GLP-1 Agonists

Class of substances used for the treatment of inadequately controlled type 2 diabetes mellitus(type 2 DM) and for the drug treatment of severe overweight and obesity.

Significance:

Initially developed and approved as an antidiabetic agent, the weight-reducing effect of GLP-1 agonists has subsequently become the focus of increasing attention.

Advances in research into the entero- and neuronal signaling pathways between the gastrointestinal tract and the brain (gut-brain axis) and the further development of pharmacokinetics have made GLP-1 agonists the first effective drug for weight reduction (Friedmann JM 2024).

Due to the enormous worldwide increase in overweight/obesity (GBD 2021 Adolescent BMI Collaborators 2025) and the associated significant increase in the risk of serious chronic diseases (cardiovascular disease, type 2 DM, dyslipidemia, metabolic fatty liver disease, cancer, osteoarthritis, sleep apnea, etc.) the newer generation of substances in particular have become extremely important (Lopez-Jimenez F et al 2022, Powell-Wiley TM et al 2021). The scientific journal 'Science' has recognized GLP-1 agonists, which have become commonly known as 'weight loss injections', as the breakthrough of the year 2023 with the title "Obesity meets its match" (Couzin-Frankel J 2023).

All GLP-1 RA are synthetically/genetically produced and chemically modified to increase the half-life (HWZ). Although the basic structure of the substances is largely the same, they differ in their chemical modification to achieve this effect and therefore have different half-lives and, in some cases, different effects on blood glucose lowering and weight loss.

Different chemical modifications of the amino acid sequence and binding of ligands prevent rapid degradation by DDP4, increase plasma protein binding and delay rapid renal clearance. This increases stability and HWZ, bioavailability and efficacy (physiological GLP-1 HWZ 1-2 minutes) (Zheng Z et al 2024)

The short-acting substance exenatide (^Byetta®) is a synthetic analog of exendin-4 (extract from the salivary gland secretion of the glial monster), which has 53% sequence homology to human GLP-1. The exchange of individual proteins increases the stability against degradation by DDP-4, extends the half-life to 2.4 hours (2x daily) and enhances the effect through stronger receptor binding. The drug has antidiabetic and weight-reducing effects, but has only been investigated and approved for its antidiabetic effect (Brandt SJ et al 2018).

In the first long-acting substance (once weekly) exenatide (^Bydureon®) , persistent, slow release is achieved by depot preparation using microsphere particles and the HWZ can also be extended to 2 weeks despite rapid renal clearance. Stronger effect on HbA1c, same weight-reducing effect as short-acting exenatide (DURATION -1 study) (Brandt SJ 2018).

The following substances are GLP-1 analogs with at least 90% structural homology with human GLP-1.

• In liraglutide (^Victosa®), depot effect is achieved by conjugation with long-chain fatty acid. This also results in increased albumin binding, reduced degradation by DDP 4 and delayed renal clearance. HWC 13 hours (once daily). Effective for blood glucose control HbA1c reduction 1.1-1.6%, less effective for weight reduction. Therefore liraglutide (Saxenda®) with higher dosage for weight reduction tested and approved, more than 5% weight reduction. Concept of dose escalation to reduce side effects with increasingly potent efficacy (series of 5 RCT SCALE studies) (Brandt SJ 2018).
• In addition to amino acid modification,dulaglutide (^Trulicity®) has a modified human immunoglobulin covalently bound as a ligand, further increase in stability and improvement of the HWZ 90 hours, approx. 4 days (1 x weekly). 1.5 mg weekly causes a significantly better reduction in HbA1c than liraglutide (1.8 mg daily) but less weight reduction (AWARD-6 study) (Brandt et al 2018).
• In semaglutide s.c. (^Ozempic®) , liraglutide is further developed and an ultra-stable GLP-1 RA with a long half-life and potent efficacy is developed by changing the amino acid sequence and a new combination of a carboxylated fatty acid with a hydrophilic linker as a ligand. HWL 165 hours, approx.7 days (once a week) Semaglutide s.c. (Ozempic®) HbA1c reduction up to 1.9%, weight reduction in diabetes up to 10%. Semaglutide s.c. (Wegovy®) Dose escalation with higher initial dose results in even greater weight reduction, clinically tested and approved for weight reduction (Tschop MH et al 2023) (STEP studies) (Brandt SJ et al 2018, ). Semaglutide 2.4 mg reduces risk of major adverse cardiovascular events (MACE) by 20% SELECT study.
• Tirzepatide (^Mounjaro®) is the first combination preparation GLP-1 RA/GIP RA, bound in one molecule (hybrid molecule with dual mechanism of action GLP-1 RA plus GIP RA agonism) HWZ approx. 117 hours approx. 5 days (1x weekly) stronger effect relative to similar NW profile, ≥20% weight reduction (SURMOUNT-1 study). Better blood glucose stability, improved antiglycemic efficacy compared to GLP-1 monopreparations plus improvement in lipid metabolism/lipid profile (Brandt SJ et al 2018).

GLP-1 agonists are enzymatically degraded and predominantly eliminated renally (only a very small proportion is excreted unchanged).

Delayed onset of action or reduced effect may occur for orally administered drugs due to delayed gastric emptying and altered enterohepatic circulation.

The effects investigated were minor and not clinically relevant and a change in dose was therefore not necessary.

Nevertheless, the blood level of vitamin K antagonists, digitoxin, etc. should be monitored at the start of therapy (for details on individual drug groups, see the information leaflet for the respective preparation).

Oral contraceptives can be unreliable, especially at the start of therapy. It is recommended to use other contraceptive methods to safely prevent pregnancy!

In combination with diuretics, there is a risk of dehydration, particularly in older patients, with the consequences of hypotension, dizziness, risk of falling and reduced kidney function with the risk of kidney failure! Ensure sufficient fluid intake (non-carbonated water)!

If insulin and insulinotropic substances are administered at the same time, there is a risk of hypoglycemia! A dose reduction should be considered in the case of concomitant therapy with insulin and insulinotropic substances.

If insulin is administered at the same time, there is a risk of diabetic ketoacidosis if the insulin is reduced or discontinued! Close blood glucose monitoring and, if necessary, ketone body determination are essential!

Be aware of possible complications with diabetic retinopathy if insulin is administered at the same time! (Ophthalmologic check-ups)

Substances with a short half-life (HWL) (subcutaneous)
Exenatide (^Byetta®) 2006 EU authorization (type 2 DM)
Liraglutide (^Victosa®) 2009 EU authorization (type 2 DM)
Liraglutide (^Victosa®) 2019 EU authorization (type 2 DM children from 10 yrs.)
Liraglutide (^Saxenda®) 2015 EU approval (weight reduction)
Liraglutide (^Saxenda®) 2021 EU approval (weight reduction children from 12 years)

Substances with a long half-life (subcutaneous)
Exenatide (^Bydureon®) 2011 EU approval (type 2 DM)
Dulaglutide (^Trulicity®) 2014 EU approval (type 2 DM)
Semaglutide s.c. (^Ozempic®) EU approval 2018 (type 2 DM);
Semaglutide s.c. (^Wegovy®) 2022 Wegovy® (for weight loss).
Semaglutide s.c. (^Wegovy®) EU approval 2024 (weight reduction for children aged 12 and over)
Tirzepatide (^Mounjaro®) combination preparation with GIP (Gastric Inhibitory Polypeptide) EU approval 2022 (type 2 DM; extension of approval for weight management 2023)

Semaglutide oral (^Rybelsus®) EU approval 2020, not yet on the market (as of Dec. 2024)

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