SGLT2 Inhibitors - New Class of Drugs for Treating Type 2 Diabetes Mellitus

As rates of type 2 diabetes mellitus continue their seemingly inexorable climb, the diabetes industry continues to push questionable dietary advice and drugs to counter the effects of that advice. Despite — or, perhaps because of — the way that diabetes is tackled many diabetics fail dismally to get their high levels of blood glucose under control.[1] The American Diabetes Association, American Heart Association, and American College of Cardiology all urge patients to get their HbA1c (glycosylated haemoglobin) levels below 7%. But it isn't working. Not only is their advice that diabetics should stock up on foods which raise blood glucose levels making things difficult for their patients, the side effects of currently available drugs also don't help. For example, many type 2 diabetics are overweight; a common side effect of the current drugs is weight gain. Another is that some drugs have to be very accurately measured or the diabetic can end up with dangerously levels of glucose (hypoglycaemia).

So rather than admit that their dietary advice is wrong, the diabetes industry has been looking for yet more drugs which are more acceptable. And they seem to have found one.

It has become clear recently that the kidneys play a key role in the overall handling of blood glucose in the body. In healthy non-diabetics, the kidneys continuously filter about 180 grams of glucose a day and actively conserve nearly all of this glucose. (The body is a great recycler and isn't about to waste anything). However, in people with type 2 diabetes mellitus who have higher blood glucose levels, more glucose is filtered than reabsorbed. It is this retention of excess glucose by this pathway which contributes to persistent high blood glucose levels which is diabetes.

New protein found

Scientists have discovered that a protein called sodium-glucose co-transporter 2 (SGLT2) plays an important role in the kidneys and is responsible for most glucose reabsorption in people with type 2 diabetes mellitus keeping blood glucose levels high. It is now known that suppressing the activity of SGLT2 in the body inhibits this reabsorption, If SGLT2 is suppressed, therefore, more excess will be excreted from the body and blood levels can fall. So what they have come up with are 'SGLT2 inhibitors'. These suppress the activity of SGLT2, without stimulating insulin secretion from the pancreas.

These, it is fondly hoped with lower blood glucose levels by allowing more glucose to be excreted in urine, rather than as with present drugs forcing glucose into fat cells. [3]

The first data for dapagliflozin, an investigational SGLT2 inhibitor, were presented to the European Association for the Study of Diabetes (EASD) 45th Annual Meeting in Vienna, Austria.[4] After 24 weeks, results from this phase 3 clinical study demonstrated that dapagliflozin, when added to metformin in people with type 2 diabetes mellitus who were inadequately controlled with metformin alone, resulted in significant reductions in both fasting blood glucose and in lower HbA1c. It also demonstrated that dapagliflozin helped weight loss.

A second drug, remogliflozin etabonate was also found to be a potent and highly selective SGLT2 inhibitor — at least on mice and rats. [5] Remogliflozin etabonate inhibits the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats, suggesting that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.

The down side

But there may be problems with these drugs. There is a theoretical concern that the process of forcing more glucose into the urine might exacerbate diabetic nephropathy (kidney disease), although there are some data that suggests this won't happen. In clinical trials, the number of reported urinary tract infections was found to be similar between dapagliflozin, metformin, and placebo groups. However, the numbers of cases of genital infections was higher with dapagliflozin vs placebo, especially at higher doses. The researchers say 'The cause for this is still unknown', which is surprising as anyone who has researched conditions such as thrush will know that glucose in urine is a cause.

So I have to come back to what I have always said: Rather than use drugs to lower high blood glucose levels, all of which have adverse side effects, wouldn't it be better not to put excess amounts of glucose into your bloodstream in the first place? And that means cutting down on carbs and eating a proper Diabetes Diet.

References

1. Eliasson B, et al; Steering Committee of the Swedish National Diabetes Register. The gap between guidelines and reality: Type 2 diabetes in a National Diabetes Register 1996-2003. Diabet Med. 2005;22:1420-1426.
2. Skyler JS, et al; American Diabetes Association, American College of Cardiology Foundation, American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation. 2009;119:351-357.
3. List JF, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650-657.
4. Bailey CJ, et al. Dapagliflozin as an add-on to metformin lowers hyperglycaemia in type 2 diabetes patients inadequately controlled with metformin alone. Program and abstracts of the European Association for the Study of Diabetes (EASD) 45th Annual Meeting; September 29-October 2, 2009; Vienna, Austria. Abstract 169.
5. Fujimori Y, et al. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther. 2008;327:268-276.