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Therapeutics Review CO PY RI RE GH PR T O SH DU ER CT BO IO RN N E PR G O IBB HI S BI LI TE M D IT ED EXENATIDE: A NEW STEP IN TYPE 2 DIABETES TREATMENT Sandra Waddingham Diabetes Co-ordinator North Lancs PCT E xenatide (Byetta) is the first glucagon-like peptide-1 analogue (GLP-1 analogue) to be approved for the treatment of type 2 diabetes. It is a twice-daily injection, currently prescribable only by consultants, given before breakfast and before the evening meal. The early signs are that this new and different medicine has the potential to be very exciting for both patients and healthcare professionals. Studies show a reduction in HbA1c as well as steady weight loss – every diabetic’s dream! In this article, we look at how exenatide works, where it fits into current practice and the pros and cons of this new preparation. Exenatide was discovered as a protein that occurs naturally in the saliva of the Gila monster lizard. The protein was found to be similar in structure to the GLP-1 incretin hormone, which is released from the intestine during food digestion and prompts insulin secretion. GLP-1 occurring in lizard spit has a much longer half-life than that which occurs in the human gut, which is approximately two minutes in humans. It was therefore chemically synthesised and developed for use in type 2 diabetes. TYPE 2 DIABETES There are approximately 1.8 million people with type 2 diabetes in the UK, and it is predicted that the numbers will continue to rise. The ageing population and increasing levels of obesity are significant factors in the increasing numbers. 26 People most at risk of type 2 diabetes are mature adults with a sedentary lifestyle, and a tendency to be overweight. Family history of diabetes also increases the risk, and women with a history of gestational diabetes are also more likely to develop the disease. INSULIN RESISTANCE Type 2 diabetes is characterised by insulin resistance, which means that the body is producing insulin but is unable to respond to it. The pancreas reacts by producing more insulin and eventually the over-worked pancreas begins to fail. Glycaemic control deteriorates gradually over the years, continuing after diabetes is diagnosed. There are several drugs on the market to improve blood glucose control and all have pros and cons. Sulphonylureas, glitazones and insulin are associated with weight gain, causing many patients to gain weight steadily over the years. This weight gain increases insulin resistance, making blood glucose control a continuing challenge requiring the addition of further hypoglycaemic agents. A patient will typically start management with diet alone, but will need tablets as their diabetes progresses. The longer a patient has had diabetes, the more likely they are to be taking several different preparations to maintain glucose control. Many people will eventually need insulin in addition to tablets to treat their diabetes. Exenatide is a new class of drug that works differently from existing preparations. It does not cause weight gain and many patients experience steady weight loss. The new agent works only in the presence of glucose and so reduces the risk of hypoglycaemia. glucose and so reduces cExenatide works only in the presencetheofrisk of hypoglycaemiad THE INCRETIN EFFECT CO PY RI RE GH PR T O SH DU ER CT BO IO RN N E PR G O IBB HI S BI LI TE M D IT ED Peptide hormones known as incretins are released into the blood stream during food digestion. These, in turn, prompt the secretion of insulin from beta cells in the pancreas, and also inhibit the production of glucagon from alpha cells. The specific incretins involved in this action are known as glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). In people with type 2 diabetes or impaired glucose tolerance this effect is either reduced or absent. This means that GLP-1 and GIP are unable to stimulate beta cells in the pancreas to produce sufficient insulin to metabolise the carbohydrates in food eaten. Exenatide mimics GLP-1 that occurs naturally, therefore promoting better glycaemic control. THE EFFECT OF EXENATIDE ON BLOOD GLUCOSE Exenatide is glucose-dependent so it stimulates the pancreas to produce only the amount of insulin required to deal with the glucose load. As glucose levels fall, insulin levels are also reduced. This means there is no risk of hypoglycaemia with exenatide. However, this new drug is licensed to be used in combination with sulphonylureas, which might give rise to hypoglycaemia, so care should be taken, particularly in the early stages of treatment with exenatide. It might be necessary to reduce or stop the sulphonylurea in some patients. GLP-1 and GIP also suppress the secretion of glucagon from alpha cells in the pancreas, which, in turn, decreases the amount of glucose from the liver. However, this action does not affect the normal mechanism and response to hypoglycaemia. The end result should be lower blood glucose levels. Overall, studies have demonstrated a reduction in HbA1c of up to 1%. EXENATIDE AND WEIGHT GLP-1 slows gastric emptying so that the patient experiences satiety sooner, leading to a reduced appetite and food intake. In this way, the person taking exenatide steadily loses weight. Studies have shown an average weight loss of 1.6-2.8 kg over 30 weeks, which is sustained at 52-week follow-up. The effect of slower gastric emptying also leads to a slower rate of glucose absorption into the blood stream, resulting in a steadier climb in blood glucose levels. How exenatide works • Increases insulin secretion from the pancreas, without the risk of hypoglycaemia. • Suppresses glucagon secretion from alpha cells in the pancreas, which reduces the amount of glucose produced by the liver. • Slows gastric emptying, giving the patient a feeling of fullness, which reduces the appetite and increases satiety. OTHER CONSIDERATIONS OF SLOW GASTRIC EMPTYING While slow gastric emptying can be advantageous it may also reduce the rate of absorption of oral medication as well as food. Nurses need to be aware and advise patients accordingly. Medicines that need to be taken with food should ideally be taken with a meal when exenatide is not going to be given. Particular care should be taken with contraceptives and