Glp1 receptor agonists

Last updated on: 21.12.2021

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History
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GLP- 1- receptor antagonists; GLP- 1- RA; GLP1- analogues; incretins; incretin mimetics;

First author

As early as 1902, Bayliss and Starling showed that the intestinal mucosa has a substance capable of influencing 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 i.v. administration, because 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).

In the saliva of the venomous American Gila crustacean Heloderma suspectum (Köthe 2011), the polypeptide exenatide was detected, which is similar to human GLP- 1 (glucagon- like peptide- 1) (Ritzmann 2008) and is a potent agonist at GLP1- receptors (Köthe 2011).

Biotechnologically derived proteins were used medicinally for the first time in 2007 as the active ingredient exenatide. In 2009 liraglutide was added (Häussler 2012).

Definition
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A GLP- 1 RA (glucagon- like peptide- 1) is an artificially produced insulinotropic (Herold 2020) peptide with a low risk of hypoglycemia 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).

General information
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Pharmacodynamics (effect)

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).

GLP- 1 together with the "gastric inhibitory polypeptide" (GIP) belongs to the incretins (Herold 2020).

The action of the enzyme GLP- 1 consists in:

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

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

Additional effect of liraglutide:

  • Reduction in cardiovascular mortality.
  • nephroprotection (Herold 2020)
  • Reduction in all-cause mortality (Bahrmann 2018).

Additional effect of dulaglutide:

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

Indications

  • Type 2 DM with
    • metabolic syndrome
    • manifest cardiovascular disease
    • cardiovascular risk factors
    • renal concomitant diseases (Diederich 2020) in combination with metformin and / or sulfonylureas (SH) and / or insulin, but these drugs alone are not sufficient to lower blood glucose 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 alongside treatment with metformin, sulfonylureas, insulin (Diederich 2020).

  • before starting any insulin therapy in type 2 DM - especially with an increased body mass index - treatment with GLP1- RA should be considered (Bundesärztekammer 2021).

Dosage and method of administration

It is taken in relation to meals and as a combination therapy with e.g. metformin and / or sulfonylureas (SH) and / or insulin. In patients receiving insulin secretagogues, a reduction of insulin secretagogues may be required due to the risk of hypoglycemia during treatment with GLP1- RA (Kasper 2015).

Dosage recommendation:

  • Byetta ®: approx. 30 min before main meals initially 2 x 5 µg / d s.c.

After approx. 4 weeks, a dose increase to 2 x 10 µg / d s.c. is possible.

  • Victoza ®: initially 1 x / d 0, 6 µg / d s.c., subsequent increase up 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)

The 1 x weekly administration of ultralong-acting GLP1- RA such as dulaglutide is not inferior to daily administration of liraglutide according to studies (Dungan 2014).

Adverse effects

  • Hyperlipasemia (common)
  • Nausea (common)
  • Vomiting (up to 10% [Ritzmann 2008])
  • Diarrhea (usually reversible)
  • Pancreatitis (very rare; in some cases clinical treatment was required, deaths have not been described so far [Ritzmann 2008])

[Herold 2020)

  • Hypoglycemia: There is no risk of hypoglycemia with GLP- 1- RA, only in combination with other antidiabetic drugs (Herold 2020)
  • under the combination with metformin in up to 39 % (also corresponds to the number of patients treated with placebo)
  • under 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. In patients with markedly high AK titers, a reduced effect with regard to exenatide has been reported (Ritzmann 2008).

Contraindication

  • terminal renal failure with a creatinine clearance < 30 ml / min (Herold 2020)
  • Not recommended in higher-grade renal insufficiency with a GFR < 50 ml / min (Bahrmann 2018).
  • Z. n. pancreatitis

(Herold 2020)

Interactions

As GLP1- RA delay gastric emptying, absorption of other drugs may be delayed or reduced (Kasper 2015) such as with:

  • Antibiotics
  • Contraceptives
  • Drugs with a narrow therapeutic range such as oral anticoagulants.

(Ritzmann 2008)

Preparations

  • Short-acting GLP1- RA:
    • exenatide (Byetta®)
  • Long-acting GLP1- RA:
    • liraglutide (Victoza ®)
  • Ultra-long-acting GLP1- RA:
    • exenatide LAR (Bydureon ®)
    • Dulaglutide (Trulicity ®)

Note(s)
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Patients should be informed about the symptoms of acute pancreatitis before starting therapy (Bundesärztekammer 2021).

Literature
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  1. Bahrmann A et al. (2018) S2k- Guideline Diagnosis, therapy and follow-up of diabetes mellitus in old age. 2nd edition AWMF register number: 057-017
  2. German Medical Association (2021) National health care guidelines: type 2 diabetes. AWMF- Register- No. nvl-001
  3. Diederich S et al (2020) Reference endocrinology and diabetology. Georg Thieme Verlag Stuttgart 494
  4. Dungan K M et al (2014) One-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomized, open-label, phase 3, non-inferiority trial, Lancet (384) 1349 - 1357.
  5. Häussler B et al (2012) Pharmaceuticals - Atlas 2012: the consumption of pharmaceuticals in the SHI system. Springer Verlag 58 - 59
  6. Herold G et al (2020) Internal medicine. Herold Verlag 735
  7. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2414 - 2415
  8. Köthe L D (2011) On the significance of the addition of human serum albumin to exogenous GLP-1 infusions exemplified by the antagonizability of GLP-1 [7-36-amide] influence on the first phase of insulin secretion after intravenous glucose administration by the GLP-1 receptor antagonist exendin [9-39] in healthy humans. Inaugural dissertation for the award of the doctorate degree of the Medical Faculty of the Georg-August-University of Göttingen.
  9. Ritzmann P (2008) Exenatide. Pharma- Kritik- Jahrgang 29, Nr. 11 PK188 DOI: https://doi.org/10.37667/pk.2007.188
  10. Schatz H et al. (2014) Diabetology compact: fundamentals and practice. Springer Verlag Berlin, Heidelberg 162
  11. Schlegel B et al (1974) Proceedings of the German society of internal medicine: 80th congress held at Wiesbaden. Springer Verlag Heidelberg - Berlin 332
  12. Sonnet M (2020) Cardiac protection included. CME 17, 48 https://doi.org/10.1007/s11298-020-0855-8.

Last updated on: 21.12.2021