From Blood Sugar to Body Weight: The Expanding Therapeutic Potential of GLP-1 Agonists

Abstract

GLP-1 receptor agonists (GLP-1 RAs), or incretin mimetics, are commonly utilized in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Drugs like Exenatide, Liraglutide, Dulaglutide, and Semaglutide enhance glycemic regulation by boosting insulin production and suppressing glucagon release. While the American Diabetes Association (ADA) advocates metformin as the initial therapy for T2DM, GLP-1 RAs are often prescribed for patients who fail to achieve optimal glucose levels, particularly those with cardiovascular or kidney-related conditions. The FDA has also approved Semaglutide and higher doses of Liraglutide for managing obesity, especially in overweight individuals with additional health issues. Emerging studies indicate that GLP-1 RAs may benefit type 1 diabetes (T1DM) patients by reducing hemoglobin A1c and aiding in weight reduction. Despite their potential, the broader adoption of these medications is limited by their expense and possible adverse effects. Ongoing research aims to increase affordability and develop oral versions to improve patient adherence and treatment efficacy. This review examines the mechanisms, clinical uses, and future directions of GLP-1 RAs in addressing diabetes and obesity

Keywords

Introduction

GLP-1 agonists, also known as incretin mimetics or GLP-1 analogs, are primarily used for treating type 2 diabetes (T2DM) and, in some cases, obesity. Common drugs in this class include Exenatide, Liraglutide, Dulaglutide, and Semaglutide. The American Diabetes Association (ADA) recommends metformin as the first-line treatment, but GLP-1 analogs are considered for patients who cannot tolerate metformin, have high hemoglobin A1c levels, or fail to achieve glycemic control within three months. These drugs are particularly beneficial for individuals with atherosclerosis, heart failure, or chronic kidney disease. The FDA has approved Semaglutide and high-dose Liraglutide for obesity management, especially in overweight individuals with comorbidities. Research suggests GLP-1 analogs may also help lower A1c levels and promote weight loss in type 1 diabetes (T1DM). However, their widespread use is limited by high costs and potential side effects ^(5,6,7,8,9). According to the 2023 ADA guidelines, GLP-1 receptor agonists are advised for reducing cardiovascular risk. These medications not only decrease the likelihood of cardiovascular events and hypoglycemia but also show promise in potentially slowing the progression of chronic kidney disease (CKD). GLP-1 agonists are particularly recommended for individuals with a history of clinical atherosclerotic cardiovascular disease (ASCVD), such as prior myocardial infarction or stroke. ^(10,11).

GLP-1 agonists, with proven cardiovascular benefits, include Liraglutide, subcutaneous Semaglutide, and Dulaglutide ⁽¹²⁾.

Human GLP-1 backbone:

• Dulaglutide

• Albiglutide - discontinued

• Liraglutide

• Semaglutide

Exendin-4 backbone:

• Exenatide (2 formulations)

• Lixisenatide - discontinued

• Tirzepatide is a GIP analog that activates both the GLP-1 and GIP receptors. 

The FDA has authorized the use of Liraglutide and insulin degludec, affirming their effectiveness and safety for managing diabetes^(13)(14) Because of safety concerns, research on another agent, taspoglutide, has been halted in phase III trials.⁽¹⁵⁾ Orforglipron, an oral GLP-1 receptor agonist with a nonpeptide structure, has exhibited encouraging efficacy and safety profiles in phase 2 clinical trials. ⁽¹⁶⁾.

Historical Development and Approval Time

During the metabolism of semaglutide for effective weekly glucose regulation, researchers discovered that it degrades quickly in the body. To address this issue, academics changed the peptide's structure by changing a section, increasing stability and receptor binding capabilities. They also attributed a fatty acid via a specific linker, allowing the medication to stick to albumin, a blood protein, and henceforth boost its duration of action.^(17). After examining many combinations, they stumbled upon that a specific fatty acid and spacer gave the optimum balance of stability and effectiveness ^{(18, 19)}. Whilst developing semaglutide, researchers sought different fatty acid derivatives ranging from C12 to C20 to find the best option. The study found that combining C18 di-acid with a γGlu-2xOEG linker provided the best balance of albumin binding and GLP-1 receptor activation. The study also found that increasing the width of the carbon chain from C12 to C18 boosted receptor potency, but any further extension beyond C18 negated the expected positive effect⁽¹⁸⁾. The C18 di-acid verified the greatest increase in affinity when bound to albumin, highlighting its strong albumin-binding capabilities. Using analytical ultracentrifugation, study participants confirmed that peptides containing di-acid derivatives exhibited an expanded affinity for albumin than native GLP-1 and liraglutide. Despite the fact that the crystal structure of semaglutide could not be identified, researchers investigated its unacylated peptide backbone in interaction with the GLP-1 receptor. The structure was quite similar to natural GLP-1(7-37), with Lys26 interacting with Glu128, which defied prior observations. B esides that, Arg34 in semaglutide remained stable, earning an electrostatic connection with Glu27 via a water molecule. This change allowed for the picky acylation of Lys26 with intact receptor interaction⁽¹⁸⁾. The development of semaglutide involved studying its pharmacokinetic and pharmacodynamic properties through in vivo experiments on rats, mini pigs, and db/db mice. Researchers identified derivatives with an extended pharmacokinetic profile and strong GLP-1 receptor activity. In rats, the half-life increased with fatty acid length, ranging from 1.2 hours for the C12 di-acid to about 7 hours for semaglutide. Mini pig studies showed a significantly longer half-life, with the C20 di-acid exhibiting a duration close to semaglutide at around 75 hours after subcutaneous administration. In db/db mice, semaglutide displayed high potency and prolonged action, with an ED50 below 2 nmol/kg, supporting its progression to clinical trials. This review also explores the pharmacology of liraglutide and semaglutide, highlighting GLP-1 receptor distribution, mechanisms of action, and ongoing research into an oral formulation that could revolutionize this traditionally injectable drug class ^(18,20).

