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Original Article
Philip A. Levin, MD1; James H. Mersey, MD1;
Steven Zhou, PhD2; Lee A. Bromberger, BS1
Objective: To examine the long-term effects of combination insulin glargine/exenatide treatment on glycemic
Methods: We conducted a 24-month retrospective US
chart review of patients with inadequately controlled type 2
diabetes (T2DM) and hemoglobin A1c (A1C) levels >7.0%
for whom glargine and exenatide were coprescribed in differing order (glargine added after exenatide [exenatide/
glargine]; exenatide added after glargine [glargine/exenatide]). Treatment order groups were combined to form a
pooled treatment group. Changes from baseline in A1C,
patients with A1C ≤7.0%, body weight, glargine/exenatide
daily dose, oral antidiabetic drug (OAD) use, and hypoglycemia were evaluated.
Results: Treatment groups were similar at baseline;
however, patients in the glargine/exenatide group (n = 121)
(vs exenatide/glargine group [n = 44]) had longer disease
duration (11.8 vs 8.0 years) and took fewer OADs (1.7 vs
2.3). Overall, baseline A1C was 8.8 ± 1.3% and weight
was 109.5 ± 25.3 kg. Significant A1C reductions emerged
at month 6 and persisted throughout 24 months (vs baseline) in both treatment groups (pooled: –0.7 ± 1.6; P<.001),
and 33.0% of patients achieved an A1C level ≤7.0%. After
Submitted for publication April 6, 2011
Accepted for publication May 20, 2011
From 1MODEL Clinical Research, Baltimore, Maryland, and 2sanofi-aventis
U.S., Bridgewater, New Jersey.
Address correspondence to Dr. Philip A. Levin, MODEL Clinical Research,
Greater Baltimore Medical Center, 6535 N Charles St, Ste 400 N, Baltimore,
MD 21204. E-mail:
Published as a Rapid Electronic Article in Press at http://www. endocrine on July 8, 2011. DOI:10.4158/EP11097.OR
Copyright © 2012 AACE.
24 months of exenatide/glargine, body weight remained
unchanged (0.7 ± 8.3 kg; P = .640). With glargine/exenatide, body weight decreased (–2.5 ± 6.7 kg; P = .001). At
month 24, daily glargine dose was 0.40 ± 0.23 units/kg for
the exenatide/glargine group and 0.47 ± 0.30 units/kg for
the glargine/exenatide group. Hypoglycemia frequency
was similar in both treatment groups.
Conclusions: Regardless of treatment order, longterm combined therapy with glargine and exenatide for
up to 24 months in patients with inadequately controlled
T2DM suggests reduction of A1C without significant
weight gain or increased hypoglycemia risk. (Endocr
Pract. 2012;18:17-25)
A1C = hemoglobin A1c; OADs = oral antidiabetic
drugs; T2DM = type 2 diabetes mellitus
Over time and largely because of declining b-cell
function in type 2 diabetes mellitus (T2DM), lifestyle
modifications and oral antidiabetic drugs (OADs) become
less effective in achieving glycemic control, at which point
insulin therapy is typically considered (1,2). Current guidelines suggest adding a long-acting basal formulation to an
existing OAD regimen when initiating insulin therapy (3).
Because of its longer duration of action and lower risk
of hypoglycemia, insulin glargine may be preferred over
other insulin options (4-7). Glucagonlike peptide 1 analogues, such as exenatide, also are effective for reducing
hyperglycemia in patients with T2DM (3,8). Although
insulin therapy, including insulin glargine, reliably reduces
hemoglobin A1c (A1C) and fasting plasma glucose, it may
cause weight gain (3). Conversely, exenatide can significantly reduce weight, although a significantly lower glycemic efficacy was found in comparison with insulin glargine
(9,10). These complimentary clinical effects provide a
rationale for combining insulin glargine and exenatide in
patients with inadequate glycemic control despite OAD
Randomized and naturalistic, observational studies
generally have described favorable efficacy and safety with
this approach in patients with T2DM (11-15). In a 4-week,
randomized, open-label, proof-of-concept study in patients
with T2DM and inadequate glycemic control, Arnolds et al
reported significant reductions in postprandial blood glucose excursions (P<.01) and A1C levels (P<.0001) after the
addition of exenatide or sitagliptin to glargine + metformin
therapy (vs glargine + metformin only) (11). Significantly
greater weight loss was also seen with exenatide + glargine
+ metformin vs glargine + metformin (–0.9 vs 0.4 kg;
P<.05) (11). While encouraging, these results prompt the
question of whether the changes in A1C and weight from
combining exenatide with glargine could be maintained
for longer periods in a real-world setting. Moreover, the
clinical importance of the chronologic order in which insulin and exenatide are combined is unknown; investigators
have examined the impact of adding exenatide to an established insulin regimen, but the impact of adding glargine to
an existing regimen of exenatide is unknown.
