SGLT2 inhibitors were originally developed to reduce glycemia in patients with diabetes mellitus type 2 by inhibiting the sodium -glucose cotransporter 2 at the proximal tubule of the nephron . This blocks the reabsorption of glucose and sodium, resulting in higher excretion.

In addition, they also inhibit sodium reabsorption by inhibiting NHE3 (sodium hydrogen exchanger 3).

The mechanism of action in heart failure patients is still being investigated, but appears to be more than just inhibition of SGLT2. The mechanism of action is multifactorial and is located on the cardiometabolic -renal axis:

• increase in natriuresis and decrease in circulating volume, hemoconcentration
• decrease in body weight due to glycosuria and loss of calories through urine
• drop in blood pressure
• decrease in intraglomerular pressure and decrease in albuminuria due to renoprotective compensatory mechanisms.
• influence on epicardial fat and adipokines 
• direct cardioprotective effects: increase in ketone use by myocardium, increased energy production in myocytes (ATP), decrease in hypertrophy and fibrosis, reduction of sodium overload in myocytes ,...
• decrease in systemic and myocardial inflammation and oxidative stress
• ...

• Reduction of CV death (approximately 15% risk reduction)
• Reduction in hospitalizations for heart failure (approximately 30% risk reduction)
• Reduction of first HF hospitalization or cardiovascular death (approximately 25% risk reduction)
• Slowing down the decline of renal function in the longer term with a decrease in renal endpoints such as end-stage renal disease and need for dialysis, death from renal causes (approximately 25% risk reduction)

Trials:

SGLT-2 inhibitor versus placebo

• Diabetes mellitus type 2: DECLARE ( dapagliflozin ), EMPA-REG- Outcome ( empagliflozin )
• HFrEF (SGLT-2 inhibitor on top of HFrEF therapy with RAAS blocker and beta blocker): DAPA-HF ( dapagliflozin ), EMPEROR- Reduced ( empagliflozin )
• HFmrEF and HFpEF : DELIVER ( dapagliflozin ), EMPEROR- Preserved ( empagliflozin )
• Chronic renal insufficiency: DAPA-CKD ( dapagliflozin ), EMPA- Kidney ( empagliflozin )

Proven effects (both in patients with and without diabetes mellitus):

• Especially a reduction in hospitalizations or urgent medical check-ups due to progressive heart failure.
• Decrease in dyspnea and improvement in quality of life.
• Slight reduction in cardiovascular mortality.
• Reduction of progressive renal insufficiency and need for dialysis: long-term renoprotective effect.

1. Diabetes mellitus type 2
   
   Refund Criteria:

• • HbA1c between 7 and 9%
  • despite already taking at least 1 antidiabetic drug
  • and ≥ eGFR 30 ml/min

2. Heart failure
   
   Start-up and certificate by cardiologist. Extension of reimbursement by cardiologist, geriatrician or internist.
   
   HFrEF
   
   Reimbursement criteria (empagliflozin and dapagliflozin):

• • LVEF ≤ 40%
  • NYHA II-IV
  • eGFR ≥ 20 ml/min
  • no diabetes mellitus type 1
  • under optimal dose of ACE inhibitor or ARB
• 
  HFmrEF and HFpEF
  
  Reimbursement criteria (empagliflozin and dapagliflozin):
• • LVEF > 40%
  • NYHA II-IV
  • no diabetes mellitus type 1

3. Chronic renal insufficiency
   
   Reimbursement criteria (dapagliflozin and empagliflozin):

• • eGFR < 60 ml/min
  • with albuminuria and uACR ≥ 200 mg/g (urinary albumin creatinine ratio)
  • no diabetes mellitus type 1

• New standard therapy: Forxiga ( dapagliflozin ) or Jardiance ( empagliflozin ) 10 mg per day.
• Always try to associate, according to the reimbursement criteria.
• Start at 10 mg per day, without the need for uptitration or higher doses.
• No need to monitor renal function, ionogram or blood pressure.

• Slight dehydration and hypotension may occur at start-up. It is sometimes possible and necessary to reduce or discontinue the loop diuretic , as the SGLT2 inhibitors also have a mild diuretic effect and enhance the effect of loop diuretics .
• SGLT2 inhibitors can cause a small drop in blood pressure after initiation.
• After starting an SGLT2 inhibitor, there is usually a slight decrease in kidney function ( eGFR ). In the long term, this will remain stable for longer. SGLT2 inhibitors are nephroprotective . In case of excessive diuresis, weight loss or signs of dehydration, loop diuretics should be reduced or stopped.
• Safe to use and proven benefit in chronic renal insufficiency with an eGFR up to 25-30 ml/min.

• Severe renal impairment with an eGFR < 15-20 ml/min or dialysis.
• History of ketoacidosis under therapy with an SGLT2 inhibitor, without a clearly demonstrable cause.
• Diabetes mellitus type 1.
• Repeated (mycotic) urinary infections.

• Genitourinary fungal infections (candida) (due to glycosuria):
  • Pursue good genital hygiene.
  • If there are signs of a urinary infection (redness, itching or white loss), pain or discomfort during urination: evaluate immediately and prescribe Diflucan 150 mg per os once. 

    PLEASE NOTE for the interaction with any NOACs : cannot be combined! The NOAC is then best not taken for 2 days, namely on the day of taking Diflucan and the day after.

• Ketoacidosis
  Rare but reported side effect.
  Alarm symptoms: nausea and vomiting, epigastric pain, excessive thirst, rapid and deep breathing, confusion, drowsiness.

• • Therefore, DO NOT take SGLT2 inhibitors if you have diarrhea, vomiting or a serious infection.
  • Therefore, DO NOT take SGLT2 inhibitors if you are not eating or need to fast for an operation or examination.