Dapagliflozin in combination therapy for treating type 2 diabetes

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 with 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's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults) recommends the use of pioglitazone as an alternative add-on treatment to a 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 be given to patients before GLP‑1 analogues because they are cheaper 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.

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 31 and 45 weeks or greater than 58 weeks were also identified in the review. However, in response to a request for clarification, the manufacturers provided a full list of identified trials, none of which were between 31 and 45 weeks' duration. 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 more studies to be included in the analysis.

The ERG commented that the manufacturers' approach to presenting the clinical effectiveness of dapagliflozin as a triple therapy add-on to metformin and a 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.

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 recommended in NICE's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults). 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.

The ERG commented that the loss in utility associated with hypoglycaemic events, taken from Currie et al. (2006), may have been too large when applied within the model. 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 should have been applied for 3 months rather than 12 months, resulting in QALY losses of −0.012 and −0.004 for severe and symptomatic hypoglycaemic events respectively.

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 these alternative utility values, which were applied in the manufacturers' scenario analyses, to be more reasonable.

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 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 a sulfonylurea (£946.26 as opposed to £886.90). With 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.

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 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.

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.

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.

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.

In the triple therapy analyses, the ERG considered that it was unnecessary for the model to include dual therapy with metformin and a 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.

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.

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.

The DSU identified several aspects of the executable model that were not described in the manufacturers' submission. In the manufacturer's model, 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 cycle and the output of the event equation for 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.

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.

The manufacturers provided a response to the concerns raised by the DSU in its report on the economic model. The manufacturers stated that the economic model produced a stable estimate of the incremental costs and QALYs after 1000 rather than 100 simulations. The manufacturers implemented changes to the risk factor progression and event equations, and to the gamma and beta distributions applied to the cost and utility parameters in the probabilistic sensitivity analysis. The manufacturers also amended the model source code to correct for errors in the calculation of transition probabilities and the adjustment of all-cause mortality.

The manufacturers presented revised network meta-analyses for the dual therapy and add-on to insulin therapy comparisons, based on the WinBUGs programme code included in the technical support documents published by the DSU (Technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials). The manufacturers also presented a validation exercise, which compared the results of the revised network meta-analyses with those presented in its original submission. The manufacturers commented that the revised analyses, which were provided as academic in confidence, produced similar results compared with the original analyses. The results of the revised 52‑week network meta-analysis were applied for the revised dual therapy analyses because these data enabled the same set of baseline characteristics and risk factors to be used for each comparator in the dual therapy analyses. The revised network meta-analysis at 24 weeks was applied for the add-on to insulin analysis in the manufacturers' revised economic model.

The manufacturers provided further clarification about how changes in body weight were modelled over time for the different treatments. In addition, the manufacturers provided unpublished follow-up data from study 4 which, they stated, showed that patients who remained on dual therapy of dapagliflozin and metformin maintained their weight loss for up to 4 years. The manufacturers therefore suggested that, for treatments associated with weight loss, the assumption in the model that this weight loss was maintained for 2 years may have been conservative.

The manufacturers made a number of revisions to the economic model to address the ERG's concerns. The revised economic model applied the same baseline risk factors for all treatment groups, which were taken from the revised network meta-analyses for the dual therapy and add-on to insulin analyses. The manufacturers applied an HbA_1c threshold level of 7.5%, as currently recommended NICE's guideline CG87 on type 2 diabetes (now replaced by NICE's guideline on type 2 diabetes in adults), for switching treatment for the dual therapy analyses. However, the manufacturers commented that this threshold may not reflect UK clinical practice because patients with type 2 diabetes are reviewed by their clinicians only once or twice a year and are therefore likely to have HbA_1c levels that exceed 7.5% at the time of review. For the triple therapy and add-on to insulin analyses, the manufacturers applied HbA_1c thresholds of 8.61% and 9.04% respectively for switching treatment. For the triple therapy analyses, the manufacturers also revised the sequence of treatments in the revised model so that the starting treatment was triple therapy rather than dual therapy.

