sitagliptin, 25mg, 50mg and 100mg film-coated tablets (Januvia ) SMC No. (1083/15) Merck Sharp and Dohme UK Ltd

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1 sitagliptin, 25mg, 50mg and 100mg film-coated tablets (Januvia ) SMC No. (1083/15) Merck Sharp and Dohme UK Ltd 07 August 2015 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in Scotland. The advice is summarised as follows: ADVICE: following a full submission sitagliptin (Januvia ) is accepted for use within NHS Scotland. Indication under review: the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control. Sitagliptin, compared with placebo, improved glycaemic control in adults with type 2 diabetes mellitus who had inadequate glycaemic control on an insulin-containing regimen. SMC has previously accepted sitagliptin for use in combination with a sulfonylurea (with or without metformin), and for restricted use with metformin and as monotherapy. This now extends the advice to include its use in combination with insulin. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium Published 07 September

2 Indication The treatment of type 2 diabetes mellitus to improve glycaemic control in adults as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control. Dosing Information 100mg once daily, taken with or without food. Product availability date 09 November 2009 Summary of evidence on comparative efficacy Diabetes mellitus is a metabolic disorder resulting from defects in insulin secretion and/or its action. It is characterised by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism. 1 Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which enhances the levels of active incretin hormones to increase insulin release and decrease glucagon levels, thereby improving glycaemic control. 2 SMC has previously accepted sitagliptin for use within NHS Scotland in combination with a sulfonylurea (with or without metformin), and for restricted use in combination with metformin (when the addition of a sulfonylurea is not appropriate), and as monotherapy (for whom both metformin and sulfonylureas are inappropriate due to contraindications or intolerance). This submission relates to sitagliptin in combination with insulin, with or without metformin. A phase III, randomised, double-blind, placebo-controlled study (PN051) evaluated the efficacy and tolerability of sitagliptin when added to insulin therapy, alone or in combination with metformin, in patients with type 2 diabetes mellitus. The study recruited adults aged 21 years with a body mass index >20kg/m 2 and <43kg/m 2, who were on a stable dose of at least 15 units/day of long-acting, intermediate-acting, or premixed insulin, alone or in combination with at least 1,500mg/day metformin, with inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5% to 11% at screening). Patients receiving treatment with any other oral antihyperglycaemic agents or exenatide within eight to twelve weeks of entry to the study were excluded. Patients were randomised equally to 24 weeks treatment with sitagliptin 100mg orally once daily (n=322) or placebo (n=319) to be taken with their current insulin±metformin regimen. Insulin doses could be reduced in response to or to prevent hypoglycaemia. Throughout the study, all patients received counselling on exercise and a weightmaintenance diet, in line with American Diabetes Association recommendations. The primary outcome was change from baseline at week 24 in HbA1c. Sitagliptin, compared with placebo, significantly reduced the mean HbA1c from baseline to week 24. Least squares (LS) mean change from baseline in the sitagliptin group was -0.59% (95% confidence interval [CI]: to -0.48) compared with -0.03% (95% CI: to -0.08) in the placebo group; difference in LS mean change -0.56% (95% CI: to -0.42) (p<0.001). Subgroup analyses by type of insulin used (long-/intermediate-acting or premixed insulin) and metformin use (yes or no) showed similar between group differences in change in HbA1c from baseline to week 24 (sitagliptin versus placebo) to the entire study cohort. 3,4,5 There was no significant change from baseline in body weight in either treatment group. 3 2

