The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using dapagliflozin in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from the NICE website.

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using dapagliflozin in the NHS in England and Wales.

For further details, see Guide to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 22 February 2013

Second Appraisal Committee meeting: 5 March 2013

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1  Appraisal Committee’s preliminary recommendations

1.1  The Committee is minded not to recommend dapagliflozin in combination therapy for treating type 2 diabetes.

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

• A response to the report produced by the Decision Support Unit (DSU). This should include explanations about the reproducibility of the model and the stability of the results.
• 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 HbA_1c, systolicblood 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.
• Further explanation of why variations in baseline characteristics and risk factors of simulated patients were not accounted for in the model.
• A review of utility values associated with urinary tract and genital infections, with further justification for the values chosen.

1.3  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-analysesfor 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 HbA_1c 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 QALYs 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
  • using utility values associated with weight change 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 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.

1.4  A comparison should also be provided of the results for the analyses requested in 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.

2  The technology

2.1  Dapagliflozin (Forxiga, Bristol-Myers Squibb and AstraZeneca) is a sodium–glucose cotransporter-2 (SGLT-2) inhibitor that blocks 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 therapy indication.

2.2  The summary of product characteristics lists the following adverse reactions for dapagliflozin: hypoglycaemia (when used with sulfonylurea or insulin), urinary tract and genital infection, back pain, dysuria, polyuria, dyslipidaemia and elevated haematocrit. Dapagliflozin is not recommended for use in people with moderate to severe renal impairment (patients with a creatinine clearance rate [CrCl] of less than 60 ml/min or an estimated glomerular filtration rate [eGFR] of less than 60 ml/min/1.73 m²) because its efficacy is dependent on renal function. Dapagliflozin is also not recommended for use in combination with pioglitazone. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  The list price of dapagliflozin is £36.59 for 28 5-mg or 10-mg tablets (excluding VAT; ‘British national formulary’ [BNF] edition 64). Dapagliflozin is administered orally as a single dose of 10 mg per day. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturers submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturers of dapagliflozin and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1  The manufacturers carried out a systematic literature search to identify all relevant trials of dapagliflozin and potential comparators in adults with type 2 diabetes. The manufacturers identified 5 randomised controlled trials of dapagliflozin (10 mg once daily): 3 of which were in patients with type 2 diabetes that is inadequately controlled on metformin alone (studies 14, 12 and 4), and 2 in patients with type 2 diabetes that is inadequately controlled on insulin with or without oral antidiabetic drugs (studies 9 and 6).

3.2  Of the 3 trials of dapagliflozin as an add-on to metformin, 2 were placebo controlled with follow-up of 24 weeks (studies 14 and 12) and 1 compared dapagliflozin with a sulfonylurea for up to 52 weeks of follow-up (study 4). The primary outcomes assessed were change in HbA_1c from baseline (studies 14 and 4) or changes in body weight from baseline (study 12). Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA_1c levels reached a specific target, change in body weight, change in blood pressure, the proportion of patients reporting hypoglycaemia, adverse reactions and tolerability. Baseline patient characteristics in the 3 trials were broadly similar: mean age 52.7–60.8 years, HbA_1c level 7.16–8.11%, body weight 86.1–92.1 kg and systolic blood pressure 126.0–135.9 mmHg.

3.3  The 2 trials of dapagliflozin as an add-on to insulin were both placebo controlled, with follow-up of 12 weeks (study 9) and 24 weeks (study 6). The primary outcome assessed was change in HbA_1c from baseline. Secondary outcomes included change in fasting plasma glucose, the proportion of patients whose HbA_1c reached a specific target, change in body weight, change in the daily dose of insulin, adverse reactions and tolerability. Baseline patient characteristics in the 2 trials were broadly similar: mean age 55.7–59.3 years, HbA_1c level 8.40–8.57%, body weight 94.5–103.4 kg and systolic blood pressure 128.9–140.6 mmHg.

3.4  In the add-on to metformin trials (studies 12 and 14), dapagliflozin was associated with a statistically significant reduction in HbA_1c compared with placebo at 24 weeks. In study 14 (n=272), reduction in HbA_1c was −0.84 for dapagliflozin versus −0.30 for placebo (p<0.0001). In study 12 (n=182), reduction in HbA_1c was −0.39 for dapagliflozin compared with −0.10 for placebo (p<0.0001). Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo at 24 weeks in study 12 (−2.96 kg versus −0.88 kg, p<0.0001)and  in study 14 (−2.86 kg versus −0.89 kg, p<0.0001). Dapagliflozin was associated with a reduction in systolic blood pressure compared with placebo at 24 weeks in both study 14 (−5.1 mmHg versus −0.2 mmHg, p value not reported) and study 12 (−2.70 mmHg versus 0.10 mmHg, p=0.06). Dapagliflozin was not associated with an increased risk of hypoglycaemia compared with placebo at 24 weeks in both studies.

3.5  In study 4 (n=814), dapagliflozin was shown to be non-inferior (based on a non-inferiority margin of 0.35%) to sulfonylurea with respect to HbA_1c at 52 weeks. Dapagliflozin was associated with a statistically significant reduction in body weight compared with sulfonylurea at 52 weeks (−3.22 kg versus 1.44 kg, p<0.0001). Dapagliflozin was associated with a statistically significant reduction in systolic blood pressure compared with sulfonylurea at 52 weeks in study 4 (−4.3 mmHg versus 0.8 mmHg, p<0.0001). Dapagliflozin also resulted in a statistically significantly lower proportion of patients experiencing at least 1 hypoglycaemic event (3.5% versus 40.8%, p<0.0001) compared with sulfonylurea by 52 weeks.

3.6  In the add-on to insulin trials, dapagliflozin was associated with a reduction in HbA_1c compared with placebo at 12 weeks (study 9) and 24 weeks (study 6). In the 12-week study (n=47), the change in HbA_1c was −0.61 for dapagliflozin versus 0.09 for placebo (p value not reported). In the 24-week study (n=387), the reduction in HbA_1c was −0.96 for dapagliflozin versus −0.39 for placebo (p<0.001). Dapagliflozin was associated with a statistically significant reduction in body weight (−1.67 kg versus 0.02 kg, p<0.0001) and systolic blood pressure (−6.9 mmHg versus −3.9 mmHg, p=0.02) compared with placebo at 24 weeks. A higher proportion of patients treated with dapagliflozin experienced at least 1 hypoglycaemic event (42.3% versus 35.0%) compared with placebo by 24 weeks. Dapagliflozin was associated with a statistically significant reduction in the calculated mean daily insulin dose (−1.16 versus 5.08 international units per day, p<0.0001) compared with placebo at 24 weeks.

3.7  The manufacturers conducted pre-planned analyses to determine if there were any variations in the clinical effectiveness of dapagliflozin for the following subgroups (as defined by the manufacturers): race, ethnicity, baseline HbA_1c, age, sex and baseline BMI. Subgroup analyses were conducted on pooled data as well some of the individual studies of dapagliflozin. The manufacturers reported that no statistically significant differences in clinical effectiveness across subgroups were observed, except for baseline HbA_1c. Dapagliflozin treatment generally resulted in greater HbA_1c reductions from baseline in people with higher baseline HbA_1c.

3.8  The manufacturers conducted network meta-analyses to compare the clinical effectiveness of dapagliflozin as an add-on to metformin or insulin with comparator therapies listed in the scope. Four outcomes were assessed: mean change in HbA_1c from baseline, mean change in weight from baseline, mean change in systolic blood pressure from baseline, and the proportion of patients experiencing at least 1 hypoglycaemic episode. Random-effects models were selected over fixed-effects models because of variations in the study characteristics. The manufacturers presented analyses that were both adjusted and unadjusted for the potential modifying effects of baseline HbA_1c.

3.9  For dapagliflozin as an add-on to metformin, the manufacturers created separate networks for the outcome of systolic blood pressure at 24 weeks (±6 weeks) and for the other 3 outcomes at 24 weeks (±6 weeks) and 52 weeks (±6 weeks). The results of the analysis at 52 weeks were not included in the cost-effectiveness analysis. For the 24-week analysis of outcomes other than systolic blood pressure, the network included dapagliflozin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, thiazolidinediones and placebo in 15 studies. For the 52-week analysis, the network included dapagliflozin, DPP-4 inhibitors, thiazolidinediones and sulfonylureas in 6 studies. For the 24-week analysis of systolic blood pressure, the network included dapagliflozin, DPP-4 inhibitors, GLP-1 analogues, sulfonylureas, thiazolidinediones and placebo in 8 studies.

3.10  The numerical results of the 24-week network meta-analyses for the add-on to metformin comparisons were provided as academic in confidence. After adjusting for baseline Hb_A1c, dapagliflozin was associated with a statistically significant reduction in Hb_A1c compared with placebo. No statistically significant differences in the change in Hb_A1c were reported between dapagliflozin and other therapies. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo, DPP-4 inhibitors, and thiazolidinediones but not compared with GLP-1 analogues. Dapagliflozin was associated with a statistically significant reduction in systolic blood pressure compared with placebo and sulfonylureas. However, no statistically significant differences in change in systolic blood pressure were reported between dapagliflozin and the other 3 drug therapies. No statistically significant differences in the risk of hypoglycaemiawere reported between dapagliflozin and other drug therapies .

