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Exenatide (Byetta®▼) for the Treatment of Type 2 Diabetes

Exenatide (Byetta®▼) for the Treatment of Type 2 Diabetes

VERDICT & SUMMARY (Byetta®▼) For the treatment of

Committee’s Verdict: CATEGORY B (Q3) BNF: 6.1 Exenatide treatment should be initiated in secondary care by diabetologists who can assess the need for this treatment. It is then suitable for continued prescribing in primary care. There are no outcome data on the effect of exenatide on cardiovascular morbidity or mortality. Category B: suitable for restricted prescribing under defined conditions Q rating: The evidence for the efficacy of exenatide was considered to be relatively strong, based on randomised controlled trials which have shown that exenatide reduces HbA1c levels to a greater extent than Q2 Q1 placebo. Two open-label comparator studies found exenatide to be non- higher place higher place weaker evidence stronger evidence inferior to glargine or biphasic in reducing HbA1c levels. In the trials, up to 57% of exenatide-treated patients reported at least one episode of nausea. The place of exenatide in the treatment of type 2 diabetes has yet to be established and this gives it a lower place Q4 Q3 in therapy in primary care. lower place lower place weaker evidence stronger evidence The Q rating relates to the drug’s position on the effectiveness indicator grid. The strength of the evidence is determined by the quality and quantity of care Place therapy in primary in studies that show significant efficacy of the drug compared with placebo or Strength of evidence for efficacy alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. MTRAC reviewed exenatide because it is a new product with potential for prescribing in primary care. Licensed indication receptors on pancreatic β-cells to potentiate insulin secretion stimulated by .4 Exenatide also Exenatide is indicated for treatment of type 2 diabetes reduces food intake, slows gastric emptying and mellitus in combination with and/or lowers plasma concentrations during sulphonylureas in patients who have not achieved periods of hyperglycaemia.1 adequate glycaemic control on maximally tolerated doses of these oral therapies.1 Clinical efficacy

Six fully published RCTs evaluated the clinical efficacy Background information and safety of exenatide for the treatment of type 2 Diabetes mellitus is a common chronic disease, diabetes.5-10 associated with markedly increased morbidity and Three 30-week double-blind RCTs (n = 1,447) mortality. The majority of people in the UK with compared the effectiveness of exenatide 5 µg or diabetes mellitus (~90%) have type 2 diabetes.2 The 10 µg twice daily with placebo added to current primary defects in type 2 diabetes are reduced insulin 5 therapy with metformin (≥ 1,500 mg daily) or a secretion and insulin resistance. Type 2 diabetes is 6 7 sulphonylurea or both. All patients had HbA1c levels associated with serious long-term microvascular and 2 of 7.1 to 11% and BMI ≥ 27 kg/m . The primary macrovascular complications. Patients with type 2 outcome measure was the change in HbA from diabetes are two to five times more likely to suffer 1c baseline to 30 weeks. Secondary outcomes included cardiovascular morbidity.3 the proportion of patients achieving HbA1c ≤ 7% and Dietary and lifestyle modifications form the mainstays change in body weight from baseline. of therapy for type 2 diabetes, but 50 to 70% of At week 30, patients treated with exenatide 5 µg twice patients will also require an antidiabetic drug. Drug daily showed a mean reduction in HbA from baseline treatments currently available include sulphonylureas, 1c of 0.4 to 0.6% and patients treated with exenatide metformin, ( and 10 µg twice daily showed a mean reduction in HbA ), , prandial glucose regulators 1c of 0.8 to 0.9%. In patients who received placebo, ( and ), and insulin. HbA1c increased by 0.1 to 0.2% (p < 0.001 vs. Exenatide is a synthetic copy of , a exenatide groups). Significantly more patients treated that is secreted in response to food intake and acts on with exenatide attained HbA1c ≤ 7% compared with

