SGLT-2 inhibitors

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SGLT-2 inhibitors (from “sodium dependent glucose transporter”) or gliflozine are drugs that are currently used to treat type 2 diabetes mellitus ( antidiabetic agents ).

Active ingredients and approval

As a first active ingredient which granted European Medicines Agency (EMA) on 12 November 2012 for dapagliflozin the Food and Drug . In a clinical trial , in which up to 10,000 test subjects participated, a significant therapeutic efficacy could be proven.

Ertugliflozin , canagliflozin and empagliflozin are now also approved . Other substances such as ipragliflozin and tofogliflozin are in advanced clinical trials or have been approved in the USA.

Mechanism of action

SGLT2 (sodium-glucose linked transporter 2) is a secondary active carrier protein that resorbs glucose and sodium in the kidneys in the proximal tubule from the primary urine . The sodium gradient built up by the sodium-potassium ATPase represents the driving force for glucose absorption. If this protein is not functional due to a hereditary disorder, the affected person will find high sugar levels in the urine without this being caused by a high blood sugar level ( renal glucosuria ).

The SGLT-2 inhibitors take advantage of this by mimicking the effect and inhibiting the renal sodium-dependent glucose transporter type 2 (SGLT2) in the renal tubules . The function is that they promote the concentration-dependent urinary excretion of glucose. This leads to both a decrease in blood sugar levels and a loss of calories. This mechanism of lowering blood sugar is independent of the action and release of insulin as well as insulin resistance or insufficient insulin production by the beta cells of the pancreas .

In addition, the SGLT1 transporter (in the distal tubule) also exists in the kidneys, which has a greater affinity for glucose than the SGLT2 transporter. Therefore, despite the use of SGLT-2 inhibitors, glucose is absorbed. Since SGLT1 transports two sodium ions in symport with glucose, the energy expenditure for this reabsorption is significantly higher. This also explains why, on the one hand, the inhibition of SGLT2 rarely leads to hypoglycemia (low blood sugar) and, on the other hand, there is no disturbance of the electrolyte balance despite the inhibition of sodium reabsorption.

application

Appropriate drugs are taken orally and used both as monotherapy or in combination with other antidiabetic agents.

Class-specific adverse drug reactions

As an adverse drug reaction  , SGLT-2 inhibitors can rarely trigger ketoacidosis , which normally occurs with very high blood sugar levels, but with SGLT-2 inhibitors it can also occur with normal blood sugar levels. If symptoms of ketoacidosis, such as nausea, vomiting, abdominal pain, or dyspnoea, should be tested for ketone bodies in the blood or urine in patients with SGLT-2 inhibitors, as ketoacidosis can be fatal if untreated. An activation of the ketone body formation by the low insulin and the increased glucagon levels is discussed as the mechanism.

In October 2019, the Medicines Commission once again advised the German medical profession that treatment with SGLT-2 inhibitors (gliflozins) should be interrupted if patients are hospitalized due to major surgery or an acute serious illness.

Fournier gangrene can rarely occur in men and women.

literature

  • G. Schernthaner, D. Müller-Wieland, B. Gallwitz: SGLT-2 Inhibitors - Glucosurics: A New Valuable Therapy Principle or a Wrong Path? Diabetology and Metabolism 2012; 7 (1): 27-29. doi: 10.1055 / s-0031-1283929
  • List JF, Woo V, Morales E, Tang W, Fiedorek FT: Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care , 2009 Apr; 32 (4): 650-7. doi: 10.2337 / dc08-1863

Individual evidence

  1. ↑ European Medicines Agency: Forxiga.
  2. ↑ Pharmazeutische Zeitung 2008: Pharmacon Meran 2008 - Drug research: Therapy concepts on the home straight
  3. ↑ https://www.aerzteblatt.de/archiv/197665/Eu-Zulassung-fuer-Ertugliflozin-Studie-bestaetigt-Nutzen
  4. ↑ VOKANAMET ™ (canagliflozin and metformin fixed dose combination) receives positive CHMP opinion recommending approval in the European Union for the treatment of adults with type 2 diabetes , PM from J&J on February 21, 2014, accessed on February 26, 2014.
  5. ↑ VOKANAMET® (canagliflozin and immediate release metformin hydrochloride fixed dose combination) approved in the European Union for treatment of adults with type 2 diabetes , PM by J&J of April 25, 2014, accessed on April 29, 2014.
  6. ↑ Boehringer Ingelheim and Eli Lilly and Company present efficacy and safety data on linagliptin and investigational compound, empagliflozin * in various diabetes subpopulations , PM by Boehringer Ingelheim (BI) of September 17, 2013, accessed on February 26, 2014
  7. ↑ FDA approves Jardiance® (empagliflozin) tablets for adults with type 2 diabetes , PM by Lilly August 1, 2014, accessed August 4, 2014.
  8. ↑ Type 2 Diabetes: CHMP recommends empagliflozin * for approval , PM by BI of March 21, 2014, accessed on March 24, 2014
  9. ↑ Type 2 diabetes: European Commission approves Jardiance® (empagliflozin) tablets for use in adults in Europe , PM by Lilly on May 23, 2014, accessed on May 25, 2014.
  10. ↑ Astellas and MSD Enter co-promotion agreement in Japan for Ipragliflozin, SGLT2 inhibitor for treatment of Type 2 diabetes ( Memento of 26 February 2014 Internet Archive ), PM Astellas September 2, 2013, accessed on February 26, 2014.
  11. ↑ Launch of Suglat® Tablets, a Selective SGLT2 Inhibitor for Treatment of Type 2 Diabetes ( Memento April 18, 2014 in the Internet Archive ), PM by Astellas April 17, 2014, accessed April 17, 2014.
  12. ↑ Product Development Portfolio , Overview from Roche, accessed February 26, 2014.
  13. ↑ Anne L. Peters, Elizabeth O. Buschur et al. a .: Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium – Glucose Cotransporter 2 Inhibition. In: Diabetes Care. 38, 2015, p. 1687, doi : 10.2337 / dc15-0843 .
  14. ^ Wataru Ogawa, Kazuhiko Sakaguchi: Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. In: Journal of Diabetes Investigation. 7, 2016, p. 135, doi : 10.1111 / jdi.12401 .
  15. ↑ Drug Safety Mail 2019-64 ; Medicines Commission of the German Medical Association of October 30, 2019, accessed on November 19, 2019