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Sodium-Glucose Cotransporter Inhibitors ( SGLT2 )

Novel antidiabetes agents which work by increasing the urinary glucose excretion due to suppression of glucose reabsorption at the proximal convoluted tubule in the kidneys. Available agents in UK are canagliflazocin , dapagliflazocin , empagliflazocin and ertugliflazocin.

 

Humans filter 160-180 glucose / day which is reabsorbed and returned to systemic circulation SGLTs are sodium glucose transporters on the luminal membrane of the proximal tubule Diabetes is associated with glomerular hyperfiltration and upregulation of SGLT2 expression -increased Sodium glucose transporter 2 ( SGLT2 ) proteins in the proximal convoluted tubules of the kidneys account for about 90 % of filtered glucose reabsorption ( 6 identified SGLTS – SGLT1 & 2 are considered most important ) In type 2 diabetes patients -renal threshold ( normally 180 mg / dL ) for reabsorption of glucose is increased and this worsens hyperglycemia -using SGLT2 inhibitors this threshold can be reduced to 40-120 mg / dL SGLT2 inhibitors reduce glucose reabsorption by 50 % to 60 % Hence use of SGLT2 inhibitors causes glycosuria of about 60-80 g/ day which is about 240-320 kcal energy loss As glucose is excreted – level in plasma falls leading to an improvement in all glycemic parameters Lower systemic BP , decreased circulatory volume by 7 % , 2-3 kgs of weight loss after about 24-52 weeks of treatment.

 

Check individual indications as in BNF
 Type 2 diabetes as monotherapy ( if metformin not appropriate ) Type 2 diabetes in combination with insulin or other anti-diabetes drug Newly diagnosed T2DM + established CVD or high CV risk Symptomatic chronic heart failure with reduced ejection fraction ( Dapagliflazocin independent of presence of T2DM ) Chronic kidney disease.

 

Check individual contraindications/ cautions as in BNF
 h/o diabetes ketoacidosis moderate to severe renal impairment ( do not start if eGFR < 60 & discontinue if eGFR < 45 ) severe hepatic impairment avoid empagliflazocin if > 85 – risk of volume depletion complicated UTI.

 

Major benefits -Improves hyperglycemia without risk of hypoglycemia , Reduce body weight and visceral adiposity , Improve metabolic abnormalities associated with metabolic syndrome as BP , lipid profile and serum uric acid levels , Recent evidence shows improvement of Cardiovascular and renal outcomes in patients with and without diabetes , beneficial effects in heart failure , CV trials have shown that they impart protection against major cardiovascular disease in those with established atherosclerotic CV disease , reduce the risk of admission in patients with heart failure and reduce CV all cause mortality.

 

Adverse effects – Genitourinary tract infections ( particularly genital mycotic infections- vulvovaginitis in females and balanitis in men ) Increased risk sarcopenia particularly in elderly patients due to loss in body weight , Increased risk of lower-extremity amputation mainly toes and metatarsal bones and bone fractures ( reported with canagliflazocin in trials ) Hypotension , acute kidney injury , Ketoacidosis without hyperglycemia ( triad of normal glycemia < 11 mmol / L , increased anion gap metabolic acidosis and ketonaemia or ketonuria ) 
( rare but severe adverse affect )

REFERENCES

  1. Lu H, Meyer P, Hullin R. Use of SGLT2 inhibitors in cardiovascular diseases: why, when and how? Swiss Med Wkly. 2020 Sep 1;150:w20341. doi: 10.4414/smw.2020.20341. PMID: 32920793
  2. Saisho, Yoshifumi. “SGLT2 Inhibitors: the Star in the Treatment of Type 2 Diabetes?.” Diseases (Basel, Switzerland) vol. 8,2 14. 11 May. 2020, doi:10.3390/diseases8020014
  3. Hsia, Daniel S et al. “An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus.” Current opinion in endocrinology, diabetes, and obesity vol. 24,1 (2017): 73-79. doi:10.1097/MED.0000000000000311
  4. SGLT2 Inhibitors: Physiology and Pharmacology Ernest M. Wright 

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