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Insulin degludec/ aspart (DegludecPlus) for type 2

January 2011

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.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

January 2011

Insulin degludec/ (DegludecPlus) for

Target group • Type 2 diabetes mellitus: uncontrolled – second line, monotherapy or add-on therapy to oral anti-diabetes drugs (OADs).

Technology description Insulin degludec/insulin aspart (DegludecPlus; NN 5401; SIAC; soluble insulin analogue combination; IDegAsp) is a combination of the long-acting basal insulin, insulin degludec, with the short-acting bolus insulin, insulin aspart. In phase III trials the combination has included 70% degludec and 30% aspart.

Insulin degludec (NN1250; SIBA; soluble insulin basal analogue) is a neutral, soluble, long-acting insulin analogue intended for basal insulin treatment of diabetes mellitus. Insulin degludec forms soluble multi-hexamers upon subcutaneous (SC) injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation providing an ultra-long and steady action profile. Insulin aspart is a fast- acting, short duration analogue of human insulin, available for clinical use in the UK, and is normally used in combination with a longer-acting insulin or insulin analogue. Recognised side-effects include: variable blood levels, tremour, tiredness, headache, nausea and palpitation1.

In phase III clinical trials, insulin degludec/insulin aspart was administered via SC injection at an individually adjusted dose, once daily with a meal. Insulin degludec/insulin aspart is also in phase III trials for mellitus.

Innovation and/or advantages If licensed, insulin degludec/insulin aspart may provide an additional injectable treatment option for this patient group who are not adequately controlled on either oral therapy or basal insulin regimens.

Developer Novo Nordisk.

Availability, launch or marketing dates, and licensing plans In phase III clinical trials.

NHS or Government priority area This topic is relevant to the National Service Framework for Diabetes (2007).

Relevant guidance 2 • NICE Technology Appraisal. for the treatment of type 2 diabetes. 2010 . • NICE Technology Appraisal. Guidance on the use of long-acting insulin analogues for the treatment of diabetes - . 20023. • NICE Clinical Guideline. Type 2 diabetes: the management of type 2 diabetes. 20094. • NICE Clinical Guideline. Diabetes in : management of diabetes and its complications from preconception to the postnatal period. 20075. 6 • Clinical Knowledge Summaries. Insulin therapy - type 2 diabetes. 2010 . 7 • SIGN. Management of diabetes. 2010 . • National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). 20088. 2 January 2011

9 • Clinical Knowledge Summaries. Diabetes type 2 - Management. 2008 . 10 • International Diabetes Federation. Global guideline for type 2 diabetes. 2005 .

Clinical need and burden of disease The prevalence of diabetes in the UK is increasing, but not accurately known, and varies with factors including age, ethnic group and social deprivation7. In England, the prevalence of diabetes (diagnosed and undiagnosed) in adults is estimated to be 7.4%11,a, which equates to 3,009,853 people above the age of 16 years10. In Wales, prevalence is estimated to be 9%b equating to 218,956 people above the age of 16 years 12. More than 85% of people with diabetes are expected to have type 2 diabetes3 and in 2009 it was estimated that there were 821,800 adults with diabetes who were not diagnosed13. Prevalence of diabetes among adults is estimated to rise to 8.5% by 2020 and 9.5% by 203012.

In England in 2005, there were 26,300 deaths between the ages of 20 and 79 years which were attributable to diabetes (11.6% of all deaths in this age group)14. However, clinical coding practice means that only a minority of deaths among people with diabetes from causes that can be associated with the disease have diabetes identified as the primary cause of death13. Life expectancy is reduced by up to 10 years in this patient group15. Cardiovascular disease is a common complication of type 2 diabetes and is a significant cause of morbidity and premature death, accounting for around 60% of all deaths from diabetes16. Other long-term complications associated with diabetes include: nephropathy, retinopathy and neuropathy, leading respectively to renal failure, reduced vision or blindness and foot ulceration and amputation.

Existing comparators and treatments Current treatment options include4, 8: Oral anti-diabetes drugs (alone or in combination): • . • : , , , , . • Alpha-glucosidase inhibitors: . • (glitazones): (EMA suspended marketing authorisation in September 2010), (becoming generic in 2011). • DPP-4 inhibitors: , , . Injectable drugs: • (twice daily SC). • Liraglutide (once daily SC). • Insulin (human or analogue).

Current practice is that treatment should aim to achieve the target glycated haemoglobin (HbA1c) level of 6.5% for the first 2 treatment steps, or 7.5% if further treatment steps are required or where there is severe risk of hypoglycaemia.

