Journal of Diabetes Mellitus, 2018, 8, 152-159

http://www.scirp.org/journal/jdm
ISSN Online: 2160-5858
ISSN Print: 2160-5831

Marked Improvement in Glycemic Control

with Exenatide on Addition to Metformin,
Sulfonylurea and Insulin Glargine in Type 2
Diabetes Mellitus, a Real World Experience

Salina Esmail1, Sonal Banzal2, Udaya M. Kabadi2,3*

1
University of Iowa, Iowa City, IA, USA
2
MGM College of Medicine, Indore, India
3
Broadlawns Medical Center, Des Moines, IA, USA

How to cite this paper: Esmail, S., Banzal, S. Abstract

and Kabadi, U.M. (2018) Marked Improve-
ment in Glycemic Control with Exenatide on Background: The major effect of Exenatide is attributed to lowering of
Addition to Metformin, Sulfonylurea and post-prandial glycemia, whereas insulin glargine mainly improves fasting
Insulin Glargine in Type 2 Diabetes Mellitus,
glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide
a Real World Experience. Journal of Diabetes
Mellitus, 8, 152-159. administration at 6 months and for at 1 year on glycemic control, lipids, body
https://doi.org/10.4236/jdm.2018.84015 weight [BW], daily insulin dose and hypoglycemic events. Methods: Records
of 164 subjects, 126 men and 38 women administered Exenatide between
Received: August 27, 2018
Accepted: November 12, 2018
January 2011 and December 2013 are included in this report. Exenatide was
Published: November 15, 2018 initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI >
30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving
Copyright © 2018 by authors and
daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glar-
Scientific Research Publishing Inc.
This work is licensed under the Creative gine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver en-
Commons Attribution International zymes > 2.5 times upper limit of normal. Indices of glycemic control include
License (CC BY 4.0). fasting plasma glucose levels and HbA1c. Lipids include serum concentra-
http://creativecommons.org/licenses/by/4.0/
tions of total, LDL and HDL cholesterol. Other endpoints are body weight,
Open Access
daily insulin dose and number of hypoglycemic events per patient during 4
weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Re-
sults: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks; 29 due to
onset of nausea and vomiting. Seven of these also complained of abdominal
pain and in these, serum amylase and lipase were elevated indicating presence
of acute pancreatitis. One subject discontinued because of chest pain. Fasting
plasma Glucose remained unchanged following Exenatide administration.
However, HbA1c declined significantly denoting improvement in overall
glycemic control without significant changes in body weight, daily insulin

DOI: 10.4236/jdm.2018.84015 Nov. 15, 2018 152 Journal of Diabetes Mellitus

 S. Esmail et al.

dose and hypoglycemic events. Lipid panel improved as well. Conclusion:

Exenatide may be an appropriate adjuvant option in obese subjects with Type
2 diabetes mellitus with lack of desirable glycemic control while receiving
therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, im-
provement in glycemic control is likely to be secondary to lowering of post
prandial hyperglycemia induced by Exenatide.

Keywords
Type 2 Diabetes Mellitus, Glycemic Control, Insulin Glargine, Metformin,
Sulfonylurea, Exenatide

1. Introduction
Exenatide is an incretin mimetic, having glucoregulatory activities similar to
those of naturally occurring mammalian hormone GLP-1 secreted by L cells lin-
ing the ileum and jejunum in response to meal [1] [2] [3]. GLP1 enhances glu-
cose-dependent insulin secretion by beta cells while simultaneously inhibiting
glucagon release by alpha cells both residing in pancreatic islets [2]-[7]. Moreo-
ver, exenatide delays gastric emptying [2]-[7]. Finally, data in animal models as
well as humans indicate that both native GLP1 and GLP1 receptor agonists cause
weight loss by reducing food intake via stimulation of satiety center [8]-[14].
However, Exenatide has a greater potency and a longer duration of action in
comparison to the native GLP-1 when administered subcutaneously [4].
The major effect of Exenatide in improving glycemic control in subjects with
type 2 diabetes is attributed to lowering of post-prandial glucose [PPG] concen-
tration [9]-[17]. Therefore, we examined the effect of administration of Exena-
tide on indices of glycemic control in subjects with type 2 diabetes with desirable
fasting plasma glucose levels, but still elevated HbA1c concentrations while re-
ceiving insulin Glargine, Glimepiride and Metformin.

