Dapagliflozin / Metformin (3) – Xigduo®

• Clinical trials
  • The DECLARE-TIMI 58 trial enrolled adult patients aged ≥ 40 years with type 2 diabetes mellitus and an HbA1c level in the range of ≥ 6.5 % and < 12 %, who were at high cardiovascular risk.
  • The DECLARE-TIMI 58 trial was a randomised, double-blind, placebo-controlled, two-arm study conducted at multiple centres in Africa, Asia, Australia, Europe, and North and South America.

a1) Treatment with another blood glucose-lowering medicinal product (other than insulin; here – in patients without high cardiovascular risk

• An additional benefit is not proven.
• No study was presented comparing the drug with the appropriate comparator therapy (metformin in combination with a sulphonylurea or with empagliflozin) that would have been suitable for assessing the additional benefit of dapagliflozin in a fixed-dose combination with metformin in adult patients without high cardiovascular risk and with inadequately controlled type 2 diabetes mellitus, where treatment with metformin alone at the maximum tolerated dose, in addition to diet and exercise, does not adequately control blood glucose levels.
• Overall assessment
  • Overall, the additional benefit of the fixed-dose combination of dapagliflozin andmetformin for patients who are inadequately controlled with metformin alone at the maximum tolerated dose or with metformin in combination with other antidiabetic agents does not provide proof that it is superior to the appropriate comparator therapy for this patient group.

a2) Treatment with another blood-glucose-lowering medicinal product (other than insulin; in this context – for patients at high cardiovascular risk who are receiving further medication to treat cardiovascular risk factors

• Hint for a minor additional benefit
• See the discussion on aspects common to all patient groups, p. 10 ff.
• Morbidity – hospitalisation due to heart failure
  • In the combined endpoint of heart failure, comprising the individual components ‘hospitalisation due to heart failure’ and ‘severe heart failure (SMQ heart failure)’, statistically significant differences in favour of dapagliflozin are evident in each of the individual components.
• Morbidity – kidney disease (combined endpoint)
  • Statistically significant differences in favour of dapagliflozin were observed both in the combined endpoint relating to kidney disease and in the individual components ‘confirmed sustained ≥ 40% reduction in eGFR’.
• Side effects
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
  • With regard to side effects, there is a statistically significant advantage for dapagliflozin compared with the comparator arm in terms of the overall rate of SAE.
  • Statistically significant effects in favour of dapagliflozin were also observed for the following specific AEs: ‘bladder cancer’, ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’.
  • For the endpoint ‘bladder cancer’ and the SOC-based endpoints ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’, there is a statistically significant difference in favour of dapagliflozin in each case.
• quality of life
  • Endpoints relating to the quality of life category were not assessed in the study.
• Overall review
  • Overall, there is a hint of a minor additional benefit for the fixed-dose combination of dapagliflozin/metformin for patients who are inadequately controlled on metformin alone at the maximum tolerated dose or on metformin in combination with other antidiabetic agents, compared with the appropriate comparator therapy in this patient group.

b1) Treatment with at least two blood glucose-lowering medicinal products (including metformin; in patients without high cardiovascular risk

• An additional benefit is not proven.
• There are no studies comparing the drug with the appropriate comparator therapy (human insulin in combination with metformin) that would have been suitable for assess the additional benefit of dapagliflozin in a fixed-dose combination with metformin and in combination with other antidiabetic medicinal products in adult patients without high cardiovascular risk who have inadequately controlled type 2 diabetes mellitus, where treatment with at least two blood glucose-lowering medicinal products, including metformin (excluding insulin), in addition to diet and exercise, does not adequately control blood glucose levels.
• Overall assessment
  • Overall, the additional benefit of the fixed-dose combination of dapagliflozin andmetformin for patients who are inadequately controlled with metformin alone at the maximum tolerated dose or with metformin in combination with other antidiabetic agents does not provide proof that it is superior to the appropriate comparator therapy for this patient group.

b2) Treatment with at least two blood-glucose-lowering medicinal products (including metformin; in patients at high cardiovascular risk who are receiving further medication to treat cardiovascular risk factors

