Exenatide Improves Glycemic Variability Assessed by Continuous Glucose Monitoring in Subjects with Type 2 Diabetes

Abstract

Background:

Daily glycemic fluctuation leads to development of long-term complications. The aim of our pilot study was to determine if exenatide reduces glycemic variability, assessed with a continuous glucose monitoring (CGM) system, compared with glimepiride.

Methods:

We enrolled six consecutive subjects with type 2 diabetes, for whom exenatide was suggested as second-line treatment, and six control subjects, for whom glimepiride was suggested as second-line treatment. CGM was performed at baseline and after 16 weeks of treatment. As measures of glycemic variability we calculated the total daily mean glucose (MG), SD, and mean amplitude of glycemic excursions (MAGE).

Results:

Exenatide significantly reduced MG, SD, and MAGE, whereas glimepiride did not. Fasting glucose and glycated hemoglobin were lowered in both groups, even if the reduction was not significant.

Conclusion:

Exenatide can reduce glycemic variability compared with glimepiride, providing additional beneficial effects in controlling glucose homeostasis.

Introduction

E xenatide is a glucagon-like peptide-1 receptor agonist showing a comparable potency to native glucagon-like peptide-1 and resistant to degradation; it improves glycemic control primarily by reducing postprandial hyperglycemia, with a modest effect on fasting plasma glucose.^1,2 The body of evidence is growing that not only chronic hyperglycemia but also daily glycemic fluctuation lead to accelerated glycation in the short term and to development of long-term micro- and macrovascular complications.³ Self-monitoring of blood glucose, even if considered a useful tool for subjects with diabetes to achieve a good metabolic control, often does not offer information about daily glucose fluctuations. Continuous glucose monitoring (CGM), a recent minimally invasive technique, has the ability to detect such fluctuations during the day in a manner that is not possible with traditional blood glucose meter readings.⁴ Based on this evidence, the aim of our pilot study was to investigate whether exenatide would improve glycemic fluctuations, assessed using a continuous glucose monitor, compared with glimepiride.

Subjects and Methods

We enrolled, at our metabolic unit, six consecutive subjects who were prescribed exenatide as second-line treatment, added-on to metformin. As control subjects six consecutive subjects who were prescribed glimepiride were also enrolled. The researcher who assigned the treatment was different from the one who inserted the instrument for CGM. This pilot observational research study was approved by the local ethical committee, and all participants gave their consent. Inclusion criteria were current treatment with maximal tolerated metformin dosage, glycated hemoglobin (HbA1c) >7.5% and <10%, age 45–65 years, and no contraindication to glimepiride or exenatide.

CGM was assessed by the GlucoDay^® (A. Menarini Diagnostics, Florence, Italy) system, composed of a subcutaneous microdialysis probe connected to a portable unit. The system takes a glucose measurement every second and stores an average value every 3 min, for a total of 480 measurements per day, for two consecutive days.⁵ All subjects underwent to three visits (baseline, additional 1-month visit, and follow-up visit). During the first visit (baseline visit) the continuous glucose sensor was inserted subcutaneously in the abdominal periumbilical area. A home blood glucose meter was provided to perform sensor calibration four times daily.⁵ A venous blood sample was collected for HbA1c and fasting blood glucose determination. Subjects added exenatide or glimepiride after the glucose monitoring procedure. The second visit (additional visit) was scheduled after 1 month in order to verify the compliance to drug prescription and the presence of possible side effects. Moreover, during this visit the exenatide dosage was escalated from 5 μg twice a day to 10 μg twice a day. Starting therapy, in subjects who were prescribed glimepiride, was 4 mg once a day; if necessary, the dose could be increased or reduced to 6 or 2 mg once a day at the 1-month visit. The third visit (follow-up visit) was scheduled after 16 weeks, and CGM and blood collection were repeated. Subjects were required to consume the same meals during both CGM procedures, as well as to avoid intensive physical activity. Metformin administration in both groups remained constant as well as antihypertensive and hypolipidemic therapy.

Statistical analyses were performed with SPSS version 11.0 (SPSS, Inc., Chicago, IL). Two-day CGM data were downloaded for analysis. As measures of glycemic variability we calculated total daily mean glucose (MG), SD, and mean amplitude of glycemic excursions (MAGE).⁶ Data are reported as mean±SD values. Clinical and biochemical parameters were not normally distributed; therefore differences were evaluated by nonparametric tests. Differences between the exenatide and glimepiride groups were evaluated using the two-independent-samples Mann–Whitney U test for unpaired data. Differences between mean values at baseline and follow-up visit within each group were evaluated using two-related Wilcoxon's signed rank sample test for paired data.

