This randomized controlled trial evaluated the effects of exenatide once weekly (QW) compared to placebo on glycemic control in patients with type 2 diabetes already taking metformin. Over 10 weeks: 1) Exenatide QW significantly reduced 24-hour mean glucose levels, fasting plasma glucose, post-prandial glucose, and glucose fluctuations compared to placebo. 2) Exenatide QW significantly increased the amount of time patients spent in the target glycemic range without increasing hypoglycemia. 3) Glycemic control improvements with exenatide QW were seen as early as 4 weeks and continued to week 10, demonstrating a robust and sustained response.

1. *
*
Exenatide QW + MET (n=60) Placebo + MET (n=56)
Δin2-hPPG(mg/dL)
–32.1
–2.0
–44.4
–6.0
–60
–50
–40
–10
0
–20
–30
Week 4 Week 10
53.4%
46.5%
Baseline
Exenatide QW + MET Placebo + MET
Week 4
Week 10
22.0%
*
77.3%
*
28.5%
70.9%
*
*
54.8%
45.1%
60.2%
39.5%
58.0%
41.7%
>180 mg/dL
70–180 mg/dL
<70 mg/dL
Characteristic
Exenatide QW
+ MET
(n=60)
Placebo
+ MET
(n=56)
Age, y 55 ± 11 56 ± 10
Male, n (%) 33 (55.0) 32 (57.1)
Race, n (%)
White 52 (86.7) 46 (82.1)
Black or African American 3 (5.0) 5 (8.9)
Asian 3 (5.0) 4 (7.1)
Native Hawaiian or Pacific Islander 1 (1.7) 0 (0.0)
Other 1 (1.7) 1 (1.8)
Duration of diabetes, yb
9 ± 6 10 ± 8
MET dose, mg 1925 ± 180 1875 ± 218
Body weight, kg 90.5 ± 19.3 90.0 ± 19.1
BMI, kg/m2
32.0 ± 6.2 31.6 ± 5.4
A1C, % 8.2 ± 1.1 8.0 ± 0.9
FPG, mg/dL 178 ± 50 168 ± 54
2-h mean PPG, mg/dL 221 ± 54 221 ± 51
24-h mean glucose, mg/dL 186 ± 42 184 ± 43
MAGE 91 ± 28 90 ± 27
Data are mean ± standard deviation, unless otherwise noted.
a
One patient in the exenatide QW group was not treated due to pregnancy and excluded from the analysis.
b
Data not available for all patients. Exenatide QW + MET, n=58; placebo + MET, n=55.
A1C, glycated hemoglobin; BMI, body mass index; FPG, fasting plasma glucose; ITT, intent-to-treat;
MAGE, mean amplitude of glycemic excursions; MET, metformin; PPG, postprandial glucose; QW, once weekly.
Introduction
• Management of type 2 diabetes (T2D) has largely focused
on lowering glycated hemoglobin (A1C), which reports
glucose control over 2 to 3 months but not daily acute
excursions, and which has been shown to reduce the risk of
development and progression of diabetes complications1,2
• Control of daily glycemic fluctuations, including postprandial
glucose (PPG) excursions and hypoglycemia, with the goal
of better matching the glucose profile of individuals without
diabetes,3
may provide physiological benefit in addition to
A1C control
• The glucagon-like peptide-1 (GLP-1) receptor agonist
exenatide once weekly (QW) has been shown to reduce
hyperglycemia in a glucose-dependent manner and is
associated with weight loss and a low risk of hypoglycemia4
• Furthermore, a small substudy of the DURATION-1 trial
demonstrated that exenatide QW improved 24-h glucose
control, as measured by continuous glucose monitoring
(CGM)5
• This randomized controlled trial used CGM to investigate the
effects of exenatide QW compared with placebo on 24-h
glucose control and glucose fluctuations in patients with T2D
on metformin (MET) therapy
Effect of Exenatide Once Weekly on Glycemic Fluctuations in Patients With Type 2 Diabetes
Juan P. Frías,1
James A. Ruggles,2
Sergey Zhuplatov,2
Samer Nakhle,3
Eric Klein,4
Rong Zhou,5
Lei Shi,6
Poul Strange6
1
National Research Institute, Los Angeles, CA, USA; 2
AstraZeneca, Fort Washington, PA, USA; 3
Palm Research Center, Las Vegas, NV, USA; 4
Capital Clinical Research Center, Olympia, WA, USA; 5