3.11  For dapagliflozin as an add-on to insulin, the manufacturers conducted a single network meta-analysis for all outcomes except systolic blood pressure at 24 weeks (± 8 weeks). The network included dapagliflozin, DPP-4 inhibitors, thiazolidinediones and placebo in 4 studies. The 12-week study of dapagliflozin (study 9) and 3 other studies comparing thiazolidinediones with placebo were excluded from this analysis because they allowed up-titration of insulin to maintain glycaemic control. One of the studies identified; a study comparing thiazolidinediones with placebo, was excluded from the main analysis of mean change in HbA_1c at 24 weeks because of the higher reported baseline HbA_1c values compared with the other 3 studies. The outcome of change in systolic blood pressure at 24 weeks could not be analysed because, of the 4 identified studies, 3 either did not report changes in systolic blood pressure or involved up-titration of insulin.

3.12  Results of the 24-week network meta-analyses for the add-on to insulin comparisons were provided as academic in confidence.Dapagliflozin was associated with a statistically significant reduction in HbA_1c compared with placebo. No statistically significant differences in changes in HbA_1c were reported between dapagliflozin and DPP-4 inhibitors. When the study comparing thiazolidinediones with placebo was included as a sensitivity analysis, dapagliflozin was less effective in reducing HbA_1c compared with thiazolidinediones. Dapagliflozin was associated with a statistically significant reduction in body weight compared with placebo  and DPP-4 inhibitors and changes were reported to be similar to thiazolidinediones. Dapagliflozin was associated with a statistically significantly lower risk of experiencing a hypoglycaemic event compared with thiazolidinediones. However, no statistically significant differences were reported for the comparison of dapagliflozin with DPP-4 inhibitors and placebo.

3.13  Data on the risk of adverse reactions associated with dapagliflozin were presented using pooled results from the placebo-controlled randomised controlled trials, including dapagliflozin as monotherapy and add-on therapy. Most results presented were based on short-term studies (24 weeks). The rates of genital and urinary tract infections and volume depletion events (hypotension, hypovolaemia or dehydration) were reported as slightly higher in patients given dapagliflozin. Renal impairment or failure events were reported for a small proportion of patients (less than 1.5%) with no apparent difference between treatment groups. The manufacturers reported that the incidence of cancer was similar between patients who received dapagliflozin (1.47%) and patients who received placebo (1.35%). However, rates of bladder cancer (0.16% versus 0.03%), prostate cancer (0.34% versus 0.16%) and breast cancer (0.40% versus 0.22%) were higher in patients treated with dapagliflozin than placebo respectively. In terms of cardiovascular safety, a meta-analysis of 14 randomised controlled trials showed that dapagliflozin was not associated with an increased cardiovascular risk based on a composite end point of cardiovascular death, myocardial infarction and stroke (hazard ratio [HR] 0.79, 95% CI 0.54to 1.17).

3.14  Evidence on the clinical and cost effectiveness of dapagliflozin in triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and sulfonylurea was submitted in an addendum to address the comparisons specified in the scope. The manufacturers stated that dapagliflozin is currently being studied in an ongoing trial as a triple therapy add-on to 2 other oral agents. Therefore, data were pooled from a subset of people who were givenmetformin and sulfonylurea at baseline from 2 placebo-controlled trials (studies 18 and 19), which were designed to assess the efficacy and safety of dapagliflozin in older people (average age 63–64 years) with type 2 diabetes and cardiovascular disease. A post hoc analysis of this subset was conducted for changes from baseline in HbA_1c, weight, systolic blood pressure and hypoglycaemic events at 24 weeks (results provided as academic in confidence).

3.15  No trials of dapagliflozin compared with active comparators in triple therapy were reported by the manufacturers. Therefore, the assessment of the clinical effectiveness of dapagliflozin compared with DPP-4 inhibitors, GLP-1 analogues and thiazolidinediones was based on indirect evidence.The manufacturers did not conduct a systematic review of triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and sulfonylurea. However, they referred to a literature review about add-on therapy to metformin and sulfonylurea for type 2 diabetes produced in 2009 by the Canadian Agency for Drugs and Technologies in Health. A summary of the results of this review suggested that DPP-4 inhibitors, GLP-1 analogues and thiazolidinediones were associated with statistically significant reductions in HbA_1c compared with continued therapy with metformin and sulfonylureas. Thiazolidinediones, but not DPP-4 inhibitors or GLP-1 analogues, were associated with significant weight gain compared with metformin and sulfonylureas. The manufacturers noted that since 2009, new data have become available including studies of the DPP-4 inhibitors linagliptin and saxagliptin.

Cost effectiveness

3.16  The manufacturers submitted an economic model to evaluate the cost effectiveness of dapagliflozin for use:

• in dual therapy as an add-on to metformin in adults with type 2 diabetes for whom metformin alone (with diet and exercise) does not provide adequate glycaemic control,
• as an add-on to insulin (with or without other oral antidiabetic therapies) when the underlying treatment regimen including insulin does not provide adequate glycaemic control, and
• for use in triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and sulfonylurea.

For the add-on to metformin analysis, the comparator treatments were sulfonylureas, DPP-4 inhibitors and thiazolidinediones (pioglitazone). For the add-on to insulin analysis, the comparator treatments were DPP-4 inhibitors. For the triple therapy analysis, the comparator treatments were DPP-4 inhibitors, thiazolidinediones and GLP-1 analogues.

3.17  The manufacturers developed a simulation model run within an Excel front end but with the main calculations performed using C++ programming. The patient cohort entered the model with a set of baseline patient characteristics and modifiable risk factors that included HbA_1c, total body weight, total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio (TC:HDL) and systolic blood pressure. The value of these variables changed as the model simulation progressed, as a result of the effects of antidiabetic treatment and through natural progression, calculated from the UK Prospective Diabetes Study (UKPDS number 68) risk factor equations. The model then predicted the incidence of 7 specific macro- and microvascular events on the basis of the UKPDS 68 event risk equations. Macrovascular events predicted in the model included ischaemic heart disease, myocardial infarction, congestive heart failure and stroke. Microvascular events included amputation, nephropathy (end-stage renal failure) and blindness. The model also calculated the probability of drug-related hypoglycaemic events (non-severe and severe), other adverse events including urinary tract infections and genital infections, and treatment discontinuation caused by adverse events.

3.18  Simulated patients moved through the model in 6-month cycles over a 40-year time horizon. At the start of the model, patients were assumed to have no complications associated with type 2 diabetes. At the end of the first 6-month cycle, the UKPDS risk equations determined the probability of fatal and non-fatal complications in addition to diabetes-related deaths (myocardial infarction, congestive heart failure, stroke and amputation) and deaths from other causes (estimated separately from UK life tables). If a patient survived beyond the first cycle, they moved to the next cycle in which they remained at risk of treatment-related adverse events and long-term macro- or microvascular events. Once a diabetes-related death or death from other causes occurred, then costs, life years and quality-adjusted life years (QALYs) were updated and the simulation ended for that patient.

3.19  The model simulated a cohort of patients who received dapagliflozin (the ‘treatment’ cohort), and a cohort with the same baseline characteristics who received comparator treatments (the ‘comparator’ cohort). Simulated patients in each cohort received a particular therapy until their HbA_1c increased up to a specified threshold (representing inadequate glycaemic control), at which point they stopped therapy and moved on to the second-line therapy (assumed to be the same in both cohorts). For the metformin and insulin add-on analyses, the model included up to 2 additional therapy lines after dapagliflozin and the comparator. The manufacturers assumed that second-line therapy was metformin and insulin, and third-line therapy for the remainder of the patients’ simulated lifetime was intensified insulin (assumed to be a 50% increase from the starting dose). For the insulin add-on analysis, second-line therapy was intensified insulin for the remainder of the simulation. For the triple therapy analysis, all comparator triple therapies were assumed to be preceded by dual therapy with metformin and sulfonylurea. The manufacturers assumed that after triple therapy, all patients would receive metformin and insulin. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%.

3.20  For the metformin add-on analyses, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from study 4 for the comparison of dapagliflozin and sulfonylurea and from the manufacturers’ network meta-analysis (at 24 weeks) for all of the other comparisons.  For the insulin add-on analysis, baseline patient characteristics, clinical-effectiveness data and adverse event rates were taken from the network meta-analysis (at 24 weeks). For the triple therapy analysis, clinical-effectiveness data were drawn from a pooled analysis of a subset of patients treated with dapagliflozin in 2 clinical trials (studies 18 and 19) and the Canadian Agency for Drugs and Technologies in Health’s review of oral antidiabetic drugs as triple therapy. The manufacturers commented that the baseline patient characteristics from studies 18 and 19 were not representative of the triple therapy patient population. Therefore, baseline patient characteristics were taken from study 4 comparing dapagliflozin with sulfonylurea in patients with type 2 diabetes that is inadequately controlled on metformin alone.

3.21  The HbA_1c thresholds for switching treatment were based on baseline HbA_1c values taken from the same sources. In the metformin add-on analyses, a threshold value of 7.72% taken from study 4 was used for the comparison of dapagliflozin and sulfonylurea and a value of 8.17% from the metformin add-on network meta-analyses was used for the comparison of dapagliflozin with DPP-4 inhibitors and thiazolidinediones. In the insulin add-on analysis, a threshold value of 8.90% was used based on the insulin add-on network meta-analyses. In the triple therapy analysis, the HbA_1c threshold for switching treatment was 7.72%, taken from study 4.

