Dapagliflozin in combination therapy for treating type 2 diabetes

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 in patients with type 2 diabetes inadequately controlled with metformin alone (studies 14, 12 and 4), and 2 in patients with type 2 diabetes inadequately controlled with insulin with or without oral antidiabetic drugs (studies 9 and 6).

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) and 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 to 60.8 years, HbA_1c level 7.16% to 8.11%, body weight 86.1 kg to 92.1 kg and systolic blood pressure 126.0 mmHg to 135.9 mmHg.

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 to 59.3 years, HbA_1c level 8.40% to 8.57%, body weight 94.5 kg to 103.4 kg and systolic blood pressure 128.9 mmHg to 140.6 mmHg.

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 both study 12 (−2.96 kg versus −0.88 kg, p<0.0001) and 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 a statistically significant increased risk of hypoglycaemia compared with placebo at 24 weeks in either study.

In study 4 (n=814), dapagliflozin was shown to be non-inferior (based on a non-inferiority margin of 0.35%) to a sulfonylurea with respect to HbA_1c reduction at 52 weeks. Dapagliflozin was associated with a statistically significant change in body weight compared with a sulfonylurea at 52 weeks (−3.22 kg versus +1.44 kg, p<0.0001). Dapagliflozin was associated with a statistically significant change in systolic blood pressure compared with a 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 a sulfonylurea by 52 weeks.

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 had 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.

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 body mass index (BMI). Subgroup analyses were conducted on pooled data as well as 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 HbA1c. Dapagliflozin treatment generally resulted in greater HbA_1c reductions from baseline in people with higher baseline HbA_1c.

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.

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). For the 24‑week analysis of systolic blood pressure, the network included dapagliflozin, dipeptidyl peptidase-4 (DPP‑4) inhibitors, glucagon-like peptide-1 (GLP‑1) analogues, sulfonylureas, thiazolidinediones and placebo in 8 studies. For the 24‑week analysis of outcomes other than systolic blood pressure, the network included dapagliflozin, DPP‑4 inhibitors, 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.

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 HbA_1c, dapagliflozin was associated with a statistically significant reduction in HbA_1c compared with placebo. No statistically significant differences in the change in HbA_1c 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 hypoglycaemia were reported between dapagliflozin and other drug therapies.

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.

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.

Data on the risks 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 manufacturers reported that dapagliflozin was associated with a higher incidence of genital and urinary tract infections and a slightly higher incidence of volume depletion events (hypotension, hypovolaemia or dehydration) compared with placebo. 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 in those treated with placebo respectively. In terms of cardiovascular safety, a meta-analysis of 14 randomised controlled trials did not find any evidence that dapagliflozin is associated with increased cardiovascular risk for a composite end point of cardiovascular death, myocardial infarction and stroke (hazard ratio [HR] 0.79, 95% CI 0.54 to 1.17).

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 a 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 given metformin and a 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 to 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).

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 a sulfonylurea. However, they referred to a literature review of add-on therapy to metformin and sulfonylureas 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. No statistically significant differences in HbA_1c reduction were reported between DPP‑4 inhibitors, GLP‑1 analogues and thiazolidinediones. Thiazolidinediones, but not DPP‑4 inhibitors or GLP‑1 analogues, were associated with statistically 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.

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

• in triple therapy for people with type 2 diabetes that is inadequately controlled with metformin and a 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.

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 to high-density lipoprotein cholesterol ratio 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.

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.

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 a 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%.

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 a 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 a sulfonylurea in patients with type 2 diabetes inadequately controlled with metformin alone.

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 a 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.

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 a 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.

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.

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.

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 annual cost of end-stage renal failure (£34,806) was based on the weighted average cost of automated peritoneal dialysis, continuous ambulatory peritoneal dialysis, hospital haemodialysis and satellite unit-based haemodialysis, taken from a separate UK-based study. The cost of a severe hypoglycaemic event (£390) 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.

The manufacturers' base-case deterministic cost-effectiveness results for the add-on to metformin analyses found that the comparison between dapagliflozin and a sulfonylurea resulted in an incremental cost-effectiveness ratio (ICER) of £2,671 per QALY gained (incremental costs £1,246, 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 £4,358 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 a sulfonylurea found that dapagliflozin dominated DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues, resulting in lower costs and higher QALYs.

