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Drug therapies in the management of diabetes

Pieter Shaw
MRPharmS MCPP
Chief Pharmacist
Whipp's Cross Hospital
London
Lecturer and Course Designer for Independent and Supplementary Nurse Prescribing
E:pieter.shaw@whippsx.nhs.uk

Diabetes is a serious medical condition caused by insulin deficiency or resistance to the actions of insulin. Insulin is essential for glucose uptake and the metabolism of fats and proteins. Under normal circumstances it acts on cells in muscle, fat and the liver by binding to specific receptors on the plasma membrane. When these mechanisms for glucose uptake cease to function normally, blood glucose levels rise, causing the symptoms characteristic of diabetes - excessive thirst, increased passing of urine, lethargy and, in type 1 diabetes, ketoacidosis.

Type 1 diabetes
Type 1 diabetes is characterised by insulin deficiency resulting from autoimmune destruction of pancreatic b-cells. Patients often have autoantibody markers of b-cell destruction. Patients are prone to ketoacidosis and require treatment with insulin.
Although type 1 diabetes was thought to be more common in juveniles and adolescents, new studies have shown that its incidence in adults is greater than once thought. The disease can develop over a period of years only to appear unexpectedly in later life. The onset of type 1 diabetes in both age groups is rapid.

Type 2 diabetes
Type 2 diabetes is the most common clinical form of diabetes and accounts for 90% of all cases. Impaired insulin secretion and peripheral resistance to the actions of insulin can both play a role in the development of the condition. Early diagnosis and treatment are essential to manage the complications associated with the disease.
Although diabetes occurs in people from all ethnic backgrounds, there is a greater incidence of type 2 diabetes in people of South-Asian or Afro-Caribbean origin. Anyone with a family history of type 2 diabetes also runs a higher risk of developing the disease. Obesity is a major risk factor for everyone, regardless of ethnicity or family history. Many people with type 2 diabetes may be unaware that they have the disease. The over-30s are more likely to develop type 2 diabetes, although its incidence among younger people appears to be growing. Type 2 diabetes is unfortunately on the increase.

Insulin resistance in type 2 diabetes
Resistance to the actions of insulin is the main cause of type 2 diabetes. What triggers insulin resistance is not yet completely understood, although its higher incidence in specific ethnic groups would point to genetic factors. Poor living environment, poor diet and lack of exercise may also play a role.(1)
At the cellular level, insulin resistance occurs when the normal mechanisms for the promotion of glucose uptake are damaged or impaired. Circulating insulin is no longer able to metabolise glucose, and blood glucose levels rise. This triggers a further production of insulin from b-cells, leading to the raised basal insulin concentrations typically seen in type 2 diabetes. Over time the b-cells become exhausted and insulin production falls.
Insulin resistance is also associated with various metabolic disorders, which lead to a greater risk of cardiovascular disease. This is known as "insulin resistance syndrome" and often presents as hypertension, obesity and dyslipidaemia, with high fatty acid and triglyceride levels.

Managing diabetes
Managing diabetes can involve changes in lifestyle or drug therapy or a combination of both. The aim of treatment is to achieve normal glycaemia. Seventy-five per cent of people with type 2 diabetes are obese. Since obesity worsens insulin resistance, a healthy diet and regular exercise are essential for the successful management of type 2 diabetes. Smoking and excessive alcohol intake worsen the condition and so need to be strongly discouraged.
For many patients, however, a change in lifestyle won't be enough and drug therapy needs to be initiated. Drug treatment usually involves an oral hypoglycaemic agent. Unfortunately this often fails to give adequate long-term glycaemic control, and many people require combination therapy, increasing doses or insulin injections.

Drugs available for the management of diabetes

There have been significant advances in the drug therapies available to treat type 2 diabetes, and several novel compounds have come onto the market in the last year or so. These are exciting developments and will undoubtedly lead to better treatment outcomes for people with diabetes. These and the older groups of drugs available are discussed below.

Sulphonylureas
Sulphonylureas act by stimulating insulin production from pancreatic b-cells where there is some residual function. They may also have some local action when administered in the long term. One of the main drawbacks is hyperinsulinaemia and hypoglycaemia. They can also cause weight gain, so they are not recommended for obese patients.
The longer-acting sulphonylureas such as chlorpropamide and glibenclamide are more likely to cause hypoglycaemia and are not recommended for use in the elderly. It is much better to use a shorter-acting alternative such as gliclazide or tolbutamide.
Sulphonylureas should be used with great care in people with any degree of renal or hepatic impairment because of the increased chance of hypoglycaemia.

Biguanides
Metformin is the only biguanide currently available in the UK. It works in a different way from the sulphonyl-ureas - it lowers blood glucose levels by inhibiting hepatic glucose production (gluconeogenesis) and increases the utilisation of glucose in other tissues. It is useful in the treatment of obese patients as it doesn't cause weight gain. It may cause gastrointestinal side-effects such as diarrhoea, nausea and vomiting, which, although often transient, may make some people reluctant to take the drug. A rare but serious side-effect of metformin is lactic acidosis. This has a mortality rate of about 50%.
Metformin is often combined with other agents such as a sulphonylurea when a single agent fails to give adequate glycaemic control.

a-glucosidase inhibitors
These delay the digestion and absorption of starch and sucrose from the intestines by inhibiting the digestive enzyme a-glucosidase. The effect on blood glucose level is small, and the principal drug in this group, acarbose, is usually given in combination with a sulphonylurea or metformin. Abdominal bloating and flatulence are common side-effects that often put people off taking acarbose.

