GLP1- receptor antagonists

A GLP- 1- RA (glucagon- like peptide- 1) is an artificially produced insulinotropic (Herold 2020) peptide with a low risk of hypoglycaemia that mimics the effect of the body's own incretin GLP- 1 (Häussler 2012). These are hormonal stimulation factors that are released by the intestine for insulin secretion (Herold 2020).

In the human body, neuroendocrine L cells in the intestine and A cells in the pancreas produce proglucagon GLP- 1. This enzyme is degraded by dipeptidyl peptidase- 4 (DPP- 4). Together with gastric inhibitory polypeptide (GIP), GLP- 1 is one of the incretins (Herold 2020).

The effect of the GLP- 1 enzyme consists of:

• Glucose-dependent stimulation of the secretion of insulin
• Delay of gastric emptying
• Inhibition of the release of glucagon (inhibits appetite and leads to weight loss) (Herold 2020)

The chemical analogs GLP- 1- RA bind with high affinity to the GLP- 1- receptors. However, unlike GLP- 1, they are not inactivated by DPP- 4. This causes an:

• Inhibition of the secretion of glucagon
• Increase the secretion of insulin
• Delay of gastric emptying
• Decrease in appetite
• Weight loss (Herold 2020)
• Preferential lowering of the postprandial BG (Kasper 2015)

Additional effect of liraglutide:

• Reduction of cardiovascular mortality
• Nephroprotection (Herold 2020)
• Reduction of overall mortality (Bahrmann 2018)

Additional effect of dulaglutide:

• Reduction of cardiovascular events by 12 % compared to placebo according to REWIND study (Sonnet 2020)

Type 2 DM with metabolic syndrome

• manifest cardiovascular diseases
• cardiovascular risk factors
• concomitant renal disease (Diederich 2020) in combination with metformin and / or sulfonylureas (SH) and / or insulin, but these drugs alone are not sufficient to lower blood glucose levels appropriately (Herold 2020).

Since 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have recommended the preferential use of GLP- 1- RA or SGLT- 2 inhibitors in addition to treatment with metformin, sulfonylureas and insulin (Diederich 2020).

Treatment with GLP1- RA should be considered before starting any insulin therapy for type 2 DM - especially in the case of an elevated body mass index (German Medical Association 2021).

Patients should be informed about the symptoms of acute pancreatitis before starting therapy (German Medical Association 2021).

Byetta ^®: approx. 30 min before the main meals initially 2 x 5 µg / d s.c. After approx. 4 weeks, the dose can be increased to 2 x 10 µg / d s.c.

Victoza ^®: initially 1 x / d 0.6 µg / d s.c., subsequent increase to 1.2 µg / d s.c., maximum dose 1.8 µg / d s.c.

Bydureon ^®: 1 x weekly 2 mg s.c.

Trulicity ^®: 1 x weekly 0.75 - 1.5 mg s.c. (Herold 2020)

Studies have shown that once-weekly administration of ultra-long-acting GLP1 RA such as dulaglutide is not inferior to daily administration of liraglutide (Dungan 2014).

Hyperlipasemia (common)

Nausea (frequent)

Vomiting (in up to 10 % [Ritzmann 2008])

Diarrhea (mostly reversible)

Pancreatitis (very rare; clinical treatment was sometimes required, no deaths have been described to date [Ritzmann 2008/Herold 2020])

Hypoglycemia: There is no risk of hypoglycemia with GLP- 1- RA, only in combination with other antidiabetic drugs (Herold 2020):

• in combination with metformin in up to 39 % (also corresponds to the number of patients treated with placebo)
• under the combination with sulfonylureas, the risk of hypoglycemia increased many times over, therefore an early dose reduction of the sulfonylureas should be considered here

Formation of antibodies against GLP1- RA: The formation of AK was found in almost 50 % of cases. The clinical significance is still unclear. A reduced effect of exenatide has been reported in patients with extremely high AK titres (Ritzmann 2008).

As GLP1- RA delays gastric emptying, the absorption of other drugs can be delayed or reduced (Kasper 2015), e.g. with:

• Antibiotics
• contraceptives
• Drugs with a narrow therapeutic range such as oral anticoagulants (Ritzmann 2008)

terminal renal failure with a creatinine clearance < 30 ml / min (Herold 2020)

not recommended for severe renal insufficiency with a GFR < 50 ml / min (Bahrmann 2018)

Z. n. pancreatitis (Herold 2020)

Short-acting GLP1- RA:

• Exenatide (^Byetta®)

Long-acting GLP1- RA:

• Liraglutide (Victoza ^®)

Ultra-long-acting GLP1- RA:

• Exenatide LAR (Bydureon ^®)
• Dulaglutide (Trulicity ^®)

As early as 1902, Bayliss and Starling showed that the intestinal mucosa has a substance that is able to influence exocrine pancreatic function via the bloodstream (Köthe 2011). Elrick et al. (1964) and McIntyre et al. (1965) were the first to describe the so-called incretin effect. They showed that insulin stimulation after oral glucose administration releases significantly more insulin than after intravenous administration, as glucose entering the gastrointestinal tract releases a hormone from the intestinal mucosa. This had long been suspected and La Barre coined the term "Incrétide" in 1932 (Schlegel 1974 / Schatz 2014 / Köthe 2011).

In 1992, Eissele et al. detected incretin in the L-cells of the jejunum, terminal ileum, colon and rectum. Orskov et al. also found it in the A cells of the pancreas (Köthe 2011). The polypeptide exenatide, which is similar to human GLP-1 (glucagon-like peptide-1) (Ritzmann 2008) and is a potent agonist at GLP-1 receptors, was detected in the saliva of the venomous American Gila crustacean Heloderma suspectum (Köthe 2011). Biotechnologically obtained proteins were first used medicinally in 2007 as the active ingredient exenatide. Liraglutide was added in 2009 (Häussler 2012).

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