How Glp-1 Receptor Agonist Work in The Body

Semaglutide fosters incretin activity via activating GLP-1 receptors. It increases glucose-dependent the creation of insulin, inhibits glucagon release, and dampens hepatic gluconeogenesis, therefore lowers overall fasting and postprandial glucose levels⁽²⁰⁾. The drug improves the proinsulin-to-insulin ratio, indicating enhanced β-cell function and increased insulin production ⁽²¹⁾. Another benefit is that it improves insulin sensitivity, most likely due to shedding pounds. Semaglutide fosters weight loss by lowering energy intake and holding off stomach motility ^{(20, 22, 23, 25)}.

Mode of Administration & Dosage
Subcutaneous Route:

In contrast to other once-weekly GLP-1 agonists, semaglutide (Ozempic; 0.5 mg and 1.0 mg) requires a progressive dose increase. Medical care begins with a baseline dose of 0.25 mg, which is gradually increased to 0.5 mg and then 1.0 mg, with a 4-week interval between each adjustment. Ozempic pens have a concentration of 1.34 mg/ml, with the crimson pen used for both the 0.25 mg commencing dose and the 0.5 mg restoration dose, and the blue pen for the 1.0 mg max maintenance dose ^{(24, 25)}.

Oral Route:

In its oral form, semaglutide (Rybelsus; available in 3 mg, 7 mg, and 14 mg doses) is combined with SNAC (Sodium-N-[8-(2-hydroxybenzoyl)amino]caprylate), a fatty acid derivative that enhances permeability ^(22,25). Emisphere Technologies' Eligen® Technology was used to manufacture this formulation, which increases the local pH and promotes absorption via the passive transcellular pathway. Furthermore, SNAC protects semaglutide from degradation in the stomach's acidic environment. To get maximum efficiency, take the tablet on an empty stomach, preferably 30 minutes before eating. ^{(25, 26, 27).}

Switching Between Ozempic and Rybelsus:
Patients can transition between the injectable form (Ozempic) and the oral form (Rybelsus) based on their individual needs and convenience ^(25,26,27).

Pharmakinetics

Absorption: GLP-1 Receptor Agonists (RAs) like Exenatide, Liraglutide, and Semaglutide are administered subcutaneously, ensuring rapid absorption and achieving peak concentrations within hours. The novel oral formulation of Semaglutide is tailored for gastrointestinal (GI) absorption, with consideration for bioavailability. Factors such as first-pass metabolism and potential interactions with food and other medications bear relevance in determining effective dosing regimens for oral Semaglutide.

Distribution: After consumption, GLP-1 receptor agonists such as Exenatide, Liraglutide, and Semaglutide have a small distribution volume and disproportionately circulate in the bloodstream. They bind specifically to GLP-1 receptors in important tissues involved in glucose regulation, with a high propensity for pancreatic cells and other metabolic regulatory sites.

Metabolism: Exenatide is chiefly hydrolyzed in the kidneys and liver, resulting in tiny inactive peptide fragments that are eliminated by the kidneys. Liraglutide goes through an acquainted metabolic process, encompassing proteolytic degradation in diverse tissues that mimics the breakdown of big proteins. Enzymes such as Dipeptidyl Peptidase-4 (DPP-4) and Neutral Endopeptidase (NEP) are likely participating in its metabolism, which produces inert peptide fragments that are then removed. Semaglutide, as a polypeptide, is degraded into individual's measurement of amino acids by proteases in the serum and cell membranes ^(28,29,5).

