Page 11 - IMO-2-1

Innovative Medicines & Omics Incretin mimetics in diabetes management

Incretin-based mimetics are also considered for production, promoting vascular smooth muscle relaxation
patients who have contraindications or intolerance to and endothelium-derived vasodilation. 32 Further,
metformin, or who have not achieved target glycated lixisenatide and dulaglutide support the differentiation of
33
hemoglobin (HbA1c) levels after 3 months of therapy. monocytes into less proinflammatory M2 macrophages.
This consideration is especially relevant for patients with This activity reduces foam cell formation, limits necrosis
atherosclerosis, chronic kidney disease, or heart failure. In within atherosclerotic plaques, and prevents plaque
addition, GLP-1 RAs such as semaglutide and liraglutide are rupture. Semaglutide, in particular, has been found to
approved for managing obesity in overweight patients with reduce intraplaque hemorrhage, thereby stabilizing
34
comorbidities. However, high costs and tolerability issues plagues and slowing their progression. Renal benefits of
remain significant barriers to their widespread use. These GLP-1 RAs include decreased urinary albumin excretion,
27
drugs have been shown to reduce total cholesterol, lower prevention of new-onset macroalbuminuria, and a slower
systolic and diastolic blood pressure, and promote weight decline in estimated glomerular filtration rate (eGFR),
loss by increasing satiety, thereby reducing caloric intake with these effects believed to contribute to favorable renal
through hypothalamic mechanisms. Cardiovascular outcomes by delaying the onset of macroalbuminuria. 35
28
disease, particularly atherosclerotic cardiovascular disease, For patients with high cardiovascular risk or
is a leading cause of death among individuals with T2DM, established atherosclerotic cardiovascular disease, the
and GLP-1 RAs provide significant cardiovascular benefits, European Society of Cardiology (ESC) recommends
including improved cardiac output, reduced infarction size, GLP-1 RAs or sodium-glucose cotransporter-2 inhibitors
and decreased risk for cardiovascular events. These drugs as first-line therapy. Risk factors such as albuminuria,
also enhance left ventricular ejection fraction, myocardial eGFR < 60 mL/min, and left ventricular hypertrophy are
contractility, coronary blood flow, and endothelial indicators of likely benefit from GLP-1 RAs. However,
function. 29 despite ESC and ADA guidelines, the actual adoption
The most common adverse effect of GLP-1 RAs is of GLP-1 RAs remains limited, largely due to their high
mild-to-moderate nausea, typically resolving within a few costs, injection requirements, and contraindications in
weeks. Hypoglycemia, a common adverse effect of some conditions such as pancreatitis, retinopathy, or medullary
36
antidiabetic therapies, is rare with incretin mimetics, thyroid cancer. Increased glucagon secretion plays a
generally occurring only when used in conjunction with central role in the hyperglycemia observed in T2DM, and
sulfonylureas. Notably, concurrent use of insulin and GLP-1 RAs have proven effective in increasing insulin
incretin mimetics is not recommended. Other potential secretion while inhibiting glucagon production, making
20
them a key therapeutic approach for T2DM, especially for
adverse effects include vomiting, diarrhea, and, in some patients unresponsive to traditional therapies. 37
cases, acute kidney injury due to volume depletion.
Additional side effects may include headaches, infections, 4. Incretin mimetic classes
30
moderate tachycardia, dyspepsia, and dizziness. Injection-
site reactions, such as erythema and pruritus, are common, Incretin mimetics are broadly categorized into two
particularly with longer-acting formulations. Some classes: Exendin-4 analogs and human GLP-1 molecules.
patients may develop antibodies against specific GLP-1 Exendin-4, a 39-amino acid peptide, exhibits 53% sequence
21
RAs, reducing their effectiveness; for instance, exenatide homology with human GLP-1. The exendin-4-based
has been associated with a higher likelihood of antibody formulations include exenatide and lixisenatide, while
formation when administered weekly rather than twice the human GLP-1-based molecules comprise dulaglutide,
daily. As a result, combination therapy with GLP-1 agonists semaglutide, albiglutide, and liraglutide. These medications
and DPP-4 inhibitors is generally not recommended due to for T2DM offer significant therapeutic benefits, such
negligible glycemic improvement and an increased risk of as delaying gastric emptying and inhibiting glucagon
production from pancreatic alpha cells during episodes of
hypoglycemia. 31
elevated blood glucose. In addition, GLP-1 RAs promote
Glucagon-like peptide-1 RAs also reduce the formation pancreatic β-cell proliferation and reduce b-cell apoptosis,
of oxidized low-density lipoproteins (LDL) and reactive thereby enhancing insulin secretion and preserving β-cell
oxygen species (ROS), both of which contribute to function over time. 12,38,39 Furthermore, beyond single RAs
atherosclerosis. In addition, GLP-1 RAs inhibit the activation (such as exenatide, liraglutide, dulaglutide, semaglutide,
of adhesion molecules and monocytes/macrophages in lixisenatide, and albiglutide), dual RAs (such as tirzepatide)
response to oxidized LDL, further decreasing monocyte and triple RAs (retatrutide) have been developed to target
accumulation in the vascular wall. GLP-1 agonists such as multiple receptors, such as GLP-1, GIP, and, in some cases,
exenatide and liraglutide stimulate endothelial nitric oxide glucagon receptors. This multi-receptor targeting aims to

Volume 2 Issue 1 (2025) 5 doi: 10.36922/imo.4911