The objective of this study was to examine the realworld use and outcomes after the combined use and different ordering of glargine and exenatide for up to 24
months—a longer duration than most previous observational studies—in patients with T2DM and inadequate glycemic control. This is the first study to evaluate the order
in which insulin and exenatide are combined during treatment. The naturalistic study design allows for the observation of therapeutic outcomes in a wider range of clinically
typical patients with T2DM.
Study Design
This was a naturalistic, retrospective, multicenter
study designed to evaluate and compare the effectiveness
of glargine and exenatide, each given as monotherapy
or added to an existing antidiabetic regimen that already
included the other. Clinical medical records of patients with
T2DM from 26 large endocrinology, internal medicine,
and family and primary care practices throughout the continental United States were reviewed from January 2005
through June 2010. Deidentified, extracted data included
assessment of glycemic control, body weight, medication
discontinuation, use of concomitant medications, and incidence of hypoglycemia for up to 24 months from baseline.
Treatment Groups
Four treatment groups were identified: 2 using glargine
or exenatide monotherapy and 2 using a combination of
glargine and exenatide therapy. This report focuses on data
from the 2 combination therapy groups. The 2 groups were
distinguished based on the order of prescribed treatment
and consisted of patients who initiated glargine before
adding exenatide (glargine/exenatide) and those who initiated exenatide before adding glargine (exenatide/glargine).
Once the patient first started either insulin glargine or
exenatide, the second agent could be added (glargine or
exenatide) to the patient’s regimen at any time the treating
physician thought it was clinically necessary without any
time restriction. During follow-up, there were no restrictions on the medications that treating physicians could prescribe once glargine or exenatide was added.
Inclusion Criteria
Selected patients with T2DM were aged 18 years or
older and had inadequate glycemic control (A1C >7.0%)
with oral therapy. Medical records were required to meet
the following criteria: available for 4 months before and 16
or more months after glargine or exenatide initiation; A1C
and body weight data available at baseline or from 4 weeks
before baseline or 10 or more days after baseline; and at
least 2 A1C values and 1 body weight measure recorded
during the 24-month follow-up period. For combination
treatment patients, the initial drug prescribed was required
to be continued at the time the second drug was added (eg,
baseline), and they could not have used the second drug
within the past 12 months. Patients with A1C levels of
7.0% or less, a terminal illness, or HIV/AIDS and pregnant
women were excluded.
Baseline Dates and Data Extracted
Baseline was established as the day glargine was first
added to the existing exenatide treatment or vice versa.
Data were extracted from the period 4 months before baseline to 16 or fewer months following baseline, until the
last date that data were available, regardless of whether
the treatment regimen was discontinued. Data obtained
included patient age, sex, body weight, duration of diabetes, A1C, duration of glargine and/or exenatide therapy,
and frequency of hypoglycemic episodes. Medical records
included information obtained from office visits, over-thephone medication dosage titrations, prescription refills,
and clinical laboratory reports.
