Rosiglitazone (Avandia®▼)

VERDICT & SUMMARY Rosiglitazone (Avandia®▼)

For the treatment of type 2 diabetes mellitus

Committee’s Verdict: D BNF: 6.1.2 Rosiglitazone cannot be recommended for prescribing, based on the current concerns about potential cardiovascular adverse effects and lack of evidence for improved patient-oriented outcomes. Patients already taking rosiglitazone should have their cardiovascular risk re-assessed and their treatment reviewed in accordance with the latest guidance from the MHRA and NICE. Category D: cannot be recommended for prescribing because of inadequate evidence for efficacy and/or safety Strength of evidence for efficacy and safety Two meta-analyses found higher risks of myocardial infarction with rosiglitazone than with control therapy; the risk of cardiovascular death was not different. Several studies found a higher risk of heart failure with rosiglitazone. There is no evidence for improved patient-oriented outcomes (mortality, morbidity, adverse effects, or health- related quality of life). In randomised controlled clinical trials, rosiglitazone has been evaluated only for its efficacy in maintaining glycaemic control; macrovascular endpoints, such as coronary heart disease, stroke and peripheral vascular disease, have not been studied as primary outcomes. Randomised controlled trials have shown that, compared with placebo, as monotherapy or added to other anti-diabetic drugs, rosiglitazone produced further reductions in HbA1c. In combination therapy, it has not been shown to be superior to other antidiabetic drugs in reducing HbA1c. MTRAC reviewed this drug because of new warnings and evidence regarding safety. Licensed indication (rosiglitazone and pioglitazone), acarbose, repaglinide 1 and nateglinide, exenatide, sitagliptin, vildagliptin and Rosiglitazone is indicated for type 2 diabetes: insulin. • as monotherapy in patients inadequately controlled by diet and exercise for whom metformin is Metformin followed by the sulphonylureas are inappropriate because of contraindications or considered to be the first choices for oral antidiabetic 4 intolerance therapy. • as dual therapy in combination with metformin in In 2003, the National Institute for Clinical Excellence patients with insufficient glycaemic control despite (NICE) recommended the use of a glitazone in maximal tolerated therapy with metformin combination with either metformin or a sulphonylurea • as dual therapy with a sulphonylurea, only in (as an alternative to a combination of metformin with patients for whom metformin is inappropriate, with a sulphonylurea) only for patients who cannot insufficient glycaemic control with a sulphonylurea tolerate either drug in the combination.5 Current • as triple therapy in combination with metformin and NICE guidance does not apply to the use of a sulphonylurea, in patients with insufficient glitazones as mono- or triple therapy. glycaemic control despite dual therapy. Clinical efficacy Background information A Cochrane meta-analysis of 18 RCTs of rosiglitazone Diabetes mellitus is a common chronic disease, which efficacy (total n = 3,888; duration ≥ 24 weeks) found is associated with markedly increased morbidity and that the studies did not provide evidence that patient- mortality. The majority of people in the UK with 2 oriented outcomes (mortality, morbidity, adverse diabetes mellitus (~90%) have type 2 diabetes. The effects, costs and health-related quality of life) were primary defects in type 2 diabetes are reduced insulin positively affected by the use of rosiglitazone.6 secretion and insulin resistance. Type 2 diabetes is associated with microvascular disease (e.g. All randomised controlled clinical trials (RCTs) of nephropathy, retinopathy, and neuropathy) and efficacy found for the MTRAC review and described macrovascular disease (e.g. coronary heart disease, below used glycaemic measures as primary endpoints 3 stroke, and peripheral vascular disease). (mostly reduction in HbA1c). All were carried out in adult patients with type 2 diabetes. First-line treatment for type 2 diabetes is modification of diet and lifestyle, but most patients will also require Monotherapy an anti-diabetic drug. Drug treatments include Two double-blind RCTs assessed monotherapy of metformin, sulphonylureas, thiazolidinediones rosiglitazone: one large study of drug treatment-naïve