Prandial glucose regulators
Repaglinide and nateglinide are relatively new agents that increase insulin secretion from b-cells by an action similar to the sulphonylureas. They have a rapid onset of action and are short-acting. Unlike the sulphonylureas, their ability to enhance insulin secretion is glucose-dependent. They are taken before each main meal. Repaglinide may be used alone or in combination with metformin. Nateglinide is licensed only for use with metformin. Like the sulphonylureas, they may cause hypoglycaemia, particularly in older people.

Thiazolidinediones (glitazones)
These are a new group of drugs that target insulin resistance. They are peroxisome proliferator-activated receptor (PPAR) gamma-agonists and they interact with the specific (PPAR) receptor, enhancing the actions of insulin, such as reducing hepatic glucose output and increasing glucose disposal. This results in increased insulin sensitivity in adipose tissue, liver and skeletal muscle, all sites of insulin resistance.
Thiazolidinediones are used only in combination with metformin or a sulphonylurea. The National Institute of Clinical Excellence (NICE) guidance recommends that people who continue to have a raised blood glucose level with metformin or a sulphonylurea should be offered combination therapy with a thiazolidinedione as an alternative to insulin. Thiazolidinediones should be used in combination with metformin in obese people.
Unfortunately thiazolidinediones have been associated with liver toxicity, so liver function should be monitored before beginning treatment and then every two months for the next year. Patients should be told to watch out for symptoms such as abdominal pain, nausea and vomiting, darkened urine or jaundice, and seek urgent medical advice if these present.

Insulin
Insulin was formerly derived from pork and beef pancreas, but human-sequence insulin produced biosynthetically is generally used nowadays. Insulin is an extremely versatile agent and can be formulated to alter its length of action. These formulations can be combined to produce treatment regimens specific to individual patients. Several new products with short-term actions have recently been developed, such as insulin aspart and insulin lispro.
Insulin is usually given by subcutaneous injection in type 1 diabetes. It is used in type 2 diabetes only when oral therapy has failed to adequately control blood glucose levels.
Subcutaneous soluble insulin has a rapid onset of action of about 30 minutes and peaks at 2-4 hours. Its duration of action is around eight hours. It is usually injected 15-30 minutes before meals. Two new human insulin analogues - insulin aspart and insulin lispro - have a faster onset and shorter duration of action than soluble insulin. This leads to a higher preprandial blood glucose concentration and a lower postprandial blood glucose concentration, resulting in a lower incidence of hypoglycaemia.

Complications
Long-term complications, particularly with type 2 diabetes, include heart disease, stroke and peripheral vascular disease, as well as microvascular complications such as retinopathy, nephropathy and neuropathy. Since type 2 diabetes often goes unnoticed for years, a large percentage of people will have experienced complications by the time they are diagnosed.
Since type 2 diabetes is associated with changes in plasma lipids and lipoproteins that promote atherosclerosis, evidence has shown that treatment with a lipid-lowering agent such as a statin is beneficial.(2)
Hypertension occurs more often in patients with diabetes. It is a major cause of diabetic nephropathy and accelerates both macrovascular and microvascular complications. The presence of proteinurea, which is a good indicator of diabetic neuropathy, is associated with a marked increase in mortality from cardiovascular disease and renal failure.(3) Cardio-vascular complications account for 75% of mortality in patients with type 2 diabetes.(4)
The most recent guidelines recommend treatment with an antihypertensive agent since studies have shown significant reductions in diabetes-related deaths and complications. Various antihypertensive intervention trials have been based on diuretics, b-blockers, ACE (angiotensin-converting enzyme) inhibitors and calcium channel blockers, and combination therapy is usually most effective. Both ACE inhibitors and other classes of antihypertensives have been shown to have a renoprotective effect.(5)

Conclusion
Both forms of diabetes are difficult to treat. There have been significant advances in the drug treatments available to treat type 2 diabetes, although the morbidity and mortality associated with the disease remains high. The UKPDS study is the largest clinical study of diabetes ever undertaken. This showed conclusively that antihyperglycaemics and other drugs, alongside intensive management, reduce the risk of complications. This means regular monitoring as well as the promotion of healthy lifestyles and patient education.

References

  1. Groop LC. Insulin resistance: the trigger for type 2 diabetes. Diabetes Obes Metab 1999;1:1-7.
  2. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham study. Ann Epidemiol 1992;2(1-2):23-8.
  3. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different antihypertensive drugs in human diabetic nephropathy. Nephrol Dial Transplant 1995;10:39-45.
  4. UKPDS. Complications of newly diagnosed type 2 diabetic patients. Diabetes Res 1990;13:1-11.
  5. Munro N, Feher M, Lawrenson R. Antihypertensive prescribing and achieved BP in type 2 diabetes. Br J Clin Cardiol 2001;8:332-6.

Resources
Diabetes UK
W:www.diabetes.org.uk
National Service Framework for Diabetes
W:www.www.doh.gov.uk/nsf/diabetes/index.htm
Nurse Prescribing
Department of Health website
W:www.doh.gov.uk/nurseprescribing