHOICE patients at baseline would classify the population at low risk according to the target of 130/80 mmHg recommended by the International Diabetes Federation [20], and a  sample sizes between the six countries also limits the robustness of inter-country comparisons, although the inter-cohort comparisons nevertheless showed a considerable degree of international consistency. There was also variation between countries in the ratios of exenatide b.i.d. and insulin patients.
In conclusion, this analysis has improved understanding of which patients are initiated on exenatide b.i.d. or insulin in routine clinical practice. The cohort of patients who initiated exenatide b.i.d. in CHOICE was younger, more obese, and had a lower HbA 1c than those who initiated insulin. These differences appear to reflect the recommendations for the use of these two therapies, with exenatide b.i.d. identified as an option when weight gain is a particular concern and when HbA 1c is modestly raised [7,12]. The data suggest that the patient profile may contribute to the prescribing of injectable glucose-lowering therapy regimen for patients with T2DM.