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New treatments for type 2 diabetes what is on the horizon?

John PH Wilding

worldwide, more than half the people with type 2 diabetes have blood glucose concentrations that are too high, leading to a greater risk of complications. This is partly because many existing treatments have limitations. metformin, for example, usually the first drug recommended if lifestyle changes are not sufficient to control blood glucose, may cause nausea and stomach upset, and cannot be given to people with kidney failure; sulphonylureas may cause weight gain and hypoglycaemia; and pioglitazone has been associated with weight gain, fluid retention, heart failure, bone fractures and bladder cancer. new drugs have become available in the last few years include dpp-4 inhibitors, such as sitagliptin, saxagliptin and linagliptin. The injectable Glp-1 analogues, such as exenatide and liraglutide, are a significant advance as they have a lower risk of hypoglycaemia and weight gain. however, blood glucose concentrations tend to rise over time in type 2 diabetes, despite drug therapies, so people need additional treatments the longer they have had the condition many eventually needing insulin. Therefore, new treatments that might help to overcome some of these problems, particularly weight gain and hypoglycaemia, both of which also are a problem with insulin treatment and loss of insulin secretion over time, are desirable. here, John wilding reviews some of the latest research into new medicines for type 2 diabetes, focusing on drugs that might become available in the next few years.

Activators of the gut and pancreas G-protein coupled-receptors Normal control of insulin release and food intake When we eat, the intestines produce a cocktail of hormones that travel in the blood to the pancreas, giving advanced warning that food is on its way. Normally, this stimulates the release of insulin to ensure that sugar, fats and proteins are correctly stored and used by the body. Some of the hormones (of which the most familiar is GLP-1, manipulation of which is already used to treat diabetes) also travel to the brain, where they help transmit the message that we are full and that it is time to stop eating. Recent research has found some of the sensor molecules in the intestines that recognize when the intestines contain food and control the release of those hormones. Two of these sensor molecules are known as G-protein-coupled receptor (GPR) 40 and GPR 119. Potential to lower glucose and reduce weight Interestingly, these receptors are also found in the pancreas, where they are

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new therapies might be particularly helpful for people struggling to control their weight.
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thought to be involved in the control of insulin release. So drugs that activate this system might assist the pancreas to produce more insulin in response to food (helping to keep blood glucose down after meals), while at the same time allowing people to feel fuller sooner after a meal which might help to control body weight. Drugs in development A number of companies have developed drugs that work by activating either GPR 40 or GPR 119, and some of these are now starting clinical trials in people with diabetes. It will be a few years before we know for sure whether this interesting new idea really is effective to help treat diabetes and perhaps a little longer before such treatments become available, assuming the preliminary studies show that this approach works in people with diabetes. Sodium glucose transporter 2 inhibitors The normal role of the kidney in controlling blood glucose Glucose is often found in the urine in people with diabetes - especially if their blood glucose is high. Most people without diabetes do not have glucose in their urine. This is because the kidney has a very efficient mechanism to catch all the glucose very early in the process of urine formation and pump it back into the bloodstream so that none of this precious body fuel is wasted. If blood glucose is high (above approximately 11 mmol/l, as can often be the case in diabetes), the capacity of this pumping system is exceeded and some glucose remains in the urine. The main pump returning glucose to the circulation from the urine is called the sodium glucose co-transporter 2 (SGLT2). A similar pump, called SGLT1, transports any leftover glucose. Importantly, SGLT2 is only found in the kidney, whereas SGLT1 is also found in the intestines where it is responsible for helping absorb sugars from the diet. A prototype drug from the apple tree It has been known for more than 100 years that a chemical called phlorizin, originally purified from the bark of the apple tree, could cause glucose to appear in the urine (glucosuria). In the 1970s, it was shown that phlorizin could lower blood glucose in rats and mice with diabetes. However, it is not practical to use phlorizin to treat people with diabetes for a number of reasons: it has a weak effect, blocks SGLT1 in the intestines (causing severe diarrhoea) and has to be given by injection. Although the structure of phlorizin is similar to that of glucose, phlorizin jams up the glucose pumping mechanism. Pharmaceutical companies have now developed

drugs that, while they are similar to phlorizin in structure, are selective: they only block SGLT2 in the kidney and can be given as tablets once a day. Clinical data on SGLT2 inhibitors in development Several SGLT2 inhibitors are being tested in people with diabetes. All of them provoke the loss in the urine of about 50 g of glucose each day (about the same amount as in a standard can of fizzy drink) and have been shown to lower blood glucose (and HbA1c, which indicates longer term glucose control). The SGLT2 inhibitors seem to work irrespective of whatever other therapy the person is taking, demonstrating their effectiveness when used as the only drug treatment in combination with metformin, sulfonylureas, pioglitazone or insulin. Because some glucose is lost in the urine, the SGLT2 inhibitors also help a little with weight people lose about 2.5 kg on average over 6 months. The drugs also appear slightly to lower blood pressure (probably because some sodium is lost with the glucose). The main side effects relate to an excess of glucose in the urine people might expect to empty their bladder once more per day than usual. There is also a slightly higher risk of developing yeast infections (thrush) and water infections (cystitis) but these tend to be mild and respond to standard treatments. The risk of hypoglycaemia is low because SGLT2 inhibitors do not provoke insulin to be secreted from the pancreas. Who might benefit? These drugs are not yet available for healthcare professionals to prescribe. However, they might be particularly helpful for people who are struggling to control their weight and some people who are already on insulin, where they have been shown to improve blood glucose control without having to increase the insulin dose.

John ph wilding
John PH Wilding is Professor of Medicine and Honorary Consultant Physician at the University of Liverpool, UK. He is Head of the Department of Obesity and Endocrinology at the Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK (J.P.H.Wilding@liverpool.ac.uk)

further reading
Nair S, Wilding JPH. Sodium glucose co-transporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010; 95: 34-42. Telvekar VN, HS Kundaikar. GPR40 Carboxylic Acid Receptor Family and Diabetes: A New Drug Target. Curr Drug Targets 2008; 9: 899-910.

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