3 A phase III, randomised, double-blind, placebo-controlled study (PN260) evaluated the effect of sitagliptin on insulin dose in patients with inadequately controlled type 2 diabetes mellitus. The study recruited adults aged between 18 to 80 years on a stable dose of insulin for at least ten weeks with inadequate glycaemic control (HbA1c 7.5% to 11% at screening). Metformin doses were kept stable, while patients not taking insulin glargine once daily in the evening were switched and stabilised to this insulin prior to randomisation. Patients taking sulfonylurea also underwent a two-week wash-out. Patients were randomised equally to sitagliptin 100mg orally once daily (n=330) or placebo (n=330) for a 24-week double-blind phase. From week two of the double-blind phase, the insulin glargine dose was adjusted according to pre-specified fasting finger-stick glucose measurements. The primary outcome was change in insulin dose (in units per day) from baseline to week 24. There was an increase in the mean insulin dose in both the sitagliptin and placebo groups; however, there was a statistically significant smaller change from baseline in the daily insulin dose in the sitagliptin group compared with the placebo group. At baseline, the mean daily insulin dose was 37.3 and 36.6 units/day in the sitagliptin and placebo groups respectively. The LS mean change from baseline in the sitagliptin group was 19.0 units/day (95% CI: 16.5 to 21.6) compared with 23.8 units/day (95% CI: 21.3 to 26.3) in the placebo group; difference in LS mean change -4.7 units/day (95% CI: -8.3 to -1.2) (p=0.009). Secondary outcome analysis of change from baseline to week 24 in HbA1c found a statistically significant reduction in the sitagliptin group compared with the placebo group. LS mean change from baseline in the sitagliptin group was -1.3% (95% CI: -1.4 to -1.2) compared with -0.9% (95% CI: -1.0 to -0.8) in the placebo group; difference in LS mean change -0.4% (95% CI: -0.6 to -0.3) (p 0.001). 6,7 At week 24, there was an increase from baseline in bodyweight in both treatment groups, 0.3kg in the sitagliptin group and 0.6kg in the placebo group; between-group difference was 0.3kg (95% CI: -0.8 to 0.2). 6 Summary of evidence on comparative safety No comparative safety data are available. Refer to the summary of product characteristics for details. The sitagliptin safety profile from Study PN051 was considered by the European Medicines Agency (EMA) to be in line with that observed from previous sitagliptin studies. 4 In the sitagliptin and placebo groups, respectively, one or more adverse events were reported by 52% (168/322) and 43% (137/319) of patients, with serious adverse events occurring in 6.2% (20/322) and 3.4% (11/319) of patients. Drug-related adverse events were reported in 16% (50/322) and 8.5% (27/319) of patients and were considered serious in 6.2% (20/322) and 3.4% (11/319) of patients. Treatment discontinuation was reported by 3.4% (11/322) and 1.3% (4/319) of patients as a result of adverse events. A significantly higher incidence of symptomatic hypoglycaemia was reported in those patients treated with sitagliptin (16% [50/322]) compared with placebo (7.8% [25/319]) (between-group difference p = 0.003). 3 In the PN260 study in which up-titration of insulin glargine dose was permitted, a lower proportion of patients reported hypoglycaemia in the sitagliptin group compared with patients in the placebo group; 28% and 44% respectively. Symptomatic hypoglycaemia was reported in 25% and 37% of patients respectively. Most episodes were classed as mild or moderate; severe episodes were reported in 3.0% and 4.0% of patients, respectively. 6 The DPP-4 inhibitors have been associated with a risk of acute pancreatitis, presenting as persistent, severe, abdominal pain. Pancreatitis may resolve following discontinuation of treatment; however, there have been reports of very rare cases of necrotising or haemorrhagic pancreatitis and/or death. There have also been reports of serious hypersensitivity reactions (including anaphylaxis, angioedema, and Stevens-Johnson syndrome) occurring within the first three months after initiation of treatment with sitagliptin. 2 3

4 A study to assess the cardiovascular safety of long-term treatment with sitagliptin (n=7,332) or placebo (n=7,339) as part of standard diabetes care (versus care without sitagliptin) was conducted in adults with type 2 diabetes and a history of cardiovascular disease (TECOS study). The primary endpoint was a composite cardiovascular endpoint (time to the first cardiovascular-related death, nonfatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospitalisation). In the primary analysis of the primary outcome in the per-protocol population, sitagliptin was found to be noninferior to placebo; hazard ratio 0.98 (95% CI: 0.88 to 1.09), non-inferiority margin pre-specified as This was supported when analysed in the intention-to-treat population. In a pre-specified analysis, no significant interaction was found when comparing sub-groups who were or were not using insulin at baseline. 