Evolution of Biochemical Effects of Byetta<sup>®</sup> in Type 2 Diabetics with Cardiovascular Risk

doi:10.4236/pp.2013.49094

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Pharmacology & Pharmacy, 2013, 4, 679-683

Published Online December 2013 (http://www.scirp.org/journal/pp)

http://dx.doi.org/10.4236/pp.2013.49094

Open Access PP

679

Evolution of Biochemical Effects of Byetta® in Type 2

Diabetics with Cardiovascular Risk

Alfonso López Ruiz1, María Ángeles Ibáñez Gil2, Pedro Pujante Alarcón3, Alicia Hernández Torres4,

Ana Belen Hernández Cascales3, María Dolores Hellín Gil3

1Pharmaceutical Care Research at the University of Granada, Granada, Spain; 2Health Center Mariano Yago, Yecla, Murcia, Spain;

3Endocrinology and Nutrition Service of the Hospital University Virgen de la Arrixaca, Murcia, Spain; 4Infectious Internal Medicine

of the Hospital University Virgen de la Arrixaca, Murcia, Spain.

Email: lablilly@gmail.com

Received September 8th, 2013; revised October 18th, 2013; accepted October 28th, 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

The objective of this study was to examine longitudinally the effects of exenatide on different physical and biochemical

markers, evaluated in adult type 2 diabetic patients with cardiovascular risk. Data were recorded from 10 patients who

attended the outpatient primary care health center Mariano Iago Yecla, Murcia province, Spain in the period of Decem-

ber 2009 to October 2011 and who were treated with Byetta®. Differences were statistically significant (p < 0.05) in

HbA1c from the third month of treatment, and trends of decrease in body weight from the third week of treatment. There

was a significant and better glycemic control. Overall effect was interpreted as a sensitizer drug of the parameters

evaluated. Randomized studies are recommended with a minimum follow-up of 2 years, to see if the results are main-

tained over time.

Keywords: Diabetes Mellitus Type 2; Exenatide; Cardiovascular Risk

1. Introduction

Exenatide (Byetta®, Eli Lilly) is an incretin mimetic, and

a synthetic peptide (amide acid peptide of 39 amino acids)

which is currently approved in several countries world-

wide (marketed since 2006 in the European Union) for

use as combination therapy with sulfonylureas and/or

metformin in patients with type 2 diabetes mellitus who

have not been achieved adequate glycemic control with

oral antidiabetic earlier [1,2]. Its therapeutic action is

related primarily to reduce both postprandial glucose and

fasting, before the consideration of the following four

aspects [3-6]:

1) Increased insulin secretion by β cells independently

of glucose (reduced insulin release with decreasing blood

glucose).

2) Inhibition of glucagon secretion and hepatic glu-

coneogenesis as well.

3) Slowing of gastric emptying and, consequently, the

transition to the movement of glucose intake.

4) Increased satiety.

Exenatide is indicated as an alternative to insulin

therapy or other measures of second line therapy in pa-

tients with obese type 2 diabetes mellitus in combination

with sulfonylurea, metformin or pioglitazone when these

options have not achieved adequate glycemic results in a

maximum dose [1,7-9].

Exenatide is available as a pre-filled pen of 5 and 10

mg subcutaneous injection administration. We recom-

mend starting the treatment administered 5 mg/2 times/

day for 1 month, to increase tolerance. The application is

recommended within 60 minutes prior to breakfast and

dinner, or two main meals, separated by a minimum of 6

hours, never after a meal. If necessary, to improve gly-

cemic control, the dose may be increased to 10 mg/2

times/day, following the above recommendations of ad-

ministration [1,2].

The Andalusian Centre of Drug Information (CADIMA)

[2] and Campoamor [3], considered high treatment ex-

enatide daily and annual cost (considering the two doses)

compared with other treatment options and oral insulin

(excluding with liraglutide has a higher cost and annual

daily exenatide). In 2009, he referred a daily cost of 4.47

€, maximum value followed by vildagliptin (2.25 €), in-

Evolution of Biochemical Effects of Byetta® in Type 2 Diabetics with Cardiovascular Risk

680

sulin detemir ornate feathers (2.09 €), insulin glargine

cartridges (2.05 €), insulin glargine ornate feathers (2.05

€), pioglitazone (2.03 €) and sitagliptin (2.00 €).

For approved indications, currently controversial in-

formation on the effectiveness of exenatide and bio-

chemical markers is associated with physical, being in

constant research, the main reason for this study. Despite

this, there is some consensus that the administration is

associated with a significant reduction in glycosylated

hemoglobin levels (HbA1c) and body weight [1,2].

It is also very limited availability of scientific informa-

tion about its use in obese patients and in combination

with other oral agents such as glitazones, as well as on

mortality and morbidity and association with cardiovas-

cular risk factors and liver.

