Thursday, 1 January 2015

SGLT2 inhibition

Red dawn sky over frosty bowling greens and clubhouse
Bowling greens at dawn, December 2014
All around are signs that a new year has started - empty roads, silent stations, Mary Poppins on TV and a host of New Year blog posts. I've been sitting on this post for a while, and as I don't have much to say about 2014 or the New Year, you can have this as my first gift of 2015.

The Diabetes Education Club meeting I attended recently featured an eminent speaker on SGLT2 inhibition in the management of high blood glucose. This is a relatively new treatment, although he described its origins in the 1800's when, following the isolation of salicylic acid from willow bark, people were mucking about with all sorts of tree bark to find something similarly therapeutic. A substance was found in apple bark, but all it seemed to do was produce glucose in the urine (glucosuria). This didn't seem useful at the time and it was even thought to cause diabetes (a symptom of which is glucosuria), so it was shelved.

More than a century later, the reality was understood - this substance inhibits the action of sodium-glucose co-transporter (SGLT) molecules which carry sodium and glucose across a cell membrane. In the gut, SGLTs enable the absorption of sodium and glucose from food into the body. In the kidney, they transport sodium and glucose from filtered blood back into the circulatory blood, and prevent glucose from being excreted in the urine.

There are two types, imaginatively named SGLT1 and SGLT2. SGLT1 works mostly in the gut but is found in the kidney as well, and SGLT2 is mostly found in the kidney. SGLT1 is a high affinity, low capacity transporter, so it catches glucose very effectively but works quite slowly. SGLT2 is a low affinity, high capacity transporter, so it lets a lot of glucose cruise on past but works very quickly. You can imagine that SGLT1 is good for low glucose concentrations, while SGLT2 works best with high glucose concentrations.

One of the functions of the kidneys is to filter the blood and get rid of waste products in the urine. Glucose in the blood passes through the kidneys and is normally totally reabsorbed back into the body; glucose is not normally found in the urine of a healthy individual. When blood glucose concentration is higher than normal, the kidneys still do a pretty good job and can cope with nearly double the usual blood glucose concentration, but eventually their capacity is exceeded and glucose is excreted in the urine.

The original apple bark extract (phlorizin) did not differentiate between the two types of SGLT. The phlorizin molecule sticks to the SGLT transporter molecules in the kidney and gut in place of glucose, and blocks the transport of glucose. The effect in the kidney results in glucosuria, and in the gut it leads to impaired absorption of glucose, with the remaining glucose fermenting in the lower intestine and causing pretty nasty side effects. Phlorizin was also too easily digested to be an effective oral treatment, so modifications were made to the molecule to inhibit digestion and to make it more selective for the SGLT2 transporter. This has resulted in the new SGLT2 inhibitor family of 'flozins', including dapagliflozin, canagliflozin and empagliflozin which are licensed in the EU (and some others are available in other parts of the world).

We burn about 250g of glucose per day, half of which is used by the brain. Some of this glucose will come from our diet, and the rest will be synthesized internally. About 180g of blood glucose a day passes through the kidney in a healthy person, and more if the blood glucose concentration is raised. Inhibiting the action of the SGLT2 transporters eliminates more than 50g of glucose per day, thus lowering the remaining blood glucose level. Although not its licensed purpose, this obviously eliminates more than 200 calories a day too, and so this treatment, unlike many diabetes treatments, has the potential to contribute to weight loss as well.

One of the disadvantages of many diabetes treatments is the risk of low blood glucose or hypoglycaemia. SGLT2 inhibition only works if blood glucose is high, because of its low affinity for glucose. If blood glucose is low it simply doesn't work very well, so there is little risk of a hypo. It also uses a different approach compared with all the other types of diabetes treatments, so can theoretically be combined with any of them, although licensing for UK prescription depends on having results of specific trials with each. Another factor in favour of the SGLT2 inhibiting treatment is that if the drug is either not effective or not acceptable (i.e. the patient doesn't take it) there will be no glucosuria, in which case it can be stopped without further ado.

Of course there are disadvantages. If kidney function is not good enough to filter blood effectively then this drug will not be effective. And glucose in the urine is all very well as long as bacteria and fungi don't take advantage. The doctors report that female patients are generally pragmatic about identifying and treating urinary tract infections and thrush, but they say that the male patients tend to either overreact or ignore the problem until it has got so bad it can't be overlooked any longer.

There doesn't appear to have been any direct comparison of treatment with SGLT2 inhibitors compared with dietary approaches to lowering blood glucose. The trials that have been done are comparing treatments with placebo, where sustained weight loss has been about 2kg and reduction in blood glucose has been demonstrated either with improved HbA1c results or a reduction in insulin dosage or a slowing of diabetes progression compared with a control group. There is also a small diuretic effect, which probably accounts for a slight improvement in blood pressure as well.

Because the inhibition affects sodium (the 'S' in SGLT) as well as glucose there are possible negative effects on sodium balance in the body. Recently, I attended a doctors' meeting (by accident) where the doctors raised this issue, but also questioned the size of the effect on HbA1c given the small amount of glucose that is actually eliminated in this way, and wondered what else might be going on. I am not entirely convinced either by the claims made or by the scepticism of the doctors. All I know is that it is another possible treatment for raised blood glucose, and I'll wait and see how it all turns out. That's the beauty of the Dietitian's job - all observation, very little responsibility, mostly trial and error.

Reference: Tahrani, Abd A et al. 'SGLT inhibitors in management of diabetes'. The Lancet Diabetes & Endocrinology, 1:2, p140-151.

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