text: Phlorizin is a compound that has been known for over a century. It is a naturally occurring botanical glucoside that produces renal glucosuria and blocks intestinal glucose absorption through inhibition of the sodium/glucose symporters located in the proximal renal tubule and mucosa of the small intestine. Phlorizin was first isolated in 1835 and was subsequently found to be a potent but rather non-selective inhibitor of both SGLT-1 and SGLT-2 proteins.
  Phlorizin seemed to have very interesting properties and the results in animal studies were encouraging, it improved insulin sensitivity and in diabetic rat models it seemed to increase glucose levels in urine and also normal glucose concentration in plasma occurred without hypoglycemia. Unfortunately, in spite of these properties, phlorizin was not suitable enough for clinical development for several reasons. Phlorizin has very poor oral bioavailability as it is broken down in the gastrointestinal tract, so it has to be given parenterally. Phloretin, the active metabolite of phlorizin, is a potent inhibitor of facilitative glucose transporters and phlorizin seems to lead to serious adverse events in the gastrointestinal tract like diarrhea and dehydration. Because of these reasons, phlorizin was never pursued in humans.
  Although phlorizin was not suitable for further clinical trials, it served an important role in the development of SGLT-2 inhibitors. It served a basis for the recognition of SGLT inhibitors with improved safety and tolerability profiles. For an example, the SGLT inhibitors are not associated with gastrointestinal adverse events and the bioavailability is much greater.
  Inhibition of SGLT-2 results as better control of glucose level, lower insulin, lower blood pressure and uric acid levels and augments calorie wasting. Some data supports the hypothesis that SGLT-2 inhibition may have direct renoprotective effects. This includes actions to attenuate tubular hypertrophy and hyperfiltration associated with diabetes and to reduce the tubular toxicity of glucose. Inhibition of SGLT-2 following treatment with dapagliflozin reduces the capacity for tubular glucose reabsorption by approximately 30–50%.