Empagliflozin (2) – Jardiance®

• Clinical trials
  • The EMPA-REG-Outcome trial was a randomised, three-arm, placebo-controlled, double-blind trial conducted at multiple centres in North America, Latin America, Europe, Africa and Asia.
  • This two-arm, double-blind, multicentre, randomised clinical trial investigated the efficacy and safety of empagliflozin 25 mg in combination with metformin compared with a combination of metformin and glimepiride over a total period of 208 weeks.
  • Study 1275.1 is a five-arm, double-blind, multicentre, randomised clinical trial which investigated the efficacy and safety of empagliflozin in combination with metformin and/or linagliptin compared with a combination of metformin and linagliptin over a period of 52 weeks.

a1) As monotherapy, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is considered unsuitable due to intolerance – a1) in patients without manifest cardiovascular disease

• An additional benefit is not proven.
• No study has been submitted to assess the additional benefit of empagliflozin monotherapy – where diet and exercise alone do not adequately control blood glucose and the use of metformin is deemed unsuitable due to intolerance – compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride) in patients without manifest cardiovascular disease.

a2) As monotherapy, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is deemed unsuitable due to intolerance – a2) in patients with manifest cardiovascular disease in combination with other medication for the treatment of cardiovascular risk factors

• An additional benefit is not proven.
• No study has been submitted to assess the additional benefit of (antidiabetic) empagliflozin monotherapy – where diet and exercise alone do not adequately control blood glucose and the use of metformin is deemed unsuitable due to intolerance – compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride in combination with other medication to treat cardiovascular risk factors) in patients with manifest cardiovascular disease.
• In the EMPA study on the additional benefit in patients with manifest cardiovascular disease and additional medication for cardiovascular risk factors-REG-Outcome study, which was submitted to assess the added benefit in patients with established cardiovascular disease in combination with other medication to treat cardiovascular risk factors, only approximately 2% of patients were treated with empagliflozin without any other antidiabetic medication.
• Furthermore, it is unclear to what extent this applies to these patients, or what proportion of patients met the authorisation criterion of ‘metformin intolerance when diet and exercise alone do not adequately control blood glucose levels’.

b1.1) In combination with another blood-glucose-lowering medicinal product (other than insulin), where this, together with diet and exercise, does not adequately control blood glucose – In dual combination with metformin – b1.1) in patients without manifest cardiovascular disease

• For the dual combination of empagliflozin with metformin, where metformin alone, together with diet and exercise, does not adequately control blood glucose, in patients without manifest cardiovascular disease, there is a hint of a minor additional benefit compared with the appropriate comparator therapy (sulphonylurea (glibenclamide or glimepiride) in combination with metformin).
• The G-BA classifies the extent of the additional benefit of empagliflozin in combination with metformin as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic goal in the treatment of the disease.
• Compared with the appropriate comparator therapy of a sulphonylurea (glimepiride) in combination with metformin, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as it results in a small reduction in the extent of serious symptoms (prevention of non-fatal myocardial infarctions) as well as a relevant reduction in individual non-serious side effects (non-severe symptomatic hypoglycaemia).
• mortality
  • In the overall study population, there was no significant difference in overall mortality (patients with an event: 8 (1.0%) on empagliflozin vs. 8 (1.0%) on glimepiride, RR 1.02, 95% CI [0.32; 2.70], p > 0.999). There is therefore no proof of additional benefit from empagliflozin with regard to the endpoint of all-cause mortality.
• Morbidity – Major Adverse Cardiovascular Events (MACE 3)
  • No statistically significant difference was observed between the treatment groups for the MACE 3 endpoint (patients with an event: 15 (2.0%) empagliflozin + metformin vs. 25 (3.2%) glimepiride + metformin, RR 0.61, 95% CI [0.33; 1.15]; p = 0.132).
  • For the component of non-fatal myocardial infarction, however, a statistically significant effect in favour of empagliflozin was observed (patients with an event: 4 (0.5%) on empagliflozin plus metformin versus 13 (1.7%) on glimepiride plus metformin, RR 0.31, 95% CI [0.10; 0.96]; p = 0.032). For the endpoint of non-fatal myocardial infarction, there is therefore an additional benefit of empagliflozin in combination with metformin compared with the appropriate comparator therapy, glimepiride in combination with metformin.
• Morbidity – change in body weight
  • Furthermore, a reduction in body weight (-3.44 kg vs. 1.21 kg, mean difference = -4.64, 95% CI [-5.04; -4.25], p < 0.001) was observed.
• Health-related quality of life
  • No usable data on quality of life were presented. An additional benefit or less benefit of empagliflozin with regard to quality of life is not proven.
  • In study 1245.28, data on health status were collected using the EQ-5D VAS (Euro-Qol-5D visual analogue scale) questionnaire. As the analysis was carried out without imputing missing values, and the proportion of patients excluded from the analysis was over 30 per cent, whilst the difference in the proportions of excluded patients between the groups was over 15 per cent, the data are not suitable for drawing conclusions regarding differences in treatment outcomes between the study arms.
• Side effects – hypoglycaemia
  • In the study, symptomatic hypoglycaemia (plasma glucose level ≤ 54 mg/dl) occurred statistically significantly less frequently in the empagliflozin arm compared with the glimepiride arm after a total of 208 weeks (5 (0.7%) vs. 84 (10.8 %); RR = 0.06, 95 % CI [0.02; 0.15], p < 0.001).
  • The same applies to symptomatic hypoglycaemia with a plasma glucose level between 54 and 70 mg/dl (13 (1.7 %) vs. 104 (13.3 %); RR = 0.13, 95% CI [0.07; 0.22], p < 0.001).
  • No relevant analyses were available for severe hypoglycaemia.
• Side effects – Serious adverse events (SAEs)
  • With regard to the rate of serious adverse events, no statistically significant difference was observed between the treatment arms after 208 weeks (161 (21.0%) vs. 153 (19.6%); RR = 1.07, 95% CI [0.88; 1.31], p = 0.533).
• Side effects – discontinuation due to adverse events (AE)
  • Similarly, with regard to discontinuation due to adverse events, there was no statistically significant difference between the treatment arms after 208 weeks (48 (6.3%) vs. 52 (6.7%); RR = 0.94, 95% CI [0.64; 1.38], p = 0.809).
• Side effects – renal and urinary tract disorders
  • However, for other endpoints relating to side effects investigated in the study, statistically significant differences were observed to the detriment of empagliflozin. This applies, on the one hand, to kidney and urinary tract disorders (146 (19.1%) empagliflozin + metformin vs. 91 (11.7%) glimepiride + metformin; RR = 1.64, 95% CI [1.28; 2.08], p < 0.001).
• Side effects – disorders of the genital organs and breast (genital infections)
  • Diseases of the genital organs and mammary glands (117 (15.3%) empagliflozin + metformin vs. 66 (8.5%) glimepiride + metformin; RR = 1.81, 95% CI [1.36; 2.40], p < 0.001), including, in particular, genital infections (104 (13.6%) empagliflozin + metformin vs. 30 (3.8%) glimepiride + metformin; RR = 3.54, 95% CI [2.38; 5.24], p < 0.001).
• Overall assessment
  • However, an overall assessment of the available results on mortality, morbidity and side effects does not reveal any sustained and, compared with the appropriate comparator therapy, previously unattained significant improvement in treatment-related benefit; in particular, there is no prolongation of life expectancy and no relevant reduction in serious side effects.
  • Therefore, classification as ‘considerable additional benefit’ is not justified.

