Page 12 - IMO-2-1

Innovative Medicines & Omics Incretin mimetics in diabetes management

improve blood glucose regulation and promote weight 4.2. Liraglutide
loss. 21 Liraglutide (Figure 3) is an acylated analog of the human
4.1. Exenatide GLP-1 hormone, designed to mimic the effects of GLP-1 in
regulating appetite and glucose metabolism. Marketed as
Exenatide (Figure 2) is a GLP-1 RA used as a monotherapy Victoza for T2DM and Saxenda for weight management,
for T2DM in adults. This synthetic form of exendin-4, liraglutide has about 97% structural homology with
originally isolated from the saliva of a Gila monster (a native GLP-1 and is produced using recombinant DNA
venomous lizard species), has an amino acid substitution technology. With a half-life of 13 h, it is administered once
at position 2, resulting in a structure with approximately daily. It has been shown to improve insulin sensitivity,
53% homology to native GLP-1. Exenatide mimics GLP- especially in patients with uncontrolled T2DM. The
1’s effects by binding to and activating GLP-1 receptors on GLP-1 peptide backbone in liraglutide includes a fatty-acyl
pancreatic β-cells, thereby stimulating insulin synthesis moiety, which confers resistance to DPP-4 degradation and
and secretion. Administered through subcutaneous allows non-covalent binding to serum albumin, thereby
injection, exenatide reaches peak plasma concentrations extending its half-life. The recommended starting dose
within about 2 h due to its rapid absorption rate. With is 0.6 mg/day for 1 week, with weekly titration up to a
a half-life of approximately 2 h, exenatide (marketed as maximum of 1.8 mg/day. Liraglutide has been shown to
Byetta) requires twice-daily dosing, typically administered significantly decrease HbA1c levels, postprandial glycemia,
1 h before the morning and evening meals for optimal and fasting glycemia. In addition, it is linked to a decreased
glycemic control. 40
risk of weight gain and hypoglycemia. 43
An extended-release formulation of exenatide,
Liraglutide is indicated as an adjunct to diet and
marketed as Bydureon, is available for once-weekly lifestyle modifications to improve glycemic control in
dosing. Unlike the native GLP-1 hormone, exenatide patients with T2DM. When used concurrently with an
is resistant to degradation by the ubiquitous enzyme insulin secretagogue, consider reducing the dose of the
DPP4 and is primarily cleared by the kidneys through latter to mitigate hypoglycemia risk. Liraglutide has been
glomerular filtration. When used as an add-on therapy approved to reduce the risk of major cardiovascular events
to metformin, exenatide has demonstrated significant and improve insulin sensitivity by upregulating glucose
improvements in glycemic control and reductions transporter-4. In the muscle and liver, it activates AMP-
in fasting plasma glucose concentrations. Although activated protein kinase, which enhances insulin sensitivity
extended-release exenatide is effective in T2DM and promotes glucose metabolism. 44
management, it lacks cardioprotective properties and
has relatively minimal effects on weight loss and HbA1c Liraglutide also exerts beneficial effects on oxidative
compared to other GLP-1 RAs. Exenatide is generally stress and inflammation, contributing to improved
41
well-tolerated, with mild side effects, including nausea, insulin sensitivity. It has positive effects on endothelial
vomiting, diarrhea, and headache. However, it should not and cardiac function, which are particularly relevant
be administered to patients with end-stage renal failure in T2DN, where low-grade inflammation plays a role
due to its renal clearance. 42 in the disease’s pathogenesis and related complications,

Figure 2. Chemical structure of exenatide. Reproduced from Al Musaimi 12

Figure 3. Chemical structure of liraglutide
Notes: Black: peptide backbone; Red: hexadecanoyl; Pink: Glu. Reproduced from Al Musaimi 12

Volume 2 Issue 1 (2025) 6 doi: 10.36922/imo.4911