Glucose is filtered in the glomerulus and then 90% is reabsorbed from the tubule by SGLT2 proximally and the remaining 10% by SGLT1 more distally. The glucose is co-transported with sodium. Glucose and sodium are then separately transported into the blood stream. [1]
SGLT1 is also present in the gut where it absorbs glucose with sodium. (This is why oral rehydration solution contains both glucose and sodium). SGLT1 is not a target for treatment since inhibition of it may cause osmotic diarrhoea.
A number of agents are in development.
Dapagliflozin "improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus" with the commonest adverse effects being genital (9.0%) and urinary tract (9.7%) infections. [2] It was not approved by the FDA in 2011 because of concerns of safety given that many of the trials were of short duration and an increase in the risk of breast and bladder cancer was noted which needs further evaluation. [3] The drug is also being evaluated by the European Medicines Agency.
Canaglifozin "[in] subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control." [4]
2. Wilding JPH, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S. Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial. Annals of Internal Medicine 2012 Mar;156(6):405–415. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22431673
3. Bhartia M, Tahrani AA, Barnett AH. SGLT-2 inhibitors in development for type 2 diabetes treatment. Rev Diabet Stud 2011;8(3):348–354. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22262072
4. Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, Ways K, Schwartz S. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes, Obesity & Metabolism 2012 Jan; Available from: http://www.ncbi.nlm.nih.gov/pubmed/22226086
Theoretically a good concept but infection rate is high and due to short duration of studies concerns about cancer remain. Sorry but found the fourth reference a bit funny! improves glycemic control over 28 days! what next 28 hours?
ReplyDeleteWhen insulin was discovered, the aim of the treatment was to eliminate renal glycosuria. Kids with type 1 diabetes perfected the skills of testing their urine for the presence of sugar in camps. Prolonged absence of urine sugar was celebrated as a great achievement.
ReplyDeleteNow we have come a full circle. We are still desperately trying to normalize the blood glucose levels by various means while the centenary of insulin discovery is around the corner. SGLT2 inhibitors reduce the renal threshold for glucose excretion, thereby improving the blood glucose levels. What was hailed as a success in the late 1920s [disappearance of urine glucose]is getting purposefully reversed by a drug. Prolonged glycosuria invites infections also.
Almost all the drugs which got introduced in the last decade have been implicated in cancer. Bladder cancer with pioglitazone, Medullary thyroid cancer with liraglutide, breast/Bladder cancer with dapagliflozin... the list may not end here. On the contrary, there is evidence that metformin may protect patients with type 2 diabetes against some of the cancers.