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).

Mechanism of action:

GLP-1 RAs act in a manner similar to the body’s own peptide hormoneGLP-1 onGLP-1 receptors, which are found in large numbers primarily inthe gastrointestinal tract, the pancreas, and the brain, but are also found, among other places , in the heart , the vascular endothelium , the lungs, and the kidneys(Baggio LL et al. 2007). 

GLP-1 is secreted from the L-cells of the intestinal mucosa upon food intake and, in a food-dependent/ glucose-dependent stimulation of insulin secretion by beta cells and inhibition of glucagon secretion by alpha cells in the pancreas. Blood glucose levels are regulated in response to food intake, blood glucose spikes are reduced, and HbA1c is sustainably lowered (Baggio LL et al 2007). This effect is utilized in the treatment of type 2 diabetes mellitus with GLP-1 receptor agonists to improve blood glucose control.

In addition, GLP-1 slows gastric emptying and, through its central action in the brain, induces a feeling of fullness, satiety, and reduced appetite, as well as regulating food intake, improving control over eating behavior (reducing food cravings), and regulating energy metabolism ( Turton MD et al. 1996, Baggio LL et al. 2007)​​​​​​​​​​

Through these mechanisms, GLP-1 receptor agonists (GLP-1 RAs) lead to highlyeffective weight loss of approximately 10%–15% of body weight, as well as sustained positive effects on weight-related risk factors and weight-related comorbidities (only weight loss of ≥ 5% is considered effective in reducing risk factors and comorbidities associated with overweight and obesity (Look ARG et al 2016)).

GLP-1 receptors are found in large numbers in the gastrointestinal tract and the brain, but also in many other parts of the body, such as the heart and the vascular endothelium. It is believed that this leads to other direct effects that have a positive impact on the cardiovascular system and metabolism. Whether directly or indirectly through reduced food intake, this also results in an improvement in the lipid profile,a reduction in blood pressure,  improved insulin sensitivity in cases of insulin resistance and metabolic syndrome, a reduced risk ofcardiovascular disease, and a reduction in liver fat content in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (Mantovani A et al 2021). Positive effects have also been demonstrated for insulin resistance in PCOS (polycystic ovary syndrome) (Siamashvilli M et al 2021) and postpartum treatment of gestational diabetes (Elkind-Hirsch KE et al 2020).

In addition, there is evidence that GLP-1 agonists also have neuroprotective effectsand mayreduce the risk of cerebrovascular events (stroke) andAlzheimer’s dementia and and may slow the progression of Parkinson’s disease (Wang T et al 2023; Meissner WG et al 2024). In addition , based on their effects on the dopaminergic system and the brain’s reward center , significant future applications could emerge for the treatmentof addiction disorders and eating disorders, and possibly as well as in psychiatric disorders (DeGiorgi R et al 2024). Preliminary results from a clinical trial on alcoholism are promising (Hendershot CS et al 2025,Dtsch. Ärztebl. News 02/19/2025).

Not all physiological effects of GLP-1 in the various organs have yet been fully investigated.

GLP-1 RAs reduce cardiovascular risk factors and lower therisk of major adverse cardiovascular events (MI, unstable angina, stroke , and death (MACE)) (see studies on the respective substance) and are among the recommended add-on therapies for patients with type 2 DM andoverweight/obesity.

GLP-1, together with GIP (glucose-dependent insulinotropic polypeptide), belongs tothe incretin family. Both peptide hormones are secreted from intestinal cells upon food intake; they complement and potentiate each other very effectively in their effects on insulin and glucagon levels and, together, lead to even more effective weight loss. This is utilized therapeutically in newer combination drugs such as tirzepatide. 

Unlike the body’s own GLP-1, which is broken down within a few minutes by the enzyme dipeptidyl peptidase 4  (DDP-4), synthetically produced GLP-1 RAs are chemically modified, which significantly prolongs their half-life and duration of action. GLP-1 RAs exceed the normally physiologically present concentrations of endogenous GLP-1 many times over.

The effects are reversible and last only for the duration of therapy; that is, weight gain resumes after therapy is discontinued. For sustained effects, therapy must be continued indefinitely. 

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).

Adults (aged 18 and over):

Type 2DM:

Glp-1 agonists are approved for the drug therapy of type 2 diabetes mellitus (type 2 DM)

as an adjunct to dietary changes, exercise and metformin in cases of inadequate blood glucose control or

as monotherapy in addition to dietary changes and exercise if metformin is not tolerated.

The newer substances are considered antidiabetic agents with a proven, beneficial profile for reducing the risk of serious cardiovascular events and should therefore be used preferentially in patients with cardiovascular risk factors or pre-existing conditions.

GLP-1 agonists are particularly suitable for patients who are also overweight or obese.