antibiotics and patients should be advised to take these at least one hour before their exenatide injection. Proton pump inhibitors (lansoprazole, omeprazole) should be taken one hour before or more than four hours after exenatide. Metformin and sulphonylureas are not thought to be affected by the slow gastric emptying process so no changes to the timings of these medicines are necessary. WHEN SHOULD IT BE USED? Exenatide can be used in combination with metformin and/or sulphonylureas when glycaemic control is inadequate with the maximum tolerated doses of these oral drugs. Care should be exercised (as discussed earlier) when initiating exenatide at the same time as maximum doses of a sulphonylurea. It might be wise to reduce the dose of SU depending on blood glucose readings to avoid hypoglycaemia. Exenatide is not licensed in the UK for use with insulin or glitazones and can only be prescribed by a consultant. INJECTION DETAILS Exenatide is given subcutaneously up to 60 minutes before each of the two main meals of the day, which must be at least six hours apart. The usual times for injections are before breakfast and before the evening meal. As exenatide is glucosedependent it would be pointless to give the injection after a meal. If an injection is missed, it is very important that the patient understands that the next dose should be given as usual with no compensatory measures for the missed dose. Exenatide is initiated at a dose of 5 micrograms twice daily for the first month, increasing the dose to 10 micrograms twice daily thereafter. Many patients suffer mild to moderate nausea when treatment is first started, but it is usual for this symptom to be temporary and it generally settles down after the first month. The patient would then stay on 10 micrograms twice daily. INJECTION SITES Injection sites for exenatide are the same as for insulin – usually the thighs and abdomen. The manufacturer also recommends the upper arm, although nurses should be aware of the reduced amount of fatty tissue in this area and ensure the patient does not risk giving the injection intramuscularly. 27 Therapeutics Review Howdoes exenatide workswork in type 2 diabetes How the treatment and what should I expect from it? The treatment is used with metformin, a sulphonylurea, or both to help keep your blood glucose under control in four ways: The medication signals the pancreas to increase the amount of insulin produced after you eat. It acts like the natural hormones in your body that help prevent high blood glucose after meals, which helps lower your blood glucose. Lilly UK 2 CO PY RI RE GH PR T O SH DU ER CT BO IO RN N E PR G O IBB HI S BI LI TE M D IT ED 1 The treatment may also reduce your appetite and the amount of food you eat. 3 The treatment helps stop the liver from making too much glucose when your body does not need it, especially after meals. 4 The treatment helps slow down how quickly food and glucose leave the stomach. This helps prevent high blood glucose levels after you eat. POSSIBLE LINK TO INCREASED RISK OF PANCREATITIS In October 2007, people using exenatide in the USA were given some additional advice following 30 cases of pancreatitis in people on the drug. In the USA the following advice was issued, warning that there may be a link between exenatide and an increased risk of pancreatitis. Therefore patients should be advised that if they experience unexplained persistent, severe abdominal pain, with or without vomiting, they should seek immediate medical advice. Exenatide should be stopped if pancreatitis is suspected and not restarted if it is confirmed. COST Exenatide is supplied in a disposable pen. The 5 microgram pen is turquoise and orange in colour and will allow the user to dial up only a 5 microgram dose. The 10 microgram pen is similar but is colour-coded turquoise and yellow. Each pen contains enough exenatide to last for one month and costs £68.24. 28 Therapeutics Review on 5 micrograms daily. Anecdotally, some patients have found that giving the injection about 10 minutes prior to eating reduces the nausea. Our patients have been keen to continue treatment and persevered until the symptoms settled. To date, no patients have withdrawn from exenatide treatment. Key points Pros and cons of exenatide Cons Reduces HbA1c by up to 1% Requires two injections daily Does not induce hypoglycaemia when used with metformin Nausea very common in early stages of treatment Sustained weight loss in many patients Comparatively expensive Possible link to an increased risk of pancreatitis THE FUTURE • Exenatide (Byetta) is a GLP-1 analogue for use in type 2 diabetes • It is a twice-daily injection taken before breakfast and before the evening meal • It is glucose-dependent and therefore must not be taken after food • Patients start on 5 micrograms twice daily for one month progressing to 10 micrograms twice daily providing any nausea has settled • Exenatide is licensed for use with metformin and/or sulphonylureas. • Studies demonstrate a sustained reduction in HbA1c of up to 1% • Most patients experience sustained weight loss • One month’s supply costs £68.24 CO PY RI RE GH PR T O SH DU ER CT BO IO RN N E PR G O IBB HI S BI LI TE M D IT ED Pros Exenatide is currently the only GLP-1 analogue available for treatment. The possibility of producing a longer-acting exenatide requiring weekly injections is being explored. Liraglutide is another GLP-1 analogue undergoing trials. LOCAL EXPERIENCE In my area, 13 patients have been started on exenatide so far. The main criterion for its use has been severe obesity. As it is commonplace for people with diabetes to gain weight when starting insulin, those with severe weight problems were given priority. Most of the patients on exenatide are achieving steady weight loss, which is a great morale boost for them. Most, if not all, have experienced some degree of nausea. One patient was vomiting up to three times each day when started • DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092-1100. • www.diabetes.org.uk • Summary of product characteristics. http://emc.medicines.org.uk • Gallwitz B. New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins. Rev Diabet Stud 2005; 2: 61-69. • Edwards CM. GLP-1: target for a new class of antidiabetic agents? J R Soc Med 2004; 97: 270-274.