March 2008 Page 1 of 3 patients (ADOPT; n = 4,360, median duration = 4 Adverse events years)7 and one smaller study of patients who were not adequately controlled by diet and exercise or oral A meta-analysis evaluated data from 42 RCTs of antidiabetic drugs (n = 598).8 rosiglitazone in patients with type 2 diabetes (n ∼ 27,800 patients; ≥ 24 weeks) to assess the In ADOPT, patients treated with rosiglitazone 4 or 8 incidence of myocardial infarction and death from mg daily had a significantly lower monotherapy failure cardiovascular causes.24 A significantly greater rate (fasting plasma glucose > 10 mmol/L) at five number of myocardial infarction events was found with years (cumulative incidence 15%) than patients rosiglitazone than with control drugs (odds ratio 1.43 treated with either metformin (21%) or glibenclamide [95% CI 1.03 to 1.98], p = 0.03); there was no 7 (34%) (p < 0.001). In the smaller study, there was no significant difference in the number of deaths from significant difference in the reduction of plasma HbA1c cardiovascular causes (odds ratio 1.64 [0.98 to 2.74], concentrations with rosiglitazone 8 mg (-0.5%) p = 0.06). Although the study had limitations, the compared with glibenclamide up to 15 mg daily finding is in agreement with results from data 8 (-0.7%), at one year. analysed by the manufacturer, which found a higher Dual therapy “overall incidence of events typically associated with cardiac ischaemia” with rosiglitazone-containing Eleven studies (n = 105 to 766; total 4,213) assessed 1 the effect of rosiglitazone 4 or 8 mg daily combined regimens (1.99%) than with comparators (1.51%). with either metformin or a sulphonylurea for 24 to 32 A smaller meta-analysis (four RCTs; n = 14, 291; ≥ 1 weeks on plasma HbA1c concentrations in patients year) also found a higher risk of myocardial infarction 9-19 inadequately controlled on oral antidiabetic drugs with rosiglitazone (RR 1.42 [1.06 to 1.91], p = 0.02), 18 (one study included treatment-naïve patients). as well as a higher risk of heart failure (RR 2.09 [1.52 Compared with placebo, or higher doses of current to 2.88], p < 0.001).25 A third meta-analysis (including therapy with metformin or sulphonylurea, rosiglitazone five RCTs of rosiglitazone) similarly found a higher in combination with usual therapy was associated with risk of heart failure (RR 2.18 [95% CI 1.44 to 3.32], p 26 a significantly greater decrease in HbA1c (range of = 0.0003 ). The risk of cardiovascular death was not mean decreases with rosiglitazone: 0.51 to 1.2%). higher with rosiglitazone in either of these studies. In one of the studies, rosiglitazone was compared with In the ADOPT study, rosiglitazone was associated glibenclamide, both in combination with metformin, with a higher risk of heart failure than glibenclamide in patients inadequately controlled on metformin alone (p ≤ 0.05).7 Other adverse events reported in the 19 (n = 318). Rosiglitazone 4 or 8 mg was found to be trials of efficacy were greater incidences of fracture in less effective than glibenclamide 5 to 10 mg daily in the feet, hands and upper arms in female patients with 7 reducing HbA1c after 24 weeks (reduction: 1.1 vs. rosiglitazone than with metformin or glibenclamide 1.5%; p < 0.001). This was the only study of dual (which prompted a warning from the manufacturer27), therapy in which an alternative anti-diabetic drug was weight gain, oedema, and increased cholesterol used as control. concentrations. A twelfth study used disease progression (fasting In a retrospective case-control study of 159,026 plasma glucose ≥ 10 mmol/L) as outcome; patients over 66 years who were using an anti- rosiglitazone was associated with a lower percentage diabetic drug, use of rosiglitazone or pioglitazone was of patients with disease progression than placebo associated with a significantly higher risk of heart after two years of treatment, when added to failure, myocardial infarction and all-cause death at 20 glipizide. median follow-up of 3.8 years; these increased risks 28 Triple therapy appeared to be limited to the use of rosiglitazone. In three RCTs (n = 365; 217; 40), rosiglitazone 4 or 8 Additional information mg was added to a sulphonylurea plus metformin in patients inadequately controlled with this combination, • Rosiglitazone is contra-indicated in patients with 21,22,23 cardiac failure, acute coronary syndrome, hepatic for 24 weeks. The largest study (double-blind) 1 compared rosiglitazone with placebo21 and found a impairment, diabetic ketoacidosis and pre-coma. greater mean reduction in HbA1c with rosiglitazone. • Rosiglitazone is given in doses of 4 or 8 mg daily. The other studies (one open-label and one double- • At current prices, one year’s treatment costs £315 or blind) compared rosiglitazone with insulin glargine; £482 for rosiglitazone 4 or 8 mg daily. there was no difference between the groups in References lowering HbA1c (rosiglitazone -1.5% vs. insulin glargine -1.7% or -1.4%).22,23 The references are listed on the next page.