Excretion: GLP-1 receptor agonists like Exenatide, Liraglutide, and Semaglutide are primarily cleared through renal elimination. The kidneys are essential in removing these compounds, influencing their duration of action and dosing frequency. Semaglutide’s extended-release formulation results in a significantly longer half-life than short-acting versions. This prolonged duration enhances its therapeutic effect and reduces dosing frequency. Renal function plays a crucial role in determining the drug’s clearance efficiency ^(28,29,5).

Role in Managing Type 2 Diabetes mellitus

The ADA and EASD recommend reviewing type 2 diabetes treatment every 3–6 months, highlighting semaglutide for improved blood sugar control, weight management, and as a preferable choice before insulin ^(30,31). Semaglutide is beneficial for patients with cardiovascular disease, as well as liver or kidney conditions, especially when SGLT-2 inhibitors are not well tolerated. It can be administered with metformin or insulin; however, insulin and sulfonylurea dosages may require adjustment to prevent hypoglycemia. No dosage modifications are necessary when combined with metformin, SGLT-2 inhibitors, or thiazolidinediones. However, using it alongside DPP-4 inhibitors does not provide additional therapeutic advantages^{(32, 33)}. Oral semaglutide offers a more convenient alternative to injectable forms, improving adherence. Encouraged by the SUSTAIN FORTE analyses' outcomes, Novo Nordisk lodged a label expansion application with the European Medicines Agency (EMA) on December 29, 2020, to provide a 2.0 mg dose of the once-weekly Ozempic® for hyperglycemia therapy. On January 20, 2021, an infringement request originated with the United States Food and Drug Administration (USFDA) for approval of the same dosage ^{(25, 34, 35)}.

Impact in management of obesity

Initially developed for the treatment of type 2 diabetes, GLP-1 receptor agonists not only optimize glycemic regulation but also exert profound effects on weight reduction. Their mechanism of action involves decelerating gastric emptying, modulating hypothalamic pathways to suppress appetite, and enhancing satiety, rendering them a compelling therapeutic option for obesity management, irrespective of diabetic status. Agents such as exenatide, liraglutide, dulaglutide, and semaglutide have revolutionized clinical practice by delivering multifaceted metabolic and cardiovascular benefits that extend well beyond glycemic control ⁽³⁶⁾. The development of newer GLP-1 receptor agonists, including dulaglutide ⁽³⁷⁾, lixisenatide, semaglutide ⁽¹⁸⁾, and tirzepatide ⁽³⁸⁾, has greatly improved diabetes management. Semaglutide, in particular, excels in glycemic control and weight loss, offering multiple formulations, flexible dosing, and a lower risk of cardiovascular issues ^{(39) (40) (41) (42)}. Extensive research supports its benefits in treating hepatic steatosis, sleep apnea, obesity-related heart failure, and delaying type 2 diabetes in prediabetic individuals ^(43-.47). Semaglutide (Ozempic®) was approved by the FDA in 2017 and the EMA in 2018 for type 2 diabetes management. It later received approval for weight management under the brand name Wegovy® in 2021 (FDA) and 2022 (EMA) for individuals with obesity or weight-related conditions. GLP-1, secreted by L-cells in the upper small intestine in response to food intake, activates receptors in the gut, hepatic portal vein, and brain. In cases of large or nutrient-rich meals, it can enter circulation and influence brain regions involved in appetite regulation⁽³⁶⁾. Semaglutide aids weight loss through central and peripheral mechanisms. It enhances satiety by activating appetite-suppressing neurons (POMC and CART) and inhibiting hunger-promoting neurons (NPY and AgRP) in the hypothalamus, with leptin playing a key role. Additionally, it slows gastric emptying, reducing calorie intake and stabilizing post-meal glucose levels ^(48,49). Some studies also suggest it may boost energy expenditure by increasing thermogenesis in brown adipose tissue ⁽⁵⁰⁾. Semaglutide is structurally modified for a prolonged half-life of approximately one week, achieved through amino acid substitutions and fatty acid attachment, enhancing albumin affinity and resistance to DPP-4 degradation. It is available as a weekly subcutaneous injection (0.25–2.4 mg) and a daily oral formulation (3–14 mg). With 94% similarity to endogenous GLP-1, it effectively regulates blood sugar and supports weight management ^(18). GLP-1 receptor agonists differ in their binding and effects. Short-acting pharmaceuticals such as exenatide and lixisenatide mimic natural GLP-1 secretion, however they require frequent administration and have minimal metabolic effects. Long-acting medicines, such as semaglutide, liraglutide, dulaglutide, and tirzepatide, provide prolonged receptor activation, which improves glycemic management and weight loss. Apart from them, weekly semaglutide (2.4 mg) has shown superior weight loss than liraglutide, the only other GLP-1 agonist endorsed for calorie control ^(50,51,52).