June 2007 Page 1 of 2 patients who had received placebo (p < 0.01). The Additional information proportion of patients achieving HbA1c ≤ 7% was 24 to 27% for exenatide 5 µg twice daily, 30 to 40% for • Exenatide therapy should be initiated at 5 µg exenatide 10 µg twice daily and 7 to 11% for placebo. exenatide per dose, administered twice daily as a Patients treated with exenatide showed reductions in for at least one month. mean body weight (1.6 kg to 2.8 kg for exenatide The dose of exenatide can then be increased to 10 µg twice daily and 0.9 to 1.6 kg for exenatide 5 µg 10 µg twice daily to further improve glycaemic twice daily). control. The dose of exenatide does not need to be adjusted on a day-to-day basis depending on A total of 974 patients who had completed one of the self-monitored glycaemia.1 above studies enrolled in an open-label extension study during which all patients received exenatide • When exenatide is added to sulphonylurea 10 µg twice daily.11 Of the patients who completed therapy, a reduction in the dose of sulphonylurea two years of exenatide treatment, the reduction in should be considered to reduce the risk of 1 HbA1c was maintained and weight loss continued. hypoglycaemia. However, the withdrawal rate was high and only 283 • At current prices, the cost of one year’s treatment patients completed 2 years of exenatide treatment. with exenatide 10 µg twice daily is £830. A further 16-week placebo-controlled RCT in 233 References patients with type 2 diabetes on glitazone treatment with or without metformin found exenatide 10 µg twice 1. Eli Lilly. Byetta. Summary of Product Characteristics daily reduced HbA1c levels to a greater extent than 2006;1-12. placebo (p < 0.001).10 Exenatide is not currently 2. Stumvoll MGBJ, van Haeften TW. Type 2 diabetes: licensed in the UK for use with glitazones. principles of pathogenesis and therapy. Lancet 2005;365:1333-1346. Two open-label non-inferiority RCTs compared 3. Nathan DM. Initial management of glycemia in type 2 exenatide 10 µg twice daily with biphasic insulin diabetes mellitus. N Engl J Med 2002;347:1342-1349. aspart twice daily (mean dose 24.4 units/day, n = 505, 4. Davidson MB, Bate G, Kirkpatrick P. Exenatide. Nature duration 52 weeks)9 or once daily Reviews Drug Discovery 2005;4:713-714. 5. DeFronzo RA, Ratner RE, Han J et al. Effects of (mean dose 25 units/day, n = 551, duration 26 8 exenatide (exendin-4) on glycemic control and weight weeks). All patients had type 2 diabetes with HbA1c 8 9 2 over 30 weeks in metformin-treated patients with type 2 levels of 7 to 10 or 11% and BMI ≥ 25 kg/m . diabetes. Diabetes Care 2005;28:1092-1100. The change in HbA in the exenatide group was 6. Buse JB, Henry RR, Han J et al. Effects of exenatide 1c (exendin-4) on glycemic control over 30 weeks in found to be non-inferior to that in the insulin glargine -treated patients with type 2 diabetes. group (both -1.1%) and the biphasic insulin aspart Diabetes Care 2004;27:2628-2635. group ( -1.0% vs. -0.9%). Patients treated with 7. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide lost body weight (2.3 to 2.5 kg) whereas exenatide (exendin-4) on glycemic control over 30 patients treated with insulin glargine or biphasic weeks in patients with type 2 diabetes treated with insulin aspart gained body weight. metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091. Adverse effects 8. Heine RJ, Van Gaal LF, Johns D et al. Exenatide versus insulin glargine in patients with suboptimally controlled The most frequently reported adverse events in the type 2 diabetes: a randomized trial. Ann Intern Med trials were nausea (up to 57% of patients reported at 2005;143:559-569. least one episode), vomiting and hypoglycaemia. 9. Nauck M, Duran S, Kim D et al. A comparison of twice- daily exenatide and biphasic insulin aspart in patients The incidence of hypoglycaemia was higher in with type 2 diabetes who were suboptimally controlled patients who were receiving exenatide in combination with sulphonylurea and metformin: a non-inferiority 7 with a high dose of a sulphonylurea. study. Diabetologica 2007;50:259-267. 10. Zinman B, Hoogwerf BJ, Duran GS et al. The effect of More exenatide-treated patients withdrew from the adding exenatide to a in suboptimally studies because of adverse events compared with 8 controlled type 2 diabetes: a randomized trial. Ann Intern patients treated with insulin glargine (10% vs. 1%) or Med 2007;146:477-485. 9 biphasic insulin aspart (8% vs. 0%). 11. Buse JB, Klonoff DC, Nielsen LL et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, For additional information on adverse events, refer to 1 and hepatic biomarkers in patients with type 2 diabetes: the Summary of Product Characteristics (SPC). An interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo- controlled trials. Clin Ther 2007;29:139-153.

Launch date: March 2007 Manufacturer: Eli Lilly EU/1/06/362/001-4 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, School of Pharmacy, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk RELEVANT NICE GUIDANCE WAS NOT AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: June 2007 ©Midlands Therapeutics Review & Advisory Committee VS07/13

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