BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) Bulletin Glucagon-like peptide 1 (GLP-1) receptor agonist review

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) February 2017 Review February 2020 Bulletin Glucagon-like peptide 1 (GLP-1) receptor agonist review JPC Recommendations:- Place in therapy of GLP 1 agonists 1) As per the NICE Guideline on the management of type 2 diabetes in adults (NG28 December 15) as follows: Use of GLP 1 agonists is supported (as part of the second intensification step including consideration of insulin treatment) in combination with metformin and sulfonylurea in patients with type 2 diabetes who:- o have a BMI of 35 kg/m 2 or higher (adjusted accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or o have a BMI lower than 35 kg/m 2, and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity-related comorbidities. 2) The NICE Clinical Guideline does not cover the complex patients seen by the Specialist Diabetes Teams and at this stage in therapy there is little to guide us in terms of absolute evidence. Use of a GLP1 agonist post NICE second intensification step should be in accordance with the Specialist Diabetes Teams recommendations. Patients at this stage in therapy must be supervised by the Specialist Diabetes Team with GPs prescribing under shared care. N.B. Use of GLP 1 agonists in this setting is likely to involve multiple treatment combinations including insulin which may sit outside of the NICE Clinical Guideline and licenses for the GLP 1 agonists. See appendix 4 for London Medicines Evaluation Network overview of GLP1 agonists (published December 2016) which gives helpful information on GLP1 agonist evidence, individual product licences and NICE recommendations. 3) GLP 1 agonists and insulin recommended in line with NICE Guideline 28 i.e. combination only to be used when initiated and supervised by a Specialist with GP prescribing under shared care. 4) Specialist use (combined use with insulin and/or use outside of NICE Guidance /product license) is subject to annual audit, reported to the JPC. Page 1 of 34

2 Initiation of GLP 1 agonists Specialist Diabetes Team (this is defined as Integrated Community Diabetes Service [ICDS] or Secondary/Tertiary Care Specialist Diabetes Teams) initiation or GP initiation after consultation with specialist if the GP has access to dietetics support. GPs should only initiate in accordance with NICE Guideline 28 (see first bullet point above) up to the second intensification, after that refer patient to the Specialist Diabetes Team which should be the ICDS in the first instance. NB. GLP 1 agonist/insulin combination Specialist Diabetes Team initiation only. Preferred GLP 1- agonist Formulary Choices (New patients from December 2016, existing patients to remain on current choices) Dulaglutide and Liraglutide - NB maximum recommended dose of liraglutide is 1.2mg except in very exceptional circumstances and only after consultation with the Specialist Diabetes Team. Not recommended:- Xultophy (insulin degludec/liraglutide combination) Albiglutide Patients receiving GLP1 agonist only (i.e. not in combination with insulin) - Criteria for continuation of therapy Only continue GLP-1 agonist therapy if the person with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months. Criteria for continuation at 12 months and beyond Consider discontinuing treatment if the response at 6 months is not maintained, taking into consideration the progressive nature of type II diabetes. Patients receiving insulin/glp 1 agonist combination - Criteria for continuation of therapy 6 month review The GLP 1 agonist should be stopped if the HbA1c has not fallen by at least 5mmol/mol. 12 month review The GLP 1 agonist should be stopped if none of the following apply Improvement in HbA1c 11mmol/mol [1.0%] and weight reduction 3% Or Page 2 of 34 Improvement in HbA1c 11mmol/mol [1.0%] and patient is taking human insulin Or Improvement in HbA1c 5mmol/mol [0.5%] and weight reduction 10% Beyond 12 months Consider discontinuing treatment if the response at 12 months is not maintained, taking into consideration the progressive nature of type II diabetes.

3 Medicine Review Glucagon-like peptide 1 (GLP-1) receptor agonists Medicine Glucagon-like peptide 1 (GLP-1) receptor agonists Document status Final February 2017 Date of last revision 22 nd February 2017 Proposed Sector of Primary, secondary and tertiary care prescribing Introduction Summary Key points Introduction The Bedfordshire and Luton Joint Prescribing Committee (JPC) has previously reviewed and approved for use (in accordance with specific criteria) the following GLP -1 receptor agonists:- liraglutide, exenatide (twice daily {Byetta } and once weekly {Bydureon }), and lixisenatide. In addition, the JPC also reviewed and approved for use (in accordance with specific criteria), exenatide (twice daily preparation) in combination with basal insulin and lixisenatide in combination with basal insulin. For all GLP-1 receptor agonists, the JPC recommended that initiation of prescribing should be undertaken by the specialist diabetes team with GPs taking over prescribing under shared care. JPC shared care guidelines are therefore available for the JPC approved GLP-1 receptor agonists. NICE issued NICE Guidance 28 Type 2 diabetes in adults: management in December and following this, the JPC agreed that this guidance would supersede the JPC guidance on the use of GLP-1 receptor agonists. Two further GLP-1 receptor agonists have been approved for use in the UK since the publication of the NICE Clinical Guideline dulaglutide (Trulicity ) and albiglutide (Eperzan ). Local specialists have specifically asked for a review of dulaglutide and in addition the combination of liraglutide and insulin degludec (Xultophy ). This review seeks to provide information on the use of GLP-1 receptor agonists in accordance with NG28 and to review the place in therapy of dulaglutide and Xultophy. Relevant information on albiglutide is included for completeness. Key Points for consideration:- GLP 1 receptor agonists NICE (NG 28) supports the use of GLP 1 receptor agonists (as part of the second intensification step including consideration of insulin treatment) in combination with metformin and a sulfonylurea in patients with type 2 diabetes. (Specific initiation and ongoing criteria for use apply.). The overall quality of evidence for recommendations made at the second intensification stage was low. NICE NG 28 supersedes the NICE Technology Appraisal (TAs) Guidance issued by NICE with respect to Exenatide Immediate Release, Exenatide Extended Release and Liraglutide. Page 3 of 34

4 Previous JPC Guidance on the use of GLP 1- receptor agonists, was based on the NICE TAs, therefore adopting the recommendations contained in NG 28 will result in a change in practice locally. The Summary of Product Characteristics (SPCs) for the GLP 1 receptor agonists have wider indications than those approved by NICE NG 28. NG 28 did not review recently approved GLP 1 receptor agonists albiglutide and dulaglutide. Albiglutide (Eperzan ) is accepted for restricted use within NHS Scotland. Scottish Medicines Consortium (SMC) restriction: an alternative once weekly glucagon-like peptide-1 (GLP-1) agonist for use in combination with oral anti-diabetic agents as a third-line pre-insulin treatment option. o As add-on combination therapy, albiglutide was superior to placebo and to some oral comparators for glycaemic control. It was inferior to an alternative GLP-1 agonist and non-inferior to insulin. o In general, the adverse event profile of albiglutide is similar to other GLP-1 agonists, with gastro-intestinal events commonly reported. o This SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of albiglutide. This advice is contingent upon the continuing availability of the PAS in NHS Scotland or a list price that is equivalent or lower. Dulaglutide (Trulicity ) is accepted for restricted use within NHS Scotland. SMC restriction: as part of a triple therapy in patients with inadequate glycaemic control on two oral anti-diabetic drugs, as an alternative glucagon-like peptide 1 (GLP-1) agonist option. o Dulaglutide 1.5mg once weekly significantly reduced glycosylated haemoglobin (HbA1c) compared with a twice daily GLP-1 agonist and compared with a long-acting basal insulin analogue in patients with inadequate glycaemic control on two oral anti-diabetic drugs. o The adverse event profile of dulaglutide is consistent with that of a GLP- 1 agonist. Albiglutide and dulaglutide are slightly less expensive than Exenatide ER. Liraglutide is the most commonly used GLP1 receptor agonist in Bedfordshire and Luton and it is the most expensive. NICE recommends using the least expensive option when more than one product is suitable for a patient. NICE supports the use of GLP 1 receptor agonists in combination with insulin but does not provide any evidence for use in the full clinical guideline. Locally the JPC has supported the use of exenatide immediate release and lixisenatide in combination with basal insulin. This agreement was subject to audit. Is an updated review of all GLP 1 receptor agonists in combination with insulin needed? NICE NG 28 only specifies that ongoing support from specialist teams is required when GLP 1- receptor agonists are used in combination with insulin. Should consideration now be given to GP initiation of GLP 1 receptor agonists? Liraglutide/insulin degludec (Xultophy ) Insulin degludec is not recommended by NICE due to a lack of costeffectiveness. Local guidelines state that use (of insulin degludec) is not generally recommended except in very exceptional circumstances. Given that the use of insulin degludec is not generally recommended, it is very difficult to find a place in therapy for the liraglutide/insulin degludec combination. The SMC accepted the combination for use in patients who are uncontrolled on basal insulin analogues (glycosylated haemoglobin [HbA1c] >7.5% [59mmol/mol]) and for whom a GLP-1 receptor agonist is Page 4 of 34

