Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Discovery and development of ACE inhibitors wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Discovery and development of direct thrombin inhibitors wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Metalloprotease inhibitor wikipedia , lookup
Discovery and development of dipeptidyl peptidase-4 inhibitors wikipedia , lookup
Commissioning Support DPP-4 inhibitors (‘Gliptins’): Sitagliptin (Januvia®), Vildagliptin (Galvus®), Saxagliptin (Onglyza®), Linagliptin (Trajenta®▼), Alogliptin (Vipidia®▼) For the treatment of type 2 diabetes Commissioning guidance points for consideration: The management of patients with type 2 diabetes involves an individualised, multifactorial approach that addresses blood pressure, blood lipids and lifestyle issues, as well as blood glucose. Controlling blood glucose requires a careful balance taking into account clinical, physical, psychological and social needs, and the individual’s own preferences for care. If a gliptin is to be used, it is advised that the gliptin is selected based on the appropriate licensed indications, with the lowest acquisition cost No significant differences were reported between the gliptins with respect to blood glucose-lowering efficacy against other oral diabetic treatments in systematic review evidence, or in one RCT head-to-head comparison of sitagliptin and saxagliptin. NICE guidance (CG87) states that treatment with DPP-4 inhibitor therapy (sitagliptin and vildagliptin were available for review at the time of publication) should only be continued if the patient has had a beneficial metabolic response (a reduction of at least 0.5% [5 mmol/mol] in HbA1c [glycosylated haemoglobin]) in 6 months. An update to this guidance is expected in August 2015. Commissioners should ensure that adequate review/audit arrangements are in place to monitor metabolic response in patients treated with DPP-4 inhibitors or other oral antidiabetic drugs covered by NICE guidance (target reduction of 5 mmol/mol or 0.5% HbA1c [pioglitazone, dapagliflozin], target reduction of 11 mol/mol or 1% HbA1c [exenatide, liraglutide]). Weight-loss targets of ≥ 3% of initial body weight after 6 months are additionally specified when exenatide and liraglutide are used as part of a triple therapy regimen. The National Diabetes Audit 2011/12 recommended that all CCGs review their overall management of patients with type 2 diabetes, including results for the proportions of patients achieving all three NICE recommended targets for glucose control, blood pressure and serum cholesterol levels (all QOF incentivised): Blood glucose control is a complex balancing act. The MeReC bulletin on diabetes suggests that reducing HbA1c to about 59 mmol/mol (7.5%) seems optimal. Blood pressure: <140/80 in all; <130/80 if complications Cholesterol: <4mmol/ or <5mmol/l MTRAC considered the gliptins as a class to place them in context in the treatment of type 2 diabetes Description of the technology The dipeptidyl peptidase 4 (DPP-4) inhibitors act on DPP-4, an enzyme responsible for the inactivation of the incretin hormones including glucagon-like peptide 1 and glucose-dependent insulinotropic peptide, which are released from gut cells in response to a meal. These hormones stimulate insulin release and reduce glucagon secretions thereby reducing blood glucose levels. Five DPP-4 inhibitors are licensed for use for the treatment of type 2 diabetes in the UK; their licensed indications are summarised in Table 1 below. Clinical evidence for efficacy and safety 1 A recent systematic review of the efficacy of all five DPP-4 inhibitors compared with placebo or standard treatment for type 2 diabetes found that, as monotherapy compared with placebo, weighted mean changes in HbA1c ranged from -0.59% to -0.8% (6 to 8 mmol/mol) across the DPP-4 inhibitors. As dual therapy with metformin or a sulfonylurea vs. metformin or a sulfonylurea alone, mean HbA1c changes were 1 -0.47 to -0.84% (5 to 9 mmol/mol). There is little comparative evidence for efficacy between gliptins. One double-blind phase 3 RCT (n = 801) showed that, as add-on treatment to metformin, saxagliptin was non-inferior to sitagliptin, with weighted mean changes in HbA1c of 5 to 6 mmol/mol (-0.42% and 2 -0.59% respectively) after 18 week’s treatment. Hypoglycaemia occurred in about 3% of all patients and body weight decreased from baseline values by a mean of 0.4 kg in all patients. Evidence that DPP-4 inhibitors improve macrovascular or microvascular outcomes is lacking. Two recently published, manufacturer-sponsored, large phase IV 3 4 RCTs (SAVOR TIMI-53; EXAMINE ), involving saxagliptin or alogliptin, found that neither increases nor reduces the risk of cardiovascular events in the short 3,4 Event rates term (median 1.5 to 2 years’ follow up). (composite of CV death, non-fatal MI, or non-fatal ischaemic stroke) were about 7% over two years in patients (with established CV disease or multiple CV 3 risk