Weight reduction in obesity and overweight:

Glp-1 agonists are approved for the indication of weight reduction for drug therapy in addition to dietary changes and exercise

for obesity from a BMI of ≥30 and

for severe obesity from a BMI of ≥27 plus additional weight-related concomitant disease (e.g. hypertension, hyperlipidemia, type 2 DM, CVD, sleep apnea, osteoarthrosis)

Children and adolescents:

from 10 years of age: type 2 DM liraglutide, tirzepatide (EMA approval extension 2025, SURPASS-PEDS study Hannon TS et al 2025)

from 12 years of age: severe overweight/obesity liraglutide, semaglutide

gender- and age-dependent from the 95th percentile. (If necessary, discontinue re-evaluation if a weight reduction of at least 5% is not achieved after 12 weeks at the maximum dose)

For all patients, regardless of age, concomitant therapy with dietary changes and exercise is essential for the long-term prognosis of successful therapy, for type 2DM and overweight/obesity, among other things. Drug therapy can be a supplement but not a substitute for dietary changes and exercise! Overweight and obesity have multifactorial causes, including mental health (Lingvay I et al 2023)

The use outside of these indications for weight control is currently without evidence, as no study results on benefits and risks are available to date and is used for weight control outside of the evidence-based approval and indication "off-label", so far only evaluated as a so-called lifestyle drug and the costs are not covered by health insurance.

Off-label use is currently viewed critically, as it leads to supply bottlenecks for patients with a necessary medical indication (see above) due to the very high demand. In a statement, the EMA has therefore pointed out that the drug should currently only be prescribed within the scope of the marketing authorization, stating the indication. To ensure the necessary supply, pharmacies are currently subject to stricter dispensing regulations for prescriptions outside the indication.

The most common side effects are gastrointestinal, such as bloating, nausea, vomiting,gastrointestinal discomfort, and reflux; in rare cases, there may also be an increased risk of gastric paralysis and intestinal obstruction. Start with a low dose and increase it gradually; if severe symptoms occur, delay the dose increase, suspend treatment, or reduce or discontinue the dose as necessary. 

Patients should drink plenty of water, eat a high-fiber diet and only small meals, get exercise, and avoid carbonated beverages and alcohol as much as possible!

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

In rare cases, pancreatitis has been observed (patients should be informed about the symptoms and monitored regularly). If pancreatitis occurs, the medication must be discontinued (with reevaluation at a later date if necessary). If the patient has a history of pancreatitis, the use of this medication should be reconsidered.

Cholelithiasis and cholecystitis may occuroccasionally.

Hypoglycemia is not expected from GLP-1 agonists themselves, as insulin secretion is merely enhanced in response to food intake. However, there is a risk of hypoglycemia when used in combination with insulin and other insulinotropic medications (e.g., sulfonylureas). 

Dehydration and its consequences (dizziness, falls) should be monitored and avoided, particularly when taken concurrently with diuretics and in older patients. Be aware of the risk of impaired renal function!

It is important to prevent or counteract muscle loss associated with weight loss (which is comparatively high with GLP-1 RA, up to 40% of weight loss) through exerciseand strength training.

Rapid and significant weight loss can also cause marked changes in facial appearance. A loss of muscle mass and subcutaneous fat—which is often particularly pronounced in the face—along with an additional reduction in interstitial fluid can lead to increased wrinkling and corresponding typical changes in appearance, which have become known in English-speaking countries as ““Ozempic face”(for more information on this, as well as possible treatment options, see “Ozempic face”).

Hypotension and dizzinessare also common in patients who are overweight or obese( be aware ofthe risk of falls in older adults!).

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

Note: During surgery under anesthesia or deep sedation,the risk of aspirationmay be increased !

Increased incidence of retinopathy associated with GLP-1 receptor agonists, particularly in diabetic patients and with concomitant insulin use: Caution and close monitoring (by an ophthalmologist) are recommended, especially in cases of pre-existing retinopathy (and, if applicable, macular degeneration). A link to the occurrence of a rare form of ischemic optic neuropathy (NAION) has been classified by the EMA’s PRAC as a very rare side effect (approx. 1/10,000) (PRAC statement dated June 6, 2025). If vision deteriorates or sudden vision loss occurs, immediate medical treatment is necessary; if NAION is confirmed, discontinue the medication immediately ! (Further information: bfam news(as of January 2025)Risk of significant vision loss and blindness! (Dtsch Ärztebl News, February 10, 2025; Dtsch Ärztebl News, February 25, 2025)).

An increased risk of C-cell tumors of the thyroid gland(preclinical in animal studies) has not yet been confirmed in humans (here, too, the assessment is still uncertain due to the long latency period). Caution is recommended in patients with relevant pre-existing conditions (Dtsch Ärztebl News, January 31, 2025)

There have been isolated recent reports of unexpected/unplannedpregnancies while taking GLP-1 agonists, which have been linked to improved fertility due to weight loss (Dtsch Ärztebl News, Dec. 12, 2024).

Long-term data are lacking, particularly for the newer substances with a prolonged half-life. Therefore, adverse effects with a long latency period cannot be reliably assessed. Pharmacovigilance has been heightened, and suspected cases of adverse effects 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)

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

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

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