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  1. 1. *. Exenatide<br />Exenatide is the synthetic version of exendin-4, a natural<br />peptide of 39 aminoacids initially identified as a salivary<br />product, and then as a meal-stimulated hormone, of Gila<br />Monster, a large lizard living in the Arizona desert. Exendin-4<br />is coded by a gene distinct from that of GLP-1, but shows a 52%<br />sequence identity to human GLP-1 [22]. Synthetic exenatide is<br />identical to exendin-4, shows a binding affinity for GLP-1<br />receptor identical to that of native GLP-1, is rapidly adsorbed<br />after s.q. injection and is resistant to DPP-4 inactivation.<br />Consequently, exenatide has a half life in the range of 10–12 h,<br />suitable for a twice daily scheme of administration for<br />therapeutic purposes [22].<br />r e f  e  r e  n c e s<br />[22] L.L. Nielsen, A.D. Baron, Pharmacology of exenatide<br />(synthetic exendin-4) for the treatment of type 2 diabetes,<br />Curr. Opin. Invest. Drugs 4 (2003) 401–405.<br />What is it?<br />Exenatide is the first injectable synthetic analogue of the incretin hormone glucagon-like peptide 1 (GLP-1). Exenatide is an ‘incretin mimetic’: it mimics the action of GLP-1. Incretin mimetics increase glucose-dependent insulin secretion, suppress inappropriate glucagon secretion, delay gastric emptying (which reduces the rate of glucose absorption) and reduce appetite.2,3<br />The action of incretin mimetics is different from that of ‘incretin enhancers’, such as the gliptins, which inhibit the breakdown of incretins. For more information about the pharmacological action of gliptins, refer to the NPS RADAR review Dipeptidyl peptidase-4 inhibitors (‘gliptins’) for type 2 diabetes mellitus.4<br />Who is it for?<br />Exenatide is a treatment option for people with type 2 diabetes mellitus who require:<br />dual therapy but for whom a combination of metformin and a sulfonylurea is contraindicated or not tolerated, or<br />triple therapy for people who are already taking metformin and a sulfonylurea.<br />How is it used?<br />Exenatide is given as a subcutaneous injection twice a day (see Dosing issues). It is used in combination with metformin and/or a sulfonylurea.<br />Where does it fit?<br />Exenatide improves glycaemic control in combination with metformin and/or a sulfonylurea. It is notapproved by the Therapeutic Goods Administration (TGA) or PBS listed for monotherapy or for use in combination with acarbose, a gliptin, a glitazone, insulin or repaglinide.<br />Other options for dual or triple therapy include insulin or an oral antidiabetes drug (Table 1). Insulin is usually the preferred option, as there are data on its effect on diabetes-related complications and mortality, it has extensive experience of use and an established long-term safety profile.<br />Table 1: Other antidiabetes drugs for dual or triple therapy†<br /> Dual therapyTriple therapyOral drugsAcarboseGlitazones (pioglitazone or rosiglitazone)Gliptins (sitagliptin or vildagliptin)RepaglinideAcarbosePioglitazoneInjectable drugsExenatideInsulinExenatideInsulin<br />† Repaglinide is not listed on the PBS: refer to www.pbs.gov.au for details about PBS restrictions for other drugs.<br /> <br />Other factors may influence the choice of antidiabetes drug, including dosage form (oral or injectable), frequency of administration, what other drugs can be co-prescribed, titrated versus fixed dose, and potential adverse effects such as weight gain and hypoglycaemia.<br />How does it compare?<br />There are no data on the effects of exenatide on diabetes-related complications or mortality. Clinical trials have been small (n = 150–733), relatively short (16–82 weeks) and have measured HbA1c levels as a surrogate for clinical outcomes. Some trial data suggest that exenatide may not affect lipids.5Exenatide’s effects on blood pressure and cardiovascular events are unknown.