Dapagliflozin (4) – Forxiga®

• 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) Adult patients with type 2 diabetes mellitus in whom diet and exercise alone do not adequately control blood glucose levels, and for whom metformin is not suitable due to intolerance – in patients without high cardiovascular risk

• The additional benefit is not proven.
• No study was presented comparing the treatment with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride) that would have been suitable for assessing the additional benefit of dapagliflozin monotherapy for the treatment of adult patients without high cardiovascular risk who have inadequately controlled type 2 diabetes mellitus, in addition to diet and exercise, when the use of metformin is considered unsuitable due to intolerance.
• Overall, the additional benefit of dapagliflozin as monotherapy compared with the appropriate comparator therapy for this patient group is not proven.

a2) Adult patients with type 2 diabetes mellitus in whom diet and exercise alone do not adequately control blood glucose levels, and for whom metformin is not suitable due to intolerance – in patients at high cardiovascular risk who are receiving further medication to treat cardiovascular risk factors

• The additional benefit is not proven.
• No study has been presented comparing the treatment with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride) that would have been suitable for assessing the additional benefit of dapagliflozin monotherapy for the treatment of adult patients at high cardiovascular risk with inadequately controlled type 2 diabetes mellitus, in addition to diet and exercise, when the use of metformin is considered unsuitable due to intolerance.
• In the DECLARE-TIMI 58 study, which was submitted to assess the added benefit in patients with high cardiovascular risk in combination with other medication to treat cardiovascular risk factors, only 1.9% of patients were treated with dapagliflozin without any further antidiabetic medication.
• Overall, the additional benefit of dapagliflozin as monotherapy compared with the appropriate comparator therapy for this patient group is not proven.

b1) treatment with another blood glucose-lowering medicinal product (other than insulin) – in patients without high cardiovascular risk

• An additional benefit is not proven.
• No study was presented comparing dapagliflozin 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 combination therapy with another blood glucose-lowering medicinal product (other than insulin) in adult patients without high cardiovascular risk and with inadequately controlled type 2 diabetes mellitus, where treatment with another blood glucose-lowering medicinal product (other than insulin), in addition to diet and exercise, does not adequately control blood glucose levels.
• Overall, the additional benefit of dapagliflozin in combination with other antidiabetic medicines compared with the appropriate comparator therapy for this patient group is not proven.

b2) treatment with another blood glucose-lowering medicinal product (other than insulin) – 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.
• Overall, there is a hint of a minor additional benefit of dapagliflozin in combination with other antidiabetic agents compared with the appropriate comparator therapy in this patient group.
• mortality
  • There are no statistically significant differences between the treatment groups with regard to all-cause mortality and the endpoints ‘fatal myocardial infarction’ and ‘fatal stroke’.
  • No statistically significant differences were observed between the treatment groups for the combined endpoint of MACE or for the endpoint of cardiovascular death.
• 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 were observed in each of the individual components.
• Morbidity – Severe heart failure (SMQ 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 were observed in each of the individual components.
• Morbidity – Kidney disease (combined endpoint)
  • ‘Kidney disease’ is a combined endpoint relating to complications arising from kidney disease, comprising the following individual components: confirmed sustained ≥ 40% reduction in eGFR to eGFR < 60 ml/min/1.73 m², end-stage kidney disease, and kidney-related death.
  • For the composite endpoint of kidney disease, as well as for the individual components ‘confirmed sustained reduction in eGFR’ and ‘end-stage kidney disease’, there was a statistically significant difference in favour of dapagliflozin compared with the control.
• Side effects – overall rate of severe adverse events (SAEs)
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
• Side effects – therapy discontinuation due to adverse events (AE)
  • For the endpoints ‘discontinuation due to AEs’, a statistically significant difference was observed to the disadvantage of dapagliflozin compared with the comparator arm.
• Side effects – Bladder cancer
  • For the endpoint of bladder cancer, there is a statistically significant difference in favour of dapagliflozin.
• Overall assessment
  • In the morbidity category, for the endpoints ‘hospitalisation due to heart failure’, ‘severe heart failure (SMQ heart failure)’, the combined endpoint relating to kidney disease or its individual components ‘confirmed sustained ≥ 40% reduction in eGFR’ and ‘end-stage kidney disease’, as well as in the ‘Side Effects’ category for the endpoints ‘overall rate of SAE’ and the specific AE ‘bladder cancer’, statistically significant differences in favour of dapagliflozin were observed in each case.
  • In contrast, the endpoints ‘therapy discontinuation due to AEs’ and the specific AE ‘confirmed diabetic ketoacidosis (DKA)’ each showed a statistically significant difference in favor of dapagliflozin that was disadvantageous.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the comparator arm, the study is, on the whole, subject to uncertainties.
  • Overall, there is a hint of a minor additional benefit of dapagliflozin in combination with other antidiabetic agents compared with the appropriate comparator therapy in this patient group.

c1) treatment with at least two blood glucose-lowering medicinal products (excluding insulin) – in patients without high cardiovascular risk

• The additional benefit is not proven.
• There are no studies comparing dapagliflozin with the appropriate comparator therapy (human insulin in combination with metformin) that would have been suitable for assessing the additional benefit of dapagliflozin in combination therapy with at least two blood glucose-lowering medicinal products (excluding insulin) in adult patients without high cardiovascular risk and with inadequately controlled type 2 diabetes mellitus, where treatment with at least two blood glucose-lowering medicinal products (excluding insulin), in addition to diet and exercise, does not adequately control blood glucose levels.
• Overall, the additional benefit of dapagliflozin in combination with other antidiabetic medicines compared with the appropriate comparator therapy for this patient group is not proven.