2. Subjects and Methods

Data was collected retrospectively by examining the records of 164 obese sub-
jects, 126 men and 38 women with type 2 diabetes attending diabetes clinics at 2
academic medical centers during a period of 6 years between January 2011 and
December 2016. The study protocol was approved by Institutional Review
Boards at both medical centers. The major inclusion criterion was the records of
subjects in whom therapy with Exenatide was initiated because of failure in at-
taining desirable HbA1c levels < 7.0% as recommended by American Diabetes
Association [18] despite achieving desirable fasting plasma glucose concentra-
tions, 90 - 130 mg/dl while receiving p maximum daily dose of Glimepiride, 8
mg; Metformin 1000 - 2000 mg as tolerated and insulin Glargine administered
subcutaneously in AM. The other inclusion criteria were obesity with BMI > 30
kg/m2, C-peptide > 1 ng/dl, HbA1c levels ranging between 7.5% - 9.0% at initia-

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S. Esmail et al.

tion and minimum duration of 1 year while receiving combination therapy. This
range of HbA1c was chosen because post prandial glycemia is documented to be
a major contributor to this range of HbA1c levels [19]. Moreover, fasting plasma
glucose in the desirable range of 80 - 130 mg/ dl confirms the contribution of
post prandial hyperglycemia to elevated HbA1c levels in subjects included in this
study. Exclusion criteria were serum creatinine levels > 1.5 mg/dL and liver en-
zymes > 2.5 times upper normal limit.
Adjunctive therapy with Exenatide was elected because the major effect of
Exenatide is well established to lower post prandial hyperglycemia [9]-[17]. Ex-
enatide was administered subcutaneously with initial dose, 5 mcg twice daily
prior to breakfast and supper. The dose was increased to 10 mcg twice daily after
2 - 4 weeks if the initial dose was tolerated without nausea, vomiting, diarrhea or
abdominal pain. Concomitant therapy with same oral agents; metformin, Gli-
mepiride and insulin Glargine was continued for at least one year. The daily
dose of insulin Glargine was adjusted as required on onset of hypoglycemia as
documented by presence of symptoms accompanied by blood glucose level < 60
mg/dl determined by self blood glucose monitoring. Data includes indices of
glycemic control e.g. HbA1c, fasting plasma glucose levels as well as serum con-
centrations of total, LDL and HDL cholesterol, urea nitrogen, creatinine and liv-
er enzymes. Daily insulin dose, body weight and all other parameters were de-
termined prior to initiation of Exenatide and again at 6 months and 1 year.
Number of hypoglycemic events during 4 weeks prior to initiation of Exenatide
and at the end of 1 year of therapy is reported as well. Comparisons between
glycemic and other outcomes prior to initiation of exenatide and at 6 months
and 1 year following the adjunctive therapy were conducted by statistical analys-
es using Student’s “t” test and analysis of variance.

3. Results
Population comprised 164 adult subjects, 126 men and 38 women with ages, 34 -
72 years. Diagnosis of type 2 Diabetes was established by documentation of de-
sirable glycemic control while receiving oral agents for several years as well as
fasting c-peptide concentration > 1 ng/dl. Duration of diabetes ranged between 8
- 20 years. 127 subjects were noted to complete a year of combination therapy
(77%) whereas in 37 subjects (23%), Exenatide was discontinued within 1 - 3
weeks; in 36 subjects because of onset of abdominal pain and/or nausea and/or
vomiting. In 7 of these subjects, further evaluation revealed elevated serum
amylase and lipase levels indicating presence of acute pancreatitis. One subject
discontinued because of chest pain. Thus, Exenatide was withdrawn soon after
initiation because of onset of adverse event.
Fasting plasma glucose concentrations remained between 80 - 130 mg/dl in all
subjects (Table 1). However, HbA1c levels declined in all subjects by 6 months
and lower concentrations were maintained at 1 year (Table 1). Desirable HbA1c
concentration < 7% was attained and maintained in 87% of subjects while re-
maining subjects achieved HbA1c levels below 7.6%.

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 S. Esmail et al.

Table 1. Fasting Plasma Glucose (FPG), HbA1c, lipid panel, body weight, daily insulin
dose and hypoglycemic events per patient during 4 weeks prior to initiation (pre Rx) and
again at 6 months and 1 year after (post Rx ) treatment with Exenatide.

PostRx Post Rx
PreRx
6 months 1 year
FPG (mg/dl ) 112 ± 6 105 ± 5 109 ± 8

HbA1c (%) 8.1 ± 0.2 6.7 ± 0.1* 6.8 ± 0.1*

Total Cholesterol (mg/dL) 152 ± 12 129 ± 10 125 ± 9†

Triglycerides (mg/dL) 269 ± 41 205 ± 38 198 ± 36*

HDL (mg/dL) 35 ± 2 38 ± 3 37 ± 3

LDL (mg/dL) 80 ± 16 75 ± 11 81 ± 10

Body weight (kg) 134 ± 7 138 ± 8. 135 ± 9

Insulin (units/day) 101 ± 22 93 ± 19 96 ± 18

Hypo G/patient 2.3 ± 0.4 1.9 ± 0.6 2.1 ± 0.5

*p < 0.01 vs Pre Rx, †p < 0.05 vs Pre Rx.

Serum cholesterol and triglyceride levels declined by 6 months with im-

provement being maintained at 1 year while no significant alterations were do-
cumented in LDL and HDL cholesterol concentrations (Table 1).
Mean body weights prior to initiation of Exenatide and at 6 months and 1 year
following therapy were not significantly different (Table 1). However, the change
in body weight was not consistent with a weight gain 1 - 3 kg noted in 56 sub-
jects and a weight loss of 0.8 - 2.2 kg in the remaining 72 subjects. Finally, mean
daily insulin glargine dose appeared to decline on addition of Exenatide (Table
1). However, daily doses at initiation of Exenatide and at 6 months and 1 year
following treatment were not significantly different (Table 1). Finally, hypogly-
cemic events during last 4 weeks of both phases of treatment, prior to initiation
of Exenatide and at the end of 1 year were not significantly different (p > 0.10).