<br />In contrast, some other antidiabetes drugs have known effects on clinical outcomes. Metformin reduces the incidence of diabetes-related complications and mortality.6 Sulfonylureas and insulin have been shown to reduce the incidence of microvascular complications.7<br />Exenatide reduces HbA1c levels with metformin and/or a sulfonylurea<br />Two trials have assessed the efficacy of exenatide as dual therapy with either metformin or a sulfonylurea.8–11 Exenatide 10 micrograms twice a day reduced HbA1c by about 1.0% after 30 weeks compared with placebo. The proportion of people who achieved an HbA1c ≤ 7% (34–40%, compared with placebo 8–11%) was maintained over the following year in unblinded extension trials.8,10<br />Exenatide has been compared with placebo and insulin (glargine, aspart) for use as triple therapy (with metformin and a sulfonylurea).12–14 Reductions in HbA1c were comparable between exenatide and insulin (average insulin dose studied was about 25 units daily) and a similar proportion in each treatment group achieved an HbA1c ≤ 7% (Table 2). However, more people receiving exenatide stopped treatment, mostly because of gastrointestinal adverse effects (see Safety issues).<br />Table 2: Exenatide compared with insulin (glargine, aspart) as triple therapy with metformin and a sulfonylurea‡13,14<br />Drug (dose)nChange in HbA1cfrom baselineAchievedHbA1c ≤ 7%Trial 1 (26 weeks)Insulin glargine(average dose 25 units daily)Exenatide(10 micrograms twice a day) 260275  – 1.1%– 1.1%48%46%Trial 2 (52 weeks)Insulin aspart(average dose 24 units daily)Exenatide(10 micrograms twice a day) 248253– 1.0%– 0.9% 30%23%<br />‡ Sulfonylureas used in the 26-week trial were not reported13<br />Long-term effect on weight is not known<br />Exenatide is associated with weight loss and thus may be a useful option for people who are overweight. However, whether weight loss with exenatide improves clinical outcomes, or is maintained in the long term, is currently unknown.<br />In trials of up to 30 weeks, people who had exenatide added to their oral therapy lost an average of 1.4 kg more than those who received oral therapy alone.5 Weight loss continued during the following year, although this observation came from uncontrolled unblinded extension studies (n = 150, n = 401).9,11 Weight loss also occurred with exenatide (2.3 kg loss) compared with insulin glargine (1.8 kg gain) in a 26-week trial; similarly, in a 52-week trial, exenatide led to a 2.5 kg weight loss compared with a 2.9 kg gain with insulin aspart.13,14<br />The effect on weight loss should be interpreted cautiously: no trial has studied weight loss with exenatide as a primary outcome, and the available data are limited to 1 year of unblinded treatment.<br />Safety issues<br />Common adverse effects with exenatide include gastrointestinal adverse effects (nausea, vomiting, diarrhoea, dyspepsia, gastro-oesophageal reflux disease and abdominal pain), headache, dizziness, jitteriness and injection-site reactions. Hypoglycaemia may also occur, mainly when exenatide is used with a sulfonylurea.2<br />Pancreatitis, allergic reactions and altered kidney function have been reported rarely with exenatide.2,15Avoid exenatide in people with severe renal impairment or end-stage kidney disease.15,16 Be cautious about starting or increasing the dose of exenatide in people with moderate renal impairment (creatinine clearance 30–50 mL/minute).16<br />Do not use exenatide in pregnant women or women planning to become pregnant (ADEC Category C).2Avoid in breastfeeding women, as there are no data on its use in lactation.2<br />Report suspected adverse reactions to the TGA online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.<br />Nausea and vomiting are common and usually improve with continued therapy<br />A meta-analysis of trials found that about one in two people experienced nausea, and about one in five experienced vomiting when exenatide was added to oral therapy.5 People receiving exenatide were about three times more likely to experience nausea or vomiting and twice as likely to experience diarrhoea than those using placebo or insulin.5 Nausea and vomiting usually improve with continued therapy.2<br />Hypoglycaemia mostly occurs in combination with a sulfonylurea<br />The risk of hypoglycaemia appears to increase with exenatide when it is combined with a sulfonylurea.5In one trial 36% of people experienced hypoglycaemia when exenatide 10 micrograms was added to a sulfonylurea (incidence for a sulfonylurea alone: 3%).10 In another trial 28% of people experienced hypoglycaemia when exenatide 10 micrograms was added to metformin with a sulfonylurea (metformin with sulfonylurea alone: 13%).12 In contrast, there was no increased risk of hypoglycaemia when exenatide was added to metformin, compared with placebo or insulin, unless used as triple therapy.