The manufacturers also presented 2 scenario analyses that included alternative BMI-related utility values. The scenarios applied utilities of ±0.0061 and ±0.0038 respectively for a ±1 unit change in BMI. Both values 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's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults) and NICE's technology appraisal guidance TA248 on exenatide in combination with oral antidiabetic therapy for the treatment of type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults). For the metformin add-on comparisons, the ICERs for dapagliflozin compared with a sulfonylurea were £8,863 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.

The Committee considered the evidence on the clinical effectiveness of dapagliflozin compared with other antidiabetic therapies, noting that most of the data came from the network meta-analyses submitted by the manufacturers. The Committee noted that, although the WinBUGs programme code used to run the original network meta-analyses provided in the manufacturers' submission differed from the code recommended by the NICE DSU in their technical support document, the manufacturers had also provided revised network meta-analyses that were based on the recommended code. The Committee also noted that the results of the manufacturers' revised network meta-analyses were similar to those from the original analyses. The Committee concluded that the results of the manufacturers' revised network meta-analyses provided an appropriate basis for making decisions about the clinical effectiveness of dapagliflozin and other antidiabetic therapies.

The Committee discussed the outcomes collected in the clinical trials and network meta-analyses, noting that the primary outcomes were intermediate rather than clinical outcomes. 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 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 shorter duration, the clinical-effectiveness data used in the cost-effectiveness analysis had to be based on the short-term clinical trial data. The Committee concluded that, despite some uncertainty about the impact of HbA_1c reduction on longer-term macrovascular complications, it was prepared to accept the link between the intermediate outcomes collected in the clinical trials and the longer-term clinical outcomes.

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 evidence came from 3 clinical trials and a network meta-analysis. The Committee also noted that only 1 of the clinical trials of dapagliflozin had an active comparator (sulfonylureas), and 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 sulfonylureas for the outcomes of weight loss and systolic blood pressure reduction and similar efficacy for HbA_1c reduction. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.10 and 3.45), dapagliflozin in dual therapy as add-on to metformin appeared to provide similar glycaemic control to other antidiabetic drugs but may result in greater weight loss.

The Committee further considered the clinical effectiveness of dapagliflozin as dual therapy, noting that the manufacturers had not provided data on dapagliflozin as add-on therapy to a sulfonylurea, 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 who cannot tolerate metformin or for whom it is contraindicated would receive sulfonylurea monotherapy. It noted that the clinical effectiveness of dapagliflozin as an add-on to a sulfonylurea appeared to be consistent with its effectiveness when used as an add-on to metformin. The Committee concluded that, because the manufacturers had not provided clinical evidence on dapagliflozin as an add-on to a sulfonylurea, it could not make recommendations on this combination regimen.

The Committee considered the clinical effectiveness of dapagliflozin for people whose type 2 diabetes is inadequately controlled by 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. 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. Further, the Committee noted that the network meta-analysis excluded trials of GLP‑1 analogues because they were not comparable to other trials included in the analysis and therefore consideration of the full range of possible comparators was restricted by the available evidence. The Committee concluded that, on the basis of the results of the network meta-analyses (see sections 3.12 and 3.45), dapagliflozin as add-on therapy to insulin appeared to have greater efficacy than DPP‑4 inhibitors for the outcome of weight loss and similar efficacy for HbA_1c reduction.

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 a post-hoc 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 a sulfonylurea. The Committee also noted that no direct head-to-head studies comparing dapagliflozin with other antidiabetic drugs currently exist and that the clinical-effectiveness data used to indirectly compare dapagliflozin with other antidiabetic drugs were taken from a previously published systematic review that had not been updated since 2009. It was aware of the limitations of these analyses highlighted by the manufacturer 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.

The Committee considered the adverse events associated with dapagliflozin. It noted that common adverse events included 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 looked 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 associated with a lower risk of hypoglycaemia than some other existing therapies 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 it was important to examine these adverse events when considering the manufacturers' economic model.

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 manufacturers had provided a revised economic model in order to address concerns raised by the DSU about the original model and that the DSU considered that their concerns had been addressed. However, it also noted that the DSU and the ERG had identified a number of errors in the revised model which were subsequently addressed by the DSU in its exploratory analyses. The Committee concluded that the manufacturers' revised economic model with the subsequent amendments made by the DSU was acceptable for assessing the cost effectiveness of dapagliflozin in combination therapy for treating type 2 diabetes.

