National Institute for Health and Care Excellence (NICE) publishes positive Final Appraisal Determination (FAD) for FORXIGA® (dapagliflozin)

Adult patients in England and Wales to gain access to first-in-class Type 2 diabetes treatment.

The National Institute for Health and Care Excellence (NICE) today issued a Final Appraisal Determination (FAD) for Bristol-Myers Squibb and AstraZeneca’s, first-in-class Type 2 diabetes medicine FORXIGA® (dapagliflozin).

NICE recommends the use of dapagliflozin as a treatment option for adults with Type 2 diabetes as dual therapy in combination with metformin, and in combination with insulin with or without other oral antidiabetic drugs.1 Currently in the UK, more than one million patients are on either metformin alone or insulin.2

The FAD recommends dapagliflozin to be used in combination with metformin instead of a sulphonylurea (SU) in certain patients. These are patients for whom an SU is not tolerated / contraindicated or are at significant risk of hypoglycaemia or its consequences. Furthermore, the addition of dapagliflozin to metformin may be preferable to a thiazolidinedione if further weight gain is a concern. This is in line with NICE guidance CG87 in relation to the use of dipeptidyl peptidase-4 (DPP-4) inhibitors in dual therapy with metformin. 3

The FAD, which will form the basis of final NICE guidance, follows Marketing Authorisation issued on 14 November 2012 by the European Medicines Agency (EMA) and advice from the Scottish Medicines Consortium (SMC) on 14 January 2013. 4 The NICE recommendation means that adults with Type 2 diabetes who are not being managed on metformin alone or insulin will soon have access to this new, cost-effective oral once-daily, first-in-class  treatment.

Professor Clifford Bailey, Professor of Clinical Science at Aston University, UK, said, "Type 2 diabetes is a complex and progressive disease with the potential for a wide range of complications.  Dapagliflozin is a once-daily tablet which is a new way to control blood glucose. It also has weight loss benefits.5,6 It works in a novel way by removing excess glucose from the body in the urine. In this way, dapagliflozin removes calories from the body.5 Dapagliflozin provides a new option for healthcare professionals and patients alike.”

Around 2.9 million people in the UK are living with diabetes,7 nearly half of whom are uncontrolled on their current treatment regimens.8 And a further 850,000 people have Type 2 diabetes but are unaware that they have the condition.9 More than 80% of people with Type 2 diabetes are overweight.10 Researchers have even coined a new term, diabesity, to acknowledge that these two conditions often coexist.11Weight gain adds to the burden of patients with Type 2 diabetes and increases the risk of cardiovascular disease.9

Gwen Hall, Diabetes Specialist Nurse, Portsmouth Community Diabetes Service, Primary Care Team, said, “I see a lot of people with diabetes who are worried about managing their blood glucose levels and who struggle to maintain a healthy weight. Some of our current therapies can carry an increased risk of hypoglycaemia, which is an additional concern for them. What people with diabetes would like is a treatment that not only effectively controls blood glucose levels but also has the secondary benefit of weight loss and, when used in combination with metformin, has a low risk of hypoglycaemia. Dapagliflozin appears to have these benefits.”

Dapagliflozin is the first in a new class of treatments called sodium-glucose cotransporter 2 (SGLT2) inhibitors,12 which work independently of insulin5. Dapagliflozin works by reducing the amount of glucose reabsorbed in the kidney and as a result, in people with Type 2 diabetes, an increased amount of glucose is passed out of the body via the urine each day, along with   the associated calories.

Unlike many other diabetes medications, dapagliflozin works in a novel way that is independent of insulin action. It therefore offers an alternative new approach for patients with Type 2 diabetes.5

Dr Malde Modhwadia, Chairman of the Trustees for the diabetes awareness charity, Silver Star Appeal, said, “We welcome NICE’s recommendation of dapagliflozin providing a new treatment option for patients living with Type 2 diabetes. Dapagliflozin works in a different way to existing treatments to lower blood glucose and may be beneficial for those many patients who also find losing weight a challenge.”

Dapagliflozin has been investigated in a comprehensive clinical development programme that assessed the safety and efficacy of the medicine as a once-daily oral therapy. These trials, which involved over 5,500 patients with Type 2 diabetes treated with dapagliflozin,13 found that it effectively lowers HbA1c and maintains glycaemic control in adults with Type 2 diabetes for two years, has the additional secondary benefit of weight loss sustained for up to two years and is generally well tolerated.5, 6

“We welcome NICE’s recommendation for dapagliflozin, the first medicine in this new class of treatment, which marks an important milestone in providing patients with Type 2 diabetes  a cost-effective new treatment option. With the incidence of diabetes continuing to increase it is important for patients to have a wider choice of options so that the treatment can be tailored to their individual needs. Our Type 2 diabetes treatment portfolio has several different classes of medicine to help patients manage this complex condition,” commented Amadou Diarra, European VP and General Manager UK and Ireland, Bristol-Myers Squibb.

