Empagliflozin / Metformin (1) – Synjardy®

• Clinical trials
  • In its dossier dated 26 February 2016 on the benefit assessment pursuant to Section 35a of the German Social Code, Book V (SGB V) of the fixed combination of the active substances empagliflozin andmetformin in patients with type 2 diabetes mellitus, including the results of the EMPA-REG-Outcome study.
  • The EMPA-REG-Outcome study investigated treatment objectives relevant to the management of patients with type 2 diabetes mellitus – in particular the prevention of cardiovascular events – over a meaningful period (242 weeks).

a1) The dual combination of empagliflozin and metformin in patients whose treatment with metformin has been discontinued due to inadequate control at the maximum tolerated dose of metformin in addition to diet and exercise – in patients without manifest cardiovascular disease

• For the fixed-dose combination of empagliflozin and metformin in patients without manifest cardiovascular disease who are inadequately controlled on the maximum tolerated dose of metformin in addition to diet and exercise, the additional benefit compared with the appropriate comparator therapy (sulfonylurea (glibenclamide or glimepiride) + metformin) does not provide proof.
• No evidence has been provided by the marketing authorisation holder to demonstrate the additional benefit of empagliflozin (25 mg) in a fixed-dose combination with metformin compared with the appropriate comparator therapy—metformin in combination with a sulphonylurea (glimepiride)—the pharmaceutical manufacturer submitted, firstly, analyses based on the direct comparative study 1245.28.
• The study investigated adult patients with type 2 diabetes mellitus who, despite treatment with metformin at a stable dose of at least 1500 mg/day (or the maximum tolerated dose or maximum dose, depending on the marketing authorisation) for at least 12 weeks had failed to achieve adequate blood glucose control (HbA1c ≥ 7% and ≤ 10% at the start of the run-in phase).
• In the dossier, the pharmaceutical manufacturer presents results from study 1245.28 for the 104-week and 208-week data cut-offs for a patient population that received a daily dose of at least 1,700 mg of metformin during the course of treatment.
• However, in its dossier, the pharmaceutical manufacturer has not provided results for several patient-relevant endpoints (endpoints: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, severe hypoglycaemia, kidney and urinary tract disorders (SOC) and disorders of the reproductive organs and mammary glands (SOC)).
• Even during the commenting procedure, the missing data were not subsequently provided for the relevant patient population, but only for the overall population of patients in study 1245.28.
• As only approximately 70% of the total study population received the required minimum dose of metformin, it cannot be assumed that the data from the total population are transferable to the relevant patient population.
• The data set for the fixed-dose combination of empagliflozin andmetformin is therefore incomplete overall; in particular, there is a lack of analyses of relevant specific adverse events, which cannot be verified due to irreconcilable discrepancies between the information in the study report and the supplementary analyses submitted with the dossier for the relevant patient population.
• In addition, the pharmaceutical manufacturer included in the dossier included indirect comparisons of empagliflozin 10 mg in combination with metformin versus glimepiride in combination with metformin, taking into account studies 1245.28, 1275.1 and 1245.23/1245.31 (indirect comparison I, including the associated sensitivity analyses, referred to by the pharmaceutical manufacturer as indirect comparisons III and IV) and on the basis of studies 1275.1 and 1218.20 (indirect comparison II).
• As already explained, since there are neither plausible nor complete analyses available for the relevant patient population in study 1245.28, the indirect comparisons (indirect comparison I and corresponding sensitivity analyses) based on study 1245.28 are also unsuitable for assessing the additional benefit.

a2) Dual combination of empagliflozin with metformin in patients whose treatment with metformin has been discontinued due to inadequate control at the maximum tolerated dose of metformin in addition to diet and exercise - in patients with established cardiovascular disease, in combination with other medication to treat cardiovascular risk factors