Study Endpoints
Diabetes-related endpoints were examined at months
6, 12, 18, and 24 after the baseline date. Primary efficacy
outcomes included change from baseline in A1C concentration and percentage of patients achieving an A1C level
of 7.0% or lower. Secondary outcomes included weight and
blood pressure change from baseline, use of concomitant
OAD medications, therapy discontinuation, and total daily
glargine and/or exenatide dosing units. Also of interest was
the duration of A1C control (≤7.0%) during the follow-up
period. Hypoglycemic events were captured from patient
self-report and from glucose meter downloads, when available, or from in-office finger sticks. Severe hypoglycemia
was denoted by a call to 911 (emergency) and defined as an
episode during which the patient had a blood glucose reading less than 56 mg/dL, required assistance from others,
and recovered after administration of countermeasures.
Statistical Analyses
Analyses were performed on available data from all
patients treated with study medication as per protocol at
baseline, and who had at least 2 postbaseline A1C values.
For analysis, the 2 treatment-order groups were combined
to form a third, pooled combination-treatment group. For
all 3 groups, descriptive statistics (mean, standard deviation for continuous variables, and number and percentage for category variables) were determined for baseline
and outcome variables. For comparisons among treatment
groups at baseline, F tests were performed on continuous
variables while chi-square testing was performed on categorical variables. For comparisons of outcome variables
between the follow-up periods and baseline, the paired
t test was applied to the continuous variables while chisquare testing was applied to the categorical variables.
Demographic and Clinical Characteristics
Overall, 165 medical charts were identified in which
combination treatment was administered (exenatide/
glargine, n = 44; glargine/exenatide, n = 121). Table 1
summarizes the baseline demographic and clinical characteristics of each group. Patients in the exenatide/glargine
and glargine/exenatide treatment-order groups were similar with regard to baseline A1C, body weight, age, and sex
(race was not captured in the available medical records).
Similar proportions of patients in each treatment-order
group received concomitant metformin; the proportions
of patients receiving thiazolidinedione and/or sulfonylurea
therapy was more variable, but not significant. At baseline, however, patients in the glargine/exenatide group had
significantly longer diabetes duration than patients in the
exenatide/glargine group and were taking fewer OADs.
A1C Reductions
Regardless of the order in which glargine and exenatide were prescribed, combining these agents was associated with significant reductions in A1C from baseline
(exenatide/glargine, –1.0 ± 1.2%; glargine/exenatide,
−0.7 ± 1.7%; P<.001 for both). Fig. 1A illustrates that the
unadjusted reductions from baseline in A1C concentrations emerged at month 6 post baseline and were maintained throughout the 24-month observation period. For
the pooled combination-treatment group, reduction in A1C
was –0.7 ± 1.6% after 24 months. Beginning at month 6
after baseline and continuing throughout 24 months of
follow-up, the proportion of patients achieving an A1C
level of 7.0% or less ranged between 29.4% and 42.5% in
the exenatide/glargine group (24 months: 30.7%; P<.001)
and between 31.7% and 36.8% in the glargine/exenatide
group (24 months: 33.7%; P<.001) group (Fig. 1B). For
the pooled combination treatment group, proportions of
patients reaching an A1C level of 7.0% or less ranged from
31.7% to 37.1% throughout follow-up (24 month: 33.0%;
Body Weight
Overall, changes in body weight were observed within
the first 6 months of therapy and were maintained through
the 24-month endpoint (Table 2). By the 24-month followup, body weight was significantly lower than baseline in
the glargine/exenatide group (–2.5 ± 6.7 kg; P = .001).
Body weight remained statistically unchanged from baseline in the exenatide/glargine group after 24 months of continuous therapy (0.7 ± 8.3 kg; P = .640) (Fig. 2, Table 2).
Blood Pressure
In the exenatide/glargine group, systolic and diastolic
blood pressures were largely unchanged from baseline (ie,
P = not significant vs baseline) throughout the 24-month
follow-up period. Similarly, for the glargine/exenatide
group, clinically nonsignificant decreases from baseline in
blood pressure were observed throughout follow-up. For
the pooled combination-treatment group, systolic blood
pressure and diastolic blood pressure also were largely
unchanged from baseline throughout the 24-month observation period (Table 2).
Total Daily Exenatide Dose, Glargine Dose,
and Total Insulin Dose
In the exenatide/glargine group, a significant increase
from baseline in daily dose of exenatide (0.16 ± 0.05 vs
0.19 ± 0.05 mg/kg; P = .019) was observed at month 24.