3.22  The economic model included changes in weight associated with treatment. UKPDS risk equations based on BMI were included in the model. Therefore, changes in patient weight over time were converted to a BMI value based on baseline weight and height characteristics. If a treatment was associated with weight loss, this involved assumptions about how long the weight loss was maintained for along with the subsequent time until the loss of effect and return to the baseline body weight. In the dapagliflozin therapy group for the add-on to metformin and insulin analyses, weight reduction was assumed to be maintained for 2 years in the model based on 2-year extension data from the trial of dapagliflozin compared with sulfonylurea. After year 2, weight was assumed to return to its baseline value until treatment was switched in a linear trend for the dapagliflozin therapy group. After this, a natural progression in weight gain of 0.1 kg per year was assumed. Because no data were available for DPP-4 inhibitors, the same assumptions were applied. All other treatments were associated with a weight gain, which was applied in the first year, after which a natural progression in weight gain of 0.1 kg per year was assumed.

3.23  The model estimated the impact of macro- and microvascular complications of diabetes, changes in body weight and other adverse events on health-related quality of life. An age-dependent baseline utility function was derived from the Department of Health Survey for England (2003) which collected EQ-5D data from patients with no major complications. Data on the impact on health-related quality of life of diabetes complications were taken from UKPDS (number 62) except for end-stage renal disease. In the UKPDS 62, the EQ-5D questionnaire was completed by 3667 UK patients. This resulted in the following utility decrements: −0.09 (ischaemic heart disease), −0.055 (myocardial infarction), −0.108 (congestive heart failure), −0.164 (stroke), −0.28 (amputation) and −0.074 (blindness). The impact of end-stage renal disease on health-related quality of life was taken from the Health Outcomes Data Repository, a database of diabetic inpatients treated at Cardiff and Vale National Health Service Hospitals Trust, resulting in a loss in utility of −0.263. The impact of change in body weight on health-related quality of life was taken from a study of 100 Canadian patients with type 2 diabetes who completed a time trade-off exercise, which was commissioned by the manufacturers .Separate values were calculated for the changes in utility caused by a 1 unit decrease (+0.0171) or increase (−0.0472) in BMI. The impact of hypoglycaemic events on health-related quality of life was taken from a study by Currie et al. (2006) that estimated separate EQ-5D utility decrements for symptomatic, nocturnal and severe events in UK patients with type 2 diabetes. The resulting utility decrements reported in the manufacturers’ submissions were −0.042, −0.0084 and −0.047 respectively. The impact of urinary tract infections on health-related quality of life was taken from a study of urinary tract infections in ambulatory women, resulting in a utility decrement of −0.00283. In the absence of any other available data, the same utility values were used for genital infections.

3.24  The economic model included the acquisition costs of antidiabetic drugs taken from the England and Wales drug tariff (February 2012). The cost of insulin in the model was applied as a cost per kilogram of body weight per day, and therefore, varied in line with changes in patient body weight in the model simulation. The manufacturers assumed that insulin used as second- or third-line treatment in the model (with or without an oral antidiabetic) involved a 50% increase in dose over the initial starting dose in the add-on to metformin analysis, and a 25% increase in the add-on to insulin analysis.

3.25  The annual costs of macro- and microvascular diabetic complications, except for end-stage renal failure, were taken from UKPDS 65, which calculated the healthcare resource use of 3488 patients with type 2 diabetes. The UKPDS 65 study provided estimates of the first year event costs and the subsequent annual maintenance costs for patients who survived until the end of the simulation. The cost of end-stage renal failure of was based on the average annual costs of automated peritoneal dialysis taken from a separate UK-based study. The cost of a severe hypoglycaemic event was taken from a study that measured health service costs incurred by 320 patients with type 2 diabetes in Germany, Spain and the UK who had experienced at least 1 hypoglycaemic event in the previous year. It was assumed that symptomatic and nocturnal hypoglycaemic events were not associated with any treatment costs. Urinary tract infections and genital infections were associated with the cost of a GP visit (£36). The costs of renal monitoring (£39), based on a GP visit and urine sample, were also included in the first year of the model only for the dapagliflozin treatment group. Treatment discontinuation was also assumed to incur the cost of a GP visit.

3.26  The manufacturers’ base-case deterministic cost-effectiveness results for the add-on to metformin analyses found that the comparison between dapagliflozin and sulfonylurea resulted in an incremental cost-effectiveness ratio (ICER) of £2671 per QALY gained (incremental costs £1246, incremental QALYs 0.467). The comparisons between dapagliflozin and DPP-4 inhibitors and between dapagliflozin and thiazolidinediones found that dapagliflozin resulted in higher QALYs (incremental gains of 0.02 and 0.42 respectively) and lower costs (−£149 and −£60 respectively). Dapagliflozin therefore dominated both comparator treatments. For the add-on to insulin analysis, the comparison between dapagliflozin and DPP-4 inhibitors resulted in an ICER of £4358 per QALY gained (incremental costs £517, incremental QALYs 0.119). The manufacturers’ base-case deterministic cost-effectiveness results for the triple therapy analyses as add-on to metformin and sulfonylurea foundthat dapagliflozin dominated DPP-4 inhibitors, thiazolidinediones and GLP-1 analogues, resulting in lower costs and higher QALYs.

3.27  For the add-on to metformin and add-on to insulin analyses, the manufacturers conducted one-way sensitivity analyses on various model input parameters, which included varying the lower and upper 95% confidence limits for the effect of antidiabetic drug therapies on modifiable risk factors, the effect of change in BMI on utility, varying the utility decrement associated with adverse events by 10%, and varying the costs associated with adverse events by 25%. For both the add-on to metformin and add-on to insulin analyses, the ICERs for the comparisons of dapagliflozin with other antidiabetic therapies were fairly robust to the changes made in these one-way sensitivity analyses.

3.28  The manufacturers also presented a range of scenario analyses, which included: varying the HbA_1c threshold switch values, alternative BMI-related utility values, assuming no impact of hypoglycaemic events on utility, varying the duration of treatment effect on body weight, applying results of the 52-week network meta-analyses (for the add-on to metformin comparisons only), assuming no treatment discontinuation and applying alternative baseline patient characteristics.  In the first of the scenarios using alternative utility values for weight change, a utility of ±0.0061 was applied for a ±1 unit change in BMI and in the second, ±0.0038 was applied for a ±1 unit change in BMI. Both were taken from a study by Bagust et al. (2005) evaluating the impact of BMI on EQ-5D utility in patients with type 2 diabetes, and had been used in NICE clinical guideline 87 and technology appraisal 248. For the metformin add-on comparisons, the ICERs for dapagliflozin compared with sulfonylurea were £8863 and £10,514 per QALY gained respectively. Dapagliflozin remained dominant for the comparison of dapagliflozin with DPP-4 inhibitors and thiazolidinediones. For the comparison of dapagliflozin with DPP-4 inhibitors as add-on to insulin, the ICERs were also sensitive to changes to the BMI-related utility values. When changes in utility of ±0.0061 and ±0.0038 were applied, the ICERs increased to £21,171 and £32,409 per QALY gained respectively.

3.29  The manufacturers conducted a limited number of scenario analyses for the triple therapy analyses. These included reducing the impact of BMI on health-related quality of life by 10%, 50% and 100% and applying a utility loss of −0.0061 for 1 unit increase in BMI. For all analyses, dapagliflozin continued to dominate the comparator drugs except for the scenario that involved removing the impact of BMI on health-related quality of life. In this scenario, dapagliflozin was associated with lower costs than DPP-4 inhibitors but also slightly fewer QALYs, resulting in an ICER of £2,358,369 per QALY lost (incremental costs: −£109, incremental QALYs 0.000). Dapagliflozin continued to dominate thiazolidinediones and GLP-1 analogues.

3.30  Results of the probabilistic sensitivity analyses for the metformin add-on comparisons showed that, at £20,000 per QALY gained, the probability of dapagliflozin being cost effective was 100% compared with sulfonylurea, 66% compared with DPP-4 inhibitors and 100% compared with thiazolidinediones. Results of the probabilistic sensitivity analysis for the insulin-add on comparison with DPP-4 inhibitors showed that, at £20,000 per QALY gained, the probability of dapagliflozin being cost effective was 99.6%. Results of the probabilistic sensitivity analyses for the triple therapy comparisons showed that, at a maximum acceptable ICER of £20,000 per QALY gained, the probability of dapagliflozin being dominant was 75% compared with DPP-4 inhibitors, 72% compared with thiazolidinediones and 80% compared with GLP-1 analogues.

3.31  The manufacturers stated that they had conducted 2 separate validation exercises of the economic model. The first validation exercise explored whether the model was able to reproduce the observed cardiovascular outcomes reported in the UKPDS 68 study and other major trials in type 2 diabetes. The second exercise compared the results of the cost-effectiveness analysis of dapagliflozin compared with sulfonylurea as add-on to metformin using the CORE diabetes model, which has been used in Liraglutide for the treatment of type 2 diabetes mellitus (NICE technology appraisal guidance 203) and Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes (NICE technology appraisal guidance 248).

Evidence Review Group comments

3.32  The ERG commented on the scope of the appraisal and how the manufacturers addressed it in their submission. The ERG noted that the manufacturers did not include adults with type 2 diabetes that is inadequately controlled on sulfonylurea monotherapy in their submission. The ERG commented that the standard first-line monotherapy in type 2 diabetes is metformin, which is usually tolerated. The ERG noted that GLP-1 analogues were not included as a comparator in the dual therapy setting, but considered that this was appropriate because their use in dual therapy is restricted. The ERG stated that NICE clinical guideline 87 recommends the use of pioglitazone as an alternative add-on treatment to sulfonylurea in people with type 2 diabetes that is inadequately controlled by metformin. However, it also noted that there are increasing concerns about the adverse reactions associated with pioglitazone. The ERG commented that, in the triple therapy setting, DPP-4 inhibitors would be expected to given to patients before GLP-1 analogues because they are less costly and are administered orally. Overall, the ERG considered that DPP-4 inhibitors are the key comparators for dapagliflozin in both the dual therapy and triple therapy settings.

