Full of (Kidney) Beans!March 5, 2013
People interested in diabetes are always talking about eyes, feet or kidneys. At the present time, the interest is in kidneys. That’s not to say that eyes and feet have taken a back seat. It’s just that a new treatment for diabetes works on the kidneys. That’s strange because we always thought that diabetes was something to do with the pancreas and insulin. Well, read on.
In times of old when men were bold, simple folk only had three drug treatments to think about in diabetes; sulphonylureas (ie gliclazide), metformin and insulin. In this brave new world of phone hacking and horse lasagne, all this has changed.
First it was thiazolidinediones, then it was GLP-1 analogues and, if those weren’t enough, DPP-4 inhibitors came along. And not just one of each. Many pharmaceutical companies jumped rapidly on the “me-too” wagon.
The latest thing to confuse us is the world’s first SGLT-2 inhibitor. Probably, as well as the referendum on Europe, just what we’ve all been waiting for. So what’s going on? This may have been facetious up to now but, actually, there is a completely new way of tackling hyperglycæmia which, basically, is what diabetes is all about.
We need to start with a little revision in the field of physiology. Can you remember the micro-anatomy of the kidney; in other words a nephron. The nephron consists of:
- proximal tube
- loop of Henlé
- distal tube
Blood passes through the glomerulus where many things pass into the proximal tube including waste products and, importantly, up to 180g of glucose a day. In the proximal tube, however, up to 90% of this glucose is reabsorbed back into the bloodstream. This reabsorption of glucose is carried out by means of a transporter which has been identified as sodium-glucose co-transporter 2 (SGLT-2).
As a matter of interest, as blood glucose levels rise so re-absorption rises until the maximum capacity of SGLT-2 is reached after which increasing levels of glucose occur in the urine. This maximum level of glucose (in a healthy adult when the blood glucose is about 11.0mmol.l) is what we call the renal threshold.
So now, the researcher’s mind says, “if we could find a substance which selectively blocks SGLT-2, less glucose would be reabsorbed and blood glucose levels would fall.” Enter dapaglifozin which does exactly what the researchers hoped it would.
Dapagliflozin in a dose of 10mg a day resulted in an average 24-hour excretion of glucose of no less than 70g which resulted in a fall of 1.17 mmol/l in blood glucose, which is just a little more than is seen with metformin. This may not seem much but greater losses should be seen in people with higher blood glucose levels. Oh yes, and don’t forget that a loss of about 1mmol/l in blood glucose leads to a 20% reduction in complications.
The even better news is that a 70g of glucose excreted in the urine is equivalent to 280 calories so dapagliflozin is at least weight neutral and may be weight favourable.
Is there any bad news? Well dapagliflozin should not be used in people with moderate or worse renal failure; it is not recommended with pioglitazone and has not been tested with GLP-1 analogues or DPP-4 inhibitors. Obviously, it is not appropriate in Type 1 diabetes.
The dose is 10mg a day although 5mg tablets are also available. The cost is about half that of GLP-1 analogues and equivalent to DPP-4 inhibitors. This drug is still very new and recommendations, or otherwise, from NICE will not be made for some time.
This is not the magic answer. Diabetes is not just about treating blood glucose levels. We must still target blood pressure, cholesterol, smoking and all the other things associated with the complications of this fascinating disease.
Would I use it? I think I would wait and see for a little while; see what my local consultant says; read what is written in the journals that we all get. But it certainly looks very promising and a really novel approach to blood glucose levels.