Also at the 24-month follow-up, the daily glargine dose
was 0.40 ± 0.23 units/kg. At baseline, 1 patient was using
prandial insulin (daily dose: 0.07 ± 0 units/kg); by the
24-month follow-up, 8 patients used prandial insulin with
a total insulin dose (ie, glargine + prandial insulin) of 0.48
± 0.37 units/kg (Table 2).
In the glargine/exenatide group, a significant increase
from baseline in daily glargine dose (0.37 ± 0.21 units/kg
vs 0.47 ± 0.30 units/kg; P = .003) was observed at month
24. At month 24, the daily exenatide dose was 0.19 ± 0.05
mg/kg. At baseline, 24 patients were using prandial insulin (0.32 ± 0.21 units/kg); by the 24-month follow-up, 34
patients were using prandial insulin, with a total insulin
dose of 0.60 ± 0.45 units/kg (P = .002 vs baseline) (Table
Concomitant OAD Use
During the 24-month follow-up, the number of OADs
used gradually decreased in the exenatide/glargine group
from 2.1 ± 1.0 to 1.7 ± 1.0 OADs (vs baseline; P<.001). By
Table 1
Patient Demographics and Baseline Clinical Characteristics
Age, y
Mean (±SD)
Female, No. (%)
T2DM duration, y
Mean (±SD)
Hemoglobin A1c, %
Mean (±SD)
Body mass index, mean (±SD), kg/m2
Weight, kg
Mean (±SD)
Systolic blood pressure, mm Hg
Mean (±SD)
Diastolic blood pressure, mm Hg
Mean (±SD)
Insulin use, No. (%)
Insulin glargine daily dose/body weight, units/kg
Mean (±SD)
Prandial daily dose/body weight, units/kg
Mean (±SD)
Premix daily dose/body weight, units/kg
Mean (±SD)
Total insulin daily dose /body weight, units/kg
Mean (±SD)
Exenatide daily dose/body weight, μg/kg
Mean (±SD)
Metformin, No. (%)
Thiazolidinedione, No. (%)
Sulfonylureas, No. (%)
Number of OADs
Mean (±SD)
2 or more OADs, No. (%)
(n = 165)
(n = 44)
(n = 121)
59 (±9.6)
21 (47.7)
61 (±9.5)
69 (57.0)
60 (±9.5)
90 (54.5)
8.0 (±5.6)
11.8 (±7.1)
8.9 (±1.3)
36.2 (±6.7)
8.7 (±1.3)
38.1 (±6.6)
8.8 (±1.3)
37.6 (±6.7)
112.2 (±35.7)
108.4 (±20.4)
109.5 (±25.3)
130.0 (±17.2)
129.7 (±16.1)
129.8 (±16.4)
76.1 (±10.1)
3 (6.8)
76.0 (±12.2)
121 (100)
76.0 (±11.7)
0.37 (±0.21)
0.07 (±0.00)
0.32 (±0.21)
0.62 (±0.54)
0.07 (±0.00)
0.45 (±0.32)
0.16 (±0.05)
24 (54.5)
21 (47.7)
27 (61.3)
2.3 (±1.0)
35 (79.5)
P valuea
0.37 (±0.21)
0.62 (±0.54)
67 (55.3)
44 (36.3)
58 (47.9)
0.16 (±0.05)
91 (55.1)
65 (39.3)
85 (51.5)
1.7 (±1.0)
73 (60.3)
Abbreviations: NA, not applicable; OADs, oral antidiabetic drugs; T2DM, type 2 diabetes mellitus.
a P values based on comparisons of the combination groups with one another, using an F test for continuous variables and
chi-square test for categorical variables.
b Not applicable; pooled-combination group values for the indicated measures are not applicable, either because of baseline group definition (eg, not using insulin glargine or exenatide at baseline), or because a significant difference was detected between the treatment
Fig. 1. Hemoglobin A1c (A1C) outcomes during 24 months of combination therapy. Change in A1C (%)
from baseline (Panel A) and proportion of patients reaching A1C ≤7.0% at 6, 12, 18, and 24 months post
baseline (Panel B). a P<.001 vs baseline; b P<.001 vs baseline.