3.33  The ERG stated that the manufacturers’ approach to the systematic review of clinical evidence for dapagliflozin, which involved separate network meta-analyses for dapagliflozin as add-on therapy to metformin and as an add-on to insulin, was appropriate. The ERG noted that analyses were conducted for outcomes at 24 weeks and at 52 weeks and that studies reporting outcomes at less than 18 weeks, between 30 and 46 weeks, or greater than 58 weeks were excluded from the review. The ERG commented that it was not clear whether studies of between 30 and 46 weeks or greater than 58 weeks follow-up were identified in the review. The ERG also noted that, for the network meta-analysis of insulin add-on therapies, a post hoc amendment to the protocol was made to include studies in the range of 24 weeks ±8 weeks instead of ±6 weeks, to allow a larger number of studies to be included in the analysis.

3.34  The ERG noted that some of the network meta-analyses for changes in HbA_1c from baseline were adjusted for differences in baseline HbA_1c and that no attempt was made to adjust the analyses for any other variables. The ERG considered that the manufacturers’ approach to model selection lacked transparency and that insufficient justification was provided about whether or not adjusted results were presented. However, the ERG noted that the results of the adjusted and unadjusted analyses were reasonably similar.

3.35  The ERG commented that the manufacturers’ approach to presenting the clinical effectiveness of dapagliflozin as a triple therapy add-on to metformin and sulfonylurea was not very clear. Overall, the ERG considered that the methodology for the review of dapagliflozin in triple therapy (submitted as an addendum) was less robust than the main submission. However, the ERG acknowledged that the manufacturers had not intended to provide clinical-effectiveness data on dapagliflozin in triple therapy because of ongoing trial-based research due to report in 2013.

3.36  The ERG noted that the decision to switch or intensify treatment in the manufacturers’ economic model was based on HbA_1c levels above the thresholds currently recommended in NICE clinical guideline 87. The ERG also noted that, when the manufacturers changed the HbA_1c threshold levels in scenario analyses, along with changes to other input parameters, the ICERs for dapagliflozin increased. Overall, the ERG considered that the HbA_1c threshold levels for switching treatment applied in the model reduced its relevance to UK clinical practice.

3.37  The ERG commented that it was able to validate most of the clinical-effectiveness data used in the economic model by the manufacturers. The ERG requested further detail from the manufacturers on the sources of the treatment-related adverse events and discontinuation rates, which were provided in appendices to the main submission. However, the ERG was unable to validate the adverse event and discontinuation data provided for the dual therapy analyses.

3.38  The ERG commented that the loss in utility associated with hypoglycaemic events, taken from Currie et al. (2006), may have been too large. The ERG noted from this study that a severe hypoglycaemic event in the previous 3 months was interpreted by the authors as causing a 4.7% loss in utility (−0.047). The ERG considered that the loss in utility associated with hypoglycaemic events may have been too large when applied within the model.

3.39  The ERG commented on the appropriateness of the utility values applied to weight change in the model. It noted that the majority of QALY gains associated with dapagliflozin arose from direct impact of weight change on health-related quality of life rather than diabetic complications or adverse events. The ERG noted that in study 12, the dapagliflozin treatment group experienced a lower gain in utility (0.018 versus 0.047) compared with placebo at 24 weeks. However, when the utility estimates associated with changes in BMI were applied to the observed weight changes in study 12, the dapagliflozin treatment group experienced a higher gain in utility (0.016 versus 0.000) compared with placebo at 24 weeks. The ERG also noted that the study by Bagust et al. involved a multivariate analysis of EQ-5D utility values that controlled for the complications of diabetes and estimated a smaller change in utility (±0.0061) associated with a unit increase or decrease in BMI. The ERG considered that these alternative utility values, which were applied in the manufacturers’ scenario analyses, to be more reasonable.

3.40  The ERG noted that the weighted average annual costs of pioglitazone (£414.07), based on the England and Wales NHS drug tariff for February 2012, were substantially higher than those estimated from the November 2012 tariff (£139.16). The ERG noted that, when a reduced cost of pioglitazone was included in the model, the ICERs changed from dapagliflozin dominating thiazolidinedione (pioglitazone) to having ICERs of £3980 and £1409 for the dual therapy and triple therapy comparisons respectively. The ERG also estimated different annual costs of DPP-4 inhibitors as add-on to metformin (£450.51 as opposed to £433.57) and GLP-1 analogues as add-on to metformin and sulfonylurea (£946.26 as opposed to £886.90).

3.41  In regard to the costs of macro- and microvascular diabetic complications, the ERG noted that the UKPDS 65 study also included annual inpatient (£157) and non-inpatient (£159) costs for patients who did not experience a complication. The ERG commented that these annual costs of £483 (after inflating from 1999 to 2011 prices) should have been applied in the model for patients who did not experience a diabetic complication.

3.42  The ERG noted that, although the model cycle length was 6 months, the probabilities of macro- and microvascular events estimated from the UKPDS 68 study appeared to be for a 12-month period and that no adjustment was made for this in the model. Further, the ERG noted from the DSU report (see sections 3.51-3.54) on the economic model that the annual costs of macro- and microvascular events were not halved to correspond with the 6-month cycle length used in the model but were applied in full immediately on the event occurring. The ERG commented that this would increase the annual costs of these events by half of the annual maintenance costs associated with the event.

3.43  The ERG noted that not all of the risk equations derived from the UKPDS 68 study were implemented in the model. From this study, the model implemented the risk of mortality in the year after a diabetic complication but not the risk of mortality in subsequent years after the event. Furthermore, risk equations for fatal myocardial infarction and fatal stroke were derived from a separate UKPDS study (number 66). This resulted in the risk of fatal myocardial infarction being a function of HbA_1c and systolic blood pressure and the risk of fatal stroke being a function of systolic blood pressure only. The ERG considered that there was no obvious justification made by the manufacturers to include risk equations from this separate study. It also noted that this may have reduced the impact of HbA_1c levels and increased the impact of systolic blood pressure in the model.

3.44  The ERG noted that, in the UKPDS 68 risk equations, baseline HbA_1c was based on patients with newly diagnosed type 2 diabetes. However, the baseline HbA_1c values implemented in the model were the trial baseline value minus the treatment-specific effect on HbA_1c and therefore baseline HbA_1c values differed between treatment groups. The ERG considered that the baseline HbA_1c should have been the same for both treatment groups in the model. It noted that using different treatment-specific baseline HbA_1c values resulted in the risk factor curves for both treatment groups not converging over time, whereas if the baseline HbA_1c values had been the same for both treatment groups, the curves would have converged after the initial treatment effects. Similar considerations would apply to the other risk factors used in the UKPDS equations. Overall, the ERG concluded that the implementation of the UKPDS risk factor equations in the manufacturers’ economic model may have been incorrect.

3.45  Similarly, the ERG noted that the event equation from UKPDS 68 used to estimate congestive heart failure included BMI at diagnosis. The ERG again noted that the baseline BMI values implemented in the model were the trial baseline value minus the treatment-specific effect on BMI and therefore that baseline BMI values differed between treatment groups. Because dapagliflozin was associated with a greater reduction in body weight compared with comparator drug therapies, the ERG considered that this may have biased the risk of congestive heart failure in favour of dapagliflozin. Furthermore, because the risk of congestive heart failure was associated with an increased risk of myocardial infarction and stroke, any overestimate of the rate of congestive heart failure would also result in an overestimate of the rate of myocardial infarction and stroke, along with the associated risk of fatality.

3.46  In the triple therapy analyses, the ERG considered that it was unnecessary for the model to include a dual therapy of metformin and sulfonylurea before switching to triple therapy. Because the model structure only permitted 3 lines of treatment, this resulted in patients switching to insulin and metformin after triple therapy. Therefore, unlike the dual therapy analyses, the triple therapy analysis did not enable patients to receive intensified insulin, which is associated with higher costs and additional weight gain.

3.47  The ERG conducted a number of sensitivity analyses after amending the manufacturers’ economic model for several input parameters. The ERG adjusted the loss in utility associated with hypoglycaemic events by assuming that these events applied for 3 months rather than 12 months, resulting in a loss in QALYs of −0.012 and −0.004 for severe and symptomatic hypoglycaemic events respectively. The ERG also applied the utility values from Bagust et al. (±0.0061) for a 1 unit change in BMI. The ERG revised the average annual cost of pioglitazone from £414.07 to £112.18 and also adjusted the annual cost of all diabetic complications (including fatal events and maintenance) by −£483 to account for the annual inpatient and non-inpatient costs (taken from the UKPDS 65 study) incurred by people who did not experience a complication.

3.48  As a result of these changes, the ICER for the comparison between dapagliflozin and sulfonylurea as add-on to metformin increased to £10,925 per QALY gained. For the other add-on to metformin analyses, dapagliflozin continued to dominate DPP-4 inhibitors, whereas the comparison with thiazolidinediones resulted in an ICER of £29,001 per QALY gained. In sensitivity analyses, the ERG removed the impact of BMI on utility, that is, a utility loss of 0 for a 1 unit change in BMI. For the comparison between dapagliflozin and sulfonylurea, this increased the ICER further, to £21,767 per QALY gained. Dapagliflozin continued to dominate DPP-4 inhibitors but was dominated by thiazolidinediones, resulting in higher costs but lower QALYs. For the add-on to insulin analyses, the ICER for the comparison between dapagliflozin and DPP-4 inhibitors increased to £19,094 per QALY gained. When the impact of BMI on utility was removed, this ICER increased further, to £105,511 per QALY gained.