<br />Trial protocols halved the sulfonylurea dose in people who had hypoglycaemia while using exenatide with a sulfonylurea.10,12–14 Consider reducing the dose of sulfonylurea when adding exenatide.15<br />Risk of hypoglycaemia appears similar to that with insulin<br />Trials found a similar incidence of self-reported hypoglycaemia between exenatide and insulin (glargine, aspart) at the insulin doses studied (average about 25 units daily).13,14 However, the comparative risk in people who frequently experience severe episodes of hypoglycaemia is unknown, because those who had more than three recent severe episodes were excluded from trials. The risk of hypoglycaemia for exenatide compared with other insulins (e.g. isophane) and escalating insulin doses is also unknown.<br />Development of anti-exenatide antibodies is common<br />Exenatide is derived from a non-mammalian source — from the venom of the Gila monster lizard (Heloderma suspectum) — and may be recognised as an antigen by the human immune system.17,18Up to 50% of people in clinical trials developed anti-exenatide antibodies8,10,12–14,19, but only about 3% of these people had no apparent glycaemic response to exenatide.17 Consider alternative antidiabetic therapy for people in whom exenatide therapy does not reduce HbA1c.20<br />Stop exenatide and check serum amylase level if severe abdominal pain occurs<br />Be alert for pancreatitis in anyone taking exenatide who complains of persistent, severe unexplained abdominal pain (with or without nausea and/or vomiting). Stop exenatide (and any other suspect drugs)15 and check amylase. Consider other antidiabetic drugs for people with a history of pancreatitis (avoid gliptins: for more information refer to the NPS RADAR review of gliptins4).21<br />Postmarketing reports of acute pancreatitis, including fatal haemorrhagic or necrotising pancreatitis, have occurred with exenatide in the US, UK, Europe and Australia.21–24 A causal association has not been confirmed and some of these cases may have involved other risk factors such as concomitant use of other suspect drugs, obesity, gallstones, severe hypertriglyceridaemia and alcohol use.<br />Do not restart exenatide if pancreatitis is confirmed.21 Recurrence of pancreatitis has been reported after restarting exenatide.23,25<br />Be alert for changes in kidney function<br />Look out for signs and symptoms including increased serum creatinine, changes in urine (such as colour, frequency and amount), unexplained swelling in the extremities, increased blood pressure, lethargy or changes in appetite and/or digestion.16<br />There have been postmarketing reports of altered kidney function (including acute renal failure, increased serum creatinine concentration) in the US, the UK and Europe.16,23,26 A causal association has not been confirmed and some of these cases occurred in people with pre-existing kidney disease or in people with risk factors such as other diseases (e.g. hypertension, heart failure) or using other drugs (e.g. nonsteroidal anti-inflammatory drugs, diuretics). Some cases reported nausea, vomiting and diarrhoea, which may have contributed to the development of altered kidney function.<br />Dosing issues<br />Start with a subcutaneous injection of 5 micrograms twice a day for at least a month. Give within 1 hour before the morning and evening meals (or before two main meals at least 6 hours apart). Do not inject after a meal. If an injection is missed, continue with the next scheduled injection.15<br />If the initial dose is tolerated, after 1 month the dose can be increased to 10 micrograms twice a day.15Stop exenatide if improved glycaemic control is not achieved after 3–4 months of therapy.<br />When adding exenatide to a sulfonylurea, consider reducing the dose of sulfonylurea to reduce the risk of hypoglycaemia (see Safety issues).15 The dose of metformin does not need to be modified in combination with exenatide.<br />Information for patients<br />Provide patients or carers with instructions on how to inject and dispose of exenatide, including the timing of the dose (not after meals).<br />Nausea, vomiting and diarrhoea commonly occur with exenatide. Inform patients or carers that the initial dose titration aims to improve tolerability to gastrointestinal adverse effects.<br />Exenatide delays stomach emptying, which can slow the absorption of oral medicines. Advise on what medicines should be taken separately from exenatide (at least 1 hour before or 4 hours after an injection) to prevent the medicine from causing gastric irritation or having a delayed effect.