8 Summary of clinical effectiveness issues Sitagliptin is one of five DPP-4 inhibitors marketed in the UK, all of which are indicated for use in combination with insulin, with or without metformin. Both linagliptin and saxagliptin have been accepted by SMC for this indication. SMC has not received submissions for the other DPP-4 inhibitors for use in combination with insulin. The GLP-1 analogues (i.e. exenatide, lixisenatide, liraglutide), the sodium glucose co-transporter-2 (SGLT-2) inhibitors (i.e. canagliflozin, dapagliflozin, empagliflozin) and the thiazolidinedione, pioglitazone, have all been accepted by SMC for use in combination with insulin. Both key studies demonstrated the efficacy of sitagliptin in combination with insulin, with or without metformin, in reducing HbA1c compared with placebo. For Study PN051, the EMA noted that although the treatment effect was modest, it was clinically relevant and consistent across all subgroups. Although a reduction in HbA1c levels is a validated surrogate endpoint in line with EMA guidance, 4 there is no evidence of the effect of sitagliptin on the longer-term microvascular complications of diabetes. Results from the TECOS study suggest sitagliptin neither improves nor worsens cardiovascular outcomes when added to standard of care. 8 There was no benefit over placebo in weight reduction/decrease in weight gain. No quality of life data were presented. Due to the lack of direct comparative data, a Bayesian network meta-analysis (NMA) was presented to compare sitagliptin, dapagliflozin, canagliflozin, empagliflozin, lixisenatide and exenatide in adults with type 2 diabetes mellitus with inadequate HbA1c control despite regular treatment with insulin plus additional oral anti-diabetic drugs. A total of eight studies were included, assessing ten outcomes at six months which were relevant to the economic model: change from baseline in HbA1c, weight, and systolic blood pressure (SBP); percentage change from baseline in high-density lipoprotein (HDL) and total cholesterol; risk of severe hypoglycaemia, any adverse event, discontinuations due to adverse events and discontinuations due to any reason; and rate of severe hypoglycaemia. Canagliflozin was not included in the base-case economic analysis due to lack of efficacy and adverse event data reported at six months. The results of the NMA showed similar outcomes for the treatments for change from baseline in HbA1c, SBP, HDL, total cholesterol and in the risk and rate of severe hypoglycaemia. Dapagliflozin, lixisenatide and exenatide showed better results for weight loss compared with sitagliptin. The risk of nausea was higher for lixisenatide and exenatide compared with sitagliptin, and the risk of vomiting was higher for lixisenatide compared with sitagliptin. The risk of discontinuation due to adverse events was higher for exenatide compared with sitagliptin. The NMA was limited due to heterogeneity across the studies in definitions of study outcomes and time points for efficacy assessments. Only fixed effects models were applied because of the paucity of data available, and statistical heterogeneity was not assessed. 4

5 There are no comparative data with other DPP-4 inhibitors. These are licensed in combination with insulin and two have recently been accepted by SMC in this setting (saxagliptin and linagliptin), and would be considered comparators in clinical practice. Sitagliptin is administered orally, which may be considered an advantage over comparator treatments that are administered by subcutaneous injection (i.e. the GLP-1 receptor agonists). In comparison with other DPP-4 inhibitors, a potential disadvantage of sitagliptin is that dose adjustment is recommended in patients with moderate or severe renal impairment, whereas this is not necessary for linagliptin. Summary of comparative health economic evidence The company submitted a cost-minimisation analysis comparing sitagliptin to SGLT-2 inhibitors (dapagliflozin and empagliflozin), and GLP-1 agonists (exenatide and lixisenatide) for the treatment of adult patients with type 2 diabetes, as an add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control. The time horizon used in the analysis was one year. SMC clinical expert responses noted a number of treatments are currently used, including GLP-1 agonists, SGLT-2 inhibitors and DPP-4 inhibitors. A comparison with other DPP-4 inhibitors was not provided on the basis that SMC advice for both saxagliptin and linagliptin in combination with insulin has been issued relatively recently. The clinical data used to support the cost-minimisation analysis were taken from a NMA, which consisted of