5 appropriate as an add-on intensification therapy to basal insulin to obtain glucose control. o In two phase III studies treatment with insulin degludec/liraglutide resulted in a significant reduction from baseline to week 26 in HbA1c compared with the basal insulin comparators. Meeting with Luton & Bedfordshire Specialist Diabetology Teams BCCG/LCCG Pharmacy Representatives met with the Luton and Bedfordshire Specialist Diabetology Teams and discussed the bulletin. The following proposed recommendations were agreed for discussion by the JPC:- The intervention Mechanism of action Dulaglutide Xultophy Albiglutide Dulaglutide and Liraglutide Initiation of GLP1 - agonists Place in therapy of GLP1 -agonists GLP1 agonists and insulin Agreed to recommend use Agreed not to recommend Agreed not to recommend Preferred formulary choices going forward (new patients only. Existing patients remain on current choices) but only at a max of 1.2mg Liraglutide except in very exceptional circumstances and only after consultation with the specialist team. Liraglutide preferred to exenatide as a once daily preparation with a good device and efficacy. Lixisenatide least expensive but in clinical practice not found to be as efficacious as liraglutide. Specialist Team initiation or GP initiation after consultation with specialist if the GP has access to dietetics support. GP should only initiate in accordance with the NICE Clinical Guideline up to the second intensification, after that refer to Specialist team NICE Clinical Guideline does not cover the complex patients seen by the Specialist Teams and at this stage in therapy there is little to guide us in terms of absolute evidence, therefore use post NICE second intensification is likely to involve multiple treatment combinations including insulin which sit outside of the NICE Clinical Guideline and licenses for the GLP1 agonists. Patients at this stage in therapy must be supervised by Specialist Team with GPs prescribing under shared care. Agreed to adopt as per NICE Clinical Guideline i.e. combination only to be used when initiated and supervised by a Specialist with GP prescribing under shared care. The GLP-1 receptor agonists bind to and activate the GLP-1 (glucagon-like peptide-1) receptor to increase insulin secretion, suppress glucagon secretion, and slow gastric emptying. 1 Page 5 of 34

6 Licensed indication See appendix 2 Formulation/Availab le Products See appendix 2 Usual dosage See appendix 2 Treatment alternatives/ place in therapy NICE Clinical Guidelines support use of GLP-1 receptor agonists as part of the second intensification stage in treatment in very specific circumstances. Likely alternatives are combination therapies including insulin. National guidance NICE Guideline 28 The NICE Guideline on the management of type 2 diabetes in adults (NG 28 Dec 2015) sets out factors to be considered in selecting drug treatments for type 2 diabetes, including: effectiveness (metabolic response), safety and tolerability, the individual s personal and clinical circumstances and preferences, the licensed indications of the treatments available, the cost (if two drugs in the same class are appropriate, choose the option with the lower acquisition cost). The HbA1c targets agreed should reflect an individual s clinical circumstances and preferences, and the balance of likely longterm benefits/adverse effects. GLP1 Receptor Agonists The NICE NG 28 supports the use of GLP-1 receptor agonists in the following circumstances (see appendix 3)- In patients who can tolerate metformin, GLP 1 receptor agonists are recommended (as part of the second intensification step including consideration of insulin treatment) in combination with metformin and a sulfonylurea in patients with type 2 diabetes who: have a BMI of 35 kg/m 2 or higher (adjusted accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or, have a BMI lower than 35 kg/m 2, and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity-related comorbidities. The guidelines go on to note the following:- Only continue GLP-1 mimetic therapy if the person with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months. In adults with type 2 diabetes, if metformin is contraindicated or not tolerated, and if dual therapy with 2 oral drugs has not continued to control HbA1c to below the person s individually agreed threshold for intensification, consider insulin-based treatment. In adults with type 2 diabetes, only offer a GLP-1 mimetic in combination with insulin with specialist care advice and ongoing support from consultant-led multidisciplinary team. The guidelines state that the recommendations refer to the drugs at class level however, as previously noted, albiglutide and dulaglutide were not available for consideration during the production of the NICE Guideline. The following recommendations for albiglutide and dulaglutide are available from the Scottish Medicines Consortium (SMC) and the All Wales Medicines Strategy Group (AWMSG):- Albiglutide SMC advice issued December 2015 Albiglutide (Eperzan ) is accepted for restricted use within NHS Scotland. Indication under review: Treatment of type 2 diabetes mellitus in adults to improve glycaemic control in combination with other glucose-lowering medicinal Page 6 of 34

7 products including basal insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. SMC restriction: an alternative once weekly glucagon-like peptide-1 (GLP-1) agonist for use in combination with oral anti-diabetic agents as a third-line pre-insulin treatment option. As add-on combination therapy, albiglutide was superior to placebo and to some oral comparators for glycaemic control. It was inferior to an alternative GLP-1 agonist and non-inferior to insulin. This SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of albiglutide. This advice is contingent upon the continuing availability of the PAS in NHS Scotland or a list price that is equivalent or lower. Albiglutide is also indicated for adults with type 2 diabetes mellitus to improve glycaemic control as monotherapy when diet and exercise alone does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to contraindications or intolerance. SMC has not reviewed albiglutide in this indication and cannot recommend its use within NHS Scotland. perzan/albiglutide_eperzan Dulaglutide SMC - advice issued January 2016 Dulaglutide (Trulicity ) is accepted for restricted use within NHS Scotland. Indication under review: in adults with type 2 diabetes mellitus to improve glycaemic control as add-on therapy in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. SMC restriction: as part of a triple therapy in patients with inadequate glycaemic control on two oral anti-diabetic drugs, as an alternative glucagon-like peptide 1 (GLP-1) agonist option. Dulaglutide 1.5mg once weekly significantly reduced glycosylated haemoglobin (HbA1c) compared with a twice daily GLP-1 agonist and compared with a longacting basal insulin analogue in patients with inadequate glycaemic control on two oral anti-diabetic drugs. Dulaglutide is also indicated for adults with type 2 diabetes mellitus to improve glycaemic control as monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. SMC has not reviewed dulaglutide in this indication and cannot recommend its use within NHS Scotland. rulicity/dulaglutide_trulicity AWMSG - advice issued June 2016 Dulaglutide (Trulicity ) is recommended as an option for restricted use within NHS Wales. Dulaglutide (Trulicity ) should be restricted for use in the following subpopulation/circumstances within its licensed indication for the treatment of type 2 diabetes in adults to improve glycaemic control: After failure, intolerance or where there is a contraindication to, standard triple therapy (metformin and two other antidiabetic medicines) as an alternative to insulin therapy. In combination with other glucose-lowering medicinal products, when these, together with diet and exercise, do not provide adequate glycaemic control, in line with current NICE guidance. Dulaglutide (Trulicity ) is not recommended for use within NHS Wales outside of this subpopulation/these circumstances. Insulin-based treatments NICE National Guideline 28 states the following:- Page 7 of 34