3.49  For the triple therapy analyses, dapagliflozin continued to dominate DPP-4 inhibitors as a result of the ERG’s changes. However, the comparison of dapagliflozin with thiazolidinediones resulted in an ICER of £11,090 per QALY gained while dapagliflozin resulted in lower costs and slightly fewer QALYs compared with GLP-1 analogues, that is, an ICER of £427,095 per QALY lost. When the impact of BMI on utility was removed, dapagliflozin resulted in lower costs and QALYs compared with DPP-4 inhibitors, that is, an ICER of £26,781 per QALY lost. However, dapagliflozin was dominated by thiazolidinediones and produced an ICER of £252,972 per QALY lost compared with GLP-1 analogues.

3.50  For the triple therapy analyses, the ERG conducted an additional sensitivity analysis which involved altering the treatment sequences in the model so that, rather than starting on dual therapy of metformin and sulfonylurea, patients started treatment with triple add-on therapy to metformin and sulfonylurea, after which they switched to insulin and metformin and then to intensified insulin. As a result of this change to the sequencing of therapies in the model, dapagliflozin was dominated by DPP-4 inhibitors, produced an ICER of £29,251 per QALY gained compared with thiazolidinediones and an ICER of £45,233 per QALY lost compared with GLP-1 analogues.

Decision Support Unit comments

3.51  The DSU 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.

3.52  The DSU identified several differences between the economic model described in the submission and the executable model provided by the manufacturers. There were some differences between the macro- and microvascular event equations and risk factor equations in the model and those described in the manufacturers’ submission. The effect of treatment on body weight was applied immediately in the model rather than gradually over the first year of treatment. All-cause mortality was not adjusted for fatal stroke and myocardial infarction events. The model did not apply the cost of renal monitoring to all patients who started treatment with dapagliflozin, although the DSU noted that this was unlikely to have a significant impact on the ICERs. There were some differences between the written submission and the model in regard to the time periods over which some of the costs and changes in utility were applied. The DSU also noted that the process used to sample from the relevant distributions in the probabilistic sensitivity analysis did not produce appropriately distributed samples, which may have underestimated the uncertainty around the QALYs estimated in the model.

3.53  The DSU identified several aspects of the executable model that were not described in the manufacturers’ submission. The probability of an event occurring in a 6-month cycle was calculated as the difference between the output of the event equation for the current time and the output of the event equation at the previous cycle. Treatment discontinuations applied in the first cycle of the model resulted in the patient switching treatment immediately without incurring costs or QALYs from the initial treatment except for the cost of discontinuation. The impact of treatment-related changes to BMI on health-related quality of life in the probabilistic sensitivity analysis was based on mean parameter values, which may have resulted in an underestimate of the uncertainty around the QALY differences estimated in the model.

3.54  The DSU commented that it was unable to reproduce the results of the probabilistic sensitivity analyses reported in the manufacturers’ submission on the basis of the C++ programming code provided. However, the ICERs generated by the DSU did not vary substantially from those reported in the submission and it was noted that these differences may have arisen because of differences in the steps taken by the DSU to set up the probabilistic sensitivity analyses. When the DSU ran the model using the C++ programming code provided for the mean parameter values (deterministic analysis), it was also unable to reproduce the results of the deterministic analyses reported in the manufacturers’ submission. Furthermore, when the DSU ran this code, it did not appear to have produced a stable estimate of the incremental QALYs after 100 runs. Finally, the DSU commented that the results generated by the programming code for the probabilistic sensitivity analyses when all parameters were set to their mean values did not match the results generated by the programming code that used mean parameter values. The DSU considered that similar results should have been produced and that this affected the confidence that could be placed on the results from the model.

3.55  Full details of all the evidence are in the manufacturer’s submission, the ERG report and the DSU report, which are available on the NICE website.

4  Consideration of the evidence

4.1  The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dapagliflozin, having considered evidence on the nature of dapagliflozin and the value placed on the benefits of dapagliflozin by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.

4.2  The Committee discussed the clinical treatment pathway for type 2 diabetes. The Committee heard from the clinical specialists that treatment for type 2 diabetes is individualised for each patient (focusing on HbA_1c reduction without weight gain or hypoglycaemia), resulting in some variation in clinical practice. However, although treatment is individualised, current UK practice broadly follows NICE guidance (NICE clinical guideline 87), which recommends a stepwise approach that includes using diet and exercise, various antidiabetic drugs and insulin. The Committee heard from the clinical specialists that each of the existing antidiabetic therapies had various advantages and disadvantages affecting their suitability for patients and that many patients do not achieve target HbA_1c levels with existing therapies. The Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia. It was noted that its use may be limited by the restrictions in the marketing authorisation, which states that dapagliflozin is not recommended for use in people with moderate to severe renal impairment. The Committee understood that a new treatment providing an additional option would be valued by clinicians.  

4.3  The Committee discussed the antidiabetic drugs that were used at each point in the treatment pathway for type 2 diabetes. The Committee heard from the clinical specialists that most people start treatment with metformin and that the use of sulfonylurea as first-line therapy is diminishing because of the associated weight gain and the high incidence of hypoglycaemia compared with other oral therapies. The Committee heard from the clinical specialists that sulfonylurea is often added to metformin as a dual therapy but if patients are unable to take sulfonylurea because of concerns about weight gain or hypoglycaemia, then thiazolidinediones (pioglitazone), DPP-4 inhibitors and GLP-1 analogues may be used. The clinical specialists also commented that the same treatments could be used in triple therapy and as add-on to insulin therapy. The Committee heard from the clinical specialists that the use of DPP-4 inhibitors was increasing and that the use of pioglitazone was decreasing because of concerns about safety. It was also aware that GLP-1 analogues were used less frequently and usually later on in the treatment pathway because they are administered by subcutaneous injection and are more costly than other antidiabetic drugs. The Committee was aware that the NICE clinical guideline Type 2 diabetes: the management of type 2 diabetes will be updated (expected publication date to be confirmed) and anticipated that changing trends in diabetes management would be addressed in the updated guidance.

4.4  The Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type 2 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job). The Committee heard from the patient experts that the potential disadvantages of dapagliflozin include more frequent urinary tract and genital infections. However, the patient experts commented that the importance of these events would vary between individual patients and that, for some patients, the higher risk of urinary or genital infections could be balanced by the lower risk of hypoglycaemia. The Committee also heard from the patient experts that because dapagliflozin causes the excretion of glucose through the urine, this may cause anxiety for some patients who understand an absence of glucose in the urine to be a sign of good diabetes management and that this may lead to non-adherence to dapagliflozin therapy. However, the clinical specialists suggested that this was a risk that could be managed by providing appropriate information to people with diabetes.

Clinical effectiveness

4.5  The Committee considered the evidence submitted by the manufacturers on the clinical effectiveness of dapagliflozin. It noted that the manufacturers had provided clinical-effectiveness data on dapagliflozin as add-on therapy to metformin but not as add-on therapy to sulfonylurea in their submission, despite clinical trial data being available. The Committee accepted that most of the patients would start on metformin monotherapy, but noted the evidence provided by the clinical specialists that a proportion of patients for whom metformin is not tolerated or is contraindicated would receive sulfonylurea monotherapy. It noted that the clinical effectiveness of dapagliflozin as an add-on to sulfonylurea appeared to be consistent with its effectiveness when used as an add-on to metformin. The Committee concluded that excluding the clinical evidence of dapagliflozin as an add-on to sulfonylurea would limit its ability to make recommendations for the whole population for which dapagliflozin is licensed.

4.6  The Committee considered the evidence on the clinical effectiveness of dapagliflozin as an add-on to metformin, noting that the evidence came from 3 clinical trials and a network meta-analysis. The Committee noted that only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylurea) and that the clinical effectiveness of dapagliflozin in dual therapy compared with DPP-4 inhibitors, thiazolidinediones and GLP-1 analogues was based solely on the manufacturers’ network meta-analysis. The Committee concluded that the comparators included in the add-on to metformin analyses were appropriate.

4.7  The Committee considered the evidence on the clinical effectiveness of dapagliflozin as add-on therapy to insulin, noting that the evidence came from 2 clinical trials and a network meta-analysis. The Committee noted that both trials were placebo controlled and that 1 of these was of 12 weeks duration only. It also noted that the clinical effectiveness of dapagliflozin as add-on therapy to insulin compared with other active treatments was based solely on the manufacturers’ network meta-analysis. The Committee was aware that the network meta-analysis excluded trials of GLP-1 analogues because they were not comparable to other trials included in the analysis. The Committee concluded that, although the consideration of the full range of comparators was restricted by the available evidence, the comparators included in the add-on to insulin analysis were appropriate.

4.8  The Committee considered the evidence on the clinical effectiveness of dapagliflozin in triple therapy. The Committee noted that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and that, in the absence of any other currently available clinical-effectiveness data, the manufacturers provided an analysis of pooled data from a subset of older patients with type 2 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin asan add-on to metformin and sulfonylurea. The Committee also noted that no direct head-to-head studies comparing dapagliflozin with other antidiabetic drugs currently exist. It was aware of the limitations that the manufacturers had highlighted about these analyses and therefore concluded that significant caution should be taken when interpreting the results of these preliminary analyses on the clinical effectiveness of dapagliflozin in the triple therapy setting.

