Product Review. Achieving control of hyperglycaemia in type 2 diabetes: A focus on treatment with Xultophy (insulin degludec/liraglutide) Endocrine

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1 This supplement has been sponsored by, and developed in partnership with Novo Nordisk Limited cpd credits Product Review Endocrine Achieving control of hyperglycaemia in type 2 diabetes: A focus on treatment with Xultophy (insulin degludec/liraglutide) This supplement has been sponsored by, and developed in partnership with Novo Nordisk Limited. The sponsorship fee included an honorarium for the author. Novo Nordisk Limited reviewed the author brief, and had the opportunity to comment on the medical content and accuracy of the supplement in accordance with the ABPI Code of Practice. The views and opinions expressed are not necessarily those of Novo Nordisk Limited, or of Guidelines in Practice, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher. Prescribing information can be found on page 6. UK/XT/0315/0068b MGP Ltd 2017 Date of preparation: June 2017

2 ACHIEVING IMPROVED GLYCAEMIC CONTROL IN TYPE 2 DIABETES Achieving control of hyperglycaemia in type 2 diabetes: a focus on treatment with Xultophy (insulin degludec/liraglutide) Dr Mo Roshan, GPwSI in Diabetes, Willows Medical Centre, Leicester, UK Introduction Type 2 diabetes mellitus (T2DM) is a complex heterogeneous group of metabolic disorders, characterised by impaired insulin secretion and resistance to the actions of insulin. 1 The aetiology is multifactorial but the main contributory components include physical inactivity, nutritional excess, and a genetic predisposition. Underlying pathophysiology includes defective glucose metabolism, with increased hepatic gluconeogenesis and a decrease in insulin secretion from pancreatic beta cells. 1 In the UK, it is estimated that 4.5 million people have diabetes, 2 approximately 90% of whom will have T2DM. 3 In England, the prevalence of prediabetes increased from 11.6% in 2003 to 35.3% in Clinical impact The life expectancy for a person diagnosed with T2DM in their 50s may be reduced, on average, by 6 years, 3 and T2DM resulted in almost 20,000 more deaths per year in England than would have been expected in The associated risks and complications can be summarised as follows: the major complication of diabetes is cardiovascular disease (CVD), and rates of CVD in people with diabetes are double those in the non-diabetic population 6 diabetes is a common reason for end-stage kidney disease 7 and a common cause of blindness in people of working age 8 each week, >140 foot or toe amputations are carried out as a result of diabetes, with the majority potentially being preventable. 3 Economic impact NHS spending on all aspects of diabetes care was almost 10 billion in 2011 (approximately 10% of the NHS budget spend across the UK); the majority was spent on managing potentially avoidable complications. 9 The National Diabetes Audit found that people of working age with T2DM received substantially worse routine care and treatment than people aged 65 years and over, and that there were worrying variations in care and treatment among different population groups and in different geographical areas of the country. 10 The audit also found that the HbA 1c target achievement (7.5%; <58 mmol/mol) for clinical commissioning groups (CCGs) in England and Wales ranged from approximately 53% to 75%. 10 In areas with a high prevalence of T2DM, it is important for CCGs to have programmes in place for effective prevention, screening, and early detection, as well as evaluating, supporting, and monitoring diabetes care, with robust management programmes so that the burden from uncontrolled T2DM can be minimised. Treatment benefits and barriers Two large studies have shown that good control of blood pressure, hyperglycaemia, and cholesterol level in patients with diabetes reduces microvascular complications and improves mortality rates. 11,12 These studies emphasise the need for regular review and monitoring, with the need for optimal call recall systems. It is concerning, then, that in only 40% of patients with T2DM met targets for all three indices in England and Wales. 10 Widespread failure to meet these targets suggests the need for a re-evaluation of our approach to treatment for these patients. With the rising prevalence of conditions such as T2DM and the accompanying morbidity, there is a risk of increasing complications such as amputation, sight-threatening retinopathy, 2