contrast, the number of OADs used in the glargine/exenatide group remained unchanged throughout the 24-month
follow-up vs baseline (1.7 ± 1.0 vs 1.7 ± 0.9 OADs; Table
Hypoglycemic events occurred in similar proportions
in the exenatide/glargine group (n = 5/44; 11.4%) and the
glargine/exenatide group (n = 15/121; 12.3%). The treatment-order groups were also similar in terms of number of
hypoglycemic events (4.0 ± 4.1 vs 3.1 ± 4.2), time to the
first hypoglycemic episode (203.4 ± 190.8 days vs 228.9 ±
202.8 days), and hypoglycemic blood glucose values (57.2
± 7.5 mg/dL vs 52.0 ± 12.1 mg/dL). For the pooled combination-treatment group, the mean number of days to a first
hypoglycemic event was 222.5 ± 195.2 and the hypoglycemic blood glucose value was 53.3 ± 11.2 mg/dL. Reported
cases of severe hypoglycemia were rare over the 24-month
period; in the exenatide/glargine group, 1 patient called the
physician, and in the glargine/exenatide group, 3 patients
called 911 for emergency medical assistance.
Treatment Discontinuation at Month 24
Regardless of treatment order, most patients continued
with the combined treatment for up to 12 months. In both
groups, most discontinuations of 1 or the other medication
occurred between follow-up months 18 and 24. At month
24, 16 of 44 patients in the exenatide/glargine group had
discontinued 1 or the other injectable medication (36.4%;
n = 4 glargine discontinuation, n = 12 exenatide discontinuation) and 51 of 121 patients in the glargine/exenatide
group had discontinued 1 or the other medication (42.1%;
n = 11 glargine discontinuation, n = 40 exenatide discontinuation). Overall, 15 (9.1%) and 52 (31.5%) patients discontinued glargine and exenatide therapy, respectively, by
the month 24 follow-up. Although the reasons associated
Fig. 2. Body weight (kg), change from baseline. White columns: exenatide therapy
was started first followed by the addition of insulin glargine. Gray columns: insulin
glargine therapy was started first followed by the addition of exenatide. a P<.001 vs
baseline; b P = .001 vs baseline.
with discontinuation of either medication were to be
extracted from the medical records, they frequently were
not available.
This 24-month naturalistic study demonstrated that in
patients with inadequately controlled T2DM taking OADs,
combining glargine and exenatide, regardless of the chronologic order in which they were prescribed, significantly
reduced A1C, with 31% to 34% of patients achieving a
A1C level of 7.0% or less. Moreover, the clinical benefits
of combined glargine and exenatide therapy were maintained during the 24-month treatment.
Body weight and blood pressure values at month 24
were either unchanged from baseline (with exenatide/
glargine) or slightly decreased (with glargine/exenatide).
Because patients who had glargine added to exenatide were
already slightly heavier at baseline than those who added
exenatide to glargine (by ~4 kg), the lack of significant
weight gain with the addition of glargine is clinically significant because it suggests that patients on this therapeutic combination may achieve A1C goals without incurring
additional risks of significant weight gain over a 24-month
period and in terms of patient adherence to the combined
therapy. Therefore, the weight increase sometimes seen
with the addition of glargine may be balanced by the
weight-reducing effects of exenatide, making the combination therapy weight neutral. Patients in the glargine/exenatide group experienced an average loss of –2.5 kg with up
to 24 months of combination therapy. This suggests that
exenatide may be useful for patients on an established regimen of glargine who may benefit from weight loss and
who have suboptimal glycemic control. This weight loss
is slightly less than that reported previously with longerterm treatment (~5-6 kg) (12-14), but may be due to the
current patient sample having a lower baseline body mass
index (overall body mass index at baseline: 37.6 ± 6.7 kg/
m2) than in 2 of the 3 previous studies where the mean
baseline body mass index was 39.0 and 43.6 kg/m2 (12,14).
