DIABETES

What is diabetes?

Diabetes is a disease in which the body fails to process glucose properly. It is a result either of a failure in the production of insulin, which occurs naturally in the beta cells of the pancreas, or because insulin does not function properly in the organs where it should act. Glucose levels in the blood are too high and, after 5-10 years, complications often arise, with serious personal, medical and economic consequences.

There are two forms of diabetes. Type 1 diabetes is an autoimmune disease that is usually diagnosed in the first three decades of life and has been known since ancient times. It is life-threatening if not treated. The second form, type 2 diabetes, occurs mostly in middle or later life, although it is increasingly seen in younger people who are obese and sedentary. Type 1 accounts for 10-15 per cent of cases in the UK and type 2 for the rest. There is some tendency for type 2 to run in families, but the pattern of inheritance is unclear.

Who does diabetes affect and what does it cost?

In the UK, diabetes has been diagnosed in more than 2 million people. A further 750,000 are believed to have undiagnosed diabetes. The number affected is growing from year to year, owing to the ageing of the population and the effects of obesity. 5,846 deaths in England and Wales were directly attributed to diabetes in 2004, but it also substantially increases the risk of heart disease (see Ischaemic Heart Disease) and stroke, and is thus indirectly responsible for many more deaths.

The cost to the NHS of treating diabetes has been estimated at £3.5 billion a year in 2002. The cost of treating diabetes, and especially its complications such as kidney disease, was found in one survey to account for 9.4 per cent of total hospital expenditure.

Present treatments and shortcomings

Before the discovery of insulin in 1921, type 1 diabetes was invariably fatal. People with type 1 diabetes make little or no insulin in their pancreas and depend on insulin injections for survival. Many forms of insulin have been marketed. Some are of animal origin, but in recent years, genetically engineered human insulin has been developed. There are now forms of human insulin available which are long- or short-acting, in addition to the regular insulins. Some are available in specially developed self-inject pens (Lilly, Novo Nordisk, Aventis). Recently an inhaled form of insulin (Exubera, Pfizer) has been authorised for use in both type 1 and type 2 diabetes. Careful choice of insulin type and continuing patient education and support are needed to ensure the best therapy and to avoid accidental hypoglycaemia - low blood sugar levels. Problems with patient compliance are a major reason for failure of diabetes therapy and the development of complications.

In type 2 diabetes, there may be a decline in insulin production, but insulin resistance in the body is more often the cause of disease. Many cope through lifestyle changes (weight loss, exercise), but if this fails, medicines (called oral hypoglycaemics)

may be needed. The most commonly used are metformin and the sulphonylureas. Sulphonylureas stimulate insulin release, while metformin reduces glucose production in the liver. A somewhat different treatment, acarbose (Glucobay, Bayer), slows the digestion of carbohydrates when taken with a meal, indirectly reducing glucose surge in the blood. More recently introduced are the 'glitazones' rosiglitazone (Avandia, GlaxoSmithKline) and pioglitazone (Actos, Takeda). These act by reducing glucose output from the liver and causing muscles to burn glucose preferentially, rather than using other energy sources, thus lowering blood glucose levels. Two oral hypoglycaemic medicines that stimulate the release of insulin from pancreatic beta cells in a glucosedependent fashion have also been launched: nateglinide (Starlix, Novartis) and repaglinide (NovoNorm, Novo Nordisk).

Many people with type 2 diabetes eventually require insulin as maintenance therapy, but their need is not for all their insulin, but for a boost to their existing levels. Though anti-diabetic medications can be life-saving, the condition of people with diabetes may slowly worsen, as they become insulin-resistant, or develop complications which pose further problems. Hence there remains an urgent need for new approaches and new medicines.

What's in the development pipeline?

Three companies have new approaches to type 1 diabetes in Phase 2 trial. TolerRx has a monoclonal antibody (TRX4) that blocks the action of the T-cells that attack the insulin-producing beta cells in the pancreas, Diamyd Medical has a vaccine (GAD65) that mimics the beta cell protein that triggers the body's immune system to attack the pancreas, and DeveloGen's DiaPep277 acts on the T-cells that cause beta cell destruction. All of these aim to slow down loss of insulin production by the pancreas.

Interest in new insulins for type 1 and type 2 diabetes is focused on new forms that eliminate or lessen the burden of the daily injection routine. Lilly and Alkermes are developing an inhaled form of insulin, and Novo Nordisk is working together with Aradigm Corp on another inhaled form (AERx iDMS). Both are in Phase 3 trial. In addition, Biocon has a form of insulin in Phase 2 trial that can be taken orally and Generex has a spray form (Oral-lyn) at the same stage, while Altea Therapeutics has a skin patch formulation (AT1391) in Phase 1 trial.

