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Pioglitazone (Actos®)

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Pioglitazone (Actos®) VERDICT & SUMMARY Pioglitazone (Actos®) For the treatment of type 2 diabetes mellitus Committee’s Verdict: Category B (Q4) BNF: 6.1.2 Pioglitazone is suitable for use in primary care by a prescriber with a particular interest in type 2 diabetes who can identify patients likely to benefit from treatment, and monitor for side effects, e.g. heart failure. There is conflicting evidence whether pioglitazone is associated with long-term clinical benefits or harms on cardiovascular outcomes, which dictates caution in its use. Category B: suitable for restricted prescribing under defined conditions Q4 rating: One RCT and two meta-analyses evaluated the effect of pioglitazone treatment on cardiovascular mortality and morbidity compared Q2 Q1 higher place higher place with control treatment. All three studies found a higher risk of heart failure weaker evidence stronger evidence with pioglitazone, but the results were conflicting for other cardiovascular outcomes. Pioglitazone has been found to improve glycaemic control compared with placebo, as monotherapy or in combination with other Q4 Q3 antidiabetic agents, but it was not superior to other agents. Therefore, it is lower place lower place considered to have a relatively low place in therapy. weaker evidence stronger evidence The Q rating relates to the drug’s position on the effectiveness indicator grid. in primary carePlace therapy in The strength of the evidence is determined by the quality and quantity of studies Strength of evidence for efficacy that show significant efficacy of the drug compared with placebo or 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 this drug because of new evidence and national guidance. Licensed indication associated with serious long-term microvascular disease (e.g. nephropathy, retinopathy, and Pioglitazone is indicated in type 2 diabetes mellitus 3 1 neuropathy ) and macrovascular complications (e.g. patients as: coronary heart disease, stroke, and peripheral • monotherapy in patients inadequately controlled by vascular disease). Patients with type 2 diabetes are diet and exercise for whom metformin is two to five times more likely to suffer cardiovascular inappropriate because of contraindications or morbidity.3 intolerance Dietary and lifestyle modifications form the mainstays • dual therapy in combination with metformin or a of therapy for type 2 diabetes, but 50 to 70% of sulphonylurea (in patients who show intolerance to patients will also require an oral antidiabetic drug, and metformin or for whom metformin is contraindicated) many will eventually need treatment with insulin. Drug in patients with insufficient glycaemic control despite treatments currently available include metformin, maximal tolerated dose of oral monotherapy with sulphonylureas, thiazolidinediones (rosiglitazone and either metformin or a sulphonylurea pioglitazone), acarbose, repaglinide and nateglinide, • triple therapy in combination with metformin and a exenatide, sitagliptin, vildagliptin and insulin. sulphonylurea in patients with insufficient glycaemic Metformin followed by the sulphonylureas are control despite dual oral therapy considered to be the first choices for oral antidiabetic • combination therapy with insulin in patients with therapy.4 insufficient glycaemic control on insulin, for whom Pioglitazone lowers blood glucose by reducing metformin is inappropriate because of peripheral insulin resistance.1 contraindications or intolerance. The National Institute for Health & Clinical Excellence Background information (NICE) recommends the use of a glitazone in combination with either metformin or a sulphonylurea Diabetes mellitus is a common chronic disease, which (as an alternative to a combination of metformin with is associated with markedly increased morbidity and a sulphonylurea) only for patients who cannot mortality. The majority of people in the UK with tolerate either drug in the combination. Current NICE diabetes mellitus (~90%) have type 2 diabetes. The guidance does not apply to the use of glitazones as primary defects in type 2 diabetes are reduced insulin mono- or triple oral therapy. secretion and insulin resistance.2 Type 2 diabetes is March 2008 Page 1 of 3 Clinical efficacy In five of the studies where pioglitazone plus an oral 5 antidiabetic medication (OAM) was compared with the One RCT (PROactive study ) used a combined OAM alone, the combination showed significantly clinical endpoint as the primary outcome; all others greater reductions in HbA1c from baseline compared 17,19,22-24 used the reduction in