Overall, these findings suggest that combining exenatide
and glargine can positively affect glycemic control without significantly affecting weight gain during a 24-month
Reported episodes of hypoglycemia were of similar
frequency and severity (based on reported hypoglycemic
blood glucose values) in both treatment-order groups, with
11% to 12% of patients in either group experiencing at least
1 hypoglycemic episode during the 24-month follow-up.
This frequency was similar to the 10% previously reported
in a retrospective chart review (13,16).
In the present analysis, the 2 treatment-order groups
exhibited similar, significant, and durable improvements
in glycemic control on the basis of A1C and the proportion of patients achieving a target A1C of less than 7.0%.
In the pooled combination-therapy group at the 24-month
follow-up, A1C levels were significantly reduced from
baseline (–0.7 ± 1.6%) and 33% of patients achieved a target A1C level less than 7.0%. These results are consistent
with a 30-week, randomized, controlled study by Buse et al
(17) who reported that A1C decreased by 1.74% (baseline:
8.35%) and weight decreased by 1.8 kg (baseline: 95.4 kg;
baseline body mass index: 33.8 kg/m2) after the addition of
exenatide to insulin glargine therapy (17).
The findings from the present analysis are also similar to those of previous chart reviews of insulin/exenatide
combination therapy (12-14). With length of follow-up
varying from 26 weeks (12) to 27 months (14), endpoint
A1C reductions persisted with longer-term treatment,
ranging between 0.54% (14) and 0.87% (13). Moreover,
the proportion of patients achieving a target A1C level less
than 7.0% in the analysis by Sheffield et al (37%) (13) was
Table 2
Summary of Key Outcomes Over 24 Months of Follow-up
Glycemic control
A1C change, mean (±SD), %
A1C ≤7.0%, No. (%)
Weight change, mean (±SD), kgb
Blood pressure, mean (±SD), mm Hg
Total daily dose, per kg, mean (±SD)b
Insulin glargine, units
Prandial insulin, units
Total insulin, units
Exenatide, mg
No. of OADs used, follow-up, mean (±SD)b
Metformin, No. (%)
Thiazolidinedione, No. (%)
Sulfonylureas, No. (%)
Glycemic control
A1C change, mean (±SD), %
A1C ≤7.0%, No. (%)
Weight change, mean (±SD), kgb
Blood pressure, mm Hg
Total daily dose, per kg, mean (±SD)b
Insulin glargine, units
Prandial insulin, units
Total insulin, units
Exenatide, mg
No. of OADs used, mean (±SD)b
Metformin, No. (%)
Thiazolidinedione, No. (%)
Sulfonylureas, No. (%)
All treatment-order patients, pooled
Glycemic control
A1C change, mean (±SD), %
A1C ≤7.0%, No. (%)
Blood pressure, mean (±SD), mm Hg
6 Months
12 Months
18 Months
24 Months
n = 44
n = 43
n = 40
n = 30
–1.0 (±1.3)a
10 (29.4)a
0.6 (±3.6)
–0.9 (±1.2)a
17 (42.5)a
0.6 (±5.0)
–0.9 (±1.3)a
14 (37.8)a
1.4 (±5.8)
–1.0 (±1.2)a
8 (30.7)a
0.7 (±8.3)
129.8 (±15.1)
76.0 (±9.6)
129.4 (±19.8)
77.9 (±8.1)
128.5 (±13.7)
75.7 (±9.5)
128.9 (±14.3)
75.8 (±8.4)
0.22 (±0.11)
0.12 (±0.09)
0.26 (±0.18)
0.16 (±0.05)
0.33 (±0.19)
0.32 (±0.36)
0.40 (±0.38)
0.17 (±0.05)
0.36 (±0.22)
0.24 (±0.29)
0.44 (±0.34)
0.16 (±0.05)
0.40 (±0.23)
0.27 (±0.28)
0.48 (±0.37)
0.19 (±0.05)c
2.1 (±1.0)
29 (65.9)
17 (38.6)
27 (61.3)
2.0 (±1.0)
29 (67.4)
13 (30.2)
22 (51.1)
2.0 (±1.0)
26 (65.0)
12 (30.0)
21 (52.5)
1.7 (±1.0)d
20 (66.6)
9 (30.0)
13 (43.3)
n = 121
n = 121
n = 112
n = 106
–0.8 (±1.5)a
31 (32.6)a
–1.8 (±3.6)a
