SGLT2 INHIBITORS IN NEPHROLOGY

1. SGLT2 INHIBITORS IN
NEPHROLOGY

2. Annexure
• Introduction & natural history
• Mechanisms of Action
• Pharmacokinetics
• Adverse events
• Drug trials (renal outcomes)

3. • SGLT1 and SGLT2 are members of the SLC5 gene family, a subdivision
of a superfamily of sodium cotransporters.
• SGLT1 (SLC5A1) is predominantly expressed in the small
intestine(restricted to the brush border membrane of mature
enterocytes), and to a lesser extent the kidney cortex (luminal
membrane of S3 segment)
• SGLT2 (SLC5A2) is virtually restricted to the renal cortex (luminal
membrane of S1 & S2 segment of PCT)

4. Natural history of SGLT2i
• Homer Smith and his colleagues in 1933 reported complete inhibition of
filtered glucose with I/V Phlorizin (naturally occurring plant glucoside)
• In 1983 Ralph DeFronzo and his colleagues found that “phlorizinising
diabetic rats diminished hyperglycemia and restored insulin sensitivity.
• Oral phlorizin was not viable due to its rapid hydrolysis by intestinal
lactase and also caused profuse diarrhoea due to inhibition of intestinal
SGLT1

5. • Cloning and characterizing of the intestinal and renal SGLTs led to invention
of the Gliflozins
• Dapagliflozin, Empagliflozin & Canagliflozin were approved in 2013 for
antidiabetic use
• As a part of FDA approval, mandatory Cardiovascular safety was to be
established for all anti-diabetic therapies.
• EMPA-REG OUTCOME trial study results showed significant CV & Renal
benefits

6. Mechanism of Action

7. Net result is strict coupling of one sodium and one glucose
transport across the membrane during one transport cycle

8. Pleotropic
effects of
SGLT2i

9. Effects on Glomerular Haemodynamics
• Glomerular hypertension and hyperfiltration are central to the
pathogenesis and progression of CKD
• SGLT2i restore Tubuloglomerular feedback by preventing proximal tubular
sodium reabsorption and increasing sodium delivery to the macula densa,
thereby causing afferent arteriolar constriction and attenuation of
glomerular hypertension.
• Clinically manifested as a characteristic eGFR dip—an acute, but short-term
fall in eGFR by 3–5 ml/min, which improves by week 12 of therapy

11. Effect on Tubular energy expenditure & Renal hypoxia
• SGLT2 inhibition shifts sodium reabsorption downstream to the distal nephron
segments thus mimicking systemic hypoxia which induces hypoxia inducible factor
and other protective genes.
• Resulting increase in erythropoietin production improves renal and systemic
oxygen supply.
• Lower incidence of anaemia and reduced need for erythropoiesis stimulating
agents has been reported with SGLT2i therapy.
• It has also been hypothesized that SGLT2 inhibition-induced reduction in energy
expenditure in the proximal tubule may contribute to a reduced risk of AKI.

13. Reduction of BP & Plasma volume
• Occurs mainly due to decrease in plasma volume, predominantly due
to osmotic diuresis and natriuresis.
• Not accompanied by a counter regulatory increase in sympathetic
tone.
• Reduction in Systolic & Diastolic pressure is 3-4mmHg & 1-2mmHg
respectively.

14. Weight loss and other metabolic effects
• SGLT2i by promoting glucosuria, have a potential to achieve a
negative energy balance with a reported weight loss of 2–3 kgs.
• There is also a shift from glucose to free fatty acid utilization which
reduces the intracellular levels of lipid metabolites.
• Lipid accumulation within glomeruli is associated with podocyte
injury and apoptosis.

16. Adverse events
• Urinary Tract Infections
• Genital Mycotic infections
• Euglycemic ketoacidosis
• Hypovolemia
• Risk of Amputation (only supported by CANVAS trial, but subsequent
CREDENCE trial did not show any such association)
• Fracture risk (Dapagliflozin > Canagliflozin)
• Hypoglycemia (If used in association with insulin secretagogues)

18. Drug Trials

21. CREDENCE Trial

25. DAPA-CKD Trial

28. Empa-CKD Trial
• 6600 participants were allocated to Empagliflozin or placebo group on
top of standard of care in patients with pre-existing CKD
• CKD-EPI eGFR ≥20 to <45 mL/min/1.73m² or CKD-EPI eGFR ≥45 to <90
mL/min/1.73m² with urinary albumin:creatinine ratio ≥200 mg/g
• Stopped early as the study showed positive efficacy that met the
study’s prespecified threshold. (March-22)
• Final results not yet published.

29. Practical Implications
When to use SGLT2i
 All CKD patients with eGFR of >20ml/min/1.73m2 (proteinuric & non-
proteinuric diseases) (KDIGO recommends eGFR>30)
 SGLT2is show great promise for patients with CKD who do not have
diabetes, but evidence is most abundant and implementation most
strongly supported for patients with type 2 diabetes.
 Diabetic patients with/without proteinuria.

31. Thank you