Medpace, Cincinnati, OH, USA; 6
Integrated Medical Development, Princeton Junction, NJ, USA
117 Adult Patients
Age 18–75 y
A1C ≥7% to ≤10%
on MET XR
Background diabetes treatment
MET XR
Randomized Treatment
10-wk intervention period
Week
Follow-up
0
CGM CGM CGM
4 10
4-wk lead-in
period
Key Secondary End Points
• FPG after 4 and 10 weeks
• 2-h PPG after 4 and 10 weeks
• MAGE after 4 and 10 weeks
• 24-h mean glucose at first and
sixth days of the week after 10 weeks
• Proportion of time in glycemic ranges
after 4 and 10 weeks
Primary End Point
• Change in 24-h mean
glucose after 4 and 10
weeks
Exenatide QW 2.0 mg (n=61)
Placebo (n=56)
AEs in ≥5% of Patients
Exenatide QW
+ MET (n=60),
n (%)
Placebo
+ MET (n=56),
n (%)
Injection-site nodule 6 (10.0) 0 (0.0)
Nausea 4 (6.7) 0 (0.0)
Urinary tract infection 4 (6.7) 5 (8.9)
Diarrhea 3 (5.0) 2 (3.6)
Hematuria 3 (5.0) 0 (0.0)
Injection-site induration 3 (5.0) 3 (5.4)
Musculoskeletal pain 3 (5.0) 0 (0.0)
Proteinuria 3 (5.0) 1 (1.8)
1014-P
Methods
Table 2. Baseline Demographics and Characteristics (Modified
ITT Population)a
Results
Table 1. Patient Disposition
A1C, glycated hemoglobin; CGM, continuous glucose monitoring; FPG, fasting plasma glucose;
MAGE, mean amplitude of glycemic excursions; MET XR, metformin extended release;
PPG, postprandial glucose; QW, once weekly.
MET, metformin; QW, once weekly.
Exenatide QW + MET (n=60)
Placebo + MET (n=56)
–40
–30
–20
–10
0
–26.0
*
–5.3
–30.8
*
–3.0
Δin24-hglucose(mg/dL)
Week 4 Week 10
Figure 2. Exenatide QW Significantly Reduced 24-h Mean
Glucose Compared With Placebo at Day 6 of Weeks 4 and 10
Data are LS mean change from baseline ± standard error.
*P<0.001, treatment difference between LS mean changes from baseline.
Day 6 is estimated as the average of the 5th, 6th, and 7th day following a visit.
LS, least-squares; MET, metformin; QW, once weekly.
–20
–10
10
0
–8.2
–3.8
Exenatide QW + MET
Placebo + MET
–15.2
*
2.9
ΔinMAGE(mg/dL)
Week 4 Week 10
Figure 5. Exenatide QW Significantly Reduced MAGE
Compared With Placebo at Week 10
Safety and Tolerability
Table 3. Summary of Treatment-Emergent Adverse Events
Reported in ≥5% of Patients in Either Treatment Group
(Modified ITT Population)
Data are LS mean change from baseline ± standard error.
*P<0.001, treatment difference between LS mean changes from baseline.
LS, least-squares; MAGE, mean amplitude of glycemic excursions; MET, metformin; QW, once weekly.
–60
–50
–40
–30
–20
–10
0
10
15
–1.9
–29.6
–5.0
–41.9
22 57 64 701
*
*
ΔinFPG(mg/dL)
Study day
Placebo + MET (n=56)
Exenatide QW + MET (n=60)
Week 4Baseline Week 10
Data are LS mean change from baseline ± standard error.
Week 4 and Week 10 were secondary end points.
*P<0.001, treatment difference between LS mean changes from baseline.
FPG, fasting plasma glucose; LS, least-squares; MET, metformin; QW, once weekly.
Figure 3. Exenatide QW Significantly Reduced FPG Compared
With Placebo at Weeks 4 and 10
Figure 6. Proportion of Time Patients Spent in Hyperglycemic
(>180 mg/dL), Euglycemic (70–180 mg/dL), and Hypoglycemic
(<70 mg/dL) Ranges at Baseline and Weeks 4 and 10
Data are mean ± standard error (A), or LS mean change from baseline ± standard error (B).
*P<0.001, treatment difference between LS mean changes from baseline.
LS, least-squares; MET, metformin; PPG, postprandial glucose; QW, once weekly.
Data are mean proportions of time within a 24-h day.
*P<0.001, treatment difference between least-squares mean changes from baseline.
MET, metformin; QW, once weekly.
AE, adverse event; ITT, intent-to-treat; MET; metformin; QW, once weekly.