factors) in the SAVOR-TIMI trial , and 11-12% of patients with diabetes and recent acute coronary 4 syndrome in the EXAMINE trial. WARNING: This sheet should be read in conjunction with the Summaries of Product Characteristics. This guidance is based upon the published information available in English at the time the drugs were considered. It remains open to review in the event of significant new evidence emerging. School of Pharmacy, Keele University, Keele, Staffordshire ST5 5BG ©Midlands Therapeutics Review & Advisory Committee Tel: 01782 734131 Email: [email protected] Web: www.mtrac.co.uk Date: May 2014 Triple oral therapy: Add-on to insulin (with or without metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycaemic control thiazolidinedione and metformin when use of a thiazolidinedione is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control sulfonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a thiazolidinedione is appropriate sulfonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of a sulfonylurea and for whom metformin is inappropriate due to contraindications or intolerance Sitagliptin 100 mg (Januvia) Vildagliptin 100 mg (Galvus) Saxagliptin 5 mg (Onglyza) Linagliptin 5mg ▼ (Trajenta ) Alogliptin 25 mg ▼ (Vipidia ) Dual oral therapy: metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin Usual daily doses quoteda Lower doses may be considered in combination with a sulfonylurea or insulin, or in moderate renal impairment* Hyperlinks to Summaries of Product Characteristics (SPC) Monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance Table 1: Licensed indications of DPP-4 inhibitors available in the UK *All gliptins require dose adjustment for moderate and severe renal impairment with exception of linagliptin. No dose adjustments required for mild and moderate hepatic impairment with exception of vildagliptin, which should not be used in patients with hepatic impairment. Adverse events A systematic review of longer-term safety of DPP-4 inhibitors (up to 104 weeks) reported no significant difference in adverse event rates or discontinuation from treatment due to an adverse event between DPP5 4 inhibitors and comparators. The review also found no significant difference in rates of hypoglycaemia between DPP-4 inhibitors and comparators unless coadministered with a sulfonylurea or insulin, where the rate was higher. This is a known risk and is reflected in the dosing guidance in the SPCs (links in Table 1). In September 2012, the MHRA described an increased risk of acute pancreatitis for all approved DPP-4 inhibitors in post-marketing reports and clinical data. Reporting rates for pancreatitis with DPP-4 inhibitors ranged from 1/1000 to 1/100 patients receiving the drug. A 2013 EMA review of findings concerning pancreatitis and precancerous, pancreatic duct metaplasia in patients with type 2 diabetes treated with DPP-4 inhibitors concluded that “presently available data do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines.” Regarding pancreatic cancer, they stated that “data from clinical trials do not indicate an increased risk with these medicines. However, the number of events is too small to draw final conclusions”. The European Commission has funded two large ongoing studies evaluating the risk profile of diabetes treatments in general, and specifically their risk profile in relation to the pancreas (results expected 3 4 in 2014). In the SAVOR TIMI-53 and EXAMINE trials, rates of acute pancreatitis were low, with similar rates of events in the drug and placebo groups. The incidence of pancreatic cancer was 5 and 12 cases, a respectively, in the drug and placebo groups in the SAVOR TIMI-53 trial, with no reports in either group in 3,4 the EXAMINE trial. Considerations for the NHS Table 2: Cost information Cost per patient per year Patent b expiry year Januvia £434 2022* Vildagliptin 100 mg Galvus £414 2019* Saxagliptin 5 mg Onglyza £412 2021† Linagliptin 5 mg Trajenta £434 2021† £347 2023† Generic name a (daily dose ) Brand name Sitagliptin 100 mg Alogliptin 25 mg Vipidia ▼ ▼ [Prices from MIMS, November 2014] References 1. Craddy P et al. Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison. Diabetes Ther 2014. 2. Scheen AJ et al. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2010; 26(7):540-549. 3. Scirica BM et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369(14):1317-1326. 4. White WB et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369(14):1327-1335. 5. Goossen K et al. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: Systematic review and meta-analysis. Diabetes, Obesity and Metabolism 2012; 14(12):1061-1072. The doses shown do not represent the full range that can be used, and they do not imply therapeutic equivalence. Patent expiry dates are estimates and are subject to change e.g. extension due to renewal of marketing authorisation; *Patent expiry dates reported in UKMi Patents expiry database; † Patent expiry dates estimated from SPC dates. b