Evidence of the Month

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Evidence of the Month
Maria Rosa Gallego

• Comment on
• Inhibition of renal glucose reabsorption a novel
  strategy for achieving glucose control in type 2
  diabetes mellitus

Investigators Abdul-Ghani MA, DeFronzo
RA Published Endocr Pract. 200814782-790
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Methods/primary outcome

SGLT2sodium-glucose cotransporter-2
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Renal glucose handling

• SGLT2 mediates 90 of filtered glucose
  reabsorption in the convoluted segment of the
  proximal renal tubule
• SGLT1 mediates 10 of reabsorption in the distal
  straight segment
• In individuals without diabetes, all filtered
  glucose is reabsorbed
• Glycosuria results when maximal reabsorptive
  capacity is exceeded
• Hyperglycaemia increases SGLT2 and maximal
  capacity excess glucose returns to the
  bloodstream

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SGLT inhibitors effects on SGLT1 vs SGLT2
EC50 for human SGLT1 and SGLT2 inhibition in
Chinese hamster ovary cells stably transfected
with human SGLT genes
EC50concentration that causes 50 inhibition
(in nM)
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Experimental effects of SGLT2 inhibition on
insulin resistance
Effect of phlorizin therapy on insulin
sensitivity in partiallypancreatectomized
diabetic rats
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Clinical findings effects of dapagliflozin in
individuals with Type 2 diabetes
Effect of dapagliflozin therapy for 12 weeks on
glycaemic control and body weight in individuals
with Type 2 diabetes
FPGfasting plasma glucose PPG AUCpostprandial
plasma glucose area under the curve
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Clinical findings safety of SGLT2 inhibition

• Long-term safety not yet studied
• Short-term studies show
• Minimally increased urine volume
• No excessive losses of fluid, sodium, or
  potassium
• Few instances of hypoglycaemia
• Increased urinary tract infections and vaginitis
• Modest weight loss
• Individuals with familial renal glycosuria are
  asymptomatic

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Clinical implications

• SGLT2 inhibition has improved glycaemic
  parameters in early-phase trials in individuals
  with Type 2 diabetes
• In the short term, enhanced glycosuria has not
  increased serious hypoglycaemia or urine volume
  nor caused excessive losses of electrolytes
  urinary tract infections have increased
• The potential for improving insulin resistance
  and ß-cell function with SGLT2 inhibition is
  indicated by animal studies and by glycaemic
  improvements in human studies
• In targeting renal glucose reabsorption, SGLT2
  inhibition offers a unique mechanism for
  achieving glucose control that may work in a
  complementary manner with existing anti-diabetic
  agents