3 and chronic kidney disease, if care is allowed to be further compromised. The increased likelihood of hypoglycaemic episodes is often cited by healthcare professionals as the reason for failing to intensify glucose-lowering therapies, 13 and it has been demonstrated that fear of hypoglycaemia has a marked effect on patient quality-of-life measures. 14 The impact of unrecognised hypoglycaemia in patients receiving oral antidiabetic agents such as sulphonylureas may also be underestimated, 15 and sub-analysis in the ACCORD study has suggested that there is a possible relationship between the number of hypoglycaemic episodes and risk of death. 16 Additionally, most patients with T2DM are overweight, 17 which adds to the cardiovascular risk from the condition and co-existing risk factors. The ACCORD study also showed that intensification of treatment was related to weight gain in patients with T2DM. 16 Glucagon-like peptide-1 receptor agonists Type 2 diabetes has long been classified as an insulin-centric disease; this model is being updated to describe a condition that has a much more complex pathophysiology, with other endocrine hormones such as glucagon-like peptide-1 playing a significant part in causation and therefore in therapeutic potential. 18 Targeting the incretin system has become an important therapeutic approach for treating T2DM with the development of two drug classes: dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Clinical data have revealed that these therapies improve glycaemic control while reducing body weight (GLP-1 receptor agonists, specifically) and systolic blood pressure in patients with T2DM. 19,20 Furthermore, the incidence of hypoglycaemia is relatively low with these treatments (except if used in combination with a sulphonylurea or basal insulin) compared with other active comparators, because of their glucose-dependent mechanism of action. 20 Studies on GLP-1 receptor agonists have shown that these agents are effective in reducing hyperglycaemia in people with T2DM, with a favourable side-effect profile in terms of weight loss* and rates of hypoglycaemia There are several GLP-1 receptor agonists on the market in the UK (albiglutide, dulagutide, exenatide, liraglutide, and lixisenatide), all of which are licensed for use with basal insulin. Within this class there are longer-acting options that allow for once-weekly injections (albiglutide, which is licensed for use with basal insulin; dulaglutide, which is licensed for use with both basal and prandial insulin; and exenatide extended-release, which is not licensed for use with prandial or basal insulin) Long-acting analogue insulins The long-acting analogue insulins, insulin glargine and insulin detemir, have a less variable profile when compared with neutral protamine hagedorn (NPH) insulin. 29,30 This lower variability will potentially lead to lower rates of nocturnal hypoglycaemic episodes compared with NPH insulin. 29,30 As T2DM is a chronic progressive disease, most patients will need exogenous insulin at some point in the disease course, and NICE Guideline 28 on the management of T2DM in adults recommends that long-acting insulin analogues should be considered in patients who: 31 have recurrent hypoglycaemic episodes that are restricting their lifestyle are unable to reach their target HbA 1c due to significant hypoglycaemia would benefit from a reduction in the frequency of injections. Insulin degludec Insulin degludec is a long-acting insulin analogue studies have shown that it is absorbed continuously and slowly into the circulation, resulting in a flat and stable blood glucose-lowering effect, with a lower coefficient of variability when compared with insulin glargine U100 over a 24 hour period. 32 Clinical trials have also shown a significant reduction in nocturnal hypoglycaemia when compared with insulin glargine U Insulin degludec/liraglutide Insulin degludec/liraglutide (IDegLira) is a fixed-ratio co-formulation product of insulin degludec and liraglutide. 33 It is licensed for the treatment of adults with T2DM 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. 34 Insulin degludec/liraglutide received EU marketing authorisation in September Health technology assessments Scottish Medicines Consortium Insulin degludec/liraglutide has been accepted for restricted use within NHS Scotland in patients who are uncontrolled on basal insulin analogues (HbA 1c >7.5% [59 mmol/mol]) and for whom a GLP-1 receptor agonist is appropriate as an add-on intensification therapy to basal insulin to obtain glucose control. 35 All Wales Medicines Strategy Group Within NHS Wales, IDegLira is recommended as an option for restricted use in combination with oral glucose-lowering *Incretin-based therapies, including GLP-1 receptor agonists, which are indicated for the treatment of type 2 diabetes are not licensed for weight management. Weight change was a secondary end point in clinical trials on people with type 2 diabetes. 3

