Diabetes and the pharmaceutical industry

Non-insulin medicines for type 2 diabetes

Changing dietary and exercise habits is an essential approach in people with type 2 diabetes or those with impaired glucose tolerance (pre-diabetes). Two large studies, the Finnish Diabetes Prevention Study and the US Diabetes Prevention Program (DPP), have both shown that overweight people with IGT can reduce their risk of going on to develop diabetes by 58 per cent through increasing their physical activity, reducing calorie intake and improving diet quality. Those in the DPP who were given daily medication (metformin) instead reduced their risk by only 31 per cent. In type 2 diabetes, the use of medicines must be considered as additional to, rather than replacing, lifestyle changes.

There are five established classes of oral medicines authorised in the UK for the treatment of hyperglycaemia in type 2 diabetes:

• Metformin (biguanide)
• Sulphonylureas
• Meglitinides
• Glitazones (thiazolidinediones)
• Acarbose (æ-glucosidase inhibitor).

These different classes of medicines work in different ways. They may be used in combination if a single medicine is not adequate. Because many patients have risk factors for the development of long-term complications, such as high blood pressure and dyslipidaemia, it is likely that many will be taking other medicines such as antihypertensives and statins as well.

The National Institute for Health and Clinical Excellence (NICE) issued guidance on the use of oral agents for the control of hyperglycaemia in type 2 diabetes in 2002 and these are shown in the chart opposite. However, some agents have been granted additional uses since then and the guidelines are due to be reviewed soon.

Metformin does not affect insulin secretion from the pancreas. Instead, it acts on the liver, inhibiting production of glucose, a process known as gluconeogenesis, increasing the oxidation of free fatty acids, and reducing triglyceride and LDL cholesterol levels. It also promotes glucose uptake by skeletal muscle.

In addition, metformin acts on the cells that line blood vessels, protecting them from damage through oxidative stress that is thought to promote atherosclerosis, the narrowing of blood vessels through deposition of fat-rich plaques that may lead to angina or heart attacks. As a result, it has a protective effect against cardiovascular disease, which is common and damaging in people with diabetes.

It has recently been discovered that these effects are all the result of metformin's action on the enzyme AMP-activated protein kinase, which is a major regulator of the formation and breakdown of both lipids and glucose.

Metformin is usually given twice or three times daily and may give rise to some gastrointestinal symptoms (nausea and diarrhoea), especially if the dose is increased too rapidly, but these symptoms generally subside over time. Rarely, it may provoke lactic acidosis, which is serious and requires immediate treatment. In 2004, a prolonged-release form was introduced which is taken once a day.

Sulphonylureas
Sulphonylureas were the first oral agents to be made available for treating type 2 diabetes and they are still widely used. They bind to a receptor on the surface of beta cells in the pancreas, stimulating the release of insulin. The released insulin acts on the liver to reduce glucose output and on skeletal muscle and fat cells to increase glucose uptake.

Five sulphonylureas are authorised for use in the UK:

• Gliquidone
• Glipizide
• Gliclazide
• Glimepiride
• Glibenclamide

Most are taken once daily, before a meal, some as divided doses if high doses are required, but the shortest-acting, gliquidone, is taken before each meal.

They differ in respect of their length of action and how they are eliminated from the body, but all work by stimulating insulin release from beta cells. Because beta cell function declines progressively as diabetes progresses, the anti-hyperglycaemic effect of these medicines declines as well, making it necessary to add another agent of a different type in order to maintain long-term control. The effectiveness of metformin declines over time in a similar way, so this escape from control reflects disease progression, rather than a specific property of sulphonylureas.

A prolonged release of insulin may result in postmeal hypoglycaemia, which is a recognised side effect of these medicines, as with insulin injection, and the longest-acting, glibenclamide, has been associated with a higher risk of hypoglycaemia. The sulphonylureas also commonly produce weight gain, as does insulin treatment.

Meglitinides
Meglitinides (repaglinide and nateglinide) also act by stimulating insulin release from beta cells and are used in a similar way to the sulphonylureas, although they act on a different receptor site. Meglitinides were developed to improve early-phase insulin secretion and their action is glucose-dependent. They are therefore less likely to provoke hypoglycaemia than sulphonylureas, but this can still occur in some individuals. The risk is higher when meglitinides are used together with metformin. As they are very rapidly absorbed and have a fast onset of action, they are taken 15-30 minutes before main meals. Acting more quickly than the short-acting sulphonylureas, they have a relatively short duration of action.

Acarbose
Acarbose is an alpha glucosidase inhibitor acting on the enzyme that breaks down complex carbohydrates, such as starches in foodstuffs, in the intestine into simple sugars such as glucose, slowing down their absorption and thus reducing the blood glucose peak that follows a meal.

Acarbose is taken at each meal, with the first mouthful of food. Very little is absorbed into the circulation when acarbose is taken orally; it acts almost entirely locally in the intestine. Hence, it does not directly affect the release of insulin from the pancreas or the production of glucose by the liver. The improvement in HbA1C level seen with acarbose is generally less than following sulphonylurea or metformin treatment.

Because acarbose inhibits the breakdown of complex carbohydrates in the small intestine, these pass further down the intestine, where their digestion may give rise to symptoms such as flatulence, abdominal pain and diarrhoea. Such symptoms are commonly experienced at first, and can be worsened by certain dietary choices, but may improve over time. Acarbose does not itself cause hypoglycaemia, but can increase the risk when taken together with sulphonylureas or insulin.

Glitazones
Two antidiabetic agents belonging to the glitazone class have been available in the UK since 2000:

• rosiglitazone
• pioglitazone

These are approved for use either singly or in combination with sulphonylureas or metformin. They do not affect insulin secretion by the pancreas, and thus do not cause hypoglycaemia. Instead, they act on receptors in the nucleus of fat, liver and muscle cells (peroxisome proliferatoractivated receptors, or PPARs), causing changes that enhance the action of insulin on these cells. They are therefore referred to as insulin sensitisers. They both reduce glucose output from the liver and increase glucose uptake into fat cells and skeletal muscle cells, lowering blood glucose levels as a result.

The principal action of glitazones is on a receptor known as PPAR-gamma. These are found in many cells, but are particularly abundant in fat cells. Glitazones markedly affect their activity. It is thought that the beneficial effects of glitazones on blood glucose regulation result from reduced secretion of lipids (especially free fatty acids) and other factors from fat cells, which results in improved regulation of glucose by the liver and, in turn, muscle cells. The resulting lowering of blood glucose levels may help preserve the functioning of the insulin-producing beta cells in the pancreas.

Glitazones are usually given once or twice daily. They are rapidly absorbed and peak levels are reached after 1-2 hours. The amount and speed of glitazone uptake is high and little affected by food intake. They should not be given to those with heart failure, as they typically cause fluid retention, which worsens heart failure. They have been associated with anaemia when combined with metformin. Glitazones should not be used in those with impaired liver function, and regular liver function testing is recommended in all patients, although liver problems have been reported only rarely. Glitazones typically produce a dose-related weight gain.