8 When starting insulin therapy in adults with type 2 diabetes, continue to offer metformin for people without contraindications or intolerance. Review the continued need for other blood glucose lowering therapies. Start insulin therapy for adults with type 2 diabetes from a choice of a number of insulin types and regimens: Offer NPH insulin injected once or twice daily according to need. Consider starting both NPH and short-acting insulin (particularly if the person's HbA1c is 75 mmol/mol [9.0%] or higher), administered either: o separately or o as a pre-mixed (biphasic) human insulin preparation. Consider, as an alternative to NPH insulin, using insulin detemir or insulin glargine if: o the person needs assistance from a carer or healthcare professional to inject insulin, and use of insulin detemir or insulin glargine [ would reduce the frequency of injections from twice to once daily or o the person's lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes or o the person would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs. Consider pre-mixed (biphasic) preparations that include short-acting insulin analogues, rather than pre-mixed (biphasic) preparations that include short-acting human insulin preparations, if: o a person prefers injecting insulin immediately before a meal or o hypoglycaemia is a problem or o blood glucose levels rise markedly after meals. Consider switching to insulin detemir or insulin glargine from NPH insulin in adults with type 2 diabetes: who do not reach their target HbA1c because of significant hypoglycaemia or who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached or who cannot use the device needed to inject NPH insulin but who could administer their own insulin safely and accurately if a switch to one of the long-acting insulin analogues was made or who need help from a carer or healthcare professional to administer insulin injections and for whom switching to one of the long-acting insulin analogues would reduce the number of daily injections. Monitor adults with type 2 diabetes who are on a basal insulin regimen (NPH insulin, insulin detemir or insulin glargine) for the need for short-acting insulin before meals (or a pre-mixed [biphasic] insulin preparation). Monitor adults with type 2 diabetes who are on pre-mixed (biphasic) insulin for the need for a further injection of short-acting insulin before meals or for a change to a basal bolus regimen with NPH insulin or insulin detemir or insulin glargine ], if blood glucose control remains inadequate. NICE does not recommend the use of insulin degludec due to lack of costeffectiveness. The SMC and AWMSG have reviewed Xultophy (Insulin degludec units/liraglutide 100 units/3.6 mg per ml solution for injection):- SMC advice issued October 2015 Insulin degludec/liraglutide (Xultophy ) is accepted for restricted use within NHS Scotland. Indication under review: Treatment of adults with type 2 diabetes mellitus to improve glycaemic control in combination with oral glucose-lowering medicinal products when these alone or combined with a GLP-1 receptor agonist or with basal insulin do not provide adequate glycaemic control. Page 8 of 34

9 SMC restriction: for use in patients who are uncontrolled on basal insulin analogues (glycosylated haemoglobin [HbA1c] >7.5% [59mmol/mol]) and for whom a GLP-1 receptor agonist is appropriate as an add-on intensification therapy to basal insulin to obtain glucose control. In two phase III studies treatment with insulin degludec/liraglutide resulted in a significant reduction from baseline to week 26 in HbA1c compared with the basal insulin comparators. ec_liraglutide_xultophy/insulin_degludec_liraglutide_xultophy AWMSG advice issued November 2015 Insulin degludec/liraglutide (Xultophy ) is recommended as an option for restricted use within NHS Wales. Insulin degludec/liraglutide (Xultophy ) is licensed for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control in combination with oral glucose-lowering medicinal products when these alone or combined with a glucagon-like peptide protein-1 (GLP-1) receptor agonist or basal insulin do not provide adequate glycaemic control. Insulin degludec/liraglutide (Xultophy ) is restricted for use in combination with oral glucose-lowering medicinal products when these combined with basal insulin do not provide adequate glycaemic control. Insulin degludec/liraglutide (Xultophy ) is not recommended for use within NHS Wales outside of this subpopulation. Local Guidance GLP1 Receptor Agonists The JPC agreed (April 2016) that local guidance would be superseded by NICE Guidance 28. Insulin Degludec The following JPC recommendations have been agreed as outlined in Bulletin 192, issued February 2014 : Insulin Degludec for the Treatment of Diabetes Mellitus Commissioning (and prescribing) of Insulin degludec is low priority and use is not generally recommended except in very exceptional circumstances as outlined by Local Specialists:- Type 1 patient still having nocturnal hypoglycaemia despite using an optimised regimen of analogue basal insulin. 'Chaotic patient' or those with psychological problem (e.g. eating disorder) and intermittent compliance with insulin injection, not supervised by carer and do not qualify to receive district nurse injections of daily glargine, who may be at significant risk of DKA/ hyper/honk if missed daily basal insulin. Patients who require analogue basal insulin but have allergic reactions to levemir/ glargine. Patients who are extremely insulin resistant and require large doses (e.g. > 500units/day) where subcutaneous injection of usual strength (100u/ml) basal insulin preparation is becoming problematic/painful due to large volume, then Insulin degludec U200 strength may be considered. Treatment should be initiated by the Specialist service and prescribing may be continued by GPs. The Specialist service must inform the GP that this insulin is available in two strengths and specify clearly the strength that should be prescribed for the patient. Regular monitoring of CCG Epact data to continue with a re-review of the recommendation should prescribing increase above anticipated very low level. rthetreatmentofdiabetesmellitus.pdf Page 9 of 34

10 Evidence for use The East of England Priorities Advisory Committee (EoEPAC) are in the process of re-reviewing insulin degludec but draft recommendations do not differ significantly to the JPC recommendations outlined above. With respect to the GLP-1 receptor agonists (Exenatide, Exenatide modified release, Lixisenatide and Liraglutide) included in NICE Guideline 28, the evidence presented below are key points only from the full guideline. For more detailed information, please consult the full guideline at First Intensification The Guideline Development Group (GDG) discussed the longterm safety risks associated with the use of GLP-1 mimetics and the evidence from the health economic model, which they considered were important in the decision-making. The GDG considered that there was strong evidence from the health economic model that showed that this treatment combination was not cost effective and agreed not to recommend this option routinely. The GDG noted that where all other dual therapy options were not appropriate, individuals would naturally progress to second intensification where GLP-1s would become an option. Second Intensification The GDG discussed the evidence of combinations including GLP-1 mimetics and noted that while triple non-insulin based drug combinations including GLP-1 mimetics had better weight profiles, there was some uncertainty in the data. In addition, none of the GLP-1s triple combinations were shown to be significantly different in changes in HbA1c levels compared to metformin-nph insulin. However, the GDG agreed that to facilitate a flexible approach to enable access for individuals most likely to benefit, this combination should be available to people for whom obesity is a concern (with due consideration given to different body mass index thresholds in ethnic minority groups), and only where other triple oral combinations are contraindicated or not effective. The GDG noted that there was a lack of evidence for combinations of GLP-1 mimetics and insulin, and therefore agreed that this option should only be offered in a specialist care setting. The GDG also noted that such treatment combinations are normally prescribed in complex cases and would therefore benefit from specialist care advice and ongoing support from a consultant-led multidisciplinary team, which may include a wide range of staff based in primary, secondary and community care. The GDG agreed that the overall quality of the evidence for second intensification was low. Albiglutide The SMC review summarises the key evidence for the use of albiglutide. 15_albiglutide_Eperzan/albiglutide_Eperzan Key information from the SMC review:- In the phase III HARMONY studies, albiglutide as monotherapy and add-on to oral antidiabetic drugs (OADs) significantly reduced HbA1c compared with placebo. The EMA notes that the placebo-corrected reduction in most studies was approximately 0.8% to 1.0%. In direct comparative studies, albiglutide was superior to glimepiride and sitagliptin. However, it was Page 10 of 34