plasma glycosylated with the OAM alone (0.64 to 1.76%, p ≤ 0.05). haemoglobin concentration (HbA1c) as a measure of In the remaining three studies in which pioglitazone glycaemic control. All clinical trials described below combined with either metformin or a sulphonylurea were carried out in adult patients with type 2 diabetes. was compared with metformin plus a sulphonylurea, 5 In the PROactive study, pioglitazone was compared there was no significant difference in HbA1c reduction with placebo in 5,238 patients who had evidence of between the treatment groups.18,20,21 extensive macrovascular disease. Patients continued Adverse effects their existing antidiabetic medication (metformin or a sulphonylurea or both, with or without insulin). The One meta-analysis of 19 pioglitazone studies found trial had a mean follow-up period of 34.5 months. that the risk of death, non-fatal MI or non-fatal stroke Results showed no significant difference between was significantly lower for pioglitazone-treated pioglitazone and placebo (p = 0.095) for the primary patients vs. controls (HR 0.82 [95%CI 0.72 to 0.94], p outcome, which was a composite of: death from any = 0.005).25 A second meta-analysis (including 2 cause, non-fatal MI, stroke, acute coronary syndrome, pioglitazone studies plus 5 rosiglitazone studies) endovascular or surgical intervention in the coronary found no significant difference in the risk of or leg arteries, and amputation above the ankle. For cardiovascular death for pioglitazone treatment vs. the secondary endpoint, a composite of death from controls (RR 1.01 [95% CI 0.51 to 2.01], p = 0.98).26 any cause, non-fatal MI or stroke, there were Both meta-analyses and the PROactive study found significantly fewer events with pioglitazone treatment that the risk of serious heart failure was significantly compared with placebo: HR 0.84 (95% CI 0.72 to greater for pioglitazone-treated patients than for 0.98, p = 0.027). controls.5,25,26 Glycaemic outcomes: monotherapy The most common adverse events seen in clinical trials included weight gain, oedema, headache, As monotherapy, pioglitazone was compared with dizziness, and arthralgia. The incidence of any placebo in four RCTs (n = 1,153; duration 16 or 26 cardiac event was in the range of 2 to 4% for all weeks),6-9 metformin 750 to 2,550 mg/day in three patients treated with antidiabetic drugs. Pioglitazone RCTs (n = 1,518; 24 to 52 weeks)10-12 and with treatment resulted in body weight increases of 3 to sulphonylureas (gliclazide [up to 320 mg/day], 5 kg. glibenclamide [up to 10.5 mg/day] and glimepiride [1 to 8 mg/day]) in five RCTs (n = 2,111; 36 to 52 Additional information weeks).12-16 The usual starting dose of pioglitazone is 15 or 30 mg, In all the placebo-controlled trials, pioglitazone which may be increased to 45 mg if necessary, taken treatment at doses of 15 to 45 mg/day resulted in as a single daily dose, with or without food. significantly greater reductions in HbA1c levels than 6-9 placebo (p ≤ 0.05). Pioglitazone is contraindicated in patients with: There was no significant difference in HbA1c reduction • cardiac failure or history of cardiac failure (New between pioglitazone and metformin or a York Heart Association stages I to IV) sulphonylurea.10-16 • hepatic impairment • diabetic ketoacidosis Glycaemic outcomes: combination therapy The Summary of Product Characteristics1 In eight RCTs (n = 2,737; 16 to 52 weeks), recommends that patients should be observed for pioglitazone 30 to 45 mg/day was evaluated as dual signs and symptoms of heart failure, weight gain or therapy in combination with: oedema particularly those with reduced cardiac • metformin or a sulphonylurea in five studies (n = reserve. It also warns that there is an increased risk 1,980) vs. metformin or sulphonylurea plus placebo, of fracture in women taking pioglitazone treatment. 17-21 or metformin plus sulphonylurea At current prices, one year’s treatment with • repaglinide in one study vs. pioglitazone or pioglitazone 30 mg/day costs £437. repaglinide alone (n = 246)22 • insulin in two studies (n = 511) vs. insulin plus References 23,24 placebo The list of references is on the next page. Launch date: November 2000 Manufacturer: Takeda EU/1/00/150/001-024 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 VS08/08 (This Verdict & Summary sheet replaces VS07/14) VERDICT & SUMMARY REFERENCES (see VS08/08) Pioglitazone for the treatment of type 2 diabetes mellitus References 1. Takeda UK Ltd. Actos Tablets. Summary of Product Characteristics 2007. 2. 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 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).
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