It presents a comparative effectiveness not less than

insulin. Its use is associated with a high level of with-

drawals from treatment due to adverse effects: 8% com-

pared with 3% of placebo and 1% insulin [2]. Among the

major adverse effects can be mentioned [1,2,10-14]:

 Nausea (45% - 51%).

 Vomiting (12% - 14%).

 Diarrhea (9% - 17%).

 Hypoglycemic episodes (28% - 36%) in combination

with sulfonylureas.

 Acute pancreatitis (89 cases in the European Union in

the period 2006-2007).

These effects depend on the continuity of treatment

and combination therapy implemented. The truth is that

against the perceived benefits of reducing HbA1c and

body weight, low risk of hypoglycemia (except in com-

bination with a sulfonylurea), low blood pressure and a

potential protective effect of β cells, has the following

disadvantages: the administration of injections, frequent

gastrointestinal side effects, high costs, little experience

in treatment, antibody formation and possible interac-

tions with other drugs given delayed gastric emptying.

Regarding the cardiovascular risk associated with diabe-

tes mellitus, there is a current controversy, the effects of

exenatide, finding favorable effects [15-21] or on heart

rate and blood pressure [15,22,23].

The aim of this study is to contribute to the evolution-

ary analysis of the effects of exenatide on physical and

biochemical markers evaluated in the specific case of

adult type 2 diabetic patients with cardiovascular risk.

2. Materials and Methods

Study Design

An experimental study was conducted, longitudinal panel,

and quantitative. The scientific data were obtained from

medical records of 10 patients with type 2 diabetes mel-

litus and cardiovascular risk who attended the outpatient

primary care health center Mariano Yago in the town of

Yecla, Murcia, Spain for the period December 2009 to

October 2011.

Physical data were collected: weight, height, shape and

body mass index (BMI) and biochemical glycosylated

hemoglobin (HbA1c).

We considered three evolutionary breakpoints: 3, 6

and 12 months. Not all participants were evaluated in the

cuts, but that they were established considering a unit of

group analysis.

Combined treatment with Byetta® was diverse, en-

compassing various alternatives and combinations, de-

pending on the needs of each patient and medical profes-

sional criteria. It included, among others: Januvia 145®,

Prevencor 40®, 20® Coropres, Enalapril 20®, Uniket Re-

tard®, add 100®, Glucophage 850® and Actos®.

In all cases reported, as appropriate: time of ingestion.

In the case of Byetta®, all patients started the first month

with Byetta® 5 mg and two months later switched to 10

mg, always 2 times/day, maintaining this dose in subse-

quent months.

The glycosylatedhemoglogina biochemical parameter

was evaluated according to the criteria for optimal con-

trol of the Spanish Society of Diabetes (SED), where:

 HbA1c ≤ 7%.

The study was conducted based on various measures

of physical and biochemical parameters of 10 adult sub-

jects with type 2 diabetes mellitus and cardiovascular

risk. The sample was prepared in a non-probabilistic,

intentional and accidental, according to glycosylated

hemoglobin detected in the patient’s analytic and BMI.

Inclusion criteria for the preparation of the sample

were: be patient with diagnosed type 2 diabetes mellitus,

adult at the time of diagnosis and treatment.

We excluded cases that did not record a BMI greater

than or equal to 30 and type 1 diabetes was based on the

discretion of the physician who treated the patient in due

course.

Considering the number of subjects, we applied the

contrast of the Shapiro-Wilk normality, to inquire about

the possibility of parametric analysis tools. All physical

and biochemical parameters of analysis, were associated

with probabilities >0.05, so that was adopted following a

normal statistical distribution.

We analyzed the existence of statistically significant

differences in both the temporal evolution of parameters

(initial-final, or initial-3-6 to 12 months, as applicable)

and months of treatment, by a factor univariate ANOVA

(time of measurement).

In cases of biochemical parameters in which such sig-

nificant differences were found, deepened trying dis-

criminate analysis results according to certain factors,

those presented in the overall profile of the participants

(except the initial height and weight, used for calculation

of initial BMI, and contour). In this case, we applied a

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Evolution of Biochemical Effects of Byetta® in Type 2 Diabetics with Cardiovascular Risk 681

univariate ANOVA on several factors. For categories of

factors were considered as follows:

 Age: <57, ≥57, according to 50th percentile.

 Sex: female, male.

 Initial BMI, pre-obesity (25.00 to 29.99 kg/m2), obe-

sity class I (30 to 34.99 kg/m2), obesity class II (35.00

to 39.99 kg/m2) and Class III obesity (≥40.00 kg/m2)

according to the criteria of the World Health Organi-

zation (WHO) and the calculation of a minimum of

28.00 kg/m2 and a maximum of 60.00 kg/m2.