11 inferior to pioglitazone and liraglutide. It was non-inferior to insulin glargine, using a margin of 0.3%, and to insulin lispro, using a margin of 0.4%.2,3 Within the positioning proposed by the company, as first injectable therapy in patients who are failing to respond to OADs, the most useful data derive from HARMONY-7 and HARMONY-4. In HARMONY-7, albiglutide 50mg weekly was inferior to liraglutide 1.8mg daily in patients with diabetes that was uncontrolled on various OADs, which comprised dual therapy (mostly metformin and sulphonylurea) for 51% of patients, triple therapy for 7.4% and monotherapy for 41% (mostly metformin, 36%). In HARMONY-4, albiglutide 30 to 50mg weekly was non-inferior to insulin glargine (a basal insulin) in patients with diabetes that was uncontrolled on metformin ± sulphonylurea, with 82% of patients on metformin plus sulphonylurea at baseline. As this review was undertaken before dulaglutide was available, the SMC notes that the only relevant comparator (for the indication requested) is extended release exenatide. An indirect comparison with extended release exenatide concluded that albiglutide and extended release exenatide have comparable efficacy in reducing HbA1c. In addition, the licensed indications for albiglutide are broader and unlike exenatide, albiglutide is licensed for use without dosage adjustments in patients with moderate renal impairment. Dulaglutide The SMC review summarises the key evidence for the use of dulaglutide. rulicity/dulaglutide_trulicity NB For both the SMC and AWMSG submissions, the manufacturer requested consideration of dulaglutide only as part of triple therapy in patients with inadequate glycaemic control on two oral anti-diabetic drugs (OADs) as an alternative to other GLP- 1 agonists. Key information from the SMC Review:- For triple therapy use, relevant data are derived from the AWARD-1 and AWARD-2 studies in patients who had inadequate glycaemic control on dual oral anti-diabetic drug (OAD) therapy: metformin plus pioglitazone and metformin plus glimepiride in the respective studies. The background dual OAD therapy in AWARD-2 is representative of many patients in NHS Scotland. However the active comparator in AWARD-2, insulin glargine, is not relevant to use as an alternative to other GLP-1 agonists. Dulaglutide 1.5mg significantly reduced HbA1c, compared to exenatide twice daily in AWARD-1, by about 0.5% at 26 weeks; and, compared to insulin glargine in AWARD-2, by about 0.45% at week 52. Supportive data were provided from the AWARD-6 study in patients with inadequate glycaemic control on metformin monotherapy, indicating that dulaglutide 1.5mg and liraglutide 1.8mg similarly reduced HbA1c at 26 weeks. There are no direct comparative data for dulaglutide 1.5mg and the GLP-1 agonists, exenatide ER, liraglutide (1.2mg and 1.8mg) or lixisenatide in patients with inadequate glycaemic control on two OAD. To address this, results for comparisons of GLP-1 agonists derived from a Bayesian network meta-analysis (NMA) were provided. These suggested that dulaglutide was at least comparable to other GLP-1 agonists and potentially superior to some, such as exenatide twice daily. Data from the NMA comparing GLP-1 agonists to placebo for change from baseline Page 11 of 34

12 in HbA1c and body weight were applied to the economic evaluation. The NMA was weakened by heterogeneity in a number of areas including timepoints for outcomes input to the analysis, definitions of non-severe hypoglycaemia, and treatment effect in the common control arms. Also Bayesian analyses were interpreted using frequentist significance. The open-label design of AWARD-1 and AWARD-2 studies may limit assessment of subjective patient-reported outcomes such as adverse events and quality-of-life assessments, including the DTSQ questionnaire. There was no evidence presented for validation of the DTSQ and the clinical significance of differences with dulaglutide relative to placebo and exenatide of 2 points on 36-point scales for DTSQ-status and DTSQchange and of <0.70 points on 6-point scale for perception of hyperglycaemia is unknown. In the overall clinical study programme (phase II and III studies) there were only 115 (1.9%) patients aged >75 years and patients with significant renal or hepatic disease or advanced heart failure were excluded from the studies. The AWARD-1 and AWARD-2 studies recruited patients previously receiving OAD monotherapy or combination therapy. Patients on OAD monotherapy or on three or more OAD at baseline were stabilised for eight weeks on two OAD during the lead-in period before commencing a third agent. These treatment paths may not be representative of usual clinical practice. In the respective studies 25% and 16% of patients were on OAD monotherapy at screening while 23% and 18% of patients were receiving more than two OAD at screening. In comparison to exenatide ER, the licensed indications for dulaglutide are broader to include use in combination with insulin and as monotherapy. Unlike exenatide ER, dulaglutide is licensed for use without dose adjustments in patients with moderate renal impairment. Dulaglutide was available via an automated injection device which may be easier for needle phobic patients. Insulin Degludec The NICE GDG reviewed the insulin-based recommendations from NICE guidance CG87 and agreed that the updated evidence supported the use of insulin detemir and insulin glargine as alternatives to NPH insulin under certain circumstances. The GDG agreed that there was strong evidence to indicate that insulin degludec was not cost-effective and therefore was confident that this option should not be recommended. Insulin degludec/liraglutide 100 units/ml / 3.6mg/mL for injection pre-filled pen (Xultophy ) The SMC review summarises the key evidence for the use of Xultophy ec_liraglutide_xultophy/insulin_degludec_liraglutide_xultophy Key information from the SMC Review:- The submitting company requested that SMC considers insulin degludec/liraglutide for use in patients who are uncontrolled on basal insulin analogues and for whom a GLP-1 receptor agonist is appropriate as an add-on intensification therapy to basal insulin. SMC has previously accepted liraglutide, exenatide and lixisenatide, for use in combination with basal insulin. In the pivotal studies, in patients receiving concomitant metformin, the decrease in HbA1c was significantly superior for insulin degludec/liraglutide versus the basal insulin comparators. Responder rates confirmed this benefit. However, the studies have limitations. Both compared insulin degludec/liraglutide with basal insulin, which is not a relevant comparator for the SMC submission. Additionally, in DUAL II, the maximum dose of insulin degludec was 50 units; therefore, the study does not fully reflect the Page 12 of 34

13 glucose lowering or adverse events of fully titrated basal insulin. Consequently, conclusions that can be drawn in terms of direct comparisons with real-life treatment with insulin degludec are limited. Patients received concomitant oral anti-diabetic treatment with metformin and there are no data on use with other oral treatments. The open-label design of DUAL V may have introduced bias, and in this study the capped dose for insulin degludec versus no maximum dose for insulin glargine may account to some extent for the differences in rates of hypoglycaemia and nocturnal hypoglycaemia. There are no direct comparative data versus a treatment strategy of GLP-1 receptor agonist plus basal insulin in addition to oral antidiabetic medicines. The submitting company included a pooled analysis of five studies conducted by Novo Nordisk using patient level data. The purpose was to compare insulin degludec/liraglutide with alternative treatment regimens for intensifying basal insulin: liraglutide plus basal insulin (glargine or detemir), basal plus bolus insulin (insulin glargine + insulin aspart) and basal insulin only (up-titration of insulin glargine). Endpoints included change in HbA1c and weight, mean daily basal insulin dose and responder rates. The results suggest that insulin degludec/liraglutide is similar to liraglutide plus basal insulin, except for change in HbA1c where the difference was significant in favour of insulin degludec/liraglutide. These data were used in the economic model. The pooled analysis has some limitations, including use of Novo Nordisk sponsored studies only (to allow use of patient level data) so that a comparison with other GLP-1 receptor agonists was not possible. Other issues are that the comparison was not randomised, with the relative effect being ignored, and an assumption that the error for each arm was fixed meaning that variability will be underestimated. A network meta-analysis (NMA), also included in the submission to SMC, was considered by the company to have limitations and therefore was not used to inform the economic model. However, in the NMA liraglutide plus basal insulin was better than insulin degludec/liraglutide for HbA1c endpoints, and insulin degludec/liraglutide better than liraglutide plus basal insulin for hypoglycaemia and non-severe hypoglycaemia. Therefore, given the differences with the indirect data available from the pooled analysis and the NMA, a conclusion of similar efficacy between insulin degludec/liraglutide and liraglutide plus basal insulin is uncertain. The availability of insulin degludec/liraglutide may offer some advantages for the patient in terms of one or two fewer subcutaneous injections per day, which will need to be balanced against the restrictions of a fixed dose combination product. Clinical experts consulted by SMC noted that fixed dose combination products have limited use due to inflexibility in individualising the patient s treatment regimen. Gough SC, Bode BW, Woo VC, et al reported on a One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab 2015 Oct; 17(10): The 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability. GLP-receptor agonist/insulin combinations See above under NICE Guideline second intensification information. The JPC has previously approved the use of lixisenatide and exenatide (twice daily preparation) Page 13 of 34