c2) treatment with at least two blood glucose-lowering medicinal products (excluding insulin) – 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.
• Overall, there is a hint of a minor additional benefit of dapagliflozin in combination with other antidiabetic agents compared with the appropriate comparator therapy in this patient group.
• mortality
  • There are no statistically significant differences between the treatment groups with regard to all-cause mortality and the endpoints ‘fatal myocardial infarction’ and ‘fatal stroke’.
  • No statistically significant differences were observed between the treatment groups for the combined endpoint of MACE or for the endpoint of cardiovascular death.
• 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 were observed in each of the individual components.
• Morbidity – Severe heart failure (SMQ 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 were observed in each of the individual components.
• Morbidity – Kidney disease (combined endpoint)
  • ‘Kidney disease’ is a combined endpoint relating to complications arising from kidney disease, comprising the following individual components: confirmed sustained ≥ 40% reduction in eGFR to eGFR < 60 ml/min/1.73 m², end-stage kidney disease, and kidney-related death.
  • For the composite endpoint of kidney disease, as well as for the individual components ‘confirmed sustained reduction in eGFR’ and ‘end-stage kidney disease’, there was a statistically significant difference in favour of dapagliflozin compared with the control.
• Side effects – overall rate of severe adverse events (SAEs)
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
• Side effects – therapy discontinuation due to adverse events (AE)
  • For the endpoints ‘discontinuation due to AEs’, a statistically significant difference was observed to the disadvantage of dapagliflozin compared with the control arm.
• Side effects – Bladder cancer
  • For the endpoint of bladder cancer, there is a statistically significant difference in favour of dapagliflozin.
• Overall assessment
  • In the morbidity category, for the endpoints ‘hospitalisation due to heart failure’, ‘severe heart failure (SMQ heart failure)’, the combined endpoint relating to kidney disease or its individual components ‘confirmed sustained ≥ 40% reduction in eGFR’ and ‘end-stage kidney disease’, as well as in the ‘Side Effects’ category for the endpoints ‘overall rate of SAE’ and the specific AE ‘bladder cancer’, statistically significant differences in favour of dapagliflozin were observed in each case.
  • In contrast, the endpoints ‘therapy discontinuation due to AEs’ and the specific AE ‘definite diabetic ketoacidosis (DKA)’ each showed a statistically significant difference in favor of dapagliflozin as a disadvantage.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the comparator arm, the study is, on the whole, subject to uncertainties.
  • Overall, there is a hint of a minor additional benefit of dapagliflozin in combination with other antidiabetic agents compared with the appropriate comparator therapy in this patient group.

d1) treatment with insulin (with or without another blood glucose-lowering agent – in patients without high cardiovascular risk

• The additional benefit is not proven.
• There are no studies comparing it with the appropriate comparator therapy (optimisation of the human insulin regimen, where appropriate + metformin) that would have been suitable for assessing the additional benefit of dapagliflozin in combination therapy with insulin in adult patients without high cardiovascular risk and with inadequately controlled type 2 diabetes mellitus, where treatment with insulin (with or without another blood-glucose-lowering medicinal product) in addition to diet and exercise does not adequately control blood glucose levels.
• Overall, the additional benefit of dapagliflozin in combination with other antidiabetic medicines compared with the appropriate comparator therapy for this patient group is not proven.

d2) treatment with insulin (with or without another blood-glucose-lowering agent) – 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.
• Overall, there is a hint of a minor additional benefit of dapagliflozin in combination with other antidiabetic agents compared with the appropriate comparator therapy in this patient group.
• mortality
  • There are no statistically significant differences between the treatment groups with regard to all-cause mortality and the endpoints ‘fatal myocardial infarction’ and ‘fatal stroke’.
  • No statistically significant differences were observed between the treatment groups for the combined endpoint of MACE or for the endpoint of cardiovascular death.
• 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 were observed in each of the individual components.
• Morbidity – Severe heart failure (SMQ 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 were observed in each of the individual components.
• Morbidity – Kidney disease (combined endpoint)
  • ‘Kidney disease’ is a combined endpoint relating to complications arising from kidney disease, comprising the following individual components: confirmed sustained ≥ 40% reduction in eGFR to eGFR < 60 ml/min/1.73 m², end-stage kidney disease, and kidney-related death.
  • For the composite endpoint of kidney disease, as well as for the individual components ‘confirmed sustained reduction in eGFR’ and ‘end-stage kidney disease’, there was a statistically significant difference in favour of dapagliflozin compared with the control.
• Side effects – overall rate of severe adverse events (SAEs)
  • These data on the overall rate of SAE show a statistically significant advantage for dapagliflozin.
• Side effects – therapy discontinuation due to adverse events (AE)
  • For the endpoints ‘discontinuation due to AEs’, a statistically significant difference was observed to the disadvantage of dapagliflozin compared with the control arm.
• Side effects – Bladder cancer
  • For the endpoint of bladder cancer, there is a statistically significant difference in favour of dapagliflozin.
• Overall assessment
  • In the morbidity category, for the endpoints ‘hospitalisation due to heart failure’, ‘severe heart failure (SMQ heart failure)’, the combined endpoint relating to kidney disease or its individual components ‘confirmed sustained ≥ 40% reduction in eGFR’ and ‘end-stage kidney disease’, as well as in the ‘Side Effects’ category for the endpoints ‘overall rate of SAE’ and the specific AE ‘bladder cancer’, statistically significant differences in favour of dapagliflozin were observed in each case.
  • In contrast, the endpoints ‘therapy discontinuation due to AEs’ and the specific AE ‘definite diabetic ketoacidosis (DKA)’ each showed a statistically significant difference in favor of dapagliflozin that was disadvantageous.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the comparator arm, the study is, on the whole, subject to uncertainties.
  • Overall, there is a hint of a minor additional benefit of dapagliflozin 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.