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 increase in overweight/obesity worldwide (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 substances have become particularly important in the treatment of obesity .etc.), the substances of the newer generation (semaglutide and the combination preparation tirzepatide) have become particularly 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).

Most common are gastrointestinal side effects such as bloating, nausea, vomiting, gastrointestinal complaints, reflux, rarely also higher risk of gastroparesis and intestinal obstruction. Start with a low dosage, increase slowly, if necessary delay increase in dosage if symptoms are severe, suspend, reduce or discontinue dosage if necessary.

Patients should drink enough water, eat high-fiber food and only small meals, exercise, avoid carbonated drinks and alcohol if possible!

Gastrointestinal side effects often lead to discontinuation of therapy. Patients should be prepared for these symptoms and informed about them in advance.

Pancreatitis has been observed in rare cases (patients should be informed about symptoms and examined regularly). If pancreatitis occurs, the drug must be discontinued (re-evaluation at a later date if necessary). If there is a history of pancreatitis, use should be reconsidered.

Occasionally cholelithiasis and cholecystitis occur.

Hypoglycemia is not to be expected from GLP-1 agonists themselves, as insulin secretion is only increased in response to food. However, there is a risk of hypoglycemia when combined with insulin and other insulinotropic drugs (e.g. sulfonylureas).

Dehydration and its consequences(dizziness, falls) should be taken into account and avoided, especially when taking diuretics at the same time and in older patients. Be aware of the risk of impaired kidney function!

It is important to avoid or counteract muscle loss during weight loss (comparatively high in GLP-1 RA, up to 40% of weight loss) through exercise and strength training.

The rapid and severe weight loss can also result in major changes to the appearance of the face in particular. A decrease in muscle and subcutaneous fatty tissue, which is often very pronounced on the face, as well as an additional decrease in interstitial fluid can lead to increased wrinkling and corresponding typical changes in appearance, which have become known as'Ozempic-face' (for more information on this and possible treatment measures, see Ozempic-face).

Hypotension and dizziness are also common in overweight and obese patients ( note therisk of falls in older people!).

Hypersensitivity reactions are also common and anaphylactic reactions or angioedema may occur in rare cases.

Please note that the risk of aspiration may be increased during surgery under anesthesia or deep sedation !

Increased occurrence of retinopathy in connection with GLP-1 RA, especially in diabetics and simultaneous use of insulin: caution and close monitoring (ophthalmologist) is recommended, especially in the case of pre-existing retinopathy (possibly also in the case of macular degeneration). A connection with the occurrence of a rare form of ischemic optic neuropathy(NAION) was classified as a very rare side effect (approx. 1/10000) by PRAC of the EMA(PRAC communication dated 06.06.2025). If visual deterioration or sudden loss of vision occurs, immediate medical treatment is necessary; if NAION is confirmed, discontinue medication immediately ! (further information: bfam news (as of January 2025) Danger of significant vision loss and blindness! (Dtsch Ärztebl News 10.02.2025, Dtsch Ärztebl News 25.O2.2025)).

Increased risk of C-cell tumors of the thyroid gland (preclinical in animal studies) has not yet been confirmed in humans (also here assessment still uncertain due to long latency period). Caution recommended in case of corresponding previous illness(Dtsch Ärztebl News 31.01.2025)

Recently, there have been isolated reports of unexpected/unplanned pregnancies while taking GLP-1 agonists, which are associated with improved fertility due to weight loss(Dtsch Ärztebl News 12.12.2024).

Long-term data are lacking, especially for the newer substances with extended half-lives. Therefore, adverse effects with a long latency period cannot be estimated with certainty. There is increased pharmacovigilance and suspected cases of adverse reactions must be reported to the Federal Institute for Drugs and Medical Devices (BfArM)www.bfarm.de

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)

1. Baggio LL et al (2007) GLP-1 and GIP. Gastroenterology 132:2131-2157.
2. Brandt SJ et al (2018) Peptide-based multi-agonists: a new par. J Internal Med 284:581-602
3. Couzin-Frankel J. Obesity meets its match. Science 2023; 382,6676:1227. /doi/epdf/10.1126/science.adn4691
4. De Giorgi R et al. An analysis on the role of glucagon-like peptide-1 receptor agonists in cignitivr and mental health disorders. Nature Mental Health 2025; doi.org/10.1038/s44220-025-00390-x.
5. Elkind-Hirsch KE et al Postpartum treatment with liraglutide in combination with metformin versus metformin monotherapy to improve metabolic status and reduce body weight in overweight/obese women with recent gestational diabetes: A double-blind, randomized, placebo-controlled study. J Diabetes Complications 2020;34(4):107548. doi: 10.1016/j.jdiacomp.2020.107548
6. Friedmann JM. The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity. PNAS 2024;121(39)e2415550121; doi.org/10.1073/pnad.2415550121
7. GBD 2021 Adolescent BMI Collaborators. Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet 2025;405(10481):P785-812.
8. Hendershot CS et al. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder A Randomized Clinical Trial. Jama Psychiatry 2025;doi:10.1001/jamapsychiatry.2024.4789
9. Lingvay I et al. There is no magic bullet for obesity. Lancet Diabetes & Endocrinology 2023;11(8):P541
10. Look ARG et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomized clinical trial. Lancet Diabetes Endocrinol. 2016;4(11):913-921 doi: 10.1016/S2213-8587(16)30162-0.
11. Lopez-Jimenez F et al. Obesity and cardiovascular disease: mechanistic insughts and management strategies. A joint position paper by the World Heart Federation and the World Obesity Federation. Europ J of Preventive Cardiology. 2022; 29:2218-2237.
12. Mantovani A et al. Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: SnUpdates Meta-Analysis of Tandomized Controlled Trials. Metabolites 2021;11,73:1-14. doi.org/10.3390/metabo11020073.
13. Meissner WG et al. Trial of Lixisenatide in Early Parkinson's Disease. N Engl J Med. 2024;390(13):1176-1185. doi:10.1056/NEJMoa2312323
14. Powell-Wiley TM et al. Obesity and Cardiovascular Disease. A Scientific Statement From the American Heart Association. Circulation 2021;143:e984-e1010. DOI: 10.116/CIR0000000000000973.
15. Siamashvilli M, Davis SN. Update on the effects of GLP-1 receptor agonists for the treatment of polycystic ovary syndrome. Expert Rev Clin Pharmacol 2021;14(9):1081-1089.DOI: 10.1080/17512433.2021.1933433.
16. Turton MD et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379,69-72.
17. Tschop MH, Friedman JM. 2023; Seeking satiety: From signals to solutions. Sci. transl. Med. 15, eadh4453.
18. Wang T et al. Liraglutide as a potetial drug repurposing candidate for Alzheimer's disease and related dementia - real world evidence. Alzheimer's & Dementia 2023;19(S21) DOI:10.1002/alz.073346.
19. Zheng Z et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy 2024;9:234 doi.org/10.1038s41392-024-01931-z

Expert information Red List: Dulaglutide (^Trulicity®) Lilly

Specialist information Red List: Semaglutide (^Ozempic®) Novo Nordisk

Red List information: Semaglutide (^Wegovy®) Novo Nordisk