Horizon Scanning Technology Summary. Liraglutide for type 2 diabetes. National Horizon Scanning Centre. April 2007

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1 Horizon Scanning Technology Summary National Horizon Scanning Centre Liraglutide for type 2 diabetes April 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

2 Liraglutide (NN-2211) for type 2 diabetes Target group Patients with type 2 diabetes mellitus who require control of hyperglycaemia throughout the day. Technology description Liraglutide (NN-2211) is a stable analogue of glucagon-like peptide-1 (GLP-1). Liraglutide will be available as a pre-filled, disposable pen. Exenatide (Amylin Pharmaceuticals & Eli Lilly) is expected to be the first subcutaneous incretin mimetic to launch in the UK in May Other recent new drugs for diabetes include sitagliptin (Merck Sharp and Dohme, launch expected May 2007) and vildagliptin (Novartis). All these products have been considered for inclusion in the NICE review of clinical guidelines (due Feb 2008) but final inclusion will depend on licensing. Innovation and/or advantages Liraglutide will be administered once a day, as opposed to exenatide, which is twice daily. Developer Novo Nordisk. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Liraglutide is in phase III trials. NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Long term neurological conditions Mental health Older people Public health Renal disease Women s health None identified Other: This topic relates to the National Service Framework for diabetes Relevant guidance NICE clinical guideline: Management of type 2 diabetes managing blood glucose levels NICE clinical guideline in development: type 2 diabetes (update). Expected date of issue February This is an update of the following guidelines: type 2 diabetes retinopathy, renal disease, blood glucose, management of blood pressure and blood lipids and footcare. SIGN management of diabetes. Published November Review report April

3 NICE have published guidance on the use of inhaled insulin 2 (2006); glitazones 3 (2003); insulin glargine 4 (2002). Guidance on ruboxistaurin for diabetic retinopathy is in development. Clinical need and burden of disease In England and Wales there were an estimated 2,018,000 people with diabetes in Type 2 diabetes accounts for more than 85% 6 i.e. at least 1,715,000 people in England and Wales. Patients with diabetes have an average reduction in life expectancy of 5-10 years 7. Cardiovascular disease accounts for up to 60% of all deaths from diabetes and is the most common complication in Europeans with type 2 diabetes 8. The risk of myocardial infarction and stroke is two to five times higher for individuals with type 2 diabetes than in the general population 7. Further diabetic complications include nephropathy, retinopathy, foot ulceration and erectile dysfunction. Existing comparators and treatments In people with diabetes who are overweight, and whose blood glucose is inadequately controlled using lifestyle interventions alone, metformin should normally be considered as the first-line glucose-lowering therapy 1. Metformin should also be considered as an option for first-line or combination therapy for people who are not overweight. When metformin is not tolerated or is contraindicated, or in people who are not overweight, the insulin secretagogues (including sulphonylureas and the rapid-acting insulin secretagogues - nateglinide and repaglinide) should be considered as a firstline option. People should be offered glitazones (pioglitazone, rosiglitazone) as oral combination therapy if they are unable to take metformin and insulin secretagogues as combination therapy, or if their HbA 1c levels remain unsatisfactory despite an adequate trial of metformin with insulin secretagogues. In most patients diabetes progresses and many will eventually need insulin to maintain satisfactory blood glucose levels. Efficacy and safety Phase III trials for liraglutide were initiated in February Liraglutide Effect and Action in Diabetes (LEAD) aims to recruit 3,816 patients in five randomised, controlled, double-blind studies. Trial name or Liraglutide Dose-Response Study NN International Study code Sponsor Novo Nordisk Novo Nordisk Status Published 9 Published 10 Location USA Scandinavia and UK Design Multicentre, randomised, double-blind, parallel-group, double-dummy trial Multicentre, randomised, double-blind, parallel-group, placebo-controlled trial Participants in trial n=210 patients with type 2 diabetes, with at least 3 months previous treatment with oral anti-diabetic monotherapy, BMI kg/m 2 and HbA 1c 10%. Randomised to liraglutide (0.045, with open-label comparator arm n=193 patients with type 2 diabetes, BMI 40 kg/m 2, treated with diet or oral hypoglycaemic agent (OHA), HbA 1c 9.5% (OHA) or % (diet). Randomised to liraglutide (0.045, 0.225, 0.45, 0.60, or 0.75mg) April