14 in combination with basal insulin. NICE has not reviewed the evidence in detail relating to this combination. Local Criteria for the addition of exenatide or lixisenatide to an existing basal insulin regimen has previously been agreed by the JPC as outlined below (the Exenatide information is given as an example):- Addition of exenatide twice daily (Byetta ) to an existing basal insulin regimen The addition of exenatide twice daily (Byetta ) as an adjunctive to basal insulin with or without metformin and /or pioglitazone in adults who have not achieved adequate glycaemic control with these agents is an option for patients who fit the following criteria: Inclusion Criteria for the addition of exenatide twice daily (Byetta ) Clinician needs to be satisfied that the patient demonstrates clinical signs of proactive self management of glucose and body Weight i.e. patient has been seen by a dietician and has demonstrated an attempt to lose weight over the previous 6 months Clinician should give consideration to the length of time a patient has been receiving insulin / duration of time since diagnosis of diabetes as exenatide potentiates endogenous insulin secretion and therefore may have limited efficacy in patients with limited ß-cell functional capacity. Consider patient acceptability (insulin and exenatide regimens will involve multiple daily injections) Basal insulin plus OHA s regimens must be optimised before considering addition of exenatide. DPP4 inhibitors should be stopped when adding exenatide. Patients who are on an insulin analogues should be reviewed and switched to human insulin where possible (and if appropriate) before exenatide is started. Review dose of basal insulin before starting exenatide consider reducing the dose of basal insulin in patients at increased risk of hypoglycaemia when adding exenatide. The patient must fit all of the following criteria for starting exenatide: 1) a body mass index (BMI) 35 kg/m 2 in those of European family origin (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight or a body mass index (BMI) < 35 kg/m 2, and intensification of existing insulin regimen would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities. (Adapted and modified from NICE TA248) (5) or or 2) Patient has a HbA1c of > 60mmol/mol (7.6%) or other higher level agreed with the individual), AND ONLY IF: o there are concerns associated with intensifying the insulin regimen (e.g. clinical reasons, practical reasons or patient refuses). o o further weight gain (expected with intensification of insulin) would be of significant concern (e.g. pt has obesity co-morbidities sleep apnoea, mobility / musculoskeletal issues / CHD / heart failure/ NASH) previous attempts at intensification of insulin regimen have been unsuccessful in reducing HBA1c to acceptable target. 3) Agreement that exenatide will be discontinued at 6 month or 12 month review date, and beyond if the required criteria for continuation are not met. Page 14 of 34

15 Discontinuation / Continuation Criteria The use of exenatide as an adjunctive treatment to basal insulin should be reviewed at 6 and 12 months and beyond. Stopping Criteria (applicable at any time point) Patient choice Drug intolerance Occurrence of any of the exclusion criteria Failure to meet the continuation criteria Failure to attend for blood tests and clinical reviews Stopping Criteria at 6 month Review date Exenatide twice daily should be stopped if the HbA1c has not fallen by at least 5mmol/mol. Continuation criteria at 12 month Review date Improvement in HbA1c 11mmol/mol and weight reduction 3% Or Improvement in HbA1c 11mmol/mol and patient is taking human insulin Or Improvement in HbA1c 5mmol/mol and weight reduction 10% Discontinuation criteria at 12 months Exenatide twice daily should be discontinued if the patient doses not fit any of the above criteria. Post the November 2016 meeting, additional feedback was obtained from Local Diabetology Specialist Teams which requested a change to the previously agreed criteria and as follows:- Updated Locally agreed Criteria (Nov 16):- Inclusion Criteria for use of GLP1 agonists in combination with insulin in patients with type 2 diabetes:- Clinician needs to be satisfied that the patient demonstrates clinical signs of proactive self-management of glucose and body weight i.e. patient has been seen by a dietician and has demonstrated an attempt to lose weight over the previous 6 months Clinician should give consideration to the length of time a patient has been receiving insulin / duration of time since diagnosis of diabetes as GLP 1 agonists potentiate endogenous insulin secretion and therefore may have limited efficacy in patients with limited ß-cell functional capacity. Consider patient acceptability (insulin and GLP 1 agonist regimens will involve multiple daily injections) DPP4 inhibitors should be stopped when adding a GLP 1 agonist. Patients who are on an insulin analogues should be reviewed and switched to human insulin where possible (and if appropriate) before a GLP 1 agonist is started. Review dose of basal insulin before starting a GLP 1 agonist consider reducing the dose of basal insulin in patients at increased risk of hypoglycaemia when adding a GLP 1 agonist. The patient must fit all of the following criteria for starting a GLP 1 agonist: 1) a body mass index (BMI) 35 kg/m 2 in those of European family origin (with appropriate adjustment for other ethnic groups) and specific Psychological or medical problems associated with high body weight or Page 15 of 34

16 a body mass index (BMI) < 35 kg/m 2, and intensification of existing insulin regimen would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities. 2). Patient has a HbA1c of > 60mmol/mol (7.6%) or other higher level agreed with the individual), AND ONLY IF: o there are concerns associated with initiation of or intensifying the insulin regimen (e.g. clinical reasons, practical reasons or patient refuses). or o or o further weight gain (expected with initiation of or intensification of insulin) would be of significant concern (e.g. pt has obesity comorbidities sleep apnoea, mobility / musculoskeletal issues / CHD / heart failure/ NASH) previous attempts at intensification of insulin regimen have been unsuccessful in reducing HBA1c to acceptable target. 3). Agreement that the GLP-1 agonist will be discontinued at the 6 month or 12 month review date, and beyond if the required criteria for continuation are not met. The above updated criteria were supported by the JPC. (Nov 16) Safety * The most frequently observed adverse events with GLP-1RAs are gastro-intestinal disorders, particularly nausea, vomiting and diarrhoea and injection site reactions. A rare/uncommon but significant adverse event is pancreatitis. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have agreed that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with current data; however the FDA and EMA have not reached a final conclusion regarding such a causal relationship. Notably, the FDA requires evidence of cardiovascular safety of new glucoselowering agents in large clinical endpoint trials, and as a by-product of these trials, clinical events related to pancreatitis and pancreatic cancer will be assessed. 1,9 In rodent models, GLP-1RAs have been linked to the release of calcitonin, and the potential formation of thyroid tumours, but there is no evidence of a causal relationship between GLP-1RAs and thyroid tumours in humans. 9 This section focuses on the new treatments under review and the information comes from the SMC reviews:- Albiglutide In general, the adverse event profile of albiglutide is similar to other GLP-1 agonists, with gastro-intestinal events commonly reported. In the comparison to liraglutide (HARMONY-7), nausea was less frequently reported by those receiving albiglutide compared to liraglutide: 10% versus 29%, respectively. Injection-site reactions (ISR) are also reported with GLP-1 agonists and in HARMONY-7 these were significantly more frequent in the albiglutide group compared with liraglutide: 6.9% versus 1.2%. In analysis that included the term ISR and other related terms, albiglutide was associated with higher frequencies of events than other injected therapies: 13% versus 5.4% for albiglutide compared to liraglutide; 9.5% versus 5.3% for albiglutide versus insulin lispro; and 17% versus 10% for albiglutide versus insulin glargine. In the integrated safety database, the main adverse event that led to treatment discontinuation in the albiglutide group, which occurred at a higher rate than with placebo, was ISR. In this database, the incidence of pneumonia was significantly higher with albiglutide versus all comparators: 1.75% versus 0.79%; this imbalance was noted across all individual studies. A mechanism for this has not been identified. Rates of hypoglycaemia when albiglutide was used as monotherapy were low. However, these Page 16 of 34