<br />Recommend that patients promptly seek medical attention if they experience persistent or severe unexplained abdominal pain (with or without nausea and/or vomiting) or changes in urine (such as colour, frequency and amount) or dehydration.<br />Discuss the Byetta consumer medicine information (CMI) leaflet with the patient.<br />Medicine Update <br />An NPS Medicine Update leaflet on exenatide is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with other medicines.<br />References<br />Department of Health and Ageing. Therapeutic relativity sheets: ATC A10 — drugs used in diabetes. Canberra, 2010. http://pbs.gov.au/info/industry/pricing/pbs-items/therapeutic-relativity-sheets (accessed 15 November 2010).<br />Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2010.<br />Prins JB. Incretin mimetics and enhancers: mechanisms of action. Aust Prescr 2008;31:102–4.http://www.australianprescriber.com/magazine/31/4/102/4/<br />National Prescribing Service. Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus. NPS RADAR August 2010. Sydney: National Prescribing Service, 2010.http://www.nps.org.au/health_professionals/publications/nps_radar/2008/august_2008/gliptins(accessed 4 August 2010).<br />Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;298:194–206. [PubMed]<br />UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 352:854–65. [PubMed]<br />UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [PubMed]<br />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;28:1092–100. [PubMed]<br />Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006;8:419–28. [PubMed]<br />Buse JB, Henry RR, Kim DD, et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628–35.[PubMed]<br />Riddle MC, Henry RP, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev 2006;22:483–91. [PubMed]<br />Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083–91. [PubMed]<br />Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143:559–69.[PubMed]<br />Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007;50:259–67. [PubMed]<br />Eli Lilly Australia Pty Ltd. Byetta product information. 22 March 2010.<br />US Food and Drug Administration — Center for Drug Evaluation and Research. Reports of altered kidney function in patients using exenatide (marketed as Byetta). Information for Healthcare Professionals Silver Spring, MD: US Department of Health and Human Services, 2009; 1.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm188656.htm(accessed 29 July 2010).<br />European Medicines Evaluation Agency. Byetta European Public Assessment Report. London: EMEA, 2006. http://www.emea.europa.eu/humandocs/Humans/EPAR/byetta/byetta.htm (accessed 29 July 2010).<br />Eng J, Kleinman WA, Singh L, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402–5. [PubMed]<br />Zinman B, Hoogwerf BJ, Garcia SD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes. Ann Intern Med 2007;146:477–85. [PubMed]<br />Amylin Pharmaceuticals Inc. Byetta product information. USA, 2007.http://www.fda.gov/cder/foi/label/2008/021773s012lbl.pdf (accessed 29 July 2010).<br />US Food and Drug Administration — Center for Drug Evaluation and Research. Information for healthcare professionals: exenatide (marketed as Byetta). Silver Spring, MD: US Department of Health and Human Services, 2008.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm(accessed 15 November 2010).<br />Medicines and Healthcare products Regulatory Agency and the Commission on Human Medicines. Exenatide (Byetta): risk of acute pancreatitis. Drug Safety Update London: MHRA, 2008;1:5.http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON015025 (accessed 15 November 2010).<br />Medicines and Healthcare Products Regulatory Agency and the Commission on Human Medicines. Exenatide (Byetta): risk of severe pancreatitis and renal failure. Drug Safety Update London: MHRA, 2009;2:6–7.http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON041211 (accessed 29 July 2010).<br />Therapeutic Goods Administration. Drug-induced pancreatitis and exenatide (Byetta). Medicine Safety Update 2010;3:3–4. http://www.australianprescriber.com/upload/pdf/articles/1098.pdf(accessed 29 July 2010).<br />US Food and Drug Administration — Center for Drug Evaluation and Research. Exenatide (marketed as BYETTA): acute pancreatitis. FDA Drug Safety Newsletter Silver Spring, MD: US Department of Health and Human Services, 2008;1.http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm109165.htm (accessed 15 November 2010).<br />Anonymous. Exenatide: renal failure. Prescrire 2009;18:124.<br />