4 ACHIEVING IMPROVED GLYCAEMIC CONTROL IN TYPE 2 DIABETES medicinal products when these combined with basal insulin do not provide adequate glycaemic control. 36 Clinical trials DUAL I The DUAL I clinical trial (randomised, open label) demonstrated that the use of IDegLira in adult insulin-naive patients (n=1663) with uncontrolled T2DM (HbA 1c 7 10%, mmol/mol) taking metformin with or without pioglitazone, resulted in a HbA 1c reduction of 1.9% (21 mmol/mol) from baseline after 26 weeks, compared with a reduction of 1.4% (15 mmol/mol) with insulin degludec (estimated treatment difference [ETD]=-0.47%, p<0.0001), and 1.3% (14 mmol/mol) with liraglutide (ETD=-0.64%, p<0.0001). 33 Additionally, people taking IDegLira experienced a lower incidence of hypoglycaemia when compared with insulin degludec (1.8 vs 2.6 hypoglycaemic events per patient year, respectively). Incidence of hypoglycaemia in the liraglutide group was 0.2 events per patient year. 33 The proportion of participants reporting nausea was 8.8%, 19.7%, and 3.6% for the IDegLira, liraglutide, and insulin degludec groups, respectively). 33 At study end, mean bodyweight decreased by 0.5 kg with IDegLira, compared with an increase of 1.6 kg with insulin degludec (ETD=-2.2 kg, p<0.0001) and a decrease of 3.0 kg with liraglutide (ETD=2.4 kg, p<0.0001). 33 DUAL II The DUAL II clinical trial (randomised, double-blind) compared the use of IDegLira with insulin degludec in adult patients (n=413) with uncontrolled T2DM (HbA 1c %, mmol/mol) taking basal insulin (20 40 units) and metformin, with or without sulphonylureas or glinides. At randomisation, participants discontinued all glucose-lowering drugs except for metformin and transferred from current basal insulin to insulin degludec or IDegLira; insulin doses were capped at 50 units in both treatment arms. 37 The trial demonstrated that IDegLira resulted in a HbA 1c reduction of 1.9% (21 mmol/mol) from baseline after 26 weeks, compared with a 0.9% (10 mmol/mol) reduction with insulin degludec (ETD=-1.1%, p<0.0001), and an incidence of confirmed hypoglycaemia (24%) comparable to insulin degludec (25%). At study end, mean weight loss with IDegLira was 2.7 kg compared with no weight change with insulin degludec (ETD=2.5 kg, p<0.0001). 37 DUAL V The DUAL V clinical trial (randomised, open-label, active control) compared the efficacy and safety of IDegLira vs. insulin glargine U100, in adult patients (n=557) with uncontrolled T2DM (HbA 1c 7 10%, mmol/mol) on insulin glargine (20 50 U) and metformin. 38 The trial demonstrated that IDegLira resulted in a HbA 1c reduction of 1.8% (20 mmol/mol) from baseline after 26 weeks, compared with a 1.1% (12 mmol/mol) reduction with insulin glargine Key points It is estimated that 4.5 million people in the UK have diabetes, 2 approximately 90% of whom have T2DM 3 Diabetes: is a major cause of mortality, accounting for almost 20,000 excess deaths every year 5 is a common cause of renal disease and blindness 7,8 causes significant morbidity from cardiovascular disease and amputations 3,6 accounts for approximately 10% of the annual NHS budget; most of this is spent on managing potentially avoidable complications 9 There are significant gaps in the care of people with diabetes, both in processes of care and in meeting targets for glycaemic, blood pressure, and lipid levels 10 Evidence from interventional studies has shown that multifactorial intervention and achieving glycaemic control reduce the burden of complications 11,12 Weight gain and hypoglycaemia resulting from drug treatment are often cited as barriers both for patients with diabetes in achieving glycaemic control, and for healthcare professionals in intensifying drug treatment: the weight gain may further increase cardiovascular risk GLP-1 receptor agonists are effective in reducing hyperglycaemia in people with T2DM, and may result in weight loss* In a head-to-head study of IDegLira vs insulin glargine U100, treatment with IDegLira: 38 resulted in HbA 1c reductions superior to insulin glargine U100 (1.8% [20 mmol/mol] vs 1.1% [12 mmol/mol], respectively) demonstrated secondary benefits of:»» a lower rate of hypoglycaemia (2.2 vs 5.1 hypoglycaemic events per patient year, respectively)»» 1.4 kg weight loss from baseline»» once-daily dosing. T2DM=type 2 diabetes mellitus; GLP-1=glucagon-like peptide-1 receptor agonist; IDegLira=insulin degludec/liraglutide * GLP-1 receptor agonists are not licensed for weight loss. Insulin degludec/liraglutide is not licensed for weight loss. U100 (ETD=-0.59%, p<0.001); the percentage of patients able to reach the target HbA 1c level of <7% (53 mmol/mol) was 72% and 47%, respectively (between group treatment difference=24.6%, p<0.001). 38 Those taking IDegLira experienced a lower incidence of hypoglycaemia when compared with insulin glargine U100 (2.2 vs 5.1 hypoglycaemic events per patient year, respectively, p<0.001), and IDegLira resulted in a mean weight loss of 1.4 kg from baseline, compared with a mean weight gain of 1.8 kg with insulin glargine U100 (ETD=-3.2 kg, p<0.001). 38 Insulin degludec/liraglutide (IDegLira) is not licensed for weight loss. 4