17 increased when it was used in combination with sulphonylurea or insulin. Rare, but more serious, adverse events associated with GLP-1 agonists include intestinal obstruction and acute pancreatitis. Pancreatic and thyroid cancers are also noted as potential safety issues and monitored in pharmacovigilance activities. In an integrated analysis of data from the eight phase III studies, atrial fibrillation or flutter occurred more frequently in the albiglutide group than in the comparators groups: 1.3% versus 0.5%. A case review did not provide an explanation for this. Albiglutide is also associated with a dose-dependent increase in heart rate. Transient ischaemic attack (TIA) occurred in a larger proportion of patients given albiglutide than all comparators: 0.6% versus 0.2%, respectively. Cerebrovascular accident (CVA) occurred in 0.33% and 0.18% of patients in the respective groups. However, atrial fibrillation prior to TIA or CVA was noted for only 2 of the 20 reported cases. The incidence of first major adverse cardiovascular event (MACE) was similar in the albiglutide group versus the all comparators group, 1.2 versus 1.1 per 100 patient-years, respectively. Dulaglutide The adverse event profile of dulaglutide is consistent with that of a GLP-1 agonist. In AWARD-1 within the dulaglutide 1.5mg once weekly and exenatide twice daily groups there were similar rates at 26 weeks of adverse events (77% and 72%); serious adverse events (4.3% and 5.4%); gastro-intestinal adverse events (47% versus 42%); nausea (28% versus 26%); vomiting (17% versus 11%) and diarrhoea (11% versus 6%). Hypoglycaemia, defined as plasma glucose of 3.9mmol/L or less and/or symptoms of hypoglycaemia was reported by 10% versus 16%, respectively, at 26 weeks (p=0.007); and by 12% versus 18% at 52 weeks. Mean increases in pancreatic enzymes (p-amylase, total amylase and lipase) were greater for dulaglutide 1.5mg than exenatide twice daily at 26 weeks and were greater for total amylase and p-amylase at 52 weeks. The incidence of patients with elevations of pancreatic enzymes above the upper limit of normal during treatment was similar across the groups. In the AWARD-2 study rates of overall and serious adverse events were similar across the groups through to week 78. At 78 weeks dulaglutide 1.5mg, compared to the insulin glargine, was associated with increased rates of nausea (15% versus 1.5%) and diarrhoea (11% versus 5.7%). The incidence of total hypoglycaemia at 78 weeks was 59% and 71% in the respective groups; and of severe hypoglycaemia was 0.7% and 0.8%, respectively. Both doses of dulaglutide were associated with increases in pancreatic enzymes from baseline, which were significant versus insulin glargine for p-amylase, total amylase and lipase. The proportions of patients with normal levels at baseline who had an elevation of these liver enzymes above the upper limit of normal was significantly greater in both dulaglutide groups compared to insulin glargine. In AWARD-6 within the dulaglutide 1.5mg and liraglutide 1.8mg groups there were similar rates of overall (62% and 63%), serious (2% and 4%); and gastro-intestinal adverse events (36% and 36%), including nausea (20% and 18%), diarrhoea (12% and 12%), vomiting (7% and 8%). Hypoglycaemia was reported by 8.7% (26/299) and 5.7% (17/300) of patients in the respective groups. Across the clinical study programme the incidence of injection site reactions with dulaglutide was low and noted by the regulatory authority to be similar to other agents in the class. Within the class of incretin mimetics, serious pancreatic adverse events, pancreatitis and pancreatic cancer, have been identified by the regulatory authority as potential risks. In common with other GLP- 1 agonists dulaglutide has cardiovascular effects, such as reducing blood pressure and increasing heart rate. The clinical relevance of these is uncertain and being investigated in an ongoing study. Insulin degludec/liraglutide 100 units/ml / 3.6mg/mL for injection pre-filled pen (Xultophy ) In DUAL II, the rates of adverse events per patient-year of exposure were similar between the groups: 4.0 versus 3.6 in the insulin degludec/liraglutide and insulin Page 17 of 34

18 Costs See appendix 2 Cost effectiveness (if available) degludec groups respectively. Adverse events leading to withdrawal occurred in one patient (<1%) in the insulin degludec/liraglutide group and three patients (1.5%) in the insulin degludec group; none was considered related to study medication. Confirmed hypoglycaemia comprised episodes confirmed by plasma glucose <3.1mmol/L (56mg/dL), regardless of symptoms, or severe episodes (requiring assistance of another person) and occurred in a similar proportion of patients in both groups (24.1% versus 24.6%). However, the rate of confirmed hypoglycaemic episodes was events per 100 patient-years of exposure for insulin degludec/liraglutide and events per 100 patient-years of exposure for insulin degludec. Nocturnal confirmed hypoglycaemia (defined as a confirmed hypoglycaemic episode that occurred between 0:01 and 5:59am [inclusive]) occurred in 6.0% of patients in the insulin degludec/liraglutide group and 8.5% of patients in the insulin degludec group. In DUAL II, treatment-emergent adverse events occurring in 5% of patients in either group included nausea (6.5% versus 3.5%), diarrhoea (6.5% versus 3.5%), headache (6.0% versus 2.0%), nasopharyngitis (2.5% versus 6.0%) and increased lipase (6.0% versus 3.5%) in the insulin degludec/liraglutide and insulin degludec groups respectively. No patients discontinued from the study because of gastrointestinal adverse events. In DUAL V, rates of confirmed hypoglycaemia and nocturnal hypoglycemia (definitions as in DUAL II) were significantly lower with insulin degludec/liraglutide, titrated to a capped maximum dose of 50 units/1.8mg than insulin glargine, which could be titrated with no capped maximum dose. The most frequently occurring adverse events ( 5%) for insulin degludec/liraglutide and insulin glargine, respectively, were nausea (9.4% and 1.1%), diarrhoea (7.2% and 2.5%),vomiting (5.0% and 1.8%), and headache (4.0% and 5.0%). The following cost-effectiveness information comes from the relevant SMC reviews of the products. Albiglutide The company submitted a cost-minimisation analysis comparing albiglutide with exenatide ER for the selective positioning as a third-line, first injectable medicine for patients with type 2 diabetes who are uncontrolled on OADs, and for whom once-weekly administration is preferable. Based on SMC clinical experts responses the comparator seems appropriate. A one-year time horizon was used and the analysis was carried out from an NHS Scotland perspective. The sensitivity analysis explored three and five year time horizons. No direct clinical studies comparing albiglutide and exenatide ER were identified by the submitting company and, therefore, a Bucher indirect comparison of albiglutide and exenatide ER, as described above, was conducted to support the costminimisation analysis. The results of the indirect comparison suggested that comparable efficacy had been demonstrated between albiglutide and exenatide ER. The only costs included by the submitting company were drug acquisition costs per patient per year. In the first year, the base case results showed estimated savings associated with albiglutide of 31 per patient assuming all patients receive the 50mg dose. A confidential Patient Access Scheme (PAS) was submitted by the company and assessed by the Patient Access Scheme Assessment Group (PASAG) as acceptable for implementation in NHS Scotland. Under the PAS, a simple discount was offered which reduced the list price of albiglutide 30mg and 50mg. With the PAS, albiglutide remained a cost-effective treatment option. Sensitivity analysis was conducted varying the proportion of patients on albiglutide 30mg and 50mg using the ratio of 30mg and 50mg dose from clinical trials which showed that 40% of patients may require the 30mg dose and 60% require 50mg. Using these proportions did not alter the conclusion of the analysis. Page 18 of 34

19 The analysis shows albiglutide has comparable efficacy to exenatide ER and, based on this assumption, it is a cost-effective treatment option. Therefore, the economic case has been demonstrated. Dulaglutide The submitting company presented a cost minimisation analysis (CMA) of dulaglutide as part of triple therapy compared to the other GLP-1 agonists liraglutide (1.2mg and 1.8mg and at an average daily dose of 1.53mg) and exenatide ER in patients inadequately controlled on two OADs as an alternative to currently available GLP-1 agonists. A cost-utility analysis (CUA) was also presented against lixisenatide and exenatide twice daily in the same population. As such, the company was not seeking acceptance for the medicine as monotherapy, dual therapy or in combination with insulin. The company considered the main comparator to be liraglutide based on prescribing patterns. The results of the various comparisons are shown below: Dulaglutide versus: Incremental cost Incremental quality adjusted life year (QALY) where relevant Incremental costeffectiveness ratio (ICER) or CMA result Liraglutide 1.2mg - 29 n/a CMA Dulaglutide is cost-minimising Liraglutide 1.8mg n/a CMA Dulaglutide is cost-minimising Liraglutide average daily n/a CMA Dulaglutide is cost-minimising dose Exenatide ER - 1 n/a CMA Dulaglutide is cost-minimising Lixisenatide Dulaglutide is dominant (cheaper, more effective) Exenatide twice daily Dulaglutide is dominant The results indicated that dulaglutide would be considered cost-effective against all comparators either on the basis of a dominant ICER versus lixisenatide and exenatide twice daily in the CUA or similar or lower price in the CMA versus liraglutide and exenatide ER. The CUA results versus lixisenatide and exenatide twice daily remained dominant in sensitivity analysis except when a treatment duration of 5 years or a 10 year model time horizon were assumed. In these cases, the ICERs were 1,057 and 996 respectively. Insulin degludec/liraglutide 100 units/ml / 3.6mg/mL for injection pre-filled pen (Xultophy ) The company submitted a cost-utility analysis comparing insulin degludec/liraglutide with basal insulin (insulin detemir or insulin glargine) plus liraglutide in patients who are uncontrolled on basal insulin analogues and for whom a GLP-1 receptor agonist is appropriate as an add-on intensification therapy. The economic analysis was based on the published CORE diabetes model which is based on a series of sub-models with a semi-markov structure. The model simulates the various complications associated with diabetes over a lifetime (40-year) time horizon, including both cardiovascular and non-cardiovascular fatal and non-fatal events, and all cause mortality. No direct study data were available comparing insulin degludec/liraglutide with basal insulin plus liraglutide. As noted above, a NMA was conducted but was found to have limitations such that the submitting company considered the results to be unreliable for use in the economic model. For this reason, a pooled naive Page 19 of 34