4. Discussion
This study documented exenatide withdrawal due to onset of established adverse
effects of intolerable abdominal pain, nausea or vomiting in 22.6% of subjects.
Moreover, acute pancreatitis occurred in 7 of 127 subjects. Both these observa-
tions are consistent with previous data in several studies [11]-[17] [20].
This study also demonstrates that in subjects with type 2 diabetes, addition of
exenatide to background therapy consisting of Metformin, Sulfonylurea and
basal insulin glargine leads to marked improvement in glycemic control as ex-
pressed by a significant lowering in HbA1c (Table 1). This finding is consistent
with previous data in the literature including several clinical trials [11]-[17]. Im-
provement in glycemic control with lowering of HbA1c may be attributed to re-
duction in post prandial hyperglycemia since fasting plasma glucose concentra-
tions were unchanged. Moreover, major physiologic effect of exenatide in lo-
wering post prandial glycemia via stimulating insulin secretion and inhibiting

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S. Esmail et al.

glucagon release is well established [2]-[7]. Finally, the role of lowering of post
prandial hyperglycemia in the decline in HbA1c is also consistent with previous
documentation of post prandial glycemia being the major contributor to HbA1c
levels noted in subjects prior to initiation of exenatide in this study [19].
This study documents mixed results in terms of the lipid panel; a significant
reduction in total cholesterol and triglyceride levels with no significant altera-
tions in LDL and HDL cholesterol concentrations. These results are apparently
analogous to two other prospective studies [12] [14], although in contrast to
another study, it documented decline in the HDL levels following treatment with
exenatide [8]. Lowering of total cholesterol and triglyceride levels may be attri-
buted to improvement in glycemic control as previously documented [21] [22]
[23] [24] [25].
In this study, significant change in body weight was not documented in sub-
jects as a group. Insignificant weight gain in some subjects and similar weight
loss in others may have contributed to this finding. However, this observation is
consistent with the data regarding body weight in the original pre-marketing
clinical trial [12]. In this trial, marked weight loss documented in subjects con-
tinuing exenatide despite experiencing adverse side effects may have contributed
to significant decline in mean body weight as minimal change in body weight
was evident in other subjects tolerating the drug. Similar significant weight loss
was noted in subjects using exenatide in another study [11]. However, data
lacked detailed information regarding body weights in individual subjects. The
differences in changes in body weights observed in some other studies as well
[12] [13] [14] [15]. This inconsistent findings regarding changes in body weights
may be attributed to the different times during the day at which exenatide was
administered coupled with various other factors, such as lack of exercise or se-
dentary lifestyle. Another potential reason for lack of significant changes in body
weight in subjects in this study is the lack of requirement of bed time snack due
to almost negligible onset of nocturnal hypoglycemia secondary to administra-
tion of insulin Glargine U100 or insulin Glargine U300 in AM as opposed to
bedtime documented in previous studies [26] [27] [28] [29]. Weight gain no-
ticed in subjects receiving insulin glargine at bedtime may be due to a consump-
tion of a snack following insulin administration because of the concern of noc-
turnal hypoglycemia on part of both patients and providers alike especially be-
cause of a fairly large dose required by most obese subjects with type 2 Diabetes.
Finally, lower daily insulin dose on addition of exenatide noted in this and other
studies may contribute to lack of weight gain as well [11]-[17].
In final analysis, in patients with type 2 DM with poorly controlled glycemic
levels while receiving combination treatment with insulin glargine, metformin
and Glimepiride , addition of exenatide induced a marked reduction in HbA1c,
serum cholesterol and triglyceride levels. Moreover, this improvement occurred
without both the weight gain and a significant rise in hypoglycemia, a distinct
advantage over administration of rapid acting insulin to lower post prandial
hyperglycemia. Therefore, addition of exenatide or another GLP 1 receptor

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 S. Esmail et al.

agonist may be preferred to use of rapid acting insulin in subjects with type 2
diabetes with lapse of glycemic control while receiving metformin, Glimepiride
and basal insulin Glargine.
However, this study has several limitations including retrospective observa-
tional nature, lack of comparisons with either placebo or other oral agents e.g.
DPP4 inhibitors or injectable rapid acting insulin, well established strategies for
lowering postprandial hyperglycemia. However, the findings are important since
use of ezenatide or other GLP1 receptor agonist may be preferential to rapid
acting insulin, especially in obese subjects with diabetes because of their benefi-
cial effect on body weight and hypoglycemia. This beneficial effect in terms of
hypoglycemia is distinctly crucial in elderly because of frequent presence of hy-
poglycemia unawareness rendering onset of hypoglycemia detrimental to well
being resulting in a seizure, a stroke, acute coronary event, arrhythmia and even
death.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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