4.9  The Committee considered the network meta-analyses submitted by the manufacturers, which provided most of the clinical-effectiveness data for the comparisons of dapagliflozin and other antidiabetic therapies. The Committee noted that the WinBUGs programme code used to run the network meta-analyses provided in the manufacturers submission differed from the code recommended by the NICE DSU (Technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials). The Committee also noted that the programme code may not have provided the correct results if all of the trials included in the network meta-analysis did not share a common treatment arm. The Committee heard from the manufacturers that the code would have been adapted for each analysis. However, the Committee considered that it was unclear which of the programme codes, provided in an appendix to the manufacturers submission, were used to run the network meta-analyses and which data from each included trial were used in these analyses. The Committee concluded that there was significant uncertainty about the validity of the results of the network meta-analyses, and requested that the manufacturers were asked to provide a revised analysis and to submit the programme code along with the trial data used for each analysis.

4.10  The Committee discussed the outcomes considered in the clinical trials and network meta-analyses, noting that the primary outcomes in the clinical trials and network meta-analysis, including changes in HbA_1c, body weight and systolic blood pressure, were intermediate rather than clinical outcomes and that these were collected over a relatively short follow-up. The Committee noted that studies including the UKPDS had then been used to provide a link between these intermediate outcomes and long term clinical outcomes including micro- and macrovascular complications. The Committee heard from the clinical specialists that there was some uncertainty about the impact of HbA_1c reduction on longer-term macrovascular complications. The Committee also heard from the manufacturers that 2-year follow-up data were available for the clinical trials of dapagliflozin but that, because most of the trials of other antidiabetic drug therapies were of 24-week duration, it was necessary that the clinical-effectiveness data used in the cost-effectiveness analysis were based on the results of the clinical trials and network meta-analyses at 24 weeks. The Committee concluded that some uncertainty remained about the impact of intermediate outcomes collected in the clinical trials on long-term diabetic complications.

4.11  The Committee considered the clinical effectiveness of dapagliflozin in dual therapy for people whose type 2 diabetes is inadequately controlled by metformin alone. The Committee noted that the clinical trial results were based on a relatively small number of patients who were given dapagliflozin at its licensed dose. However, on the basis of these clinical trial results, the Committee considered dapagliflozin to have greater efficacy than sulfonylurea for the outcomes of weight loss and systolic blood pressure reduction and similar efficacy for HbA_1c reduction. The Committee noted that on the basis of the results of the network meta-analyses, dapagliflozin appeared to have similar glycaemic control to other antidiabetic drugs but may have resulted in greater weight loss. However, the Committee concluded that, based on their concerns raised in section 4.9, a revised network meta-analysis should be provided by the manufacturers.

4.12  The Committee considered the clinical effectiveness of dapagliflozin for people whose type 2 diabetes is inadequately controlled by insulin alone. Again, the Committee noted that the clinical trial results for dapagliflozin were based on a relatively small number of patients who were treated with dapagliflozin at its licensed dose. On the basis of the results of the network meta-analyses, dapagliflozin appeared to have greater efficacy than DPP-4 inhibitors for the outcome of weight loss and similar efficacy for HbA_1c reduction. However, the Committee concluded that, based on their concerns raised in section 4.9, a revised network meta-analysis should be provided by the manufacturers.

4.13  The Committee considered the adverse events associated with dapagliflozin. It noted that the most common adverse events were urinary tract and genital infections and that these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low. It also heard from the manufacturers that, because of the mechanism of action of dapagliflozin, the clinical trials had actively sought for such infections and that only a small proportion of these infections needed treatment. The Committee also noted that the incidence of hypoglycaemia was low when dapagliflozin was added to metformin and that the currently available evidence suggested that dapagliflozin was not associated with increased risk of cardiovascular events. However, it was aware that regulatory agencies had identified some uncertainty about the risk of some cancers associated with dapagliflozin. The Committee heard from the patient experts that adverse events were a concern for patients with type 2 diabetes if they result in the need for additional drug therapies, especially for patients who are already receiving many drug therapies for their condition. However, it also recognised that a new drug therapy that was not associated with an increased risk of hypoglycaemia would also be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood. The Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that how these adverse events were included in the economic model needed further detailed consideration.

Cost effectiveness

4.14  The Committee considered the cost effectiveness of dapagliflozin as an add-on to metformin and insulin and as triple therapy in the manufacturers’ submission, and the critique and exploratory analyses provided by the DSU and the ERG. The Committee noted that the economic model submitted by the manufacturers was developed in a non-standard package (C++ programme). However, it was aware that previous models of treatments for type 2 diabetes had been developed using the CORE diabetes model which was also developed using the C++ programme (NICE technology appraisal guidance 203 and 248). The Committee acknowledged the concerns raised by the DSU that identified differences between the economic model described in the submission and the executable model provided by the manufacturers, and also identified several aspects of the executable model that were not described in the manufacturers’ submission. The Committee also expressed concern that the DSU was unable to reproduce the results of the probabilistic sensitivity analyses reported in the manufacturers’ submission. The Committee considered that these concerns raised by the DSU undermined the credibility of the manufacturers’ cost-effectiveness estimates. The Committee considered that there was significant uncertainty about whether the economic model was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type 2 diabetes. It therefore concluded that the manufacturers should be requested to respond to the issues identified in the DSU report, in particular that the results of the probabilistic sensitivity analyses when all parameters were set to their mean values did not produce similar values to those generated by the deterministic analyses that used mean parameter values.

4.15  The Committee was aware that the manufacturers provided a validation report accompanying their model, which compared the outputs of the manufacturers’ model with the CORE diabetes model. However, the Committee noted that this was limited to the comparison of dapagliflozin with sulfonylurea as add-on to metformin and only reported a selective set of outcomes. The Committee considered that, because the CORE diabetes model had been used in previous NICE appraisals of treatments for type 2 diabetes, a comparison of the outputs from the manufacturers’ model with those from the CORE diabetes model for all relevant analyses would provide reassurance about the integrity of the results, and allow a comparison with the results of the cost-effectiveness analyses conducted in previous appraisals. The Committee concluded that the manufacturers should provide a comparison of the outputs from the manufacturers’ model with those that would have been obtained from the CORE diabetes model.

4.16  The Committee discussed the cost-effectiveness analyses presented by the manufacturers, noting that these included a more restricted set of comparators than were specified in the scope. It was aware that GLP-1 analogues had been included in the network meta-analysis but then subsequently excluded from the cost-effectiveness analysis for the dual therapy analyses. The Committee considered that it would have been more appropriate for all treatments in the network meta-analysis to have been included in the cost-effectiveness analysis. However, it noted the comments from the ERG and clinical specialists that GLP-1 analogues were used in dual therapy on a restricted basis. On balance, the Committee concluded that the manufacturers had included the appropriate comparators for the cost-effectiveness analysis of dapagliflozin as an add-on to metformin.

4.17  The Committee discussed the clinical-effectiveness data that were applied in the model. The Committee noted that, for the dual therapy analyses, rather than presenting a single analysis of all relevant treatments, clinical-effectiveness data for the cost-effectiveness analysis of dapagliflozin compared with sulfonylurea were taken from the clinical trial of dapagliflozin and sulfonylurea and the results of the network meta-analyses were used for the comparison of dapagliflozin with DPP-4 inhibitors and thiazolidinediones. It heard from the manufacturers that, for the metformin add-on analyses, the trials of other antidiabetic therapies as add-on to metformin were at a fixed dose but the trials of sulfonylurea did not have a stable dose over 24 weeks. Therefore, the manufacturers excluded the trials of sulfonylurea as an add-on to metformin from the 24-week network meta-analysis that provided the data for the cost-effectiveness analysis of dual therapies. The Committee considered that, although it would have been preferable to use clinical-effectiveness data from the same source for all relevant comparators for the dual therapy analysis, it was reasonable for the manufacturers to take this approach. The Committee also noted that the effect of using 2 separate sources of clinical-effectiveness data resulted in different baseline patient characteristics and clinical risk factors for the comparison of dapagliflozin with sulfonylurea and the comparison of dapagliflozin with DPP-4 inhibitors and thiazolidinediones. The Committee considered that the baseline patient characteristics and clinical risk factors used to estimate the relative cost effectiveness of dapagliflozin as an add-on to metformin should have been taken from the same source. It concluded that the manufacturers should apply the same baseline patient characteristics and clinical risk factors in the cost-effectiveness analysis of all the relevant comparators for the dual therapy analysis.

4.18  The Committee discussed the manufacturers’ assumptions about the decision to switch or intensify treatment in the model, noting that this was based on baseline HbA_1c levels taken from the clinical trials and network meta-analysis. The Committee noted that the HbA_1c threshold levels for switching treatment in the dual therapy and triple therapy analyses were above those recommended in NICE clinical guideline 87 and therefore may not reflect UK clinical practice. The Committee considered that, although the manufacturers applied the HbA_1c threshold levels from NICE clinical guideline 87 in scenario analyses, these should have been applied in the base-case analyses. The Committee concluded that the decision to switch or intensify treatment in the model should have been based on HbA_1c thresholdlevels recommended in NICE clinical guideline 87.

4.19  The Committee discussed the manufacturers’ approach to modelling changes in body weight. The Committee noted that the effect of treatment on changes in weight was applied immediately in the model rather than gradually over the course of the first year. The Committee considered that applying the treatment effect on weight loss gradually over the first year would have been more plausible. The Committee noted that, for treatments associated with weight loss, the manufacturers made assumptions about how long weight loss was maintained for in the model (weight plateau), and about how long it took for the weight to increase to its baseline level after the plateau (loss of effect). The Committee considered that it was unclear why different assumptions for these parameters were made in the dual therapy, add-on to insulin and triple therapy analyses. The Committee discussed the values presented by the ERG for therapies that were associated with weight gain, but again considered that it was unclear how these had been applied in the model. The Committee noted that the different assumptions applied suggested that differences in weight change between treatments were maintained over the horizon of the model. It considered that it was more plausible that any initial differences in weight change between treatments would converge over time. The Committee concluded that, because of the impact of dapagliflozin on changes in body weight, further explanation was needed from the manufacturers about how the impact of treatment on weight change was applied in the model.

