Empagliflozin in combination therapy for treating type 2 diabetes

Clinical effectiveness

4.3 The Committee considered the evidence on the clinical effectiveness of empagliflozin compared with other antidiabetic treatments and noted that most of the trials compared empagliflozin with placebo. The Committee noted the Evidence Review Group (ERG)'s comment that the trials were generally of good methodological quality and that demographic characteristics were well balanced. The Committee noted that in general, compared with placebo, empagliflozin was proven to be effective in reducing HbA_1c, body weight and systolic blood pressure in dual therapy (plus metformin), in triple therapy (plus metformin and a sulfonylurea or a thiazolidinedione) or as an add‑on to insulin. The Committee also heard from the clinical specialists about their anecdotal experience of using SGLT‑2 inhibitors for treating type 2 diabetes in the trials. The clinical specialists were satisfied with their experience so far and recalled that they had not witnessed any immediate safety concerns. They also stated that their patients achieved better glycaemic control and weight reduction than had been suggested by the results in the trials. The clinical specialists also suggested that although the trials did not show any improvement in quality‑of‑life scores, patients generally valued the weight reduction achieved by empagliflozin. However, the clinical specialists stressed that they had limited experience, having treated only a small number of people with empagliflozin. The Committee concluded that empagliflozin in combination with other antidiabetic agents is proven to be an effective treatment compared with placebo for type 2 diabetes.

4.4 The Committee discussed the original network meta‑analyses which reported the relative effectiveness of empagliflozin with the relevant comparators in the absence of head‑to‑head trials. The Committee noted the ERG's concerns with the way in which the original network meta‑analyses were done and reported. The Committee was reassured by the company, which stated that it had corrected many of the errors identified by the ERG and that the overall conclusion was that empagliflozin, canagliflozin, dapagliflozin and sitagliptin had similar clinical effectiveness. The Committee also considered the new network meta‑analyses provided by the company in response to the appraisal consultation document. It noted that the results of the new analyses also showed that the clinical effectiveness of empagliflozin, canagliflozin, dapagliflozin and sitagliptin was similar. The Committee heard from the ERG that results of an independent unpublished network meta‑analysis, comparing SGLT‑2 inhibitors as dual therapy plus metformin, support the conclusion of similar clinical effectiveness among SGLT‑2 inhibitors. The Committee concluded on the basis of the network meta‑analyses that empagliflozin as part of dual therapy, triple therapy and as an add‑on to insulin appeared to provide comparable glycaemic control both to other SGLT‑2 inhibitors and DPP‑4 inhibitors.

4.5 The Committee discussed the adverse events associated with empagliflozin. It noted that common adverse events associated with SGLT‑2 inhibitors include urinary tract and genital infections, and that these are more common in women than in men. The Committee heard from the clinical specialists that in their experience, in patients treated with empagliflozin the incidence of these infections was low. The Committee was aware that the European public assessment report for empagliflozin reported that cardiovascular adverse events were lower for empagliflozin compared with placebo, even though the follow‑up was short and the analysis included a small number of people. The Committee was concerned about the lack of long‑term efficacy and safety data and heard from the clinical specialists that like other SGLT‑2 inhibitors, empagliflozin therapy would be stopped in patients in whom no adequate clinical response was seen within 6 months. The Committee concluded that the short‑term adverse events of empagliflozin seemed similar to those of other SGLT‑2 inhibitors. The Committee also noted that like other SGLT‑2 inhibitors, long‑term outcomes of empagliflozin treatment were uncertain because of a lack of data.

Cost effectiveness

4.6 The Committee then discussed the original economic model submitted by the company. The Committee noted the ERG's comments regarding its quality and robustness, with the ERG highlighting several errors in the construct of the model which would invalidate any results. The Committee concluded that the company's original model was inherently flawed and so its results could not be considered reliable for making recommendations. The Committee requested further analyses from the company which included revised estimates of the incremental cost‑effectiveness ratios (ICERs) for empagliflozin using a validated economic model, informed by the corrected results of network meta‑analyses and compared with relevant comparators (SGLT‑2 inhibitors and DPP‑4 inhibitors).

