Gliflozine

Gliflozines are among the newer incretin-based drugs that can be used to treat type 2 DM (Diederich 2020). In 2012, dapagliflozin was initially launched in Germany. It is approved for monotherapy and combination therapy. Two years later, canagliflozin was approved. However, due to the lack of additional benefit, canagliflozin was withdrawn from the market in the same year (Schwabe 2017).

Also in 2014, empagliflozin was approved in Germany as the third representative of the gliflozines (Schwabe 2015).

Pharmacodynamics (effect)

The effect of gliflozines is completely independent of insulin sensitivity and insulin secretion (Kasper 2015). The effect is due to:

• an inhibition of the sodium dependent glucose transporter 2 (SGLT2) in the proximal tubule of the kidneys.
• which leads to a reduced renal re-absorption of glucose
• and consequent lowering of the renal threshold for glucose with increased glucosuria and lowering of the glucose level in the blood (Herold 2020 / Kasper 2015 / Diederich 2020)
• cardioprotective effect in diabetics and metabolically healthy individuals (Stiefelhagen 2021)
• reduction of cardiovascular events
• Reduction of cardiovascular mortality (Diederich 2020)

In one study (EMPA- REG), treatment with empagliflozin was shown to significantly reduce cardiovascular events to a degree not achievable with other SGLT2 inhibitors (Herold 2020).

The reduction in cardiovascular events in patients with atherosclerotic disease is 24%. This is higher than in patients with cardiovascular risk factors but without arteriosclerotic damage, where it is 16% (Holzgreve 2019).

According to recent studies, empagliflozin may beneficially affect not only systolic heart failure but also diastolic heart failure. No evidence-based therapy has been available for the latter (Stiefelhagen 2021).

• After initial short-term reduction of renal function, a nephroprotective effect sets in (Diederich 2020).

Functional deterioration was reduced by 46% in patients with pre-existing renal disease and by 44% in patients without pre-existing renal disease (Holzgreve 2019).

• Reduction of oxidative stress
• Reduction of uric acid levels (Schwabe 2017).

Indication

• Type 2 DM as monotherapy or combination therapy (Herold 2020).

Since 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend preferential treatment with SGLT2- inhibitors in type 2 DM and concomitant cardiovascular risk factors or renal comorbidities (Diederich 2020).

Heart failure with reduced pump function (HFrEF): approval for empagliflozin (reduces cardiac morbidity) and dapagliflozin (additionally reduces cardiac mortality).

(Stiefelhagen 2021)

• Intolerance or contraindication to metformin (Schwabe 2017).

Dosage and mode of administration

Dosage recommendation:

• Empagliflozin 10 mg 1 x / d (maximum dose 25 mg / d).
• Dapagliflozin 10 mg / d (maximum dose 10 mg / d [German Medical Association 2021])

(Herold 2020)

The patient should be advised of the need for adequate hydration (Diederich 2020).

Adverse effects

• Recurrent genital infections (occur in up to 10% [Herold 2020]).
• recurrent urinary tract infections (sometimes with pyelonephritis and urosepsis [Bundesärztekammer 2021])
• initial short-term reduction of renal function (Diederich 2020)
• Fournier gangrene

So far, this has only been observed during therapy with dapagliflozin. It occurs very rarely overall, but can also affect women [Bundesärztekammer 2021]).

• (atypical) ketoacidosis

This also occurs only rarely. It is already possible at BG values < 250 mg / dl and is mainly combined with dehydration (Herold 2020). Typically, often no ketone bodies are detectable in the urine, the blood glucose is only moderately elevated or may also be normal (Bundesärztekammer 2021).

• in the case of already existing advanced PAVK, there may be a deterioration of the blood circulation (Herold 2020)
• Polyuria
• Thirst
• Dry mouth
• Pruritus
• Dizziness

(Bahrmann 2018)

• Potential risk of fractures increased (with empagliflozin).

(German Medical Association 2021)

• Hypoglycemia only possible with combination therapy with antidiabetic agents that lower blood glucose (Diederich 2020)

Contraindications

• Type 1 DM
• Volume deficiency
• Contrast medium administration
• Ketoacidosis
• Hypersensitivity to Gliflozine

(Herold 2020)

• diabetic foot syndrome (Diederich 2020)
• Do not initiate therapy with dapagliflozin in > 75-year-olds
• Do not initiate therapy with empagliflozin in > 85 year olds.

(Bahrmann 2018)

• Because of the risk of ketoacidosis:
  • Discontinue before surgery
  • Discontinue in case of acute deterioration of general condition (sick days [Bundesärztekammer 2021]).

The amputation rate is increased with the administration of SRLT2 inhibitors (Diederich 2020).

From a glomerular filtration rate (GFR) of < 60 ml / min, the guidelines no longer recommend the use of dapagliflozin and for empagliflozin to start therapy. In patients who have previously tolerated empagliflozin well, treatment can be continued at a reduced dose of 10 mg / d until a GFR < 45 ml / min (Bahrmann 2018).

Preparations

• Dapagliflozin e.g. Forxiga ®
• Empagliflozin e.g. Jardiance ®

(Herold 2020)

Gliflozine is one of the newer drugs against type 2 DM, so clinical experience is still limited. Studies regarding cardiovascular events and the incidence of bladder cancer have been ongoing since its approval in 2013 (Kasper 2015).

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 484, 492, 494
4. Herold G et al (2020) Internal medicine. Herold Publishers 733
5. Holzgreve H (2019) The star of gliflozines continues to rise. MMW- Advances in Medicine (161) 31 https://doi.org/10.1007/s15006-019-0445-4
6. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2414
7. Schwabe U et al. (2015) Prescription drug report 2015: current data, costs, trends and commentary. Springer Verlag 90
8. Schwabe U et al. (2017) Prescription drug report 2017: current data, costs, trends and commentary. Springer Verlag 304
9. Stiefelhagen P (2021) Gliflozine also good for the heart. MMW- Advances in Medicine (163) 13 https://doi.org/10.1007/s15006-021-0288-7