National Institute for Health and Care Excellence Final appraisal determination Dapagliflozin in combination therapy for treating type 2 diabetes.

This guidance was developed using the single technology appraisal (STA) process.

Full guidance can be found on http://www.nice.org.uk from Thursday 30 May 2013.

Guidance

    • Dapagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if it is used as described for dipeptidyl peptidase-4 (DPP-4) inhibitors in Type 2 diabetes: the management of type 2 diabetes
      (NICE clinical guideline 87).
    • Dapagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes.
    • Dapagliflozin in a triple therapy regimen in combination with metformin and a sulfonylurea is not recommended for treating type 2 diabetes, except as part of a clinical trial.
    • People currently receiving dapagliflozin in a dual or triple therapy regimen that is not recommended for them in 1.1 or 1.3 should be able to continue treatment until they and their clinician consider it appropriate to stop.

SMC advice: dapagliflozin

The guidance can be accessed via
http://www.scottishmedicines.org.uk/SMC_Advice/Advice/799_12_dapagliflozin_Forxig
a/dapagliflozin_Forxiga


The SMC advice as per the official document is as follows:
ADVICE: following a full submission dapagliflozin (Forxiga®) is accepted for restricted use within NHS Scotland.

Indication under review: For use in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:

Add-on combination 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: Dapagliflozin is restricted to use as dual therapy in combination with metformin, when metformin alone with diet and exercise does not provide adequate glycaemic control and a sulphonylurea is inappropriate.

In three phase III randomised, controlled studies, dapagliflozin when added to metformin was non-inferior to a sulphonylurea in combination with metformin, and superior to placebo in terms of glycaemic control, as measured by change in HbA1c. This was accompanied by reductions in body weight and the risk of hypoglycaemia with dapagliflozin treatment was similar to placebo and lower, when compared with sulphonylurea.

In a phase III randomised, controlled study, dapagliflozin treatment, when added to an insulin-containing regimen, was associated with; greater reductions in HbA1c, in body weight; and similar rates of hypoglycaemia when compared with placebo.

The submitting companies did not present a sufficiently robust economic analysis to gain acceptance by SMC for use in addition to insulin in patients who have inadequate glycaemic control.

Dapagliflozin is also licensed for use 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. The manufacturers’ submission related only to the use of dapagliflozin when used as dual therapy in combination with either metformin or insulin. SMC cannot recommend the use of dapagliflozin as monotherapy.

The full therapeutic indication for dapagliflozin is provided below.

Dapagliflozin is indicated in adults aged 18 years and older with Type 2 diabetes mellitus to improve glycaemic control as:

      • Add-on combination therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate 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.

Dapagliflozin is not recommended for elderly patients (over 75) and in those with moderate to severe renal impairment. Dapagliflozin is not recommended for use with pioglitazone.12

For further information about dapagliflozin please see the Summary of Product Characteristics (SmPC) available from: http://www.medicines.org.uk/emc/

Up to now, the development of treatments for Type 2 diabetes has focused primarily on mechanisms that rely on the body’s own insulin, a hormone that helps to keep blood glucose at normal levels. However, as the body gradually becomes resistant to insulin, or insulin levels decline, many ‘insulin-dependent’ therapies are unable to maintain consistent blood glucose levels over time. 14,15,16 Dapagliflozin works in a novel way, independent of insulin action and via the kidney.

The kidney plays an important role in glucose balance, normally filtering and reabsorbing approximately 180g of glucose each day, with virtually all glucose being reabsorbed back into circulation. SGLT2 is a major sodium-glucose co-transporter in the kidney responsible for the re-absorption of glucose back into the blood. Selective inhibition of SGLT2 facilitates the excretion of glucose and its associated calories in the urine, thereby lowering blood glucose levels in an insulin-independent manner.

