Subanalyses of Elderly Type 2 Diabetes Patients or Type 2 Diabetes Patients With Renal Impairment

Background: In January 2012, the US Food and Drug Administration approved a once-weekly form
of exenatide, Bydureon, for the treatment of type 2 diabetes mellitus. Evidence from clinical
trials suggested that Bydureon improves glucose control with low risk of hypoglycemia.
Bydureon does not require a dose titration as necessary for other glucagon-like peptide-1
agonists (GLP-1RAs), and appears to have other advantages, such as reducing insulin
resistance, reducing weight, and improving blood pressure and lipid profiles. However, the
degree to which these advantages of Bydureon lead to improve outcomes in patients with renal
impairment or who are elderly is unknown.

Aims: The aim of this study is to evaluate the effectiveness and tolerability of Bydureon
relative to basal insulin initiated as first-ever injectable therapeutic regimens among
elderly patients and patients with renal impairment.

The specific study objectives are as follows:

- To quantify the effectiveness of Bydureon initiation relative to initiation of basal
insulin, on improving:

- Glycated hemoglobin (HbA1c)

- Weight (body mass index (BMI))

- HbA1c simultaneous to reduction in weight

- Blood pressure and lipid profiles

- To examine the tolerability of Bydureon initiation relative to initiation basal insulin,
on the occurrence of :

- Hypoglycemia

- Gastrointestinal symptoms (nausea, vomiting, diarrhea, and constipation)

- Change in the markers for renal function (estimated glomerular filtration rate (eGFR),
serum creatinine, and albumin/creatinine ratio (ACR), and the stability of liver
function test (AST, ALT) and standard blood counts (WBC, RBC, HCT, Hgb, PLT)

- To examine these measures of effectiveness and tolerability within potentially
vulnerable subgroups of Bydureon and basal insulin initiators:

- T2D patients with renal impairment

- Elderly T2D patients Study Population and Design: This retrospective cohort study will
use Optum's EHR data from July 2011 through March 2015 and identify injectable-naive T2D
patients who initiated either Bydureon or basal insulin during the accrual period,
January 2012 and January 2015. Injectable-naive T2D patients will be indetified.
Propensity score methods will be used to match Bydureon initiators with basal insulin
initiators.

Subgroup Comparisons: Within the EHR data, serum creatinine values will be used to calculate
the eGFR using an equation developed by the Chronic Kidney Disease (CKD) Epidemiology (EPI)
Collaboration, called the CKD-EPI Equation.

Renal Impairment: Patients will be stratified by eGFR ranges in baseline indicative of the
renal impairment, as follows:

- Normal, eGFR ≥ 90.00 mL/min/1.73m2

- Mild impairment, 60.00 < eGFR < 89.99 mL/min/1.73m2

- Moderate and Severe impairment, eGFR < 59.99 mL/min/1.73m2

Elderly T2D Patients: Elderly subgroups will be defined as 65+ years of age. Patients will be
stratified by age on index date, as follows:

- < 65 years

- 65 to 74 years

- 75+ years Outcomes and Analysis: To measure the effectiveness of Bydureon relative to
basal insulin are changes in HbA1c and body weight, as well as changes in HbA1c and
simultaneous reduction in weight. Changes in BMI, lipid profiles, and blood pressure
will be assessed. These variables are part of the clinical and laboratory data in the
EHR. Each outcome will be evaluated for completeness, multiply imputed, and reported
across standardized time intervals. HbA1c, weight and BMI will be summarized in baseline
and quarterly (3-month intervals) in the first year following drug initiation. Lipid
measurements and blood pressure will be summarized in baseline and bi-annually (6-month
intervals) in the first year following drug initiation.

To assess drug tolerability, incidence of hypoglycemia, and gastrointestinal symptoms
(nausea, vomiting, diarrhea, and constipation) will be calculated. These outcomes will be
ascertained using an ICD-9 algorithm applied to the structured fields and by extracting
mentions of hypoglycemia using a natural language processing (NLP) algorithm developed by
Optum and applied to the free text clinical notes available in the data. In addition the
stability of renal function evaluated by change in eGFR, or albumin/creatinine ratio (ACR);
the change in serum hepatic enzymes [aspartate aminotransferase (AST), alanine
aminotransferase (ALT)], and hematologic measures [red blood cells counts (RBC), white blood
cell counts (WBC), platelets (PLT), hemoglobin (Hgb) and hematocrit (Hct) will be evaluated.
Each of these laboratory values will be evaluated for completeness, multiply imputed, and
reported across standardized time intervals. eGFR and ACR are summarized in baseline and
quarterly (3-month intervals) in the first year following drug initiation. Hepatic enzymes
and hematologic measures are summarized in baseline and semi-annually (6-month intervals) in
the first year following drug initiation.

Inclusion Criteria:

- At least 18 years old;

- had received care documented in EHR (including at least one out-patient provider
visit) for a minimum of 6-months prior index date;

- had at least one diagnosis of Type 2 diabetes (ICD-9-CM: 250.X0 or 250.X2) prior to
and including the date of the study drug initiation, with no prior diagnosis of type1
diabetes (ICD-9-CM: 250.X1 or 250.X3), or gestational diabetes within the 6-months
prior to index date;

- No evidence of prior injectable antidiabetic treatment, specifically no dispensing of
a GLP-1-RA or any insulin during the 6-months baseline period prior to study drug
initiation

Exclusion Criteria:

- Prior diagnosis of type 1 diabetes (ICD-9-CM: 250.X1 or 250.X3), or gestational
diabetes within the 6-months prior to index date;

- Prior dispensing of a GLP-1RA or any insulin

- Missing data on renal function defined by eGFR or age