Research also continues into new treatments for type 2 diabetes. The insulin-sensitising glitazones enhance the action of insulin on its target tissues (fat, liver and muscle cells) without affecting insulin secretion (and without the risk of causing hypoglycaemia, which can be an undesirable side-effect of the sulphonylureas and of injected insulin). They achieve their effect by acting on cellular receptors known as peroxisome proliferator-activated receptors (PPARs). Additional PPAR-gamma agonists are in development, including AMG 131 (Amgen) and rivoglitazone (Daiichi-Sankyo), both at Phase 2, but several types of PPAR agonists are in development that act favourably on lipid levels as well as on glucose processing. PPAR agonists in Phase 2 development include netoglitazone (Perlegen), ONO-5129 (Ono Pharmaceuticals), R1439 (Roche), AVE 8134 and AVE 0847 (sanofi-aventis), while GlaxoSmithKline has GSK 677954 and Wyeth has PPM-204. Further examples in Phase 1 trial are GlaxoSmithKline's GSK 625019 and 376501and AVE 0897 from sanofi-aventis.

Box 1: Complications of diabetes

A different approach to glucose control exploits the ability of the naturally occurring peptide hormone GLP-1 to re-balance insulin and glucagon secretion from the pancreas. This hormone is released from cells lining the small intestine in response to the intake of food. GLP-1 itself is not suitable for therapeutic use, as it is broken down extremely rapidly by the enzyme dipeptidyl peptidase-IV (DPP-IV), but various GLP-1 analogues that are resistant to this enzyme are under study. The furthest advanced is exenatide (Byetta, Lilly). This compound has been shown to be able to control blood glucose as effectively as insulin in people with type 2 diabetes and did not exhibit the weight gain often seen with insulin. Liraglutide (Novo Nordisk) is another GLP-1 analogue and this is currently in Phase 3 trial. At Phase 2 are a long-acting form of exenatide, (CJC-1131, ConjuChem), the slow-release GLP-1 analogue BIM 51077/R1583 (Ipsen/Roche), and the GLP-1 receptor agonists AVE 0010 (sanofi-aventis) and albiglutide (GSK).

GLP-1 analogues mostly have the disadvantage that they must be injected; an alternative strategy for controlling GLP-1 level is to find an oral inhibitor of the DPP-IV enzyme that breaks it down so fast. A great number of DPP-IV inhibitors are in development, led by vildagliptin (Galvus, Novartis). This is followed at Phase 3 by saxagliptin (Bristol-Myers Squibb and AstraZeneca), sitagliptin (Merck Sharp & Dohme) and SYR-322 (Takeda). Companies with such compounds in Phase 2 trial include Merck Pharmaceuticals (EMD 674992), Pfizer (PF-734200), Phenomix (PHX1149), Prosidion (PSN9301), and Tanabe (TA-6666). Phase 1 compounds are being studied by Alantos (ALS 2-0426), and Lilly (TS-021).

A great variety of other interesting approaches are in research at Phase 2 and earlier, but it is likely to be at least five years before the compounds become available for use.

Complications of diabetes that often develop later in the course of the disease are a major cause of illness and death and pharmaceutical companies are trying to develop compounds to prevent and manage them. For example, disturbances to lipid levels in blood (dyslipidaemia) are common and lead to an increased rate of heart disease (see Atherosclerosis). Solvay is developing a combination (Synordia, Phase 3) of fenofibrate and metformin to treat this problem.

Diabetes is a leading cause of blindness and Lilly has ruboxistaurin (Arxxant) in Phase 3 trial for this. Also at Phase 3 is pegaptanib (Macugen, Pfizer), currently available for treating age-related macular degeneration, which is being studied in retinopathy, including diabetic macular oedema.

Intractable pain due to nerve damage (neuropathy) is another troublesome complication and does not always respond to conventional painkillers. Lilly's serotonin and noradrenaline reuptake inhibitor duloxetine (Cymbalta) has now been indicated for use in this situation and Eisai has ranirestat in Phase 3 trial. GW Pharmaceuticals has a cannabis-based spray (Sativex) under development in Phase 2 trial for this type of pain.

The longer-term future

There are a huge number of new compounds in development for the treatment of diabetes, and this reflects its enormous impact on public health. However, major changes to lifestyle factors such as diet and, especially, exercise will also be needed if the growing burden of diabetes is to be contained.

FOR FURTHER INFORMATION CONTACT:

Diabetes UK
Macleod House, 10 Parkway
London, NW1 7AA
Phone: 0845 120 2960 (Helpline)
Website: www.diabetes.org.uk