SGLT2 inhibitors, glycosuria and osmotic diuresis
SGLT2 inhibitors block glucose reabsorption in the proximal tubule (the first coiled section of the kidney's drainage tubes), so glucose is lost in the urine, which is called glycosuria.
Remember
SGLT2 inhibitors reduce the glucose the kidney takes back from the filtered fluid, so more glucose is passed in the urine and pulls water and sodium with it. Blood glucose falls without relying on insulin, and weight and blood pressure fall modestly.
Memory aid
-flozin drugs make glucose flow out in the urine
Use the suffix to recall what the class does: glucose flows out in the urine.
The kidney filters glucose out of the blood together with water and salts. The proximal tubule normally takes that glucose back into the blood using a carrier protein called the sodium-glucose cotransporter 2, or SGLT2. One carrier moves sodium and glucose together, so blocking it loses both.
SGLT2 inhibitors, the "-flozin" drugs such as dapagliflozin, empagliflozin and canagliflozin, block this carrier. Less filtered glucose is reabsorbed, so more is passed in the urine. Glucose in the urine is called glycosuria. Blood glucose falls without relying on insulin.
The glucose left in the tubule holds water with it, an osmotic diuresis (the extra urine made when dissolved particles pull water along). Some sodium is lost too. Plasma volume (the fluid part of the blood) therefore falls a little, contributing to the modest drop in blood pressure. The same diuresis explains the increased urinary frequency, and because glucose is also lost as calories, there is modest weight loss.
Because the drug lowers the renal threshold (the blood glucose level above which the kidney starts to lose glucose in the urine), glycosuria appears even when the serum glucose is normal or only mildly raised. A second carrier called SGLT1, further along the tubule, partly compensates, so only part of the filtered glucose is lost.
Key facts
- Target
- SGLT2 in the proximal tubule, which normally reabsorbs filtered glucose.
- Effect
- glycosuria and a fall in blood glucose without relying on insulin.
- Water and sodium
- glucose in the urine pulls water and sodium into the urine (osmotic diuresis and natriuresis, which means sodium loss).
- Expected effects
- modest weight loss (about 3 kg in typical use) and a modest fall in blood pressure.
- Wider benefit
- the class reduces heart failure admissions and slows the progression of chronic kidney disease.
- Predictable harms
- glucose in the urine encourages genital and urinary tract infections, and the loss of water can cause volume depletion (a fall in plasma volume, the fluid part of the blood).
- Rare harm
- diabetic ketoacidosis (a dangerous build-up of acids called ketones), which can occur even when blood glucose is only mildly raised.
Exam traps
- Metformin does not cause glycosuria, because it works mainly by reducing glucose production by the liver and improving insulin sensitivity, not by altering glucose handling in the kidney.
- Sulphonylureas lower blood glucose by raising insulin secretion, not by changing what the kidney reabsorbs, so they do not make the kidney excrete glucose.
- DPP-4 inhibitors (the -gliptin drugs) stop the breakdown of the hormone GLP-1, so they act on gut hormones rather than on the kidney and do not cause glycosuria.
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