In their revised model, the manufacturers applied utility values of ±0.0061 per unit increase or decrease in BMI taken from the study by Bagust et al. The manufacturers commented that the ERG had misinterpreted how the loss in utility associated with hypoglycaemic events was applied over a 6‑month cycle in the economic model. Therefore, the manufacturers did not reduce the loss in QALYs associated with hypoglycaemia to −0.012 for a severe event and −0.004 for a symptomatic event in their revised base-case analyses (instead, retaining the original utility values). In scenario analyses, the manufacturers applied a range of upper (−0.0104) and lower (−0.000657) estimates of the loss in utility associated with urinary tract and genital infections taken from a systematic literature review as requested by the Committee. The manufacturers also reduced the average annual cost of pioglitazone from £414.07 to £112.18 and included an annual cost of £483 for people not experiencing diabetic complications in the revised economic model.

The manufacturers presented ICERs for the revised dual therapy analyses, which included clinical-effectiveness data from the revised 52‑week network meta-analyses, changes to the model in response to the DSU report, the same baseline patient characteristics and risk factors for all treatment groups, and an HbA_1c switch threshold of 7.5%. As a result of these changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £1,498 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and thiazolidinediones, the ICERs were £689 and £5,342 per QALY gained respectively. A scenario analysis which applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICERs for all comparisons.

The manufacturers also presented ICERs for the revised dual therapy analyses which included the changes described in section 3.49 and additional changes, which included reduced costs of pioglitazone, adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER for the comparison between dapagliflozin and sulfonylureas was £7,735 per QALY gained. For the comparisons between dapagliflozin and DPP‑4 inhibitors and between dapagliflozin and thiazolidinediones, the ICERs were £3,337 and £77,615 per QALY gained respectively.

The manufacturers presented ICERs for the revised add-on to insulin analyses, which included clinical-effectiveness data from the revised 24‑week network meta-analyses, changes to the model in response to the DSU report and an HbA_1c switch threshold of 9.04%. As a result of these changes, the ICER for the comparison between dapagliflozin and DPP‑4 inhibitors was £2,509 per QALY gained. A scenario analysis that applied the upper and lower estimates of the loss in utility associated with urinary tract and genital infections resulted in very small changes to the ICER. The manufacturers also presented an ICER that included adjusted costs of diabetic complications and utility values of ±0.0061 per unit increase or decrease in BMI. As a result of these additional changes, the ICER increased to £5,634 per QALY gained.

The manufacturers also presented ICERs for the revised triple therapy analyses, which included altering the treatment sequences in the model so that patients in the model started treatment with triple add-on therapy to metformin and a sulfonylurea, incorporating model structural changes and applying an HbA_1c switch threshold of 8.61%. As a result of these changes, dapagliflozin continued to dominate DPP‑4 inhibitors, thiazolidinediones and GLP‑1 analogues. The manufacturers did not present any additional scenario analyses for the relevant comparisons in triple therapy.

The manufacturers presented the results of a validation exercise, which compared the results from the revised model with the results that would have been obtained from using the CORE diabetes model for all relevant comparisons in dual therapy, insulin add-on therapy, and triple therapy. For the dual therapy analyses, the CORE model produced an ICER of £8,879 per QALY gained for the comparison of dapagliflozin with sulfonylureas and ICERs of £2,014 and £7,093 per QALY gained for the comparisons of dapagliflozin with DPP‑4 inhibitors and with thiazolidinediones. For the insulin add-on analyses, the CORE model resulted in an ICER of £1,675 per QALY gained for dapagliflozin compared with DPP‑4 inhibitors. For the triple therapy analyses, the CORE model produced ICERs of £1,759 per QALY gained for the comparison of dapagliflozin with DPP‑4 inhibitors and £16,054 per QALY gained for the comparison of dapagliflozin with thiazolidinediones. The CORE model also produced an ICER of £32,243 per QALY lost for the comparison of dapagliflozin with GLP‑1 analogues.

Both the ERG and the DSU reviewed the manufacturers' revised economic model and analyses provided in response to the appraisal consultation document. Overall, the DSU considered that the manufacturers had adequately addressed all of the significant areas of concern about the model. The ERG noted that the revised dual therapy analyses used clinical-effectiveness data from the revised 52‑week network meta-analyses rather than the revised 24‑week network meta-analyses, which resulted in significant changes to the model input parameters. The ERG noted that, as a result of applying a lower HbA_1c threshold for switching treatment, the revised model resulted in switching treatment earlier and thus reducing the costs of first-line dapagliflozin treatment whilst maintaining any long-term weight loss. The ERG also noted that the manufacturers' revised economic model had incorrectly amended the costs for people who did not experience diabetic complications.