• Hint for a minor additional benefit
• See the discussion on aspects common to all patient groups, p. 10 ff.
• Morbidity – hospitalisation due to heart failure
  • In the combined endpoint of heart failure, comprising the individual components ‘hospitalisation due to heart failure’ and ‘severe heart failure (SMQ heart failure)’, statistically significant differences in favour of dapagliflozin are evident in each of the individual components.
• Morbidity – kidney disease (combined endpoint)
  • Statistically significant differences in favour of dapagliflozin were observed both in the combined endpoint relating to kidney disease and in the individual components ‘confirmed sustained ≥ 40% reduction in eGFR’.
• Side effects
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
  • With regard to side effects, there is a statistically significant advantage for dapagliflozin compared with the comparator arm in terms of the overall rate of SAE.
  • Statistically significant effects in favour of dapagliflozin were also observed for the following specific AEs: ‘bladder cancer’, ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’.
  • For the endpoint ‘bladder cancer’ and the SOC-based endpoints ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’, there is a statistically significant difference in favour of dapagliflozin in each case.
• quality of life
  • Endpoints relating to the quality of life category were not assessed in the study.
• Overall review
  • Overall, there is a hint of a minor additional benefit for the fixed-dose combination of dapagliflozin/metformin for patients who are inadequately controlled on metformin alone at the maximum tolerated dose or on metformin in combination with other antidiabetic agents, compared with the appropriate comparator therapy in this patient group.

c1) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with insulin (or another blood-glucose-lowering medicinal product, in this case metformin) do not adequately control blood glucose levels – in patients without high cardiovascular risk

• The additional benefit is not proven.
• There are no studies comparing the treatment with the appropriate comparator therapy (optimisation of the human insulin regimen) that would have been suitable for to assess the additional benefit of dapagliflozin in a fixed-dose combination with metformin and in combination with other blood glucose-lowering medicinal products, including insulin, in adult patients without high cardiovascular risk who have inadequately controlled type 2 diabetes mellitus, where treatment with insulin (or another blood-glucose-lowering medicinal product, in this case metformin), in addition to diet and exercise, does not adequately control blood glucose levels.
• Overall review
  • In the overall review, the additional benefit of the fixed-dose combination of dapagliflozin andmetformin for patients who are inadequately controlled with metformin alone at the maximum tolerated dose or with metformin in combination with other antidiabetic medicines does not provide proof that it is superior to the appropriate comparator therapy for this patient group.

c2) Adult patients with type 2 diabetes mellitus whose blood glucose levels are not adequately controlled by diet and exercise and by treatment with insulin (with another blood-glucose-lowering medicinal product, in this case metformin) do not adequately control blood glucose – in patients at high cardiovascular risk who are receiving further medication to treat cardiovascular risk factors

• Hint for a minor additional benefit
• See the discussion on aspects common to all patient groups, p. 10 ff.
• Morbidity – hospitalisation due to heart failure
  • In the combined endpoint of heart failure, comprising the individual components ‘hospitalisation due to heart failure’ and ‘severe heart failure (SMQ heart failure)’, statistically significant differences in favour of dapagliflozin are evident in each of the individual components.
• Morbidity – kidney disease (combined endpoint)
  • Statistically significant differences in favour of dapagliflozin were observed both in the combined endpoint relating to kidney disease and in the individual components ‘confirmed sustained ≥ 40% reduction in eGFR’.
• Side effects
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
  • With regard to side effects, there is a statistically significant advantage for dapagliflozin compared with the comparator arm in terms of the overall rate of SAE.
  • Statistically significant effects in favour of dapagliflozin were also observed for the following specific AEs: ‘bladder cancer’, ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’.
  • For the endpoint ‘bladder cancer’ and the SOC-based endpoints ‘disorders of the respiratory tract, thoracic cavity and mediastinum’ and ‘liver and biliary tract disorders’, there is a statistically significant difference in favour of dapagliflozin in each case.
• quality of life
  • Endpoints relating to the quality of life category were not assessed in the study.
• Overall review
  • Overall, there is a hint of a minor additional benefit for the fixed-dose combination of dapagliflozin/metformin for patients who are inadequately controlled on metformin alone at the maximum tolerated dose or on metformin in combination with other antidiabetic agents, compared with the appropriate comparator therapy in this patient group.

Courtesy translation only, please refer to the German original.