• For the fixed-dose combination of empagliflozin and metformin in patients whose treatment with metformin has been discontinued due to inadequate control, in addition to diet and exercise, and with established cardiovascular disease, in combination with other medication to treat cardiovascular risk factors, the additional benefit compared with the appropriate comparator therapy ((sulphonylurea (glibenclamide or glimepiride) + metformin in combination with further medication to treat cardiovascular risk factors) does not provide proof.
• See the discussion on aspects common to all patient groups, page 7 ff.
• However, for the fixed-dose combination of empagliflozin and metformin, the EMPA-REG-Outcomestudy, no additional benefit can be inferred for patients with type 2 diabetes mellitus who have previously had inadequate blood glucose control and manifest cardiovascular disease, and who are also receiving at least one other blood glucose-lowering medicinal product and further medication to treat cardiovascular risk factors (corresponding to patient groups a2, b2 and c2), as it is not possible to present the results of the EMPA-REG-Outcome study for the fixed-dose combination of empagliflozin and metformin.
• The pharmaceutical manufacturer has based its assessment of the additional benefit of empagliflozin/metformin on the overall population rather than on the relevant patient population – the combination of empagliflozin with metformin at a daily dose of at least 1700 mg.
• However, this is not appropriate, as the relevant patient population comprises only approximately 66 per cent of the EMPA-REG Outcome study and the pharmaceutical manufacturer has not demonstrated that the results from the overall patient population can be extrapolated to the relevant patient population.
• Irrespective of whether a negative interaction test alone is sufficient to assume that the results are transferable, the analyses carried out by the pharmaceutical manufacturer are flawed, as the interaction test was not carried out on the overall population, but on the subgroup of patients treated with metformin.
• Specifically, the pharmaceutical manufacturer is therefore not investigating the generalisability of the results from the overall patient population to the relevant patient population, but rather the generalisability of the results from the subgroup of patients treated with metformin to the relevant patient population, namely those treated with metformin ≥1700 mg; yet, subsequently, it nevertheless analyses the overall population.
• This approach is inherently contradictory and unsuitable for the evaluation of the fixed-dose combination of empagliflozin and metformin.

b1) Combination therapy with other blood glucose-lowering medicinal products (other than insulin) in patients who are inadequately controlled with metformin in combination with these other blood glucose-lowering medicinal products (other than insulin), in addition to diet and exercise - in patients without manifest cardiovascular disease

• For the combination of empagliflozin/metformin with other blood glucose-lowering medicinal products, where these do not adequately control blood glucose levels in addition to diet and exercise, in patients without manifest cardiovascular disease, the additional benefit compared with the appropriate comparator therapy (metformin + human insulin). No proof.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with empagliflozin/metformin in combination with other blood glucose-lowering medicinal products compared with the appropriate comparator therapy (metformin + human insulin).

b2) Combination therapy with other blood glucose-lowering medicinal products (other than insulin) in patients who are inadequately controlled with metformin in combination with these other blood glucose-lowering medicinal products (other than insulin), in addition to diet and exercise - in patients with established cardiovascular disease, in combination with other medication for the treatment of cardiovascular risk factors

• For the combination of empagliflozin/metformin with other blood glucose-lowering medicinal products (other than insulin) in patients who are inadequately controlled with metformin in combination with these other blood glucose-lowering medicinal products (other than insulin) in addition to diet and exercise, and who have established cardiovascular disease in combination with further medication to treat cardiovascular risk factors, the additional benefit compared with the appropriate comparator therapy (metformin + human insulin in combination with further medication to treat cardiovascular risk factors) does not provide proof.
• See the discussion on aspects common to all patient groups, page 7 ff.

c1) Combination therapy with insulin in patients whose glycaemic control is inadequate with metformin in combination with insulin, in addition to diet and exercise – in patients without manifest cardiovascular disease

• For the combination of empagliflozin/metformin with insulin in patients who are inadequately controlled with metformin in combination with insulin, in addition to diet and exercise, and who do not have manifest cardiovascular disease, the additional benefit compared with the appropriate comparator therapy (metformin + human insulin). No proof.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with empagliflozin/metformin in combination with insulin compared with the appropriate comparator therapy (metformin + human insulin).

c2) Combination therapy with insulin in patients who have had their metformin-based treatment discontinued in combination with insulin, in addition to diet and exercise – in patients with manifest cardiovascular disease in combination with further medication to treat cardiovascular risk factors

• For the combination of empagliflozin/metformin with insulin in patients who are inadequately controlled with metformin in combination with insulin, in addition to diet and exercise, and who have manifest cardiovascular disease in combination with further medication to treat cardiovascular risk factors, the additional benefit compared with the appropriate comparator therapy (metformin + human insulin in combination with other medication to treat cardiovascular risk factors) does not provide proof.
• See the discussion on aspects common to all patient groups, page 7 et seq.

Courtesy translation only, please refer to the German original.