Dapagliflozin (6) – Forxiga®

• Clinical trials
  • The DAPA-CKD trial was a placebo-controlled, double-blind, randomised trial involving 4,304 patients with chronic kidney disease.
  • The DAPA-HF trial was a placebo-controlled, double-blind, randomised trial involving 4,744 patients with symptomatic heart failure (NYHA class II to IV) and reduced ejection fraction.
  • The DECLARE-TIMI 58 trial is a randomised, double-blind, placebo-controlled, two-arm trial that enrolled patients with type 2 diabetes mellitus who were at high cardiovascular risk.

a) Adults with chronic kidney disease without symptomatic, chronic heart failure as a comorbidity

• Hint for a considerable additional benefit
• Taking into account the uncertainties mentioned, the G-BA concludes that there is a hint of considerable additional benefit when considering the positive effects as a whole.
• mortality
  • In the DAPA-CKD study, a statistically significant lower number of patients died in the dapagliflozin arm compared with the control arm
• Morbidity – end-stage renal disease (ESRD)
  • Statistically significant advantages in favour of dapagliflozin were observed both for the composite endpoint and for the two individual components ‘eGFR < 15 ml/min/1.73 m²’ and ‘chronic dialysis treatment’.
  • For the individual component ‘receipt of a kidney transplant’, no statistically significant difference was observed between the treatment arms; however, very few events occurred in either group.
• Morbidity – total hospitalisations
  • For the endpoint ‘total hospitalisations’, the DAPA-CKD study showed a statistically significant reduction in hospitalisations in the dapagliflozin arm compared with the control arm.
• Morbidity – Myocardial infarction
  • For the composite endpoint ‘myocardial infarction’, comprising the individual components ‘non-fatal myocardial infarction’ and ‘fatal myocardial infarction’, there were no statistically significant differences between the treatment arms.
• Morbidity – Stroke
  • For the composite endpoint ‘stroke’, comprising the individual components ‘non-fatal stroke’ and ‘fatal stroke’, there were no statistically significant differences between the treatment arms.
• Morbidity – Health status (EQ-5D VAS)
  • For a deterioration of ≥ 15 points, there is a statistically significant advantage in favour of dapagliflozin compared with the comparator arm. However, this advantage is no more than marginal.
• Health-related quality of life – impact of renal insufficiency on daily life (KDQOL-36)
  • For the ‘Impact of kidney insufficiency on daily life’ subscale, the DAPA-CKD study showed a significant advantage for dapagliflozin compared with the control arm.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, the DAPA-CKD study showed a statistically significant advantage for dapagliflozin compared with the control arm.
• Side effects – Discontinuation due to adverse events (AE)
  • For the endpoint ‘discontinuation due to AEs’, the DAPA-CKD study showed no statistically significant difference between the treatment arms.
• Side effects – Specific adverse events
  • For the endpoints ‘pneumonia’ and ‘metabolic and nutritional disorders’, the DAPA-CKD study showed a statistically significant advantage for dapagliflozin compared with the control arm in each case.
  • Diabetic ketoacidosis occurred in only 2 (0.1%) patients in the comparator arm; there were no such events in the dapagliflozin arm. No statistically significant difference was observed between the treatment groups for this endpoint.
• Overall assessment
  • The placebo-controlled, double-blind, randomised DAPA-CKD study is available for the benefit assessment; it evaluated the efficacy and safety of dapagliflozin compared with placebo (in each case in addition to optimal standard therapy for renal impairment) over approximately 33 months in patients with chronic renal impairment with an eGFR of ≥ 25 to ≤ 75 ml/min/1.73 m² and albuminuria (UACR: ≥ 200 to ≤ 5000 mg/g).
  • In the mortality category, a statistically significant advantage in favour of dapagliflozin compared with the control arm was observed for the endpoint ‘all-cause mortality’.
  • In the morbidity category, a statistically significant advantage in favour of dapagliflozin was observed for the combined endpoint of ESRD and the individual components eGFR < 15 ml/min/1.73 m² and chronic dialysis treatment.
  • The results regarding the prevention of total hospitalisations support this finding.
  • With regard to health status, as assessed using the EQ-5D VAS, there was a statistically significant advantage for dapagliflozin compared with the control arm in terms of a deterioration of ≥ 15 points; however, this advantage was no more than marginal.
  • For the other endpoints in the morbidity category – myocardial infarction and stroke – there were no statistically significant differences between the treatment arms.
  • In the health-related quality of life category, statistically significant advantages in favour of dapagliflozin were observed only for one subscale of the KDQOL-36 questionnaire (‘impact of renal insufficiency on daily life’).
  • In the ‘side effects’ category, it should be noted that the DAPA-CKD study did not systematically record AEs regardless of severity.
  • Statistically significant advantages in favour of dapagliflozin were observed for SAEs, as well as, in detail, for the specific AEs of pneumonia and metabolic and nutritional disorders.
  • Taking an overall view of the results, based on the positive effects of dapagliflozin in the endpoint categories of mortality, morbidity (ESRD, total hospitalisations) and side effects (SAE, and, in detail, the specific AEs), a considerable additional benefit for dapagliflozin compared with the appropriate comparator therapy is inferred overall.
• Confidence in the findings (probability of additional benefit)
  • Overall, the DAPA-CKD study exhibits uncertainties that limit the statistical significance of the results.
  • With regard to the implementation of the appropriate comparator therapy, there are uncertainties as to the extent to which all opportunities for optimisation were exploited in the study, where a treatment adjustment was indicated.
  • Further uncertainties arise from the fact that no patients with albuminuria and a UACR <200 mg/g were included in the DAPA-CKD study.
  • Furthermore, due to the lack of systematic recording of AEs regardless of severity, the side effects cannot be fully assessed.
  • Against the background of these uncertainties, the certainty of the evidence is therefore classified as ‘a hint’.