4 0.225, 0.45, 0.6 or 0.75mg) or metformin 1000mg twice a day for 12 weeks after a 4-week metformin run-in period. 179 (85%) completed the study. Follow-up Visit at week weeks Outcome(s) Bodyweight; glycaemic control (fasting plasma glucose (FPG) & HbA 1c ); serum insulin & C-peptide levels Key results Major adverse effects HbA 1c : mean HbA 1c change from baseline for 0.045, 0.225, 0.45, 0.6, 0.75mg liraglutide and metformin were +1.28%, +0.86%, +0.22%, +0.16%, +0.30% and +0.09% respectively. No significant differences in HbA 1c were observed between liraglutide and metformin groups at the 3 highest liraglutide doses. FPG: for changes from baseline, there were modestly increased FPG values in the higher dose liraglutide groups and little change in the metformin group. Fasting serum insulin: except for the 0.045mg liraglutide group, 12 weeks of liraglutide treatment resulted in an increase of fasting serum insulin levels. Bodyweight change: after 12 weeks, metformin group had a weight loss of -0.61% (p=0.124 relative to baseline) and 5 liraglutide groups had weight loss ranging from -0.05% (0.045mg, p=0.825 relative to baseline) to -1.87% (0.225mg, p=0.006 relative to baseline). The percentage of weight change in the 5 liraglutide dosage groups was not significantly different from metformin. C-peptides: Increases in C-peptide levels were significantly different from metformin for 0.75mg liraglutide. Episodes of nausea and/or vomiting were reported by 11 patients (6.3%) receiving liraglutide and 3 (8.8%) receiving metformin. No major hypoglycaemic events were reported during the trial. or placebo, or to the open-label reference group (a sulphonylurea - glimepiride, 1-4mg) for 12 weeks. 190 were included in the intention-totreat analysis. HbA 1c (primary); fasting serum glucose, weight, islet cell function HbA 1c : decreased in all but the lowest liraglutide dosage group. HbA 1c reduction of 0.70, 0.75 and 0.74% was seen for the 0.60, 0.75mg liraglutide groups and glimepiride group respectively (p=0.0002, < & compared to placebo respectively). Fasting serum glucose: statistically significant decreases for the 0.225, 0.60 and 0.75mg liraglutide dosage groups compared to placebo. The effect of the highest dosages of liraglutide was comparable to glimepiride. Body weight: A statistically significant decrease was observed in the 0.45mg compared to placebo (-1.2kg, p=0.0184) Islet cell function: mean β-cell function was significantly higher in the 0.75mg liraglutide group after 12 weeks than in the placebo group. No differences were seen among the 3 treatments for insulin resistance. Proinsulin-to-insulin ratio decrease was statistically significant after treatment with liraglutide 0.75mg compared with placebo. No change in the proinsulin-to-insulin ratio was seen after glimepiride treatment. No statistical differences for fasting insulin, C-peptide and glucagon were seen between liraglutide and placebo. Gastrointestinal events nausea, diarrhoea and constipation were reported in the liraglutide groups, but not the placebo or glimepiride groups (except one patient vomiting in the glimepiride group). Trial Liraglutide vs placebo Liraglutide and metformin Status Abstract 11,12 Published 13 Location Europe & Australia April

