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Innovative Medicines & Omics Incretin mimetics in diabetes management

1. Introduction signaling pathways. This disruption in insulin sensitivity
leads to elevated blood glucose levels, increasing the
Type 2 diabetes mellitus (T2DM) is a chronic metabolic demand on pancreatic β-cells to produce insulin. Over
disorder characterized by the progressive failure of time, this strain can lead to β-cell dysfunction, further
pancreatic beta-cells (β-cells) to meet the increased the complicating glucose regulation and worsening T2DM
body’s increased insulin demand, resulting in relative progression. Consequently, obesity not only increases
insulin deficiency and resistance to insulin action. The the risk of developing T2DM but also accelerates its
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primary aim of T2DM management is to alleviate symptoms progression and the onset of related complications, such
of hyperglycemia and reduce the risk of microvascular as cardiovascular disease, kidney failure, and neuropathy.
and macrovascular complications, such as nephropathy, Obesity also complicates T2DM management, making
neuropathy, retinopathy, and cardiovascular disease.
Compared to the general population, individuals with it challenging to control blood glucose through lifestyle
changes alone. Obese patients may require higher doses of
T2DM face a significantly higher risk of both fatal and non- insulin or other medications to achieve optimal glycemic
fatal cardiovascular events, which contribute to increased control. In addition, obesity increases the likelihood of
mortality rates. The treatment approach for T2DM typically comorbidities such as hypertension and dyslipidemia,
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involves lifestyle modifications – such as diet and exercise
– along with oral antidiabetic medications and injectable further heightening cardiovascular risk in patients with
therapies. A strong correlation exists between the severity diabetes. Therefore, implementing effective strategies to
of hyperglycemia, the metabolic dysfunctions characteristic manage obesity in diabetic patients is critical for preventing
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of T2DM, and vascular damage, all of which heighten the and mitigating these complications.
risk of macrovascular complications. Consequently, the Most T2DM treatments target various pathways but
development of medications that not only control blood are often associated with adverse effects, such as edema,
glucose but also address other metabolic risk factors weight gain, hypoglycemia, and reduced insulin sensitivity.
and improve cardiovascular outcomes is of high clinical However, emerging therapies targeting incretin hormones
importance. Key factors contributing to the rising prevalence have emerged as safer alternatives for managing T2DM.
of T2DM include obesity, aging, and genetic susceptibility. 3 The incretin pathway plays a crucial role in regulating

Insulin resistance, pancreatic β-cell dysfunction, and blood glucose levels, as it accounts for the majority of
abnormal glucagon secretion are the key contributors to insulin secretion by β-cells in response to oral glucose
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T2DM progression. At present, T2DM is recognized as a intake. Metformin remains the first-line treatment for
systemic disease in which chronic hyperglycemia causes managing T2DM, particularly in overweight patients, and
long-term damage, dysfunction, and failure of multiple is used in conjunction with lifestyle modifications and
organs. Effective management requires continuous measures to reduce cardiovascular risk. The American
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patient education on adopting and maintaining lifestyle Diabetes Association (ADA) recommends a patient-
changes, with treatment plans tailored to each patient’s centered approach to guiding additional T2DM treatments,
comorbidities and cultural beliefs. T2DM is primarily considering factors such as cost, side effects, weight changes,
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characterized by insulin resistance in peripheral tissues – hypoglycemia risk, and drug efficacy. Add-on therapies
such as skeletal muscle and adipose tissue – compounded to metformin include thiazolidinediones, dipeptidyl
by pancreatic β-cell failure. The resulting hyperglycemia peptidase-4 (DPP-4) enzyme inhibitors, insulin, sodium-
increases the risk of microvascular complications and glucose co-transporter 2 inhibitors, glucagon-like peptide-1
cardiovascular diseases, which not only lower patients’ (GLP-1) receptor agonists (RAs), luminal glucosidase
quality of life but also contribute to increased economic inhibitors, dietary interventions, and sulfonylureas. 10,11
burden and reduced life expectancy. In this overview, we summarize the T2DM disease

For obese patients, achieving stricter glycemic control process, its deleterious effects along with comorbidities, the
is necessary, as obesity is strongly associated with T2DM role of incretin hormones, and the development of incretin
pathophysiology and increased macrovascular risk. mimetics as emerging treatment options. Various classes of
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Medication, coupled with lifestyle changes, is essential in common incretin mimetic drugs—GLP-1 single, dual, and
managing the condition effectively. Obesity is a significant triple RAs—are discussed, along with their indications and
risk factor in both the development and progression of reported side effects.
T2DM, as it exacerbates insulin resistance and impairs the
body’s ability to produce and effectively utilize insulin. 2. Incretin hormones
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Excess adipose tissue in obese individuals contributes to Incretin hormones, such as GLP-1 and gastric inhibitory
chronic low-grade inflammation, which disrupts insulin peptide (GIP), also known as glucose-dependent

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