Comparative analysis with other anti- diabetic and weight loss drugs

Early clinical trials (phase 2 and phase 3a) of semaglutide aimed to determine its optimal subcutaneous dose and evaluate its safety and efficacy in individuals with type 2 diabetes. The phase 2 trial confirmed a dose-dependent effect with no unexpected safety concerns, establishing 0.5 mg and 1.0 mg as the ideal weekly subcutaneous doses with gradual escalation every four weeks ⁽⁵¹⁾. In phase 3a, semaglutide exhibited a higher incidence of adverse events compared to sitagliptin but maintained a safety profile consistent with other GLP-1 receptor agonists. Both trials demonstrated significant weight reduction compared to placebo and liraglutide, reinforcing its effectiveness for weight management ^(50,52) .

Clinical Compliance

Semaglutide, in both subcutaneous and oral forms, significantly lowers HbA1c levels while improving cardiovascular, renal, and hepatic health. Its weight loss effects are dose-dependent, reducing both body weight and waist circumference. Additionally, it helps control appetite, decrease energy intake, and curb food cravings ^{(16, 53, 54)}. Compared to placebo and other glucose-lowering drugs, semaglutide consistently proves more effective in weight reduction. Patients transitioning from other GLP-1 receptor agonists to semaglutide also experience further weight loss. However, studies indicate that weight regain is common within a year after stopping treatment ^{(50, 55, 56, 57)} . Semaglutide is mainly administered via subcutaneous injection, though its oral form (Rybelsus®) offers convenience and may improve adherence. While weight loss is slightly lower with the oral version, studies like PIONEER and OASIS 1 support its effectiveness, particularly at higher doses (50 mg). Its safety profile aligns with other GLP-1 receptor agonists, and ongoing OASIS 2–4 studies may provide further insights ^{(50, 58)}. Primarily used for type 2 diabetes (Ozempic®) and obesity-related conditions (Wegovy®), semaglutide's benefits in cardiovascular, renal, and hepatic health suggest potential for broader applications. The STEP TEENS study also highlights its potential in addressing childhood obesity ^(50,59). Semaglutide (SMG) commonly causes mild to moderate side effects such as nausea, vomiting, diarrhea, cholelithiasis, and constipation, typical of GLP-1 receptor agonists ⁽⁵⁵⁾. While SMG increases the likelihood of adverse effects, its significant weight loss benefits outweigh similar-risk treatments, though gastrointestinal side effects lead to higher discontinuation rates. Both oral and subcutaneous SMG are cost-effective for long-term weight management. The subcutaneous 2.4 mg dose is particularly effective for obesity and weight-related conditions, outperforming lifestyle interventions and other anti-obesity drugs. Oral SMG (14 mg) provides comparable benefits to subcutaneous SMG (1.0 mg) and surpasses dulaglutide and liraglutide in managing type 2 diabetes while being a more affordable option ^{(50, 60, 61)}. The cost of semaglutide (SMG) treatment varies widely across countries, influencing accessibility. In the U.S., monthly prices for Ozempic® and Rybelsus® are around $936, while Wegovy® costs $1349. In contrast, significantly lower prices are seen in countries like France ($83), the U.K. ($93), and Canada ($147)^(62). High demand has also led to supply shortages, limiting new prescriptions. Some regions, including Spain and Romania, offer both oral and injectable SMG, while others only provide the injectable form ⁽⁶³⁾. Considering its cost-effectiveness for type 2 diabetes and obesity, policymakers should explore incorporating both SMG formulations into treatment plans, with potential government support to improve affordability and healthcare sustainability ^(64-67). A study in Canada analyzed weight loss responses to GLP-1 analogs in 483 adults with obesity, where 86% received SMG and 14% liraglutide. Over 17.3 months, the average weight reduction was 12.2%. Responses were classified as non-response (<5% weight loss), moderate response (5–15%), and hyper-response (>15%), with a higher likelihood of significant weight loss in females. Other factors such as age, diabetes status, and lifestyle habits did not show a notable impact, suggesting a need for further research into biological predictors of treatment response ^{(68, 50)}.

CONCLUSION

Semaglutide (SMG) improves glycemic control, supports significant weight loss, and offers cardiovascular benefits. Its success in treating type 2 diabetes has led to expanded use for obesity management (Wegovy®), outperforming other GLP-1 receptor agonists. While initial weight loss results with oral SMG were modest, the 50 mg formulation has shown comparable effectiveness to the subcutaneous version. Ongoing OASIS trials will further evaluate its efficacy and safety, potentially increasing accessibility. Future research aims to explore SMG’s applications beyond diabetes and obesity, assess long-term effects, and develop personalized treatment strategies based on patient response.

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