The Kidney as a Target for Diabetes Treatment?Monday, September 20, 2010
This week, I am attending the 46th European Association for the Study of Diabetes (EASD) Annual Meeting in Stockholm, Sweden, where there is considerable enthusiasm about the many new drugs and drug classes for diabetes treatment, which are likely to hit the market in the next few years.
One such group of novel orally active anti-diabetic agents are the sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), which act by blocking this transporter in the renal proximal tubule.
As reader may know, blood glucose is freely filtered in the kidney and is normally entirely reabsorbed in the renal tubule (which is why there is usually almost no glucose in the urine of non-diabetic individuals).
Experts may care that SGLT2 is a low-affinity high-capacity transporter sodium/glucose co-transporter, in contrast to SGLT1, located later in the tubule, which is a high-affinity low-capacity transporter and normally reabsorbs any remaining glucose missed by SGLT2.
As outlined by Clifford Bailey from Aston University, Birmingham, UK, the history of SGLT2 inhibitors dates as far back as 1835, when phlorizin, a naturally occurring flavonoid, later shown to be a competitive inhibitor of renal glucose transport, was identified in the bark of the apple tree.
Phlorizin’s glycosuric effect was reported in the 1860s, its renal actions in rat kidneys was shown in 1903 and in humans in 1933. Subsequently, it was shown that phlorizin may well have a significant glucose-lowering effects in patients with diabetes.
However, because phlorizin inhibits both SGLT2 and SGLT1 it had to be pharmacologically tweaked to make it specific for SGLT2 but also to make it longer acting. SGLT2 inhibitors that are currently in development, include dapagliflozin (AstraZeneca), canagliflozin (Johnson & Johnson), sergliflozin (GSK), ASP1941 (Astellas), BI 10773 (Boehringer Ingelheim), and LX4211 (Lexicon).
At blood glucose levels of 8 mmol/L, about 260 g (or almost half a pound of glucose) is filtered every day.
SGLT2 inhibitors reduce glucose reabsorption by about 25%, which means that about 70g of glucose or 280 calories are lost in the urine per day; the higher the blood glucose levels, the greater the caloric loss.
To put this in perspective, if the 280 calories lost in the urine are not replaced by dietary energy intake (in any form), weekly caloric deficit would be around 2000 Kcal, theoretically resulting in about 0.75 lbs weight loss.
Thus, although the primary objective of SGLT2 inhibitors is to help improve blood glucose levels in diabetic patients (which they do), an interesting “side effect” of this treatment is modest weight loss (2-3.5%).
The SGLT2 inhibitors appear to be well tolerated with almost no renal side effects but perhaps a minor increase in genital infection in women.
Numerous clinical trials (many presented at this conference) show that the gliflozins can be combined with both oral and injectable anti-diabetic agents and generally result in relevant improvements in glycemic control.
As a nephologist, who now works mainly in the area of obesity and metabolic diseases, I am particularly intrigued by the mode of action of these compounds and the fact that this novel class of agents specifically targets the kidney.
The fact that gliflozins also, albeit modestly, promote weight loss, makes these particularly attractive for my patients, as most other oral agents (except metformin and DPP IV inhibitors) tend to promote clinically significant weight gain.
Vallon V, & Sharma K (2010). Sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Current opinion in nephrology and hypertension, 19 (5), 425-31 PMID: 20539226