 Duration of treatment: 3, 6 and 12 months.

Also, in such cases, we analyzed the existence of sta-

tistically significant differences by parameter, time and

between groups using a univariate ANOVA of a factor.

In the univariate ANOVA was applied on several fac-

tors test or Duncan multiple range means separation test

as a method of comparing them, in cases in which the

categories of factors were more than two.

All analysis was performed with SPSS software ver-

sion 15.0 for Windows, considering a significance level

of p < 0.05.

3. Results

The general profile of the patients presented in Table 1.

In the same average age is observed associated with older

subjects, mainly male, obese, and average height.

Table 2 shows the average baseline biochemical IN-

DICATORS evaluated in the study.

In the group treated with Byetta® for 3 months, statis-

tically significant differences (p < 0.05) in HbA1c pa-

rameter (F1.10 = 7.531, p = 0.021). In this case, we found

a significant decrease in the indicator towards the end of

treatment: 9.55%, SD = 1.086 in the initial instance, and

7.77%, SD = 1.164 in the final instance.

Table 1. General profile of patients.

Age Average 59.70 years, standard deviation

(SD) of 9.073 years

Sex Female: 6 (60.0%)

Male: 4 (40.0%)

Weight (initial) Average of 119.94 kg, SD = 13.86 kg.

Height 1.72 m, SD = 0.054 m.

Circumference 125.60 cm, SD = 13.867 cm.

BMI (initial) 40.60 kg/m2, SD = 6.542 kg/m2.

Table 2. Mean baseline glycated hemoglobin by treatment

group.

Biochemical

parameter

Group 3

months

Group 6

months

Group 12

months

HbA1c (%) 9.55,

SD = 0.629*

8.71,

SD = 0.932*

8.70,

SD = 1.556*

*Statistically significant difference (p < 0.05).

3 MESES

10.00

9.50

9.00

8.00

8.50

7.50

7.77

9.55

Inicial Final

Momento

Media de HbA

6 MESES

9.00

8.00

7.21

8.71

Inicial Final

Momento

Media de HbA

3 meses

8.50

7.50

7.00

8.28

12 MESES

9.00

8.00

8.70

Inicial Final

Momento

Media de HbA

3 meses

8.50

7.50

7.00

6 meses

7.90

7.30

7.00

Figure 1. Graphs the means by treatment group and the

corresponding cutoff.

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Evolution of Biochemical Effects of Byetta® in Type 2 Diabetics with Cardiovascular Risk

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In the group treated with Byetta® for 6 months, statis-

tically significant differences (p < 0.05) in HbA1c pa-

rameter (F1.12 = 12.277, p = 0.004), finding a significant

decrease towards the end of treatment: 8.71%, SD =

0.932 in the initial instance, and 7.21, SD = 0.644 in the

final instance.

Related to that, the statistically significant differences

(p < 0.05) was found to consider jointly the initial request,

3 and 6 months (F2.17 = 5.839, p = 0.012). In this case,

Duncan’s test identified two homogeneous subgroups:

early times and 3 months in one (mean 8.71% and 8.28%,

respectively) and the other 6 months (mean 7.21%), thus

indicating that a significant reduction occurs by 6 months

of treatment.

Finally, regarding the group treated with Byetta® for

12 months, were found statistically significant differ-

ences (p < 0.05), corresponding to average values of

6.70%, SD = 1.556 in the initial instance, 7.90%, DT =

1.272 at 3 months, 7.30%, SD = 0.849 at 6 months and

6.70%, SD = 0.707 at 12 months.

At the end of treatment, we found similar effects of

Byetta®, effects correlated with the decrease in HbA1c. It

is observed that HbA1c is smaller (maximum reduction)

in the group treated for 12 months (Figure 1).

4. Discussion

Significant effects of treatment with Byetta® in patients

with type 2 diabetes mellitus were recorded for the pa-

rameter of HbA1c from 3 to 6 months of administering

the drug. Even in the latter case, the differences which

were statistically significant (p < 0.05) were consistent

with intermediate levels. Significant effects occurred for

all patients indiscriminately about sex, age and initial

BMI.

Despite this, and they were presented as baseline bio-

chemical parameters inadequate, according to the criteria

of optimal control of the SED [10,24], the final results of

HbA1c reached the limit of adequacy.

Exenatide was associated with a loss of weight com-

pared to baseline values in Table 2. Exenatide appears to

worsen the cardiovascular status of patients who specifi-

cally included in the study by having the risk of that dis-

ease.

Therefore, the recommendations of this study, in con-

clusion, result in the need for randomized studies to

evaluate the effects of Byetta®, interpreted as sensitizers,

on different physical and biochemical parameters in a

greater long-term, proposing to do, at a minimum of 2

years.

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