Results

Table 1 shows clinical characteristics, baseline and follow-up biochemical parameters, and measurements of glycemic variability of subjects categorized on the basis of suggested treatment. The prevalence of subjects with hyperlipidemia and hypertension was comparable between groups (exenatide vs. glimepiride), as well as the prevalence of subjects who were assuming statins (80% in both groups) and renin–angiotensin system blockers (70% in the exenatide group vs. 60% in the glimepiride group). No subject had history of previous acute cardiovascular event, but two and three subjects among those taking, respectively, glimepiride and exenatide had a positive history of background diabetic retinopathy. No side effect was reported during the observation time in both groups. During 1-month follow-up visit the exenatide dose was increased to 10 μg twice a day in all subjects, and use of glimepiride 4 mg once a day was confirmed. As reported, baseline characteristics were comparable between groups except for MG, which was significantly higher in the exenatide group. After the 16-week treatment fasting glucose as well as HbA1c decreased in both groups, even if not significantly. Additionally, exenatide significantly reduced MG, SD, and MAGE compared with glimepiride.

Table 1.

Clinical, Biochemical, and Continuous Glucose Monitoring Parameters in the Exenatide and Glimepiride Groups at Baseline and After 16 Weeks of Treatment

	Exenatide+metformin		Glimepiride+metformin
Parameter	Baseline	Follow-up	Baseline	Follow-up
Clinical and biochemical
Number of subjects	6	6	6	6
Age (years)	58.5±5.7	—	59.3±6.6	—
Sex (M/F)	3/3	—	3/3	—
Duration of disease (years)	10.2±5.1	—	9.3±5.5	—
BMI (kg/m²)	31.0±1.9	30.7±1.9	32.3±4.0	32.6±4.1
Fasting glucose (mg/dL)	185.3±20.7	162.8±24.9	153.8±36.0	149.3±19.5
HbA1c (%)	8.5±0.9	7.7±0.9	8.0±0.5	7.4±0.8
CGM
MG (mg/dL)	222.8±21.3^{b c}	173.2±36.0	151.3±33.2	166.6±28.5
SD	79.38±35.2^a	42.1±19.6	66.49±37.42	71.14±38.8
MAGE	146.8±56.7^b	94.35±49.0	108.95±64.0	104.22±48.7

Data are mean±SD values.

P<0.01, ^b P<0.05 versus follow-up; ^c P<0.01 versus glimepiride.

BMI, body mass index; HbA1c, glycated hemoglobin; MAGE, mean amplitude of glucose excursions; MG, mean glucose.

Discussion

Results of our pilot study first demonstrate that exenatide administered twice a day improves, in the short term, indexes of glycemic variability. So far two articles have been published demonstrating the efficacy of exenatide in improvement of glucose stability: one has demonstrated a significant reduction in daytime periods glucose excursion among seven subjects treated with exenatide once a week;⁷ the other reported a significant reduction in low and high blood glucose indices, evaluated by self-monitored blood glucose, after exenatide treatment compared with glargine.⁸ Even if self-monitoring blood glucose is considered a valid tool to check daily metabolic status, CGM provides many useful data to establish the dynamics of daily fluctuations in blood glucose. Clinically, an increasing body of evidence supports the impact of glycemic variability in development of acute and chronic negative consequences.⁸ Although the small number of patients enrolled in the present study does not allow any firm conclusion, our data strongly suggest that exenatide improves MG, SD, and MAGE, compared with glimepiride, favoring glucose stability and reducing the number of glycemic excursions.^9,10

The improvement in controlling glycemic variability observed in subjects taking exenatide could be explained by the physiologic action stimulated by glucagon-like peptide-1. Indeed, the key feature of glucagon-like peptide-1 is the glucose-dependent stimulation of insulin secretion and concomitant suppression of glucagon. Even if our results agree with exenatide function, further randomized studies including a larger number of subjects, well matched for baseline metabolic parameters, should confirm this finding.

In conclusion, exenatide seems to provide additional beneficial effect in controlling glucose homeostasis beyond fasting plasma glucose and HbA1c reduction, compared with glimepiride. These additional benefits could, in the long term, reduce the incidence of chronic complications.¹¹

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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