5 Design Randomised Multi-centre, randomised, placebocontrolled, double-blind Participants in trial n=165 patients with type 2 diabetes, treated with diet or single oral antidiabetic agents (after 4 weeks washout) were randomised to liraglutide (0.65mg, 1.25mg or 1.9mg) or placebo once daily. n=144 patients with type 2 diabetes on metformin, treated with at least 50% of maximum dose of one or two oral hypoglycaemic agent(s) for at least 3 months, BMI kg/m 2, HbA 1c 8-13% & FPG>10mmol/l. Randomised to (1) continuation of metformin monotherapy and placebo liraglutide, (2) addition of liraglutide, (3) addition of glimepiride, (4) liraglutide monotherpay and metformin placebo. Primary outcome HbA 1c Fasting serum glucose Secondary Body weight HbA 1c, body weight outcomes Key results Significant improvement in HbA 1c was seen with liraglutide versus placebo (p<0.0001), with an estimated difference versus placebo of -1.74% with the 1.9mg dose. An HbA 1c 7.0% was achieved by between 0.43 and 0.50 with liraglutide versus 0.08 for placebo. Dose dependent weight reduction was achieved. In the high-dose liraglutide group, change in body weight was -2.99kg from baseline compared to -1.21kg for placebo (p=0.039). Significant reduction in systolic blood pressure & triglycerides versus placebo was seen with liraglutide. Major adverse effects Main adverse events were from the GI system diarrhoea was the most frequent, with an incidence of 19.5% and 12.5% in the high-dose liraglutide group and placebo group respectively. In the high-dose group 10% experienced nausea. Estimated cost and cost impact The cost of liraglutide is currently unknown. Adding on liraglutide to existing metformin resulted in a 3.9mM difference in fasting serum glucose in favour of liraglutide (p<0.0001). HbA 1c was significantly lowered after treatment with metformin plus liraglutide compared to metformin alone (0.8%, p<0.001). Significant difference in the reduction in body weight between patients in the metformin plus liraglutide group compared to metformin plus glimepiride group (-2.9kg; p<0.0001). Nausea was most frequently reported adverse event following liraglutide therapy and was transient in nature. Approximate per annum costs for current alternatives a : Metformin - 50 (2g per day dose) Sulphonylureas e.g. glipizide 162 (maximum dose of 20mg per day) Glitazone e.g. pioglitazone (45mg per day) Insulin glargine ( 26 for 1,000 IU vial at 40 IU per day) a British National Formulary, no. 52, Sep 2006 April

6 Potential or intended impact speculative Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Other: Services Increased use e.g. length of stay, Service reorganisation required out-patient visits Decreased use e.g. shorter length of stay, reduced Other: referrals Staff or training required Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: References 1 National Institute for Clinical Excellence. Inherited Clinical Guideline G. Management of type 2 diabetes: Management of blood glucose National Institute for Health and Clinical Excellence. Diabetes (type 1 and 2) inhaled insulin. Date issued December TA National Institute for Clinical Excellence. Guidance on the use of glitazones for the treatment of type 2 diabetes. London. National Institute for Clinical Excellence. August National Institute for Clinical Excellence. Guidance on the use of long-acting insulin analogues for the treatment of diabetes insulin glargine. London. National Institute for Clinical Excellence. December Diabetes UK. Reports and Statistics. Diabetes prevalence Accessed on 26 th March National Institute For Health and Clinical Excellence. Final scope for type 2 diabetes guideline. June Marshall SM & Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. BMJ 2006; 333: Diabetes Mellitus an update for healthcare professionals. British Medical Association Feinglos MN, Saad MF, Pi-Sunyer FX, An B & Santiago O on behalf of the Liraglutide Dose-Response Study Group. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabetic Medicine 2005;22: Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR on behalf of the NN International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after oncedaily treatment with the long-acting glucagons-like peptide 1 analog liraglutide (NN2211). Diabetes Care 2004:27: Vilsboll T et al. Liraglutide significantly improves glycemic control, and lowers body weight without risk of either major or minor hypoglycaemic episodes in subjects with type 2 diabetes (abstract). American Diabetes Association (ADA) annual meeting Oral presentation. 12 Vilsboll T et al. Liraglutide treatment, blood pressure and biomarkers of cardiovascular risk in patients with type 2 diabetes: 14 weeks monotherapy study (abstract). American Diabetes Association (ADA) annual meeting Poster presentation. 13 Nauck MA, Hompesch M, Filipczak R et al. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes 2006; 114: April

7 The is a constituent of the NHS National Institute for Health Research and is managed under contract from the Department of Health's R&D Division. The views expressed in NHSC publications are those of the author(s). They are not necessarily shared by the Department of Health and should not be taken as representing Government policy. The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) April