gliflozins / SGLT2 inhibitors

see also:

• SGLT2 inhibitor induced diabetic ketoacidosis (gliflozin DKA)
• oral hypoglycaemic agents
• chronic renal failure
• diabetes mellitus

• SGLT2 inhibitors have revolutionized the treatment of patients with T2DM with established or at risk for atherosclerotic cardiovascular disease (ASCVD) and patients with diabetic kidney disease and well as non-diabetic patients with chronic renal failure and those with congestive cardiac failure

• gliflozins cause dose-dependent renal sodium-glucose co-transport inhibition which increases glucose excretion to 20-70g/day with an aim to reduce hyperglycaemia, improve HbA1c levels, and the loss of calories may assist weight reduction (typically 2-3kg in 1st 2-3 months then plateaus).
• do not cause significant hypoglycaemia when used alone
• “induce a mild acute decline in eGFR by 5 mL/min/1.73 m2, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure and a decline in eGFR” but studies do not seem to support any increased risk of AKI ¹⁾
• they lower uric acid levels
• are associated with a sustained modest reduction in systolic blood pressure of approximately 3 to 6 mm Hg and diastolic BP of approximately 1 to 2 mm Hg via natriuresis, associated plasma volume contraction, reduction in arterial stiffness, and improvement in endothelial function ²⁾
• they have emerged as a key disease-modifying therapy to prevent the progression of chronic kidney disease (CKD) ³⁾
  • “primary mechanism by which SGLT2 inhibitors are thought to be nephroprotective is through increasing distal sodium delivery and inhibiting tubuloglomerular feedback resulting in afferent vasoconstriction and reduction in intraglomerular pressure - a marker of this reduction in intraglomerular pressure is the reduction in albuminuria, which is largely independent of concomitant changes in metabolic parameters or eGFR”
  • reduces risk of hyperkalaemia in CRF patients without causing hypokalaemia possibly via enhanced kaliuresis by increasing distal delivery of sodium and stimulating aldosterone
• appear to reduce cardiac events after AMI independent of glucose control
  • reduces incidence of in-stent re-stenosis-related events, reduces NT-proBNP as well as improving structural and functional LV markers, lowers inflammation parameters and stabilises plaque, but does result in even higher increases in Trimethylamine N-oxide (TMAO) which is involved in pro-atherogenic pathways ⁴⁾

• C/I if eGFR < 45 or severe hepatic impairment
• causes glycosuria and osmotic diuresis with ~5x increased risk of UTIs, balanitis, vulvovaginitis and dehydration
  • this increases the risk of Fournier's gangrene
• may contribute to risk of acute kidney injury especially if on ACE inhibitors, angiotensin II receptor blockers (ARBs) and non-steroidal anti-inflammatory drugs (NSAIDs)
• may cause euglycaemic SGLT2 inhibitor induced diabetic ketoacidosis (gliflozin DKA)!

• dapaglifozin
  • introduced in Aust in 2013
  • 10mg once daily dose appears to reduce HbA1c by 0.6-0.9 percentage units compared with 0.2 for placebo, and similar to degree of effect of metformin, but causes more weight loss than metformin
  • can be used as monotherapy but not approved on PBS for monotherapy
  • lowers systolic BP by 1-5mmHg
  • perhaps best used with metformin until further studies
  • in Sept 2022, approved in Aust for use in Rx of CKD (even in non-diabetics) as addition to standard care and patient must be stabilised on an ACE inhibitor or ARB for at least 4 weeks prior to initiation, unless contraindicated.⁵⁾
• canagliflozin
  • introduced in Aust in 2013
  • dose: 100mg once daily in addition to metformin or a sulphonylurea
• empagliflozin
• sotagliflozin
  • first dual SGLT1 and SGLT2 inhibitor and is approved in Europe for both type 1 DM and T2DM
  • SGLT1 inhibition is thought to delay intestinal glucose absorption and reduces postprandial glucose levels but may cause diarrhoea