20 indirect comparison approach was undertaken using patient level data to estimate the relative effectiveness of the relevant treatments. The results of this analysis suggested that insulin degludec/liraglutide is similar to basal insulin plus liraglutide, except for change in HbA1c where the difference was statistically significant in favour of insulin degludec/liraglutide. There were no other statistically significant differences between the treatments but the numerical differences in other outcomes were included in the model. In the base case analysis, the company estimated that insulin degludec/liraglutide would dominate basal insulin plus liraglutide (i.e. it was more effective and less costly) with estimated savings of 698 and a QALY gain of A range of one-way and probabilistic sensitivity analyses (PSA) were conducted. In the one-way sensitivity analysis, insulin degludec/liraglutide remained dominant in the majority of scenarios and the highest cost per QALY was 6k when the comparator cost was changed to reflect the cost of lixisenatide. A key sensitivity analysis was the exclusion of the non-significant differences between the treatments, but this did not alter the conclusion of dominance. The PSA showed there was a 98% probability of insulin degludec/liraglutide being costeffective at a willingness to pay threshold of 20k per QALY. The following limitations were noted: The base case analysis estimates that insulin degludec/liraglutide is more effective than basal insulin plus liraglutide based on the results of the pooled indirect comparison analysis. However, there are several weaknesses with the indirect comparison approach used to estimate the relative treatment effects and using an alternative NMA approach resulted in contradictory results. Therefore, the clinical data used to derive the base case estimates are uncertain. The analysis included some differences in outcomes from the pooled indirect comparison analysis that were not statistically significant and, given the limitations with the indirect evidence, a cost-minimisation analysis was requested. This analysis showed insulin degludec/liraglutide was cost-saving compared to basal insulin plus liraglutide based on mean doses from the pooled analysis with estimated savings of 375 per year. Sensitivity analysis was also provided which assumed equivalent dosing in each arm and this analysis resulted in equivalent drug costs but an overall saving of 35 per year with insulin degludec/liraglutide due to a reduction in the number of needles required with the combination product. The analysis did not explore the cost-effectiveness of insulin degludec/liraglutide when compared to basal insulin used in combination with other GLP-1 receptor agonists used in practice, such as lixisenatide and exenatide. These treatments are available at a lower cost than liraglutide. However, prescribing information indicates liraglutide has the largest market share. Despite the limitations outlined above, the economic case has been demonstrated. Potential number of patients in Bedfordshire and Luton Impact per 100,000 population Affordability considerations As noted above NICE does not recommend insulin degludec on grounds of lack of cost-effectiveness. Bedfordshire CCG Cost and Volume Data from Epact July June 2016 is outlined below:- Drug/Formulation No of Items Total Cost ( ) Albiglutide 0 0 Albiglutide (Eperzan ) 0 0 Dulaglutide 99 7,243 Dulaglutide (Trulicity ) 81 5,773 Exenatide ,546 Exenatide (Byetta ) 104 7,322 Exenatide (Bydureon ) ,640 Lixisenatide ,298 Page 20 of 34

21 Lixisenatide (Lyxumia ) 32 2,036 Liraglutide ,255 Liraglutide (Victoza ) ,069 Insulin Degludec and Liraglutide Xultophy 14 1,061 Insulin Degludec ,749 The equivalent 12 month data from LCCG is shown below:- Drug/Formulation No of Items Total Cost ( ) Albiglutide 0 0 Dulaglutide 37 2,574 Exenatide ,093 Ins Degludec 13 1,332 Ins 19 2,593 Degludec/Liraglutide Liraglutide ,568 Decisions from other bodies Local Specialist Diabetology Teams have advised that the proposed recommendations are in line with current practice and should not result in an increase in costs. For SMC and AWMSG see above. Comments sought from Diabetologists from Bedford Hospital and the Luton and Dunstable Hospital PAC New Drug Template Adapted from East Anglia Medicines Information, NHS Suffolk, NHS Cambridgeshire and NHS Derby templates *Consult Summary of Prescribing Characteristics for full prescribing detail. 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. References:- Embedded in the document and as outlined below 1) ebnf accessed 11/8/16 and 14/08/16. 2) Summary of product characteristics for Eperzan accessed 14/08/16. 3) Summary of product characteristics for Trulicity accessed 14/08/16. 4) Summary of product characteristics for Byetta accessed 14/08/16. 5) Summary of product characteristics for Bydureon accessed 14/08/16. 6) Summary of product characteristics for Lyxumia accessed 14/08/16. Page 21 of 34

22 7) Summary of product characteristics for Victoza accessed 14/08/16. 8) Summary of product characteristics for Xultophy 14/08/16. 9) Madsbad S et al, Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists, Diabetes, Obesity and Metabolism (2016), 18: Appendix 1- Search Strategy Initial information based on NICE National Guideline 28 (full and summary) and literature search carried out by Ipswich Regional Medicines Information Department. Page 22 of 34

23 Appendix 2 GLP - 1 receptor agonists indications, dosage, formulations and costs Drug Albiglutide (Eperzan ) Approved Indication For the treatment of type 2 diabetes mellitus, alone (if metformin is inappropriate) or in combination with other antidiabetic drugs in patients who have not achieved adequate glycaemic control with these drugs. 1 Albiglutide has not been studied in combination with prandial insulin, DPP-4 inhibitors, or SGLT2 inhibitors. There is limited experience of albiglutide when combined with thiazolidinediones alone, sulphonylureas + thiazolidinediones, and metformin + sulphonylureas + thiazolidinediones. 2 Dosage Available Formulations Cost/ (28 days unless otherwise stated) (Chemist & Druggist Aug 16) By subcutaneous injection, ADULT over 18 years, initially 30 mg once weekly; increased if necessary to 50 mg once weekly on the same day each week. 1 Injection, powder for reconstitution, albiglutide, 4 30 mg pre-filled pen (with solvent) 4 50 mg pre-filled pen (with solvent) Annual Cost (unless otherwise stated) (Chemist & Druggist Aug 16) Dulaglutide (Trulicity ) Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for By subcutaneous injection, ADULT over 18 years, 0.75 mg weekly (as monotherapy) or 1.5 mg Injection, dulaglutide, mg/0.5 ml pre-filled pen; mg/0.5 ml pre-filled pen Page 23 of 34

24 whom the use of metformin is considered inappropriate due to intolerance or contraindications. Add-on therapy In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. 3 weekly (in combination with other glucose lowering drugs) 1 Exenatide (Byetta ) Byetta is indicated for treatment of type 2 diabetes mellitus in combination with: - metformin - sulphonylureas - thiazolidinediones - metformin and a sulphonylurea - metformin and a thiazolidinedione in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies. Byetta is also indicated as adjunctive therapy to basal insulin with or without metformin and/or pioglitazone in adults who have not achieved adequate By subcutaneous injection, ADULT over 18 years, initially 5 micrograms twice daily within 1 hour before 2 main meals (at least 6 hours apart), increased if necessary after at least 1 month to max. 10 micrograms twice daily. 1 Injection, exenatide 250 micrograms/ml, 5 microgram/dose prefilled pen (60 doses); 10 microgram/dose prefilled pen (60 doses) (30 days) 887 Page 24 of 34

25 glycaemic control with these medicinal products. 4 Exenatide (Bydureon ) Bydureon is indicated for treatment of type 2 diabetes mellitus in combination with Metformin Sulphonylurea Thiazolidinedione Metformin and sulphonylurea Metformin and thiazolidinedione in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies. 5 By subcutaneous injection, ADULT over 18 years, 2 mg once weekly. 1 Injection, m/r, powder for reconstitution, exenatide, 2-mg vial (with solvent); dual-compartment singledose pen containing powder for reconstitution, exenatide and solvent Lixisenatide (Lyxumia ) Lyxumia is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycaemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control. Lixisenatide has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors. 6 By subcutaneous injection, ADULT over 18 years, initially 10 micrograms once daily within 1 hour before the first meal of the day or the evening meal for 14 days, increased to 20 micrograms once daily thereafter. 1 Injection, 50 micrograms/ml, 10 micrograms/dose prefilled pen (14 doses); 100 micrograms/ml, 20 micrograms/dose prefilled pen (14 doses); treatment initiation pack, 10 micrograms/dose prefilled pen and 20 micrograms/dose prefilled pen (28 doses of 20 micrograms). 753 Page 25 of 34

