NICE unable to recommend dapagliflozin for type 2 diabetes and requests more information from the manufacturer

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NICE unable to recommend dapagliflozin for type 2 diabetes and requests more information from the manufacturer

In draft guidance published today (1 February), NICE is minded not to recommend dapagliflozin (Forxiga, Brstol-Myers Squibb and Astra Zeneca) in combination therapy for treating type 2 diabetes.

NICE is requesting further clarification and information from the manufacturers ahead of the second Appraisal Committee meeting in Marchi.

Dapagliflozin (Forxiga, Bristol-Myers Squibb and AstraZeneca) works by blocking the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. It has a UK marketing authorisation in adults aged 18 years and older 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 use of metformin is considered inappropriate due to intolerance
  • add-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.

The subject of this appraisal is the add-on combination therapy indication.

In considering the evidence on the clinical effectiveness of dapagliflozin as add-on therapy to insulin, the Committee noted that the evidence came from two placebo-controlled clinical trials, one of which was of short duration (only 12 weeks), and an additional network meta-analysis. The clinical effectiveness of dapagliflozin compared with other active treatments that might be added on to insulin was based on the manufacturers' network meta-analyses, and the Committee concluded there was significant uncertainty about the validity of the results.

For dapagliflozin as an add-on to metformin, the Committee noted that the evidence came from three clinical trials and a network meta-analysis. Only one of these clinical trials of dapagliflozin had an active comparator (sulfonylurea) and the clinical effectiveness of dapagliflozin compared with DPP-4 inhibitorsiii, thiazolidinedionesivand GLP-1 analoguesv was based solely on network meta-analysis.

The Committee concluded that there was significant uncertainty about the validity of the results of the network meta-analyses, and requested that the manufacturers provide a revised analysis and to submit the programme code along with the trial data used for each analysis.

The Committee considered that the ICERs for dapagliflozin in combination therapy compared with other anti-diabetic drug therapies presented by both the manufacturers and the Evidence Review Group (ERG), although all below £30,000 per QALY gained, were obtained from an economic model that could not be adequately replicated by the DSU. The Committee also noted that these ICERs were obtained from analyses that did not account for their concerns about the network meta-analysis or the utility values applied to changes in weight, hypoglycaemic events and urinary tract and genital infections.

Professor Carole Longson, Health Technology Evaluation Centre Director at NICE said: "Type 2 diabetes is a serious problem in the UK and it is important that there is a range of different treatment options available. Unfortunately the Appraisal Committee is currently unable to recommend dapagliflozin, one of the options, for the treatment of this condition. They have requested further information from the manufacturer, which will be considered at the next Appraisal Committee meeting in March."

NICE has not yet issued final guidance to the NHS; these decisions may change after consultation.

Until NICE issues final guidance, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its guidance on a technology it replaces local recommendations across the country.

Final guidance is likely to be published in June 2013.

Ends.

Notes to Editors

References

i. This information should include:

  • A response to the report produced by the Decision Support Unit (DSU)ii. This should include explanations about the reproducibility of the model and the stability of the results.
  • Revised network meta-analyses for dual therapy and add-on to insulin therapy. This should include the code used for each analysis, and the individual trial data used for each comparison in each analysis.
  • Further explanation of how changes in weight are modelled over time for the different treatments, and further justification for differences assumed between lines of therapy.
  • Further clarification of the sources of the treatment-related adverse events and discontinuation rates included in the economic model.
  • Further clarification of how the effect of treatment on risk factors (including HbA1c, systolic blood pressure and body mass index [BMI]) evolves in the economic model and the impact of this on how long these effects are maintained in the model.
  • A review of utility values associated with urinary tract and genital infection, with further justification for the values chosen.

ii. The Decision Support Unit was commissioned by NICE to examine the economic model submitted by the manufacturers. The DSU was asked to report on whether the model functioned as described in the manufacturers' submission, to report any important aspects of the model that were not described in the submission, to examine whether the C++ programming code followed the steps described by the manufacturers and used the data described in the submission, and to check that the economic model produced the results described in the submission. For further information on the NICE Decision Support Unit, please go to: http://www.nicedsu.org.uk/

iii. DPP-4 inhibitors lower blood sugar levels by blocking an enzyme known as dipeptidyl peptidase IV (DPP-4), which is responsible for breaking down the proteins that stimulate the insulin-producing cells, and slow gastric emptying time after a meal.

iv. Thiazolidinediones work by reducing insulin resistance and improving insulin sensitivity, allowing the insulin that the body produces to work more effectively.

v. Glucagon-like peptide analogues are a class of drugs that mimic the hormone glucagon-like peptide (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation after meals. GLP-1 regulates glucose levels by stimulating insulin production and secretion, and by suppressing glucagon secretion, gastric emptying and appetite.