Launch date: July 2000 Manufacturer: GlaxoSmithKline EU/1/00/137/006,007,011 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, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk

Date: March 2008 ©Midlands Therapeutics Review & Advisory Committee VS08/07

(This Verdict & Summary sheet replaces VS07/15)

VERDICT & SUMMARY REFERENCES (see VS08/07) Rosiglitazone for the treatment of type 2 diabetes mellitus

1. GlaxoSmithKline UK. Avandia 4mg & 8mg tablets. Summary of Product Characteristics 2008. 2. Stumvoll MGBJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005;365:1333-1346. 3. Nathan DM. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342-1349. 4. National Institute for Clinical Excellence. Management of type 2 diabetes - Managing blood glucose levels (Clinical Guideline G). NICE. 2002. http://guidance.nice.org.uk/page.aspx?o=36737 5. National Institute for Health & Clinical Excellence. Guidance on the use of the glitazones for the treatment of type 2 diabetes. Technology Appraisal 63. NICE. 2003. http://guidance.nice.org.uk/TA63/guidance/pdf/English 6. Richter B, Bandeira-Echtler E, Bergerhoff K et al. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007. 7. Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443. 8. Hanefeld M, Patwardhan R, Jones NP. A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes. Nutr Metab Cardiovasc Dis 2007;17:13-23. 9. Davidson JA, McMorn SO, Waterhouse BR et al. A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and tolerability of combination therapy with rosiglitazone and sulfonylurea in African American and Hispanic American patients with type 2 diabetes inadequately controlled with sulfonylurea monotherapy. Clin Ther 2007;29:1900-1914. 10. Wolffenbuttel BH, Gomis R, Squatrito S et al. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000;17:40-47. 11. Fonseca V, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;283:1695-1702. 12. Kerenyi Z, Samer H, James R et al. Combination therapy with rosiglitazone and glibenclamide compared with upward titration of glibenclamide alone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004;63:213-223. 13. Barnett AH, Grant PJ, Hitman GA et al. Rosiglitazone in Type 2 diabetes mellitus: an evaluation in British Indo-Asian patients. Diabet Med 2003;20:387-393. 14. Baksi A, James RE, Zhou B et al. Comparison of uptitration of gliclazide with the addition of rosiglitazone to gliclazide in patients with type 2 diabetes inadequately controlled on half-maximal doses of a sulphonylurea. Acta Diabetol 2004;41:63-69. 15. Gomez-Perez FJ, Fanghanel-Salmon G, Antonio BJ et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev 2002;18:127-134. 16. Vongthavaravat V, Wajchenberg BL, Waitman JN et al. An international study of the effects of rosiglitazone plus sulphonylurea in patients with type 2 diabetes. Curr Med Res Opin 2002;18:456-461. 17. Weissman P, Goldstein BJ, Rosenstock J et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin 2005;21:2029- 2035. 18. Stewart MW, Cirkel DT, Furuseth K et al. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Diabet Med 2006;23:1069-1078. 19. Garber A, Klein E, Bruce S et al. Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2006;8:156-163. 20. Rosenstock J, Goldstein BJ, Vinik AI et al. Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study. Diabetes Obes Metab 2006;8:49-57. 21. Dailey GE, III, Noor MA, Park JS et al. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 2004;116:223-229. 22. Rosenstock J, Sugimoto D, Strange P et al. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care 2006;29:554-559. 23. Reynolds LR, Kingsley FJ, Karounos DG et al. Differential effects of rosiglitazone and insulin glargine on inflammatory markers, glycaemic control, and lipids in type 2 diabetes. Diabetes Research and Clinical Practice 2007;77:180-187. 24. Nissen, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:doi:10.1056NEJMoa072761. 25. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone. JAMA 2007;298:1189-1195. 26. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta analysis of randomised clinical trials. Lancet 2007;370:1129-36. 27. Increased incidence of fractures in female patients who received long-term treatment with Avandia. GlaxoSmithKline UK. 2007. www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=con2030644&RevisionSelectionMethod=Latest 28. Lipscombe LL, Gomes T, Levesque LE et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298:2634-2643.