Efficacy and safety Trial NCT00614055, NN5401-1791; two dose BOOST, NCT01045707, NN5401- levels of insulin degludec/insulin aspart 3590; insulin degludec/insulin aspart vs insulin glargine, all in combination vs insulin glargine, both combined with metformin; phase II. with metformin; phase III. Sponsor Novo Nordisk. Novo Nordisk. a Uncertainty limits 5.3%-10.8%. b Uncertainty limits 6.9%-11.9%. 3 January 2011

Status Complete but unpublished. Ongoing. Source of Trial registry17, oral presentation18. Trial registry19. information Location EU. EU, USA and other countries. Design Randomised, active-controlled. Randomised, active-controlled. Participants and n=178; adults; type 2 diabetes mellitus; n=529; adults; type 2 diabetes mellitus schedule insulin naïve; stable treatment regimen ≥6 months; insulin naïve; treatment of 1 or 2 OADs for ≥2 months. with metformin and 1 or 2 additional All patients receive metformin 1.5- OADs ≥3 months prior to trial entry. 2g/day. Randomised to formulation 1 Randomised to insulin (70% degludec) or 2 (55% degludec) of degludec/insulin aspart; or insulin insulin degludec/aspart SC once daily; glargine, both individually adjusted SC or insulin glargine SC once daily. All dose, once daily with morning meal. doses individually adjusted. Follow-up Active treatment period 16 weeks. Active treatment period 26 weeks. Primary HbA1c. HbA1c. outcome Secondary Plasma glucose profiles; hypoglycaemic Plasma glucose. outcome episodes; AEs. Key results HbA1c decreased from 8.4% to 7.0% in Insulin degludec/insulin aspart showed all groups. 20 hypoglycaemic episodes no inferiority in lowering HbA1c, with reported in the insulin degludec/insulin a higher rate of hypoglycaemia aspart groups and 12 in the insulin (statistically significant) and lower rate glargine group. Doses of insulin were of nocturnal hypoglycaemia compared smaller in the insulin degludec/aspart to insulin glargine. groups compared to the insulin glargine group (0.38 vs 0.45 units/kg). Adverse effects Reportedly very few, mild AEs. No reported differences between (AEs) treatment groups.

Trial NCT01169766, NN5401-3726; insulin BOOST, NCT01045447, NN5401- degludec/aspart vs insulin glargine; 3593; insulin degludec/aspart vs phase III, extension to trial insulin glargine; phase III. NCT01045707. Sponsor Novo Nordisk. Novo Nordisk. Status Ongoing. Completed. Source of Trial registry20. Trial registry21. information Location EU, USA and other countries. EU, USA and other countries. Design Non-randomised, active-controlled. Randomised, active-controlled. Participants and n=335; adults; type 2 diabetes mellitus; n=465; adults; type 2 diabetes mellitus schedule completed trial NCT01045707. ≥6 months; stable treatment regimen Patients continued treatment regimen with basal insulin once daily and allocated in previous trial. All doses metformin with or without additional individually adjusted. OADs ≥3 months prior to trial entry, and continuing throughout trial. Randomised to insulin degludec/aspart; or insulin glargine, both individually adjusted SC dose, once daily with main meal. Follow-up Active treatment period 26 weeks (52 Active treatment period 26 weeks. week total). Primary AEs; hypoglycaemic episodes. HbA1c. outcome Secondary HbA1c. Plasma glucose profile. outcome 4 January 2011

Key results - Insulin degludec/aspart showed no inferiority in lowering HbA1c, higher rate of hypoglycaemia (p<0.05) and lower rate of nocturnal hypoglycaemia (p<0.05) compared to insulin glargine. Expected May 2011. - completion date Adverse effects - No reported differences between (AEs) treatment groups.

Trial BOOST, NCT01059812, NN5401-3597; BOOST, NCT01009580, NN5401- insulin degludec/aspart vs biphasic 3592; insulin degludec/aspart vs insulin aspart 30; phase III. biphasic insulin aspart 30; phase III. Sponsor Novo Nordisk. Novo Nordisk. Status Ongoing. Completed. Source of Trial registry22. Trial registry23. information Location Hong Jong, Japan, Malaysia, Republic EU, Australia and other countries. of Korea and Taiwan. Design Randomised, active-controlled. Randomised, active-controlled. Participants and n=424; adults; type 2 diabetes mellitus n=384; adults; type 2 diabetes mellitus schedule ≥6 months; stable insulin based ≥6 months; stable insulin based treatment regimen with or without treatment regimen with or without metformin for ≥3 months. metformin or other OADs for ≥3 Randomised to insulin degludec/aspart; months. or biphasic insulin aspart 30. Both Randomised to insulin individually adjusted SC dose, twice degludec/aspart; or biphasic insulin daily with morning and evening meal. aspart 30. Both individually adjusted SC dose twice daily with morning and evening meal. Follow-up Active treatment period 26 weeks. Active treatment period 26 weeks. Primary HbA1c. HbA1c. outcome Secondary Plasma glucose profiles; hypoglycaemic Plasma glucose profiles; outcome episodes; body weight. hypoglycaemic episodes. Expected Feb 2011. Feb 2011. reporting date

Estimated cost and cost impact The cost of insulin degludec/aspart is not yet known. The cost of other selected type 2 diabetes mellitus treatments are24:

Drug Dose Unit cost Insulin glargine 1-100 units, individually adjusted £26.00 for 100 units. (Lantus) dose. Biphasic insulin 1-60 units, individually adjusted £32.00 for 5 x 3ml prefilled disposable aspart (NovoMix dose. injection devices. 30) Metformin 1.5-2g/day. £1.61 for 84 500mg tab pack.