26 Liraglutide (Victoza ) Liraglutide is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance or contraindications. Combination therapy In combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control. There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I-II and liraglutide should therefore be used with caution. There is no experience in patients with congestive heart failure NYHA class III-IV and liraglutide is therefore not recommended in these patients. There is limited experience in patients By subcutaneous injection, ADULT over 18 years, initially 0.6 mg once daily, increased after at least 1 week to 1.2 mg once daily, further increased if necessary after an interval of at least 1 week to max. 1.8 mg once daily Injection, liraglutide 6 mg/ml, 2 3-mL prefilled pens, 3 3-mL prefilled (1.2mg/day) (1.8mg/day) 30 days Page 26 of 34

27 Insulin Degludec + liraglutide (Xultophy ) with inflammatory bowel disease and diabetic gastroparesis. Use of liraglutide is not recommended in these patients since it is associated with transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea. 7 Xultophy is indicated for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control in combination with oral glucose-lowering medicinal products when these alone or combined with a GLP-1 receptor agonist or basal insulin do not provide adequate glycaemic control. Xultophy has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors, glinides or prandial insulin. There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I-II and Xultophy should therefore be used with caution in these patients. By subcutaneous injection, ADULT over 18 years, as add-on to oral antidiabetics, initially 10 dose-steps once daily (adjusted according to response); when transferring from basal insulin, initially 16 dose-steps once daily (adjusted according to response); max. 50 dose-steps once daily. 1 Injection, insulin degludec (recombinant human insulin analogue) 1 unit/dose-step, liraglutide 36 micrograms/dose-step), prefilled pens. 1 3 x 3mL (300 dose steps) day cost is dependent on insulin dosage. Page 27 of 34

28 There is no experience in patients with congestive heart failure NYHA class III-IV and Xultophy is therefore not recommended in these patients. 8 Insulin Degludec* NPH* N.B. Doses are for general comparison and do not imply therapeutic equivalence *Information included for cost-comparison purposes only. 100 units/ml; 5 x 3 ml prefilled pen 100 units/ml: 5 x 3 ml prefilled pen day cost is dependent on insulin dosage (Insulatard ) 28 day cost is dependent on insulin dosage. Page 28 of 34

29 Appendix 3 Page 29 of 34

30 Following on from the publication of the NICE Guideline NG, NICE has published the following relevant Technology Appraisal Guidance: Dapagliflozin in triple therapy for treating type 2 diabetes NICE Technology appraisal guidance [TA418] Published date: 23 November This guidance updates and replaces recommendation 1.3 of NICE technology appraisal guidance on dapagliflozin in combination therapy for treating type 2 diabetes. Recommendations 1.1 Dapagliflozin in a triple therapy regimen is recommended as an option for treating type 2 diabetes in adults, only in combination with metformin and a sulfonylurea. 1.2 This guidance is not intended to affect the position of patients whose treatment with dapagliflozin in other triple therapy regimens was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop. Appendix 4 London Medicines Evaluation Network Overview: Glucagon- Like Peptide 1 receptor analogues, published December Page 30 of 34

31 Bedfordshire and Luton Joint Prescribing Committee (JPC) Assessment against Ethical and Commissioning Principles Treatment assessed (November 2016/February 2017): Glucagon-like peptide 1 (GLP -1) receptor agonist review JPC Recommendations Place in therapy of GLP 1 agonists 1)As per the NICE Guideline on the management of type 2 diabetes in adults (NG28 December 15) as follows: Use of GLP 1 agonists is supported (as part of the second intensification step including consideration of insulin treatment) in combination with metformin and sulfonylurea in patients with type 2 diabetes who:- o have a BMI of 35 kg/m 2 or higher (adjusted accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or o have a BMI lower than 35 kg/m 2, and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity-related comorbidities. 2)The NICE Clinical Guideline does not cover the complex patients seen by the Specialist Diabetes Teams and at this stage in therapy there is little to guide us in terms of absolute evidence. Use of a GLP1 agonist post NICE second intensification step should be in accordance with the Specialist Diabetes Teams recommendations. Patients at this stage in therapy must be supervised by the Specialist Diabetes Team with GPs prescribing under shared care. N.B. Use of GLP 1 agonists in this setting is likely to involve multiple treatment combinations including insulin which may sit outside of the NICE Clinical Guideline and licenses for the GLP 1 agonists. See appendix 4 for London Medicines Evaluation Network overview of GLP1 agonists (published December 2016) which gives helpful information on GLP1 agonist evidence, individual product licences and NICE recommendations. 3)GLP 1 agonists and insulin recommended in line with NICE Guideline 28 i.e. combination only to be used when initiated and supervised by a Specialist with GP prescribing under shared care. Page 31 of 34

32 4) Specialist use (combined use with insulin and/or use outside of NICE Guidance /product license) is subject to annual audit, reported to the JPC. Initiation of GLP 1 agonists Specialist Diabetes Team (this is defined as Integrated Community Diabetes Service [ICDS] or Secondary/Tertiary Care Specialist Diabetes Teams) initiation or GP initiation after consultation with specialist if the GP has access to dietetics support. GPs should only initiate in accordance with NICE Guideline 28 (see first bullet point above) up to the second intensification, after that refer patient to the Specialist Diabetes Team which should be the ICDS in the first instance. NB. GLP 1 agonist/insulin combination Specialist Diabetes Team initiation only. Preferred GLP 1- agonist Formulary Choices (New patients from December 2016, existing patients to remain on current choices) Dulaglutide and Liraglutide - NB maximum recommended dose of liraglutide is 1.2mg except in very exceptional circumstances and only after consultation with the Specialist Diabetes Team. Not recommended:- Xultophy (insulin degludec/liraglutide combination) Albiglutide Patients receiving GLP1 agonist only (i.e. not in combination with insulin) - Criteria for continuation of therapy Only continue GLP-1 agonist therapy if the person with type 2 diabetes has had a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months. Criteria for continuation at 12 months and beyond Consider discontinuing treatment if the response at 6 months is not maintained, taking into consideration the progressive nature of type II diabetes. Patients receiving insulin/glp 1 agonist combination - Criteria for continuation of therapy 6 month review The GLP 1 agonist should be stopped if the HbA1c has not fallen by at least 5mmol/mol. 12 month review The GLP 1 agonist should be stopped if none of the following apply Improvement in HbA1c 11mmol/mol [1.0%] and weight reduction 3% Or Improvement in HbA1c 11mmol/mol [1.0%] and patient is taking human insulin Or Page 32 of 34

33 Improvement in HbA1c 5mmol/mol [0.5%] and weight reduction 10% Beyond 12 months Consider discontinuing treatment if the response at 12 months is not maintained, taking into consideration the progressive nature of type II diabetes. 1) Clinical Effectiveness Clinical effectiveness assessed and recommended by NICE Guideline 28 up until the second intensification stage. Absolute evidence for use beyond this stage is lacking. 2) Cost Effectiveness Considered cost-effective by NICE up to the 2 nd intensification stage. Costeffectiveness beyond this stage is lacking. Local Specialist Diabetology Teams have advised that the proposed recommendations are in line with current practice and should not result in an increase in costs. 3) Equity No issues identified. 4) Needs of the community There are 4 million people living with diabetes in the UK with 90% of these people having type 2 diabetes. 5) Need for healthcare (incorporates patient choice and exceptional need) Alternative anti-diabetic agents are available. The use of GLP-1 agonists offers an additional therapy for complex patients. 6) Policy drivers NICE Guideline 28 Type 2 diabetes in adults: management in December ) Disinvestment None this treatment is likely to be in addition to current therapy. The JPC agreed the following sections within the PCT Ethical and Commissioning Framework were not relevant to JPC discussions: Health Outcomes, Access, and Affordability. Page 33 of 34

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