eight studies. The analysis was conducted using a fixed effects model. Based on the results from this, sitagliptin demonstrated comparable efficacy for the outcomes change from baseline at 6 months in HbA1c, change in SBP from baseline at 6 months; change in HDL from baseline at 6 months; change in total cholesterol from baseline at 6 months; the risk of severe hypoglycaemia. It should be noted that the economic analysis is dependent on the assumption of comparable efficacy. The analysis included drug costs only. No administration or monitoring costs were included as these were considered to be part of routine clinical management and therefore apply to all treatments. Sitagliptin resulted in savings versus all comparators. Compared to dapagliflozin and empagliflozin, sitagliptin resulted in annual savings of 43, and compared to exenatide and lixisenatide, sitagliptin resulted in annual savings of 397 and 272 respectively. The following limitations were noted: The lack of comparison with DPP-4 inhibitors is a weakness. In practice DPP-4 inhibitors are likely to be displaced. However, it was considered that SGLT-2 inhibitors and GLP-1 agonists are reasonable comparators based on current SMC guidance. There is a lack of direct study data comparing sitagliptin (as an add-on to insulin with or without metformin) to the comparators. As such, the economic analysis is dependent on the assumption of comparable efficacy. The NMA underpinning the economic analysis was considered to be appropriate but some concerns were identified, including heterogeneity, leading to some uncertainty surrounding the conclusion of comparable efficacy. Due to lack of data reported at 6 months, canagliflozin was not included in the base case analysis. A sensitivity analysis which compares sitagliptin to canagliflozin is based on assumption of comparable efficacy. Although sitagliptin results in annual savings of 43 versus canagliflozin, the assumption of comparable efficacy has not been validated via the NMA. Despite the weaknesses outlined above, the economic case has been demonstrated. 5

6 Summary of patient and public involvement The following information reflects the views of the specified Patient Group. A submission was received from Diabetes Scotland, which is a registered charity. Diabetes Scotland has received pharmaceutical company funding in the past two years, but not from the submitting company. Diabetes is a complex condition that when poorly controlled leads to complications such as blindness, amputation, renal disease and reduced life expectancy due to coronary heart disease and stroke. One of the most difficult things for patients to come to terms with is that diabetes is for life. People frequently feel a sense of failure when the need to progress to injectable therapy occurs. Living with diabetes can have a pronounced impact on the family unit from affecting physical relationships to causing financial hardship due to loss of earnings. The medication list for type 2 diabetics is long and confusing. Side effects such as weight gain and gastric disturbances from oral diabetic treatments can result in non-adherence and a reduction in effective self management. Sitagliptin would provide another oral treatment alongside insulin which has evidence of efficacy. Any treatment regimen which improves glycaemic control and hence reduces the likelihood of developing some of the long-term complications of diabetes has the potential to positively impact on patients and their family members and/or carers. Additional information: guidelines and protocols The Scottish Intercollegiate Guidelines Network (SIGN) published updated guidance on the management of diabetes (SIGN 116) in March The treatment algorithm notes several options for second- and third-line treatment of type 2 diabetes mellitus for administration in combination with metformin and/or a sulphonylurea, including pioglitazone or a DPP-4 inhibitor, injection of a GLP-1 analogue or commencement of insulin. Treatment should be continued if an individualised target is reached or the HbA1c falls at least 0.5% in three to six months. With respect to using insulin in patients with type 2 diabetes, oral sulphonylurea and metformin therapy should be continued when insulin is initiated to maintain or improve glycaemic control. Once daily neutral protamine Hagedorn insulin is the first choice of insulin to be used, but basal insulin analogues can be considered if there are concerns regarding the risk of hypoglycaemia. The bedtime basal insulin should be titrated against the morning or fasting glucose and if HbA1c targets are not reached then the addition of prandial insulin should be considered. 