–0.8 (±1.3)a
33 (31.7)a
–2.3 (±5.3)a
–0.7 (±1.3)a
35 (36.8)a
–2.5 (±5.7)a
–0.7 (±1.7)a
26 (33.7)a
–2.5 (±6.7)d
128.9 (±17.2)
73.1 (±10.8)
128.5 (±17.4)
74.6 (±11.2)
127.9 (±17.6)
73.3 (±10.1)
125.4 (±14.5)
72.7 (±7.8)
0.40 (±0.22)c
0.31 (±0.28)
0.52 (±0.38)d
0.15 (±0.04)
1.7 (±1.0)
69 (57.0)
44 (36.3)
57 (47.1)
0.42 (±0.25)c
0.27 (±0.29)
0.53 (±0.37)d
0.18 (±0.05)
1.6 (±1.0)
67 (59.8)
36 (32.1)
44 (39.2)
0.46 (±0.26)a
0.28 (±0.26)
0.59 (±0.42)a
0.18 (±0.05)
1.6 (±0.9)
67 (63.2)
32 (30.1)
40 (37.7)
0.47 (±0.30)d
0.30 (±0.27)
0.60 (±0.45)d
0.19 (±0.05)
1.7 (±0.9)
47 (57.3)
26 (31.7)
29 (35.3)
n = 165
n = 165
n = 155
n = 146
–0.8 (±1.3)a
50 (34.7)a
–0.8 (±1.3)a
49 (37.1)a
–0.7 (±1.6)a
34 (33.0)a
128.7 (±18.0)
75.5 (±10.5)
128.0 (±16.6)
73.9 (±10.0)
126.2 (±14.5)
73.4 (±8.0)
–0.9 (±1.4)a
41 (31.7)a
129.1 (±16.6)
73.9 (±10.5)
Abbreviations: A1C, hemoglobin A1c; OADs, oral antidiabetic drugs; SD, standard deviation.
a P<.001 vs baseline.
b Because of the differences between the treatment-order groups at baseline and during follow-up in patterns of weight change,
insulin glargine and exenatide dosing, and the number of OADs used, data for these variables are not provided for the pooled
combination-treatment group.
c P≤.02 vs baseline.
d P≤.003 vs baseline.
similar to that observed in the present analysis at endpoint
(33%). In a prospective, uncontrolled, naturalistic medical chart review of insulin/exenatide combination therapy,
Nayak et al (15) showed that adding exenatide to insulin
therapy significantly decreased A1C at 3 months’ followup (8.4 ± 1.8; P = .001), but the decreases were similar to
baseline values after 1 year (9.1 ± 2.0; P = .74) (15). Body
weight, daily insulin dose, and blood pressure were significantly reduced at the 1-year follow-up (P<.05). However,
the specific type(s) of insulin taken was not noted and
65% of patients were taking large doses of insulin (>100
units daily) at baseline (15). These observational studies
and the current results suggest that combination glargine/
exenatide treatment leads to significant and durable glycemic improvements over time. Findings from the present
investigation, which was the first to examine the order in
which glargine and exenatide are added to an antidiabetic
regimen using a naturalistic study design, demonstrate that
A1C improvements occur regardless of the order in which
these medications are prescribed and administered.
Exenatide dosing throughout the follow-up period was
largely constant, considering initial upward titration, with
the average daily exenatide dose at 0.19 mg/kg at month 24
for both treatment-order groups. Of note, there was more
than a 3-fold greater rate of discontinuation among patients
who had received exenatide vs the discontinuation rate
of those who had received glargine. It was expected that
patients in the glargine/exenatide group (eg, patients with
an established insulin regimen at baseline) may require
lower total daily insulin doses after adding exenatide on the
basis of previous reports by Sheffield (13) and Yoon (14),
who found reduced prandial insulin requirements with
such treatment. In the present investigation, however, the
prandial insulin dose remained constant, and the total daily
insulin dose and total daily glargine dose showed clinically
small but significant increases from baseline in this group.