Claimed or potential impact – speculative

Patients Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease 5 January 2011

Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings:  Other: uncertain unit cost compared to alternative therapies

Other issues Clinical uncertainty or other research question identified:  None identified

References

1 Electronic Medicines Compendium (eMC). http://www.medicines.org.uk/EMC. Accessed 22 December. 2 National Institute for Health and Clinical Excellence. Liraglutide for the treatment of type 2 diabetes. Technology appraisal TA203. London: NICE October 2010. 3 National Institute for Health and Clinical Excellence. Guidance on the use of long-acting insulin analogues for the treatment of diabetes - Insulin glargine. Technology appraisal TA53. December 2002. 4 National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes. Clinical guideline CG87. London: NICE; May 2009. 5 National Institute for Health and Clinical Excellence. Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the post-natal period. Clinical guideline CG63. London: NICE; March 2008. 6 NHS Clinical Knowledge Summaries. Insulin treatment – type 2 diabetes – management. November 2010. http://www.cks.nhs.uk/insulin_therapy_type_2_diabetes. 7 Scottish Intercollegiate Guidelines Network (SIGN). National clinical guideline 116. Management of diabetes. March 2010. Edinburgh: SIGN; www.sign.ac.uk. 8 National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians, 2008. 9 NHS Clinical Knowledge Summaries. Diabetes type 2- Management. December 2008. http://www.cks.nhs.uk/diabetes_type_2. 10 International Diabetes Federation. Global guideline for type 2 diabetes. 2005. 11 Yorkshire and Humber Public Health Observatory. Diabetes Prevalence Model for England http://www.yhpho.org.uk/default.aspx?RID=81090 Accessed 6 January 2011. 12Yorkshire and Humber Public Health Observatory. Diabetes Prevalence Model for Wales http://www.yhpho.org.uk/default.aspx?RID=81090 Accessed 6 January 2011. 13 Yorkshire and Humber Public Health Observatory. Diabetes Prevalence Model: Key findings for England. YHPHO: June 2010. 14 Yorkshire and Humber Public Health Observatory. Diabetes attributable deaths; estimating the excess deaths among people with diabetes. YHPHO: May 2008. 15 Marshall S and Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. British Medical Journal 2006;333:475-480. 16 British Medical Association. Diabetes mellitus an update for healthcare professionals. London:2004. 17 Clinicaltrials.gov. Comparison of two NN5401 formulations versus insulin glargine, all in combination with metformin in subjects with type 2 diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT00614055?term=NN5401&rank=11 Accessed 13 December 2010. 18 Heise T, Nosek L, Ronn BB et al. Once-daily use of a new generation ultra-long acting basal insulin with a bolus boost in insulin naive people with type 2 diabetes: comparison with insulin glargine. Oral presentation no. 34-OR, presented at the American Diabetes Association (ASA) Scientific Sessions 2010, Orlando, Florida. June 2010. 19 Clinicaltrials.gov. Comparison of NN5401 versus insulin glargine, both combined with metformin treatment, in subjects with type 2 diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT01045707?term=nct01045707&rank=1 Accessed 13 December 2010.

6 January 2011

20 Clinicaltrials.gov. Comparing safety and efficacy of NN5401 with insulin glargine in subjects with type 2 diabetes: an extention to trial NN5401-3590. Available at: http://clinicaltrials.gov/ct2/show/NCT01169766?term=NCT01169766&rank=1 Accessed 13 December 2010. 21 Clinicaltrials.gov. Comparison of NN5401 with insulin glargine, both in combination with oral antidiabetic drugs, in subjects with type 2 diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT01045447?term=NCT01045447&rank=1 Accessed 13 December 2010. 22 Clinicaltrials.gov. Comparison of NN5401 with biphasic insulin aspart 30 in type 2 diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT01059812?term=nct01059812&rank=1 Accessed 13 December 2010. 23 Clinicaltrials.gov. Comparison of NN5401 with biphasic insulin aspart 30 in type 2 diabetes. Available at: http://clinicaltrials.gov/ct2/show/NCT01009580?term=nct01009580&rank=1 Accessed 13 December 2010. 24 British Medical Association and Royal Society of Great Britain. British National Formulary. No. 60, BMJ Group and RPS Publishing. London; September 2010.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

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