4.20  The Committee discussed the manufacturer’s approach to implementing baseline characteristics and risk factors in the model. It noted that simulated patients had the same characteristics and risk factors based on the mean values at baseline in the clinical trials and network meta-analysis. The Committee considered that, in order to reflect the variation seen in clinical practice, the model should have accounted for any between-patient variation in baseline characteristics and risk factors. The Committee also considered that this between-patient variation would have a significant impact on the outputs of the UKPDS risk equations for the micro- and macrovascular diabetic complications. It also noted that the baseline risk factors implemented in the model were the trial baseline value minus the treatment-specific effect and that, as a result, baseline risk factors differed between treatment groups. The Committee considered that this resulted in risk factor curves for both treatment groups that did not appear to converge over time, which may not be clinically plausible. The Committee concluded that further explanation was needed from the manufacturers about how baseline characteristics and risk factors were implemented in the model.

4.21  The Committee considered the utility values applied in the model, noting that most of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than diabetic complications and other adverse events. The Committee noted that utility values associated with changes in BMI were taken from a study commissioned by the manufacturers and that the methods by which these values were obtained were not in line with the NICE reference case for measuring and valuing health effects. The Committee also noted that this study produced different utility values associated with a 1 point increase or decrease in BMI and that these were larger than other utility values that were identified in the literature. The Committee acknowledged that the manufacturers presented scenario analyses using alternative utility values for weight change and that these resulted in higher ICERs for the metformin and insulin add-on analyses. The Committee also noted that the loss in utility associated with a 1 point increase in BMI (−0.0472) was similar to the loss in utility associated with a myocardial infarction (−0.055), which may not be credible. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values (±0.0061 per BMI unit decrease or increase) applied in the manufacturers’ scenario analyses were more reasonable.

4.22  The Committee considered the utility values associated with hypoglycaemic events. The Committee noted from the ERG that the loss in QALYs associated with hypoglycaemic events may have been too large because the study from which the values were taken applied to a 3-month period and the model cycle was 6 months. The Committee was also aware that the loss in utility associated with severe hypoglycaemic events (−0.047) was higher than that applied in the economic model of third-line therapy with insulins, thiazolidinediones or exenatide in NICE clinical guideline 87 (−0.010). However, the Committee noted that after the publication of this guideline, the Driving and Vehicle Licensing Agency issued new regulations for people who have experienced a severe hypoglycaemic event in the previous 12 months. Therefore, the Committee acknowledged that any loss in utility associated with severe hypoglycaemic events may be higher in people for whom driving might be a significant factor in their lifestyle or livelihood. The Committee also noted that it was not clear from the manufacturers’ submission which utility values were used for symptomatic hypoglycaemic events. The Committee concluded that the loss in QALYs associated with hypoglycaemic events was too large, and that the alternative values proposed by the ERG (−0.012QALYs for a severe event and −0.004QALYs for a symptomatic event) were more reasonable.

4.23  The Committee considered the utility values applied to urinary tract and genital infections in the model, noting that the loss in utility (−0.00283) associated with these events was much lower than the loss in utility associated with other adverse events. The Committee considered that it was likely that there would be a greater loss in utility associated with these events than had been proposed by the manufacturers. The Committee also noted that the study commissioned by the manufacturers to examine the impact of weight change on health-related quality of life had also estimated the impact of urinary tract and genital infections, although these data were not presented in the manufacturers’ submission. The Committee concluded that the manufacturers should provide a systematic review of the evidence on utility values associated with urinary tract and genital infections and to provide sensitivity analyses that incorporated the range of estimates identified in this review.

4.24  The Committee was aware that the ERG had proposed alternative estimates for some costs, including drug acquisition costs for pioglitazone and the costs associated with diabetic complications. The Committee noted that pioglitazone is now off-patent and that the latest acquisition costs are substantially lower than those presented in the manufacturers’ submission. The Committee acknowledged that the manufacturers were unable to provide this estimate in their submission, but considered that the ERG estimate of £112.18 was reasonable. The Committee also noted that the model did not include the annual inpatient and non-inpatient costs (estimated as £483 in the UKPDS 65 study) for people who did not experience a macro- or microvascular diabetic complication. The Committee concluded that the model should include a lower acquisition cost of pioglitazone and account for the annual costs incurred by people who do not experience a macro- or microvascular diabetic complication.

4.25  The Committee considered the manufacturers’ approach to modelling triple therapy for people whose type 2 diabetes is inadequately controlled by metformin and sulfonylurea. The Committee noted that the model structure and assumptions were similar to those used for the dual therapy and insulin add-on analyses. However, the Committee considered that the sequencing of treatments in the triple therapy analysis, which assumed that people started treatment with metformin and sulfonylurea before switching to triple therapy, was inconsistent with the approach taken for the dual therapy and add-on to insulin analyses. The Committee noted that this had been addressed in exploratory analyses conducted by the ERG and considered this to be a more reasonable approach. The Committee concluded that people in the triple therapy model should have started on triple therapy rather than dual therapy.

4.26  The Committee discussed the results of the manufacturer’s base-case analyses and noted that the ICERs for dapagliflozin in combination therapy compared with other antidiabetic drug therapies were all below £20,000 per QALY gained. It also noted that the probabilistic sensitivity analysis showed that dapagliflozin had a high probability of being cost effective at £20,000 per QALY gained. The Committee noted that the ERG’s exploratory analyses, which included changes to the utility values associated with weight change and hypoglycaemic events and the annual costs of pioglitazone and diabetic complications, resulted in higher ICERs, although they were all below £30,000 per QALY gained. The Committee also noted that, for the triple therapy analyses, when the ERG altered the sequencing of therapies so that the model started treatment with triple therapy, dapagliflozin produced higher costs and lower QALYs compared with DPP-4 inhibitors. However, the Committee considered that the ICERs presented by both the manufacturers and the ERG 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 its concerns about the network meta-analysis or the utility values applied to changes in weight, hypoglycaemic events and urinary tract and genital infections. Therefore, the Committee was minded not to recommend dapagliflozin in combination therapy for treating of type 2 diabetes as a cost-effective use of NHS resources. The Committee requested further clarification and analyses from the manufacturers that address the issues identified, and which should be made available for the second Appraisal Committee meeting (see sections 1.2-1.4).