The ERG highlighted a number of concerns about how changes in body weight were modelled in the manufacturers' revised analyses. The ERG noted that the manufacturers stated that, in order to simulate a linear, gradual regain of weight, the time to loss of weight effect was set such that weight was regained by the time of switch to next treatment. However, the ERG noted that in the manufacturers' comparisons of dapagliflozin with sulfonylureas and with DPP‑4 inhibitors in the revised dual therapy analyses, weight loss associated with dapagliflozin was largely maintained and not reversed at the time of switching to next treatment. The ERG also noted that the manufacturers' revised economic model and analyses did not address the Committee's concerns about the duration over which differences in weight change were maintained between treatments.

In response to the concerns about the manufacturers' revised economic model raised by the ERG, the DSU was asked to review the manufacturers' revised economic analyses and to assess further how changes in weight were modelled over time for different treatments in the revised model. The DSU was also asked to conduct a range of further exploratory analyses for dapagliflozin in dual therapy and add-on to insulin therapy.

The DSU noted that, in the manufacturers' revised economic model, the assumptions about the duration over which any treatment-related weight change was reversed for the comparison of dapagliflozin with thiazolidinediones as add-on to metformin and the add-on to insulin analyses were consistent with those used in the original model. Therefore, for treatments associated with weight loss, weight was regained before first treatment switch. However, the DSU noted that for the comparisons of dapagliflozin as add-on to metformin with sulfonylureas and DPP‑4 inhibitors, treatment-related weight loss was not reversed at treatment switch in the revised model. The DSU suggested that the weight profiles for dapagliflozin and DPP‑4 inhibitors may have been incorrectly amended in the model.

The DSU noted that, for second- and third-line treatments, the weight at the start of treatment in the revised model was based on the weight at the time of switching from the previous treatment. The DSU noted that this was problematic if the treatment switch occurred before the treatment-related weight loss was regained. The DSU stated that where this happened this resulted in a weight difference between treatment groups that is maintained throughout the duration of the model. The DSU amended the manufacturers' revised model to ensure that, if a treatment switch occurred before the weight loss was fully regained, the starting weight at the next line of treatment was set equal to the weight that would have been achieved after the weight regain for the previous treatment. This resulted in a convergence of weight profiles over time for treatments associated with weight loss.

The DSU applied a number of changes and assumptions to the manufacturers' revised model, in addition to the amendment described in section 3.58. These included:

• for the dual therapy analyses, using clinical-effectiveness data from the revised 24‑week network meta-analyses for the comparisons of dapagliflozin with DPP‑4 inhibitors and thiazolidinediones and from study 4 for the comparison of dapagliflozin with a sulfonylurea

• applying an HbA_1c threshold of 7.5% for switching to second-line and third-line treatment in the dual therapy analysis and for switching to second-line treatment in the add-on to insulin analysis

• for any treatments associated with weight loss, assuming weight regain during year 3 to the level expected in a patient who experiences a natural weight gain of 0.1 kg per year from the start of treatment

• assuming no diabetic complications at the start of treatment

• reducing the loss in QALYs associated with hypoglycaemia to –0.012 for a severe event and –0.004 for a symptomatic event

• using utility values associated with weight change of ±0.0061 per unit of BMI

• reducing the annual cost of pioglitazone to £69.09 based on the latest NHS drug tariff

• using an annual cost of £483 for people not experiencing diabetic complications.

For the dual therapy analyses, using data from the 24‑week network meta-analysis, the DSU base-case deterministic pair-wise analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £13,947 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £13,338 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £136 and incremental QALYs of 0.008). Using data from study 4, the pair-wise comparison of dapagliflozin and sulfonylureas resulted in an ICER of £12,405 per QALY gained.