b) Adults with chronic kidney disease and symptomatic, chronic heart failure as a comorbidity

• Hint for a minor additional benefit
• Overall, a hint of a minor additional benefit is derived.
• mortality
  • For the endpoint ‘all-cause mortality’, no statistically significant difference was observed between the treatment arms in the CKD patient population of the DAPA-HF study.
• Morbidity – end-stage renal disease (ESRD)
  • No statistically significant differences were observed between the treatment arms, either for the composite endpoint or for its individual components.
• Morbidity – total hospitalisations
  • For the endpoint ‘total hospitalisations’, there were statistically significantly fewer hospitalisations in the dapagliflozin arm compared with the control arm in the CKD patient population of the DAPA-HF study.
• Morbidity – Myocardial infarction
  • For the composite endpoint ‘myocardial infarction’, comprising the individual components ‘non-fatal myocardial infarction’ and ‘fatal myocardial infarction’, there were no statistically significant differences between the treatment arms.
• Morbidity – Stroke
  • For the composite endpoint ‘stroke’, comprising the individual components ‘non-fatal stroke’ and ‘fatal stroke’, there were no statistically significant differences between the treatment arms.
• Morbidity – Health status (EQ-5D VAS)
  • No statistically significant difference was observed between the treatment arms for an improvement of ≥ 15 points.
• Health-related quality of life
  • In the DAPA-HF study, only the disease-specific quality of life for heart failure was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). The pharmaceutical manufacturer did not submit the KCCQ analyses for the CKD patient population of the DAPA-HF study. Consequently, no conclusions regarding quality of life can be drawn.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, a statistically significant advantage was observed in the CKD patient population of the DAPA-HF study, favouring dapagliflozin compared with the control arm.
• Side effects – Discontinuation due to adverse events (AE)
  • For the endpoint ‘discontinuation due to AEs’, no statistically significant difference was observed between the treatment arms in the CKD patient population of the DAPA-HF study.
• Side effects – Specific adverse events
  • Diabetic ketoacidosis did not occur in either treatment arm in the CKD patient population of the DAPA-HF study.
  • For the endpoints ‘non-cardiac chest pain’ and ‘disorders of the respiratory tract, thoracic cavity and mediastinum’, a statistically significant advantage was observed in the CKD patient population of the DAPA-HF study in each case, in favour of dapagliflozin compared with the control arm.
• Overall assessment
  • The placebo-controlled, double-blind, randomised DAPA-HF trial is available for the benefit assessment; this study evaluated the efficacy and safety of dapagliflozin compared with placebo (in each case in addition to optimal standard therapy for heart failure) over approximately 18 months in patients with symptomatic heart failure (NYHA Class II to IV) and reduced ejection fraction.
  • The relevant patient population (CKD patient population) comprises patients with chronic kidney disease with an eGFR < 60 ml/min/1.73 m², who account for 41% of the total population in the DAPA-HF trial.
  • In the mortality category, there were no statistically significant differences between the treatment arms for the endpoint ‘all-cause mortality’.
  • In the morbidity category, there were no statistically significant differences between the treatment arms for the combined endpoint of ESRD or its individual components.
  • For the endpoint ‘total hospitalisation’, statistically significant advantages were observed in favour of dapagliflozin.
  • With regard to health status, as assessed using the EQ-5D VAS, there were no statistically significant differences between the treatment arms for an improvement of ≥ 15 points.
  • For the other endpoints in the morbidity category – myocardial infarction and stroke – there were no statistically significant differences between the treatment arms.
  • In the ‘side effects’ category, it should be noted that the DAPA-HF study did not systematically record AEs regardless of severity.
  • For the ‘specific SAE’ endpoint, statistically significant advantages were observed in favour of dapagliflozin, as well as, in detail, for the specific SAE ‘non-cardiac chest pain’ and ‘disorders of the respiratory tract, thoracic cavity and mediastinum’.
  • Taking an overall view of the results, based on the positive effects of dapagliflozin in preventing total hospitalisations and the advantages in the ‘side effects’ (SAE) category, a minor additional benefit for dapagliflozin compared with the appropriate comparator therapy is inferred.
• Certainty of the findings (probability of additional benefit)
  • Overall, the DAPA-HF study exhibits uncertainties that limit the validity of the results for the CKD patient population.
  • The implementation of the appropriate comparator therapy is subject to uncertainties, resulting in particular from the fact that, despite the data submitted during the commenting procedure, no detailed information is available on treatment optimisations during the course of the study; for example, whether the treatment adjustments involved initiation of treatment, dose increases or dose reductions.
  • Further uncertainties arise from the fact that no data are available on the proportion of patients with albuminuria, as the UACR was not measured.
  • Furthermore, due to the lack of systematic recording of AEs, regardless of their severity, the side effects cannot be fully assessed.
  • Against the background of these uncertainties, the certainty of the evidence is therefore classified in the ‘hint’ category.

Courtesy translation only, please refer to the German original.