About the guidance

1. The draft guidance (appraisal consultation document / ACD) can be found from Friday 1 February on the NICE website.

Embargoed copies are available on request; please contact the press office.

2. Closing date for comments is Friday 22 February 2013. The second appraisal committee meeting is on Tuesday 5 March 2013. Final guidance is expected in June 2013.

3. Dapagliflozin has a UK marketing authorisation 'in adults aged 18 years and older 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 use of metformin is considered inappropriate due to intolerance
  • add-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.

The subject of this appraisal is the add-on therapy indication.

4. The manufacturers' submission states that the cost of dapagliflozin is £36.59 for 28 5-mg or 10-mg tablets (excluding VAT). Dapagliflozin is administered orally as a single dose of 10 mg per day. Costs may vary in different settings because of negotiated procurement discounts.

5. The Committee recommends that NICE requests further analyses from the manufacturers, which should be made available for the second Appraisal Committee meeting, and should include the following:

  • Revised network meta-analyses for dual therapy and add-on to insulin therapy. This should include the programme code used for each analysis, and the individual trial data used for each comparison in each analysis.
  • For the dual therapy cost-effectiveness analyses, the same baseline characteristics and risk factors should be used for each analysis.
  • For all cost-effectiveness analyses, the model should apply the same baseline risk factors for both treatment groups rather than the baseline value minus the treatment-specific effect.
  • For all cost-effectiveness analyses, the decision to switch or intensify treatment in the model should be based on HbA1c levels that are currently recommended in Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87) rather than from the clinical trials included in the submission.
  • For the triple therapy cost-effectiveness analyses, the sequence of treatments should be revised so that the starting treatment is triple therapy rather than dual therapy.
  • The changes proposed by the Evidence Review Group:
    • reducing the loss in utility associated with hypoglycaemia to −0.012 for a severe event and −0.004 for a symptomatic event
    • reducing the annual cost of pioglitazone to £112.18
    • including an annual cost of £483 for people not experiencing diabetic complications and
    • a disutility associated with weight gain and loss of ±0.0061 per unit of BMI.
  • Changes to the model as a result of responding to the DSU report and the revised network meta-analyses.
  • Analyses using the upper and lower estimates of utility values associated with urinary tract and genital infections identified in the review requested in recommendation 1.2.

Analyses should be presented including disaggregated lifetime predicted events per person, disaggregated costs per person and mean surrogate values at model termination. No other changes should be made to the model.

A comparison should also be provided of the results for the analyses requested in recommendation 1.3 with the results that would have been obtained from using the CORE model for all relevant comparisons in dual therapy, insulin add-on therapy and triple therapy, and an explanation of any reported differences.

6. A patient access scheme has not been submitted by the manufacturer.

7. Type 2 diabetes is a long-term (chronic) condition that occurs when the body does not produce enough insulin for it to function properly, or when the body's cells do not use insulin properly. Insulin is a hormone made by the pancreas, and is central to regulating carbohydrate and fat metabolism in the body.

8. Diabetes currently affects almost 3 million people in the UK, of which about 90% will have type 2 diabetes. This is estimated to rise to 5 million - that is, nearly 10% of the population - by 2025. (Diabetes UK).

9. Diabetes is a major risk factor for cardiovascular disease and stroke among people of working age. An estimated 850,000 people in the UK may have diabetes but don't know it and may remain undiagnosed. Many more may have blood glucose levels above the normal range, (impaired glucose regulation) but not high enough for a diabetes diagnosis. (Diabetes UK).

10. Dapagliflozin is accepted for restricted use within NHS Scotland as a treatment option of type 2 diabetes in adults aged 18 and over.

11. For further details on NICE technology appraisals, please see the NICE website

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