5 ACHIEVING IMPROVED GLYCAEMIC CONTROL IN TYPE 2 ACHIEVING DIABETES IMPROVED GLYCAEMIC CONTROL IN TYPE 2 DIABETES Dosage Insulin degludec/liraglutide is taken once-daily by subcutaneous injection, independently of meals; it may be taken at any time of day, but preferably at the same time each day. If administration at the same time each day is not possible, ensure a minimum of 8 hours between injections. 34 Insulin degludec/liraglutide is supplied in a 3 ml fixed-ratio co-formulation, pre-filled pen. It is administered as dose steps with one dose step containing 1 unit of insulin degludec and mg liraglutide. The pre-filled pen can provide up to 50 dose steps in one injection in increments of one dose step: 34 when transferring from basal insulin or a GLP-1 receptor agonist, the recommended initial dose is 16 dose steps, and therapy with basal insulin or GLP-1 receptor agonists should be discontinued before initiating treatment (refer to the summary of product characteristics 34 for further information on transferring from a long-acting GLP-1 receptor agonist) the maximum daily dose is 50 dose steps (50 units insulin degludec and 1.8 mg liraglutide). Side-effects Common side-effects of IDegLira include those arising from the component parts (e.g. nausea and other gastrointestinal sideeffects) as well as hypoglycaemia. When IDegLira is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered. 34 Please refer to the summary of product characteristics for further information on adverse events and side-effects. 34 Conclusion Given the high levels of unattained glycaemic targets in people with T2DM, and the morbidity that results from poor control, therapies are needed that can deliver glycaemic control for patients with uncontrolled diabetes, and which have lower rates of adverse effects such as hypoglycaemia and weight gain. Treatment with IDegLira has been associated with an HbA 1c reduction of 1.8% (20 mmol/mol) after 26 weeks, 38 and is a welcome addition to the armamentarium against hyperglycaemia in T2DM. Conflicts of interest Dr Roshan has received honoraria for serving on advisory boards for Novo Nordisk Limited and Sanofi. References 1. DeFronzo R, Ferrannini E. Diabetes Care 1991; 14: Diabetes UK. Diabetes prevalence 2016 (November 2016). org.uk/professionals/position-statements-reports/statistics/diabetesprevalence-2016/ 3. Diabetes UK. Facts and stats. London: DUK, Available at: Facts_Stats_Oct16.pdf 4. Mainous III A, Tanner R, Baker R et al. BMJOpen 2014; 4: e doi: /bmjopen Health and Social Care Information Centre. National Diabetes Audit Report 2: complications and mortality. Available at: content. digital.nhs.uk/catalogue/pub16496/nati-diab-audi rep2.pdf 6. The Emerging Risk Factors Collaboration. Lancet 2010; 375: NHS Kidney Care. Diabetes with kidney disease: key facts. March Available at: 8. NHS diabetic eye screening programme website. NHS diabetic eye screening programme. Facts and figures. diabeticeye.screening.nhs.uk/statistics (accessed 26 January 2017) 9. Hex N, Bartlett C, Wright D et al. Diabet Med 2012; 39 (7): NHS Digital. National Diabetes Audit Report 1: care processes and treatment targets. Available at: PUB23241/nati-diab-rep1-audi pdf 11. UKPDS Group. Lancet 1998; 352: Gæde P, Vedel P, Larsen N et al. N Engl J Med 2003; 348: Cryer P. Diabetologia 2002; 45: Green A, Fox K, Grandy S. Diabetes Res Clin Pract 2012; 96: Amiel S, Dixon T, Mann R, Jameson K. Diabet Med 2008; 25: Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein H, Miller M, Byington R et al. N Engl J Med 2008; 358 (24): Astrup A, Finer N. Obes Rev 2000; 1: Drucker D, Nauck M. Lancet 2006; 368 (9548): Katout M, Hong Z, Rutsky J et al. Am J Hypertens 2014; 27 (1): Amori R, Lau J, Pittas A. JAMA 2007; 298 (2): DeFronzo R, Ratner R, Han J et al. Diabetes Care 2005; 28 (5): Kendall D, Riddle M, Rosenstock J et al. Diabetes Care 2005; 28 (5): Feinglos M, Saad M, Pi-Sunyer F et al. Diabet Med 2005; 22 (8): Marre M, Shaw J, Brandle M et al. Diabet Med 2009; 26: Nauck M, Frid A, Hermansen K et al; LEAD-2 Study Group. Diabetes Care 2009; 32: GlaxoSmithKline. Eperzan 30 mg and 50 mg powder and solvent for solutiin for injection summary of product characteristics. December Eli Lilly and Company Limited. Trulicity 1.5mg & 0.75mg solution for injection summary of product characteristics. October AstraZeneca UK Limited. Bydureon 2 mg powder and solution for prolongedrelease suspension for injection summary of product characteristics. November Sanofi. Lantus 100 units/ml solution for injection in a vial summary of product characteristics. January medicine/ Novo Nordisk