The Committee discussed the validation report provided by the manufacturers which compared the results from the revised model with the results that would have been obtained using the CORE diabetes model, which has been used in previous appraisals of treatments for type 2 diabetes (such as NICE's technology appraisal guidance TA203 on liraglutide for the treatment of type 2 diabetes mellitus and exenatide in combination with oral antidiabetic therapy for the treatment of type 2 diabetes [both now replaced by NICE's guideline on type 2 diabetes in adults]). The Committee noted that the results generated from the CORE diabetes model were comparable to those obtained from the manufacturers' original and revised economic models for the dual therapy and insulin add-on therapy analyses. The Committee concluded that the results of the validation exercise with the CORE diabetes model provided reassurance about the integrity of the results obtained from the manufacturers' revised economic model.

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 for dual therapy but then subsequently excluded from the cost-effectiveness analysis. 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 an adequate range of comparators for the cost-effectiveness analysis of dapagliflozin in dual therapy as an add-on to metformin.

The Committee discussed the clinical-effectiveness data that were applied in the economic models. The Committee noted that the DSU had completed analyses of dual therapy add-on to metformin using different sources of clinical-effectiveness data. One analysis used the 24‑week network meta-analysis data for dapagliflozin, DPP‑4 inhibitors and thiazolidinediones and presented a separate comparison using head-to-head data from study 4 for dapagliflozin and sulfonylureas. The other analysis considered all treatments in a single analysis using the 52‑week network meta-analysis data. It heard from the manufacturers that, for the metformin add-on analyses, the trials of other antidiabetic therapies as add-on to metformin used a fixed dose but the trials of sulfonylureas did not have a stable dose over 24 weeks. Therefore, trials of sulfonylureas as an add-on to metformin were excluded from the 24‑week network meta-analysis. The Committee discussed which set of analyses was the most appropriate, noting that the estimates of efficacy differed between analyses. It considered that it was more appropriate to use a single source as was available in the 52‑week network meta-analysis, but was aware of the limited number of trials informing this analysis. The Committee noted that the 24‑week network meta-analysis only excluded sulfonylureas, and that the evidence from the clinical specialists suggested that dapagliflozin would be used where sulfonylureas were not appropriate. On this basis the 24‑week network meta-analysis data were appropriate. The Committee concluded that the results of the revised 24‑week network meta-analysis provided the most appropriate clinical-effectiveness data for the dual therapy analyses.

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 original dual therapy and triple therapy analyses were above those recommended in NICE's guideline CG87 on type 2 diabetes and therefore may not reflect UK clinical practice. However, the Committee noted that the DSU's revised analyses applied an HbA_1c threshold for switching treatment that is recommended in NICE's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults). The Committee heard from the DSU that the results from the revised model were sensitive to the timing of treatment switching in the model which was dependent on the relationship between HbA_1c at the start of treatment, treatment-related changes in HbA_1c levels and the HbA_1c threshold levels for switching treatment. The Committee concluded that HbA_1c threshold levels for switching treatment as recommended in NICE's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults) were appropriate to use in the economic modelling and as a basis for decision-making.

The Committee discussed the manufacturers' approach to modelling changes in body weight. The Committee noted that in the revised model the effect of treatment on changes in weight was applied gradually over the course of the first year, and considered that this was more plausible than the original model in which the effect of treatment on changes in weight was applied immediately. The Committee noted that, for treatments associated with weight loss, the manufacturers made assumptions about how long weight loss was maintained 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 understood that the changes made by the DSU meant that for treatments associated with weight loss, the weight profiles of the treatment groups now converged over time, but that for treatments associated with weight gain, differences in weight were maintained over the model time horizon. The Committee acknowledged that unpublished data from the clinical study of dapagliflozin and sulfonylureas as add-on to metformin provided by the manufacturers showed that patients who remained on dapagliflozin treatment without switching to other treatments maintained their weight loss over 4 years. However, the Committee considered that uncertainty remained about the effects of stopping treatment with dapagliflozin and the impact on weight gain. Therefore, it concluded that the scenario analysis conducted by the DSU, which involved the convergence of differences in weight profiles between treatment groups at the time of switching to the last line of treatment, was more appropriate for decision-making.

The Committee considered the utility values applied in the model, noting that in all analyses 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 from a reduction of 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-unit 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-unit 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 and DSU analyses were more reasonable.