Burden of diabetes

  • Life expectancy for people with Type 2 diabetes is reduced by up to 10 years9
  • Poorly controlled Type 2 diabetes is associated with long-term complications including blindness, impotence, heart disease and stroke 9

    Risk factors
    • Studies have shown that people at risk can prevent or delay Type 2 diabetes by losing weight and increasing physical activity17
    • More than 80% of people with Type 2 diabetes are overweight at the time of diagnosis10
    • Modest weight losses of 5 to < 10 per cent are associated with significant improvements in cardiovascular disease risk factors in overweight and obese individuals with Type 2 diabetes18

Financial cost

  • It is currently estimated that 10 per cent of the NHS budget is spent on diabetes.This works out at around £9 billion a year.9
  • More than 7 million sickness days were taken due to Type 2 diabetes in 2010/2011, costing over £850 million19
  • Through better understanding and management of people with Type 1 and Type 2 diabetes, the NHS could save £170 million per year20

Bristol-Myers Squibb and AstraZeneca entered into an alliance in January 2007 to enable the companies to research, develop and commercialise select investigational drugs for Type 2 diabetes. The Bristol-Myers Squibb/AstraZeneca diabetes alliance is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of Type 2 diabetes. The diabetes alliance portfolio includes five medications across four different classes of medicines including Onglyza® (saxagliptin), part of the innovative class of DPP-4 inhibitors, Komboglyze™ (saxagliptin and metformin HCl immediate-release), Byetta®? (exenatide 5 mcg and 10 mcg solution for injection, pre-filled pens) and Bydureon®? (exenatide 2 mg powder and solvent for prolonged release suspension for injection) and Forxiga® (dapagliflozin), an SGLT2 inhibitor.

Date of preparation: May 2013 BMS: 732UK13NP04556-01
Atlas: 2694800

References

1. NICE Final Appraisal Determination: Dapagliflozin in combination therapy for treating type 2 diabetes. http://www.nice.org.uk

2. Patient Data, Cegedim Strategic Data UK Ltd, MAT Mar 2013

3. NICE short clinical guideline 87. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes
Available at: http://www.nice.org.uk/nicemedia/live/12165/44318/44318.pdf

4. Scottish Medicines Consortium (SMC) Advice on dapagliflozin. Available at: http://www.scottishmedicines.org.uk/SMC_Advice/Advice/799_12_dapagliflozin_Forxiga/dapagliflozin_Forxiga. Accessed May 2013

5. Bailey C et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial. Lancet. 2010;375(9733):2223-2233

6. Bailey CJ et al. Long-term efficacy of dapagliflozin as add-on to metformin (MET) in T2DM inadequately controlled with MET alone. Diabetes.2011;60(suppl 1):A271. Poster: American Diabetes Association (ADA): June 24-28, 2011

7. Diabetes UK State of the Nation England 2012. Available at: http://www.diabetes.org.uk/Documents/Reports/State-of-the-Nation-2012.pdf.  Accessed  May  2013

8. NHS Information Centre. Quality and Outcomes Framework. Online GP practice results database. Available at: http://www.qof.ic.nhs.uk . Accessed May 2013

9. Diabetes UK: Diabetes in the UK 2011/2012. Available at:  http://www.diabetes.org.uk/documents/reports/diabetes-in-the-uk-2011-12.pdf.  Accessed  May  2013

10. Diabetes UK. Beware the silent assassin report. October 2008 http://www.diabetes.org.uk/Documents/Reports/Silent_assassin_press_report.pdf. Accessed May 2013

11. Diabesity in Practice. The journal for healthcare professionals managing people with coexisting diabetes and
obesity. Available at: http://www.diabesityinpractice.co.uk. Accessed May 2013

12. FORXIGA Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc. Accessed May 2013

13. Ptaszynska A, Johnsson K, et al. Safety of dapagliflozin in clinical trials for T2DM. Poster 1011-P presented at the 72nd Scientific Sessions of the American Diabetes Association (ADA). 8–12 June 2012; Philadelphia, USA.

14. Komoroski B, Vachharajani N, Boulton D et al. Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects. Clin Pharmacol Ther. 2009;85(5):520-526

15. Srinivasan BT, Jarvis J, Khunti T et al. Recent advances in the management of type 2 diabetes mellitus: a review. Postgrad Med J. 2008;84:524-531

16. UK Prospective Diabetes Study (UKPDS) Group. UKPDS 16. Diabetes. 1995;44 (11): 1249-1258.

17. The American Diabetes Association. Diabetes basics: Genetics of diabetes. Available at: http://www.diabetes.org/diabetes-basics/genetics-of-diabetes.html. Accessed May 2013

18. Wing RR et al. Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals With Type 2 Diabetes. Diabetes Care. 2011 Jul;34(7):1481-6. Epub 2011 May 18

19. Hex N et al.  Estimating the current and future costs of Type 1 and Type diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabetic Medicine. 2012; 29: 855-862

20. Department of Health (2012). The management of adult diabetes services in the NHS. National Audit Office