4.27  The Committee considered whether NICE’s duties under the equalities legislation required it to alter or to add to its recommendations in any way. It was aware that dapagliflozin works through elimination via the kidneys and that its effectiveness was dependent on renal function. The Committee also noted that there is a higher prevalence of established renal failure in people of African Caribbean and South Asian family origin. However, the summary of product characteristics for dapagliflozin states that it is not recommended for use in people with moderate to severe renal impairment and therefore the Committee considered that this did not present an equality issue. The Committee concluded that its preliminary recommendation would not have a particular impact on any of the groups whose interests are protected by the equalities legislation and that there was no need to alter or add to its preliminary recommendations.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Dapagliflozin in combination therapy for treating type 2 diabetes		Section
Key conclusion
The Committee is minded not to recommend dapagliflozin in combination therapy for treating type 2 diabetes. The Committee considered that the ICERs presented by both the manufacturers and the ERG were obtained from an economic model that could not be adequately replicated. The Committee also noted that these ICERs were obtained from analyses that did not account for its concerns about the network meta-analysis or the utility values applied to changes in weight, hypoglycaemic events and urinary tract and genital infections. The Committee requested further clarification and analyses from the manufacturers that address the issues identified, and which should be made available for the second Appraisal Committee meeting.			1.1 4.26
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard evidence from the patient experts that an advantage of dapagliflozin is that it will provide a further treatment option for people with type 2 diabetes who are reluctant to start treatment with insulin or wish to avoid insulin therapy because of fear of hypoglycaemia and its impact on their lifestyle (for example, the threat of losing their driving licence or their job).	4.4
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee recognised that a new drug therapy that was not associated with an increased risk of hypoglycaemia would be valued by patients for whom driving might be a significant factor in their lifestyle or livelihood.	4.13
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialists that dapagliflozin may be more likely to be used as a triple therapy but could be used as a dual therapy if there was a perceived risk of hypoglycaemia.	4.2
Adverse reactions		The most common adverse events were urinary tract and genital infections and these events were more common in women than in men. However, the Committee heard from the manufacturers that the recurrence of these events in the clinical trials was low. The Committee concluded that the adverse-events profile of dapagliflozin was different from those of other antidiabetic therapies and that how these adverse events were included in the economic model needed further detailed consideration.	4.13
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The manufacturers had provided clinical-effectiveness data on dapagliflozin as add-on therapy to metformin but not as add-on therapy to sulfonylurea, despite clinical trial data being available. The Committee considered that excluding this evidence would affect its ability to make recommendations for the whole population for which dapagliflozin is licensed. For dapagliflozin an as add-on to metformin, the evidence came from 3 clinical trials and a network meta-analysis. Only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylurea) and the clinical effectiveness of dapagliflozin compared with DPP-4 inhibitors, thiazolidinediones and GLP-1 analogues was based solely on network meta-analysis. For dapagliflozin as add-on therapy to insulin, the evidence came from 2 clinical trials and a network meta-analysis. Both trials were placebo controlled and that 1 was of 12 weeks duration only. The clinical effectiveness of dapagliflozin as add-on therapy to insulin compared with other active treatments was based solely on the manufacturers’ network meta-analysis. Dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents and in the absence of any other currently available clinical-effectiveness data, the manufacturer provided an analysis of pooled data from a subset of older patients with type 2 diabetes and cardiovascular disease recruited in 2 trials of dapagliflozin as an add-on to metformin and sulfonylurea. The Committee concluded that significant caution should be taken when interpreting the results of these preliminary analyses.	4.5 4.6 4.7 4.8
Relevance to general clinical practice in the NHS		The Committee discussed the outcomes considered in the clinical trials and network meta-analyses, noting that the primary outcomes in the clinical trials and network meta-analysis, including changes in HbA1c, body weight and systolic blood pressure, were intermediate rather than clinical outcomes and that these were collected over a relatively short follow-up.	4.10
Uncertainties generated by the evidence		The Committee concluded that there was significant uncertainty about the validity of the results of the network meta-analyses, and requested that the manufacturers were asked to provide a revised analysis and to submit the programme code along with the trial data used for each analysis.	4.9
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that, although dapagliflozin in dual therapy as add-on to metformin therapy, and as add-on to insulin therapy, appeared to offer benefits in terms of weight loss and a similar effect on glycaemic control compared with other antidiabetic therapies, given their concerns these results should be reproduced in a revised network meta-analysis.	4.11, 4.12
Evidence for cost effectiveness
Availability and nature of evidence		The DSU identified a number of concerns with the manufacturers’ model. The Committee considered that the concerns raised by the DSU undermined the credibility of the cost-effectiveness estimates generated. The Committee considered that there was significant uncertainty about whether the economic model was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type 2 diabetes. It therefore concluded that the manufacturers should be requested to respond to the issues identified in the DSU report, in particular that the results of the probabilistic sensitivity analyses when all parameters were set to their mean values did not produce similar values to those generated by the deterministic analyses that used mean parameter values.	4.14
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee concluded that the manufacturers should apply the same baseline patient characteristics and clinical risk factors in the cost-effectiveness analysis of all the relevant comparators for the dual therapy analysis. The Committee concluded that the decision to switch or intensify treatment in the model should have been based on HbA1c threshold levels recommended in NICE clinical guideline 87. The Committee concluded that, because of the impact of dapagliflozin on changes in body weight, further explanation was needed from the manufacturer about how the impact of treatment on weight change was applied in the model. The Committee concluded that further explanation was needed from the manufacturers about how baseline characteristics and risk factors were implemented in the model.	4.17 4.18 4.19 4.20
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee considered the utility values applied in the model, noting that the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than diabetic complications and other adverse events. The Committee concluded that the utility values associated with changes in weight may have been too large and that the values applied in the manufacturers’ scenario analyses were more reasonable. The Committee concluded that the loss in QALYs associated with hypoglycaemic events was too large, and that the alternative values proposed by the ERG were more reasonable. The Committee concluded that the manufacturers should provide a systematic review of the evidence on utility values associated with urinary tract and genital infections and to provide sensitivity analyses that incorporated the range of estimates identified in this review.	4.21 4.22 4.23
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		The Committee noted that the majority of the QALY gains associated with dapagliflozin arose from the direct impact of weight change on health-related quality of life rather than diabetic complications and other adverse events.	4.21
Most likely cost-effectiveness estimate (given as an ICER)		The ICERs for dapagliflozin in combination therapy compared with other antidiabetic drug therapies were all below £20,000 per QALY gained. The ERG’s exploratory analyses, which included changes to the utility values associated with weight change and hypoglycaemic events and the annual costs of pioglitazone and diabetic complications, resulted in higher ICERs, although they were all below £30,000 per QALY gained. However, the Committee considered that the ICERs presented by both the manufacturers and the ERG 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 its concerns about the network meta-analysis or the utility values applied to changes in weight, hypoglycaemic events and urinary tract and genital infections.	4.26
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		The Committee concluded that its preliminary recommendation would not have a particular impact on any of the groups whose interests are protected by the equalities legislation and that there was no need to alter or add to its preliminary recommendations.	4.27

 

5  Implementation

5.1  The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2  The technology in this appraisal may not be the only treatment for type 2 diabetes. If a NICE technology appraisal recommends use of a technology, it is as an option for the treatment of a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes and the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3  NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6  Related NICE guidance

Published

• Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes. NICE technology appraisal guidance 248 (2012).
• Liraglutide for the treatment of type 2 diabetes mellitus. NICE technology appraisal guidance 203 (2010).
• Type 2 diabetes: the management of type 2 diabetes (partial update of CG66). NICE clinical guideline 87 (2009).
• Type 2 diabetes: the management of type 2 diabetes (partially updated by CG87). NICE clinical guideline 66 (2008).
• Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. NICE clinical guideline 63 (2008).
• Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus (review). NICE technology appraisal guidance 151 (2008).
• Type 2 diabetes: prevention and management of foot problems. NICE clinical guideline 10 (2004).

7  Proposed date for review of guidance

7.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Iain Squire
Vice-Chair, Appraisal Committee
January 2013

Appendix A: Appraisal Committee members and NICE project team

A  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam (Chair)

Department of Diagnostic Radiology, St George’s Hospital

Professor Iain Squire (Vice-Chair)

Consultant Physician, University Hospitals of Leicester

Professor A E Ades

Professor of Public Health Science, Department of Community Based Medicine, University of Bristol

Professor Thanos Athanasiou

Professor of Cardiovascular Sciences and Cardiac Surgery and Consultant Cardiothoracic Surgeon, Imperial College London and Imperial College Healthcare NHS Trust

Dr Jeremy Braybrooke

Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

Dr Gerardine Bryant

General Practitioner, Heartwood Medical Centre, Derbyshire

Dr Fiona Duncan

Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Mr Andrew England

Lecturer in Medical Imaging, NIHR Fellow, University of Liverpool

Professor Jonathan Grigg

Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London

Dr Brian Hawkins

Chief Pharmacist, Cwm Taf Health Board, South Wales

Dr Peter Heywood

Consultant Neurologist, Frenchay Hospital

Dr Sharon Saint Lamont

Head of Quality and Innovation, North East Strategic Health Authority

Dr Ian Lewin

Consultant Endocrinologist, North Devon District Hospital

Dr Anne McCune

Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

Professor John McMurray

Professor of Medical Cardiology, University of Glasgow

Dr Alec Miners

Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Dr Mohit Misra

General Practitioner, Queen Elizabeth Hospital, London

Ms Sarah Parry

CNS Paediatric Pain Management, Bristol Royal Hospital for Children

Ms Pamela Rees

Lay Member

Dr Ann Richardson

Lay Member

Ms Ellen Rule

Programme Director, NHS Bristol

Dr Peter Sims

General Practitioner, Devon

Mr David Thomson

Lay Member

Dr John Watkins

Clinical Senior Lecturer / Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales  

B  NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Matthew Dyer

Technical Lead

Zoe Garrett

Technical Adviser

Bijal Joshi

Project Manager

 Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by Aberdeen HTA Group:

• Cummins E, Scott N, Rothnie K et al. Dapagliflozin for the treatment of type 2 diabetes. Aberdeen HTA Group, Institute of Applied Health Sciences, University of Aberdeen, 2012.

B  The Decision Support Unit (DSU) report for this appraisal was prepared by:

• Davis S and Sheard J. A review of the Bristol-Myers Squibb / AstraZeneca economic model on the cost-effectiveness of dapagliflozin, November 2012.

C  The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I            Manufacturer/sponsor:

• Bristol Myers-Squibb and AstraZeneca

II           Professional/specialist and patient/carer groups:

• Black Ethnic Minority Diabetes Association
• Diabetes UK
• National Diabetes Nurses Consultant Group
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III          Other consultees:

• Department of Health
• Welsh Assembly Government
• NHS Middlesborough

IV       Commentator organisations (did not provide written evidence and without the right of appeal):

• Aberdeen HTA Group
• Boehringer Ingelheim and Lilly UK (linagliptin)
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Eli Lilly (exenatide, insulin)
• Health Improvement Scotland
• National Institute for Health Research Health Technology Assessment Programme
• Novo Nordisk (insulin, liraglutide)
• Pfizer (glipizide)

D  The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on dapagliflozin by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor Eric Kilpatrick, Consultant in Chemical Pathology, Hull and East Yorkshire Hospitals NHS Trust nominated by organisation representing Royal College of Pathologists – clinical specialist
• Dr Peter Winocour, Consultant Physician and Clinical Director of Diabetes and Endocrine Services nominated by organisation representing Association of British Clinical Diabetologists (ABCD) and Royal College of Physicians (RCP) – clinical specialist
• Mrs Cathy Moulton, Clinical Advisor nominated by organisation representing Diabetes UK – patient expert
• Ms Aderonke Kuti, Executive Director, nominated by organisation representing Black and Ethnic Minority Diabetes Association – patient expert

E  The following individuals were nominated as NHS Commissioning experts by the selected Commissioning Group allocated to this appraisal. They gave their expert/NHS commissioning personal view on dapagliflozin by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Ms Joanne Linton,Assistant Director Medicines Management selected by NHS Tees – NHS commissioning expert
• Dr Victoria Ononeze, Public Health Specialist selected by NHS Tees – NHS commissioning expert

F  Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Bristol Myers-Squibb and AstraZeneca (dapagliflozin)