The Committee considered the utility values associated with hypoglycaemic events. The Committee heard from the ERG that they considered that the loss in QALYs associated with hypoglycaemic events may have been too large. 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's guideline CG87 on type 2 diabetes (−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 noted that the DSU had completed analyses that included both the higher and lower estimates of loss of utility associated with hypoglycaemic events, and that these had made small differences to the estimates of the ICER. The Committee therefore concluded that the utility values associated with hypoglycaemic events were not a critical factor in the decision-making.

The Committee considered the utility values applied to urinary tract and genital infections in the model, noting that the loss in utility associated with these events was much smaller 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 noted that in scenario analyses the manufacturers had applied a range of estimates for the loss in utility associated with urinary tract and genital infections. It was also aware that the results of the revised analyses were not sensitive to changes in these utility values. The Committee concluded that, although the loss in utility associated with urinary tract and genital infections was likely to be greater than that proposed by the manufacturers, it was satisfied that this did not significantly impact on the relative cost effectiveness of dapagliflozin as dual therapy or add-on to insulin.

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 DSU estimate of an average annual cost of £69.09 was reasonable. The Committee also noted that the manufacturers' revised model did not correctly adjust 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 it was appropriate to consider the latest acquisition cost of pioglitazone and that the manufacturers' revised model should be amended to correctly account for the annual costs incurred by people who did not experience a macro- or microvascular diabetic complication.

The Committee considered the most plausible ICERs for dapagliflozin as dual therapy in combination with metformin. The Committee considered that, on the basis of clinical specialist opinion that suggested that the use of pioglitazone in UK clinical practice was decreasing, a thiazolidinedione was not a key comparator in the dual therapy setting. The Committee also noted the evidence from the clinical specialists supported by the manufacturers that, in clinical practice, dapagliflozin would predominantly be used in combination with metformin when a sulfonylurea is not appropriate. Therefore, the Committee also considered that sulfonylureas were not a relevant comparator in the dual therapy setting. The Committee considered the DSU deterministic analysis and scenario analyses, which included the convergence of differences in weight between treatment groups at the time of switching to the last line of treatment. It noted that these showed that DPP‑4 inhibitors were associated with higher costs and QALYs than dapagliflozin, but that these differences were small. It noted further that in the DSU probabilistic sensitivity analysis these differences were even smaller. The Committee noted that the differences in QALYs were largely explained by the changes in health-related quality of life (utility) associated with changes in weight (BMI). Overall, the Committee concluded that because of the small differences in costs and QALYs between dapagliflozin and DPP‑4 inhibitors, dapagliflozin in a dual therapy regimen in combination with metformin could be recommended as a treatment option for people with type 2 diabetes that is inadequately controlled with metformin alone if it is used in the same scenario as described for the use of DPP‑4 inhibitors in NICE's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults).

The Committee considered the most plausible ICERs for dapagliflozin as add-on to insulin. It noted that in all the analyses conducted by the DSU the estimate of the ICER for dapagliflozin compared with DPP‑4 inhibitors was below £20,000 per QALY gained. The Committee considered that, in comparison to DPP‑4 inhibitors, dapagliflozin had been shown to be a cost-effective use of NHS resources. The Committee recommended dapagliflozin as a treatment option for people with diabetes inadequately controlled by insulin with or without other oral antidiabetic drugs.

The Committee discussed the results of the manufacturers' revised base-case analyses for dapagliflozin as triple therapy add-on to metformin and a sulfonylurea. It noted that the sequence of treatments in the manufacturers' revised economic model had been amended so that the approach was consistent with the dual therapy and insulin add-on analyses, with patients in the model starting treatment with triple add-on therapy. The Committee noted that in both the manufacturers' original and revised triple therapy analyses, dapagliflozin dominated other comparator drug therapies, meaning that dapagliflozin was associated with lower costs and higher QALYs than the comparators. However, the Committee noted that the clinical-effectiveness data applied in the triple therapy model were based on an indirect comparison of pooled data of 2 trials of dapagliflozin and a separate systematic review of other antidiabetic drug therapies conducted in 2009. The Committee was also aware that dapagliflozin is currently being studied as a triple therapy add-on to 2 other oral agents. The Committee considered that the cost-effectiveness analyses should be considered as exploratory in nature. The Committee concluded that dapagliflozin as triple therapy in combination with metformin and a sulfonylurea should not be recommended for treating type 2 diabetes except as part of the ongoing clinical trials.