Conclusions
• Exenatide QW significantly reduced glycemic fluctuations
by multiple measures and significantly improved glycemic
control throughout the week
• Exenatide QW increased time in the euglycemic range
without increasing time in the hypoglycemic range
• Exenatide QW resulted in significant, clinically relevant
reductions in FPG and PPG at the first assessment at
Week 4 that continued to improve until steady state was
reached, as demonstrated by Week 10 reductions
• Exenatide QW was generally well tolerated
• The effect of exenatide QW on multiple measures of
glycemic control provides reassurance to clinicians on the
robust responses demonstrated as early as Week 4 and
sustained via the continuous presence of exenatide
Presented at the American Diabetes Association’s 76th Scientific Sessions (ADA 2016), New Orleans, LA, June 10–14, 2016.Supported by:
• Beginning at the first lead-in visit, patients with T2D were counseled on
medical nutrition and exercise
• Following lead-in, patients with T2D inadequately controlled on
background MET therapy (A1C of 7.0–10.0%) were randomized 1:1 to
double-blinded treatment with exenatide QW 2.0 mg plus open-label
MET extended release (XR) 1500 or 2000 mg once daily, or placebo
(matched to exenatide powder) plus MET XR for 10 weeks
• Glucose concentration was measured every 5 min over 7 days during
the last week of lead-in (baseline) and at Weeks 4 and 10 using a
Dexcom G4®
CGM system (Dexcom, San Diego, CA, USA)
• CGM data were analyzed for the change from baseline to Day 6
of Week 4 and Day 6 of Week 10 in 24-h mean glucose (primary
outcome), 24-h mean amplitude of glycemic excursions (MAGE), the
proportion of time spent in glycemic ranges, and 24-h mean glucose at
the first day and sixth day of Week 10
• Fasting plasma glucose (FPG) and PPG (following a standardized
breakfast meal of ~700 kcal) were central laboratory measures obtained
from blood draws
Statistical Analyses
• Efficacy and safety were assessed in the modified intent-to-treat (ITT)
population, consisting of all randomized patients who received ≥1 dose
of study drug
• Change from baseline in 24-h mean glucose was analyzed using a
maximum likelihood-based mixed model repeated measures (MMRM)
method, with treatment, baseline A1C, baseline 24-h mean glucose,
week of visit, and treatment-by-week interaction as fixed effects and
patient and error as random effects
• A similar MMRM model was used to analyze change from baseline in
FPG, 2-h mean PPG, MAGE, and the proportion of time within glycemic
ranges, with the baseline level of the dependent variable as the fixed
effect
• Safety data were summarized as incidence
• The 24-h mean glucose concentrations (± standard deviation) with
exenatide QW were 150 ± 36 mg/dL at the first day and 151 ± 37 mg/dL
at the sixth day of Week 10, demonstrating consistent glycemic control
throughout the week
• Exenatide QW significantly increased time in the euglycemic range
versus placebo at Weeks 4 and 10
• Despite decreasing time spent in the hyperglycemic range, exenatide
QW did not increase time spent in the hypoglycemic range (inter-group
comparisons: Week 4, P=0.266; Week 10, P=0.180)
• Serious adverse events were observed in 4 patients in the exenatide
QW group (1 case each of acute pancreatitis, non-cardiac chest pain,
chest pain, and nephrolithiasis) and in 1 patient in the placebo group
(upper respiratory tract infection); all were considered by the investigator
to be unrelated to treatment
References
1. The Diabetes Control and Complications Trial Research Group.
N Engl J Med. 1993;329(14):977–986.
2. UK Prospective Diabetes Study (UKPDS) Group. Lancet.
1998;352(9131):837–853.
3. Suh S, et al. Diabetes Metab J. 2015;39(4):273–282.
4. Grimm M, et al. Postgrad Med. 2013;125(3):47–57.
5. Mazze R, et al. Endocr Pract. 2009;15(4):326–334.
Acknowledgments
The study (NCT02288273) was supported by AstraZeneca. The authors would
like to acknowledge Karen Goldsborough of AstraZeneca for her management
of study operations. Amanda Sheldon, PhD, CMPP, of inScience Communi-
cations, Springer Healthcare (Philadelphia, PA, USA), provided medical writing
support funded by AstraZeneca.
Figure 1. Randomized, Controlled, Double-Blind Study Design
Exenatide QW
+ MET
Placebo +
MET
Randomized n=61 n=56
Withdrew, n (%) 8 (13.1) 8 (14.3)
– Adverse event 3 (4.9) 2 (3.6)
– Lost to follow-up 2 (3.3) 3 (5.4)
– Pregnancy 1 (1.6) 0 (0.0)
– Protocol violation 1 (1.6) 0 (0.0)
– Withdrew consent 1 (1.6) 2 (3.6)
– Other 0 (0.0) 1 (1.8)
Completed, n (%) 53 (86.9) 48 (85.7)
Figure 4. Exenatide QW Significantly Reduced PPG Compared
With Placebo After a Standardized Breakfast Meal at Weeks 4
and 10
120
140
160
180
200
220
240
260
Time (hours)
PPGconcentration(mg/dL)
Placebo + MET (n=56)Exenatide QW + MET (n=60)
3
2
1
0.5
0
3
2
1
0.5
0
3
2
1
0.5
0
Week 4Baseline Week 10
A.
B.