4.7 The Committee discussed the new cost‑effectiveness model the company had provided. It noted that as requested in the appraisal consultation document, the new model was a validated model and had been used for previous NICE technology appraisal guidance. The Committee noted that the clinical‑effectiveness data used in the new model were mostly sourced from the new network meta‑analyses. The Committee concluded that the new model and associated results provided a suitable basis for decision‑making.

4.8 The Committee considered the most plausible ICERs for empagliflozin in combination with metformin as dual therapy. Based on clinical specialist opinion, the Committee decided that thiazolidinediones and sulfonylureas were not key comparators in this setting (see section 4.2). The Committee noted that both the company's and ERG's analyses showed that the incremental differences between the costs and QALYS for empagliflozin, canagliflozin 100 mg, canagliflozin 300 mg, dapagliflozin and sitagliptin were small (see sections 3.29 and 3.36). The Committee understood that these low incremental costs and health benefits meant the ICERs could vary dramatically in response to even small changes. The Committee considered that it was important to take this into account when interpreting the ICERs. Overall, the Committee concluded that because of the very small differences in costs and QALYs between empagliflozin and either canagliflozin, dapagliflozin or sitagliptin, empagliflozin as part of a dual therapy with metformin had been shown to be a cost‑effective use of NHS resources. The Committee therefore recommended empagliflozin 10 mg and 25 mg as a treatment option when the alternative treatments would be canagliflozin, dapagliflozin or a DPP‑4 inhibitor, in line with the recommendations in NICE's guideline on type 2 diabetes and NICE technology appraisal guidance on dapagliflozin in combination therapy for treating type 2 diabetes and canagliflozin in combination therapy for treating type 2 diabetes (that is, if there is a significant risk of hypoglycaemia or its consequences or if a sulfonylurea is not tolerated or contraindicated).

4.9 The Committee considered the most plausible ICERs for empagliflozin with metformin and a sulfonylurea as triple therapy. The Committee noted that both the company's and ERG's results showed that there were only small incremental differences in costs and QALYs between empagliflozin, canagliflozin (100 mg and 300 mg) and sitagliptin. It also noted that in the company's analyses, empagliflozin 10 mg was subject to extended dominance (a treatment is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline). The Committee was aware that the marketing authorisation for canagliflozin allows for dose escalation from 100 mg to 300 mg in people who need tighter glycaemic control. The Committee noted that for people having canagliflozin 300 mg, HbA_1c levels would have failed to adequately respond to canagliflozin 100 mg. This is a different population from those who would start empagliflozin in clinical practice. The Committee agreed that there was uncertainty around the ICERs presented for canagliflozin 300 mg compared with empagliflozin 10 mg and empagliflozin 25 mg. Despite this uncertainty, the Committee concluded that because of the small differences in costs and QALYs between empagliflozin, canagliflozin and sitagliptin, empagliflozin 10 mg and 25 mg with metformin and a sulfonylurea in a triple therapy regimen had been shown to be a cost‑effective use of NHS resources and should be recommended as a treatment option for people with type 2 diabetes.

4.10 The Committee considered the most plausible ICERs for empagliflozin with metformin and a thiazolidinedione as triple therapy. The Committee noted that there were only small differences in costs and QALYs between the addition of empagliflozin compared with canagliflozin or sitagliptin. The Committee concluded that empagliflozin 10 mg and 25 mg with metformin and a thiazolidinedione as part of a triple therapy regimen had been shown to be a cost‑effective use of NHS resources and should be recommended as a treatment option for people with type 2 diabetes.

4.11 The Committee considered the most plausible ICERs for empagliflozin as an add‑on treatment to insulin. The Committee concluded that empagliflozin 10 mg and 25 mg had been shown to be a cost‑effective use of NHS resources compared with canagliflozin, dapagliflozin or sitagliptin as an add‑on treatment to insulin because of its very small incremental costs and incremental QALYs. The Committee recommended empagliflozin as a treatment option for people with diabetes that is inadequately controlled by insulin with or without other oral antidiabetic drugs.

Summary of Appraisal Committee's key conclusions