Limited. Levemir Cartridge 100 units/ml - Penfill, Levemir Pre-filled Pen 100 units/ml - FlexPen and InnoLet summary of product characteristics. January NICE. Type 2 diabetes in adults: management. NICE Guideline 28. NICE, Novo Nordisk Limited. Tresiba 100 units/ml, 200 units/ml pre-filled pen (FlexTouch), 100 units/ml cartridge (Penfill) summary of product characteristics. April Gough S, Bode B, Woo V et al; on behalf of the NN (DUAL-I) trial investigators. Lancet Diabetes Endocrinol 2014; 2 (11): Novo Nordisk Limited. Xultophy 100 units/ml insulin degludec mg/ ml liraglutide solution for injection in a pre-filled pen summary of product characteristics. January Scottish Medicines Consortium. Insulin degludec/liraglutide 100 units/ ml/3.6mg/ml solution for injectiong pre-filled pen (Xultophy ) SMC No. (1088/15). SMC, Advice/1088_15_insulin_degludec_liraglutide_Xultophy/insulin_ degludec_liraglutide_xultophy 36. All Wales Medicines Strategy Group. Final appraisal recommendation insulin degludec/liraglutide (Xultophy ) 100 units/ml/3.6 mg/ml solution 5

6 for injection. AWMSG, appraisalinfo/2544 (accessed 26 January 2017) 37. Buse J, Vilsbøll T, Thurman J et al; on behalf of the NN (DUAL-II) Trial Investigators. Diabetes Care 2014; 37 (11): Lingvay I, Manghi F, García-Hernández P et al. JAMA 2016; 315 (9): Prescribing Information Xultophy Insulin degludec and Liraglutide. Xultophy is a pre-filled dial-a-dose pen. 1 ml solution contains 100 units insulin degludec and 3.6 mg liraglutide. One pre-filled pen contains 3 ml equivalent to 300 units insulin degludec and 10.8 mg liraglutide. One dose step contains 1 unit of insulin degludec and mg of liraglutide. Indication: 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. Posology and administration: Xultophy is given once daily by subcutaneous administration. Xultophy can be administered at any time of the day, preferably at the same time of the day. Xultophy is to be dosed in accordance with the individual patient s needs. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose. Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness. Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule. A minimum of 8 hours between injections should always be ensured. This also applies when administration at the same time of the day is not possible. Xultophy is administered as dose steps. One dose step contains 1 unit of insulin degludec and mg of liraglutide. The pre-filled pen can provide from 1 up to 50 dose steps in one injection in increments of one dose step. The maximum daily dose of Xultophy is 50 dose steps (50 units insulin degludec and 1.8 mg liraglutide). The dose counter on the pen shows the number of dose steps. The recommended starting dose of Xultophy is 10 dose steps (10 units insulin degludec and 0.36 mg liraglutide) when added to existing oral anti-diabetic treatment. When Xultophy is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered. Therapy with GLP-1 receptor agonists should be discontinued prior to initiation of Xultophy. When transferring from a GLP-1 receptor agonist, the recommended starting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide). The recommended starting dose should not be exceeded. If transferring from a long-acting GLP-1 receptor agonist (e.g. once-weekly dosing), the prolonged action should be considered. Treatment with Xultophy should be initiated at the moment the next dose of the long-acting GLP-1 receptor agonist would have been taken. Therapy with basal insulin should be discontinued prior to initiation of Xultophy. When transferring from basal insulin therapy, the recommended starting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide). The recommended starting dose should not be exceeded. Close glucose monitoring is recommended during the transfer and in the following weeks. Xultophy can be used in elderly patients. Glucose monitoring is to be intensified and the dose adjusted on an individual basis. The therapeutic experience in patients 75 years of age is limited. When Xultophy is used in patients with mild or moderate renal impairment, glucose monitoring is to be intensified and the dose adjusted on an individual basis. Xultophy cannot be recommended for use in patients with severe renal impairment including patients with end-stage renal disease. The therapeutic experience with Xultophy in patients with hepatic impairment is currently too limited to recommend the use in these patients. There is no relevant use of Xultophy in the paediatric population. Xultophy is for subcutaneous use only. Xultophy must not be administered intravenously or intramuscularly. Xultophy is administered subcutaneously by injection in the thigh, the upper arm or the abdomen. Injection sites are always to be rotated. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Xultophy should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia. In combination with sulphonylurea, the risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes of the Xultophy dose. Patients whose blood-glucose control is greatly improved (e.g. by intensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia, and must be advised accordingly. Usual warning symptoms of hypoglycaemia may disappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delay recovery from hypoglycaemia. Inadequate dosing and/or discontinuation of anti-diabetic treatment may lead to hyperglycaemia. In case of discontinuation of Xultophy, ensure that instruction for initiation of alternative anti-diabetic medication is followed. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased requirement for anti-diabetic treatment. Administration of rapid-acting insulin should be considered in situations of severe hyperglycaemia. Untreated hyperglycaemic events eventually lead to hyperosmolar coma/diabetic ketoacidosis, which is potentially lethal. Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin medicinal products, especially in patients with risk factors for development of cardiac failure. If the combination of pioglitazone and Xultophy is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Intensification of therapy with insulin, a component of Xultophy, with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. Administration of Xultophy may cause formation of antibodies against insulin degludec and/or liraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the Xultophy dose in order to correct a tendency to hyper- or hypoglycaemia. Very few patients developed insulin degludec specific antibodies, antibodies cross-reacting to human insulin or anti-liraglutide antibodies following treatment with Xultophy. Antibody formation has not been associated with reduced efficacy of Xultophy. Use of GLP-1 receptor agonists including liraglutide, a component of Xultophy, has been associated with a risk of developing acute pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Xultophy should be discontinued; if acute pancreatitis is confirmed, Xultophy should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy, in particular in patients with pre-existing thyroid disease, and Xultophy should therefore be used with caution in these patients. There is no experience with Xultophy in patients with inflammatory bowel disease and diabetic gastroparesis. Xultophy is therefore not recommended in these patients. Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy. Patients treated with Xultophy should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. Patients must be instructed to always check the pen label before each injection to avoid accidental mix-ups between Xultophy and other injectable diabetes medicinal products. Transfer to Xultophy from doses of basal insulin < 20 and > 50 units has not been studied. 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. There is no experience in patients with congestive heart failure NYHA class III-IV and Xultophy is therefore not recommended in these patients. Fertility, pregnancy and lactation: If a patient wishes to become pregnant, pregnancy occurs or is breast feeding; treatment with Xultophy should be discontinued. There is no clinical experience with Xultophy in relation to fertility. Animal reproduction studies with insulin degludec or liraglutide have not revealed any adverse effects on fertility. Undesirable effects: Adverse reactions associated with Xultophy are given below, listed by system organ class and frequency. Very common ( 1/10): Hypoglycaemia. Common ( 1/100 to <1/10): Decreased appetite, nausea, diarrhoea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux disease, abdominal distension, increased lipase, increased amylase and injection site reactions. Uncommon ( 1/1,000 to <1/100): Urticaria, hypersensitivity, dehydration, rash, pruritus and increased heart rate, eructation, flatulence and lipodystrophy acquired. Unknown (cannot be estimated from the available data): Anaphylactic reactions. The Summary of Product Characteristics should be consulted for a full list of side effects. MA numbers and Basic NHS Price: 3 x 3 ml 100 U/mL, EU/1/14/947/002, Xultophy pre-filled dial-a-dose pen. Legal category: POM. Full prescribing information can be obtained from: Novo Nordisk Limited, 3 City Place, Beehive Ring Road, Gatwick, West Sussex, RH6 0PA. Marketing Authorisation Holder: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark. Date last revised: January 2017 Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Novo Nordisk Limited (Telephone Novo Nordisk Customer Care Centre ). Calls may be monitored for training purposes. Xultophy, NovoTwist and NovoFine are trademarks owned by Novo Nordisk A/S, Denmark.