Incretin mimetics

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Incretin mimetics , or GLP-1 receptor agonists are drugs for the treatment of diabetes mellitus ( diabetes ), showing the effect of hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mimic whose hypoglycemic properties collectively called incretin Effect can be called. GLP-1 receptor agonists are given as an injection.

Incretin effect

On the clinical effectiveness of incretin mimetics, two meta-analyzes from a total of 21 randomized comparative studies with a duration of at least 20 weeks on the issue of glucose and weight reduction were published (Vilsbøll et al., 71st Annual Meeting of the American Dietetic Association , 2011). Compared to other antidiabetic agents, the examined GLP-1 receptor agonists exenatide and liraglutide reduced the HbA 1c value by an average of 0.66 percent; the weight reduction in adults was 2.9 kilograms on average. A higher dose of liraglutide resulted in more weight loss than the lower dose. There was no difference between the daily and once weekly exenatide administration. Side effects showed a slight decrease in blood pressure and a decrease in total cholesterol . Liraglutide has been approved in the USA since December 2014 under the trade name Saxenda for daily injection against obesity.

Another class of drugs, the effect of which is also based on the incretin effect, are the inhibitors of dipeptidyl peptidase 4 , which inhibit an enzyme by which GLP-1 is broken down after its release.

Adverse drug effects

The main side effects are nausea , diarrhea and vomiting . No data are available on whether incretin mimetics can prevent the consequences of diabetes such as amputations , blindness and kidney failure . However, as found in an autopsy study on diabetes patients, the GLP-1-based therapies could negatively affect the pancreas . Both the American drug approval authority FDA and the European Medicines Agency announced corresponding investigations in 2013.

Contraindications

Severe renal insufficiency is one of the contraindications . Liraglutide is not recommended in patients with impaired liver function.

Drugs with approval

  • Exenatid : The synthetically produced polypeptide exenatide, which corresponds to the substance exendin-4 , which occurs naturally in the saliva of the Gila crustacean and is similar in structure and effect to GLP-1, is the first incretin mimetic available on the pharmaceutical market. It thus represents the lead substance in this new class of active ingredients. Exenatide (trade name Byetta ) received approval from the American Food and Drug Administration (FDA) in April 2005 for use in combination with metformin or glitazones . Under the trade name Bydureon one is sustained-release formulation for weekly application available.
  • Liraglutide : In July 2009, the European Medicines Agency approved liraglutide (trade name Victoza ) developed by Novo Nordisk for the treatment of type 2 diabetes mellitus in adults, an analogue of human GLP-1 with a duration of action of 24 hours was extended. It is approved under the name Saxenda for weight regulation in the case of obesity. Under the name Xultophy, there is a combination of liraglutide and insulin degludec .
  • Albiglutide (trade name Eperzan ) from GlaxoSmithKline has been on the market in Germany since October 2014. It is approved for monotherapy in adults with type 2 diabetes when diet and exercise alone are not sufficient to control blood sugar levels and when the use of metformin is not an option. Albiglutide is given as a weekly injection.
  • Dulaglutide (trade name Trulicity ) from Lilly has been on the market in Germany since February 2015. The weekly injection is also common, whereby the dosage can be made dependent on the individual blood sugar.
  • Semaglutide : The closely related successor to liraglutide was developed - as the first GLP-1 receptor agonist - for administration in tablet form (oral), but was then also launched on the market for subcutaneous injection in 2018.

Substances without approval

  • Taspoglutide : The GLP1 analog developed by Roche was in phase III studies at the end of 2009 , and the market launch was expected in 2011 or 2012. In September 2010 Roche announced that it had stopped all studies with taspoglutide. The reasons for this were sometimes severe allergic reactions and frequent side effects in the gastrointestinal tract, mainly nausea and vomiting.
  • Lixisenatide (former trade name Lyxumia ) came onto the market in Germany in May 2014, but was taken off the market in June 2014.
  • Pseudin-2 : Pseudin-2, isolated from the skin secretion of the great harlequin frog ( Pseudis paradoxa ), was identified as a further possible active ingredient .

literature

Individual evidence

  1. ^ Meta-analyzes on GLP-1 mimetics, B. Wilms, Congress Report December 2011, p. 21f.
  2. ↑ AE Butler, M. Campbell-Thompson, T. Gurlo, DW Dawson, M. Atkinson, PC Butler: Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with increased Exocrine Pancreas Dysplasia and the potential for Glucagon-producing Neuroendocrine Tumors . In: Diabetes . Volume 62, pp. 2595-2604, doi: 10.2337 / db12-1686 .
  3. ↑ EMA: European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes (PDF; 92 kB).
  4. ↑ FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes .
  5. ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 2015, pp. 162–165.
  6. ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 162.
  7. ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 2015, p. 165.
  8. ↑ medpageTODAY, Medical News, Roche Halts Trials of Taspoglutide , September 13, 2010, accessed October 10, 2010.