Nevertheless, these patients had an 11.8-year history of
T2DM at baseline, and progressing disease severity may
have made such dosing increases necessary. Moreover,
patients in the glargine/exenatide group exhibited less sulfonylurea and thiazolidinedione use, with a slightly higher
proportion taking metformin at the 24-month endpoint,
although the average number of OADs used did not change
during follow-up. This relative lack of change in OAD use
may reflect the potentially more advanced state of illness
in these patients. Similar total daily insulin doses (0.48
units/kg) and changes in OAD use were seen at month 24
among exenatide/glargine patients, marked by relatively
larger decreases in sulfonylurea and thiazolidinedione use,
and by increases in the use of metformin. In this group,
the number of OADs used was significantly decreased during follow-up (2.3 vs 1.7), which may have contributed
to increased requirements for basal and prandial insulin.
Relative to the glargine/exenatide group, it is reasonable
to hypothesize that these patients may have exhibited less
advanced disease at baseline (8.0- vs 11.8-year diabetes
history) and may have responded more favorably to combination therapy.
The present study has several limitations. This was a
retrospective chart review that lacked a comparison group,
such as patients who continued their baseline antidiabetic
treatment regimen. Thus, it is possible that treatment patterns and subsequent outcomes may have been influenced by
individual physician preferences for particular medication
combinations/doses. Findings based on the overall pooled
combination-therapy group should also be interpreted with
caution, because the groups who pooled together differed
from one another in certain parameters at baseline (eg, diabetes duration, number of OADs used) and during followup. Baseline differences in the number of patients in each
group and in illness duration and treatment pattern between
the groups may account for some of the differences in outcomes. The patients in the glargine/exenatide group may
have been sicker, given their nearly mean 12 years of diabetes duration vs 8 years for the patients in the exenatide/
glargine group. Information regarding patients’ race was
not available for evaluation. Furthermore, adverse events
(other than hypoglycemia) and reasons for discontinuation
associated with combination therapy were not systematically determined, and hypoglycemia was based on patient
report, possibly resulting in underestimation. Nevertheless,
the naturalistic, observational nature of the investigation
provides a snapshot of how a heterogeneous population
of patients with poorly controlled T2DM may respond to
combined glargine and exenatide therapy in real-world
clinical settings, thus providing a more realistic observation of therapeutic responses over a larger sample of the
treatment population.
The combination of glargine and exenatide, regardless
of the chronologic order of their addition to the therapeutic
regimen, significantly improved A1C and glycemic goal
attainment (A1C ≤7.0%) without additional risk of weight
gain. This evaluation also suggested no increased risk of
hypoglycemia. Combination glargine/exenatide therapy
also may help stabilize insulin dose and blood pressure
while reducing OAD therapy. Thus, it represents an effective, persistent, and well-tolerated strategy for achieving
measurable clinical benefits in patients with poorly controlled T2DM already receiving glargine or exenatide
monotherapy. The results of this retrospective naturalistic
study suggest that combining glargine and a glucagonlike
peptide 1 analogue, such as exenatide, has clinical benefits
and that further examination in randomized clinical trials is
Study funding was provided by sanofi-aventis U.S.
Editorial support was provided by Richard Fay, PhD, and
Eleanor O’Rangers, PharmD, of Embryon, LLC, and was
funded by sanofi-aventis U.S. The authors, however, were
fully responsible for all content and editorial decisions and
received no financial support or other form of compensation related to the development of this article. Preliminary
results from this study were presented in abstract and
poster form at the annual meeting of the American Diabetes
Association, June 25-29, 2010, in Orlando, Florida.
Dr. Levin is a consultant to sanofi-aventis U.S. Dr.
Zhou is an employee of sanofi-aventis U.S. Dr. Mersey and
Mr. Bromberger have no multiplicity of interest to disclose.
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