1 The National Institute for Health and Care Excellence (NICE) published guidance on the management of type 2 diabetes (Clinical Guideline 87) in May 2009 (updated December 2014). The guideline considered a sulphonylurea, DPP-4 inhibitor or pioglitazone as a suitable second-line treatment option to be used in combination with metformin, and advised on the cost-effective use of exenatide as a third-line agent. The guideline recommended that patients using basal insulin regimens (e.g. neutral protamine Hagedorn or long-acting analogues) be monitored for the need to increase the dose and/or intensify the regimen using short-acting insulin before meals, or pre-mixed insulin. Patients using pre- 6

7 mixed insulin should be monitored to determine if they need further injections of short-acting insulin before meals or conversion to a basal-bolus regimen. Combination of pioglitazone and insulin was considered appropriate for patients who have inadequate glycaemic control despite high-dose insulin therapy or who have had a significant response to thiazolidinedione therapy in the past. 9 This guideline is currently being updated and is expected to be published in October Additional information: comparators DPP-4 inhibitors (i.e. alogliptin, linagliptin, saxagliptin, vildagliptin) Thiazolidinediones (i.e. pioglitazone) GLP-1 receptor agonists (i.e. exenatide, lixisenatide, liraglutide) SGLT-2 inhibitors (i.e. canagliflozin, dapagliflozin, empagliflozin) Cost of relevant comparators Drug Dose Regimen Cost per year ( ) DPP-4 inhibitors Sitagliptin 100mg orally once daily 432 Linagliptin 5mg orally once daily 432 Vildagliptin 50mg orally twice daily 413 Saxagliptin 5mg orally once daily 411 Alogliptin 25mg orally once daily 346 SGLT-2 inhibitors Canagliflozin 100mg to 300mg orally once daily 476 to 607 Dapagliflozin 10mg orally once daily 476 Empagliflozin 10mg to 25mg orally once daily 476 GLP-1 receptor agonists Liraglutide 0.6mg once daily for seven days then 1.2mg to 1.8mg once daily by subcutaneous injection 943 to 1,401 Exenatide 5 micrograms to 10 micrograms twice daily by subcutaneous injection 828 Lixisenatide 10 micrograms once daily for 14 days, then 20 micrograms once daily by subcutaneous injection 704 Thiazolidinediones Pioglitazone 15mg to 45mg orally once daily 16 to 22 Doses are for general comparison and do not imply therapeutic equivalence. Costs are from MIMS on 29 May Additional information: budget impact The submitting company estimated the population eligible for treatment to be 26,207 in year 1, rising to 33,085 in year 5, with an uptake rate of 0.75% in year 1, rising to 1.4% in year 5. A discontinuation rate of 6.3% was applied each year. The gross impact on the medicines budget was estimated to be 80k in year 1 and 188k in year 5. As other drugs are assumed to be displaced, sitagliptin was estimated to result in savings of 21k in year 1 and 49k in year 5. These savings assume displacement of GLP-1 agonists and SGLT-2 inhibitors; however, if sitagliptin is already used in practice, the savings are unlikely to be realised. 7

8 References The undernoted references were supplied with the submission. The reference shaded in grey is additional to those supplied with the submission. 1. Scottish Intercollegiate Guidelines Network (SIGN). Clinical Guideline 116. Management of diabetes. March Merck Sharp & Dohme Limited. Januvia 25mg, 50mg, 100mg film-coated tablets. Summary of product characteristics. Last updated 26 March Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010 Feb;12(2): European Medicines Agency. European public assessment report for sitagliptin (Januvia ) EMEA/H/C/722/II/ September NCT Sitagliptin added-on to insulin study ( ). accessed 18/05/ Mathieu C, Shankar RR, Lorber D, et al. A randomized clinical trial to evaluate the efficacy and safety of co-administration of sitagliptin with intensively titrated insulin glargine. Diabetes Ther NCT Study of sitagliptin for the treatment of type 2 diabetes mellitus with inadequate glycemic control on insulin (MK ). accessed 18/05/ Green JB, Bethel A, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New Eng J Med DOI: /NEjMoa National Institute for Health and Care Excellence (NICE). Clinical Guideline 87. Type 2 diabetes: management of type 2 diabetes. May This assessment is based on data submitted by the applicant company up to and including 15 June Drug prices are those available at the time the papers were issued to SMC for consideration. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC. Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. 8