The DSU also conducted a probabilistic sensitivity analysis based on a mean of 1000 samples. Using data from the 24‑week network meta-analysis, the analysis resulted in pair-wise ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £15,511 per QALY gained for the comparison of DPP‑4 inhibitors with thiazolidinediones. An incremental analysis resulted in ICERs of £15,257 per QALY gained for the comparison of dapagliflozin with thiazolidinediones and £41,654 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin (based on incremental costs of £17 and incremental QALYs of less than 0.001). Using data from study 4, the comparison of dapagliflozin and sulfonylureas resulted in an ICER of £15,148 per QALY gained. The DSU noted that in the probabilistic sensitivity analysis, people spent longer on first-line treatment because of the interaction between baseline HbA_1c values, treatment switching threshold and effectiveness data, thus resulting in higher incremental costs and ICERs than the deterministic analysis. The results of these probabilistic sensitivity analyses also showed that, at £20,000 per QALY gained, dapagliflozin had the highest probability (40.4%) of being cost effective compared with DPP‑4 inhibitors (35.5%) and thiazolidinediones (24.1%) and also the highest probability (61.0%) of being cost effective compared with sulfonylureas.

The DSU conducted a scenario analysis that applied the manufacturers' original utility values associated with hypoglycaemia (–0.047 for a severe event and –0.042 for a symptomatic event). As a result of this change, dapagliflozin was extendedly dominated by DPP‑4 inhibitors and thiazolidinediones, because the ICER of dapagliflozin compared with thiazolidinediones was higher than that of the next most effective alternative (DPP‑4 inhibitors). The comparison of dapagliflozin and sulfonylureas resulted in an ICER of £10,317 per QALY gained. The DSU also conducted a scenario analysis which used the same clinical-effectiveness data from the 52‑week network meta-analysis as those used in the manufacturers' revised model, thus allowing all treatments to be compared with each other in a single analysis. On the basis of a full incremental analysis, DPP‑4 inhibitors were dominated by thiazolidinediones. The comparison of thiazolidinediones and sulfonylureas resulted in an ICER of £12,108 per QALY gained and the comparison of dapagliflozin and thiazolidinediones resulted in an ICER of £94,466 per QALY gained.

The DSU conducted an additional scenario analysis to explore the impact of weight convergence between treatment groups at the time of switching to the last line of treatment. In the manufacturers' revised model for the dual therapy analyses, the DSU modelled weight convergence between dapagliflozin (associated with weight loss) and a sulfonylurea (associated with weight gain) by increasing the weight gain for the last treatment in the sequence (insulin treatment). For this scenario analysis the DSU presented pair-wise ICERs using the data from the 24‑week network meta-analysis and separately the data from study 4. Applying the 24‑week meta-analysis data resulted in a higher ICER of £60,965 per QALY gained for the pair-wise comparison of dapagliflozin with thiazolidinediones and an ICER of £16,847 per QALY gained for the comparison of DPP‑4 inhibitors with dapagliflozin. The ERG noted that the latter ICER was largely unchanged from its base-case analysis because the weight profiles at last treatment switch were very similar across the 2 treatment groups. The pair-wise comparison of dapagliflozin and sulfonylureas using study 4 data resulted in an ICER of £21,200 per QALY gained.

The DSU noted that in the manufacturers' revised add-on to insulin analysis, the time to weight regain was set to occur before first treatment switch based on an HbA_1c threshold of 9.04%, resulting in a switch to second-line treatment at 8 years. The DSU explored the impact of setting a time to weight regain of 1 year and an HbA_1c switching threshold of 7.5% in line with the dual therapy analyses. The DSU also applied all other changes as described in section 3.59. The DSU base-case deterministic pair-wise analysis of dapagliflozin compared with DPP‑4 inhibitors resulted in an ICER of £3,706 per QALY gained. The probabilistic sensitivity analysis resulted in a longer duration of first-line treatment and incremental costs for dapagliflozin, and consequently in a higher ICER of £7,402 per QALY gained. When the DSU applied the manufacturers' original utility values associated with hypoglycaemia, the ICER was reduced to £2,959 per QALY gained. When the DSU applied the assumption of weight convergence at last treatment switch, the ICER increased to £12,879 per QALY gained. The DSU noted that this scenario resulted in longer first-line treatment duration for people before switching to insulin treatment in both treatment groups and consequently, higher incremental costs for dapagliflozin.