b1.2) In combination with another blood glucose-lowering medicinal product (other than insulin), if this does not adequately control blood glucose levels in conjunction with diet and exercise – In dual combination with metformin – in patients with manifest cardiovascular disease, in combination with other medication for the treatment of cardiovascular risk factors

• For the combination of empagliflozin with metformin, where metformin alone, together with diet and exercise, does not adequately control blood glucose, in patients with established cardiovascular disease, in combination with other medication to treat cardiovascular risk factors, there is a hint of considerable additional benefit compared with the appropriate comparator therapy (sulfonylurea (glibenclamide or glimepiride) plus metformin, in combination with other medication to treat cardiovascular risk factors).
• The G-BA classifies the extent of the additional benefit of empagliflozin as considerable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a significant improvement in treatment-related benefit that has not previously been achieved, as it results in a moderate prolongation of life expectancy and the prevention of serious symptoms (heart failure, renal failure).
• Morbidity – renal failure and long-term renal replacement therapy
  • For the endpoints of renal failure (HR 0.56, 95% CI [0.39; 0.79]; p < 0.001) and the initiation of long-term renal replacement therapy (HR 0.45, 95% CI [0.21; 0.97]; p = 0.041), a statistically significant advantage of empagliflozin was demonstrated in each case.
• Morbidity – Non-fatal heart attacks and strokes
  • For non-fatal myocardial infarctions and when fatal and non-fatal myocardial infarctions are considered together, the result is not statistically significant.
  • For strokes, the trend was unfavourable for empagliflozin; the result was also not statistically significant.
• Morbidity – Diabetes-related eye diseases
  • For endpoints relating to diabetes-related eye diseases (retinal photocoagulation, vitreous haemorrhage, diabetes-related blindness), no statistically significant result is observed in any case.
• Health-related quality of life
  • Data on quality of life were not collected in the study.
• Side effects – overall rates of adverse events (AEs)
  • The results on overall AE rates (serious adverse events and discontinuations due to AEs) are not interpretable, as these endpoints also included secondary complications that are already reflected in the endpoints mentioned above.
  • Analyses of overall AE rates excluding secondary complications were not provided by the pharmaceutical manufacturer.
• Side effects – hypoglycaemia
  • With regard to specific AEs, there is no notable difference in the incidence of hypoglycaemia, although no valid analyses were available for the endpoint ‘severe hypoglycaemia’.
• Side effects – disorders of the genital organs and mammary glands (genital infections)
  • For the SOC endpoints ‘disorders of the genital organs and mammary glands’ (RR 1.60, 95% CI [1.33; 1.93]; p < 0.001), including ‘genital infections’ (RR 3.57; 95% CI [2.59; 4.91]; p < 0.001), a statistically significant result was observed in each case to the detriment of empagliflozin.
• Side effects – diseases of the kidneys and urinary tract
  • However, for the SOC ‘kidney and urinary tract disorders’, the result is not statistically significant.
• Overall assessment
  • In the overall assessment of the results, an advantage of empagliflozin – particularly with regard to all-cause mortality, mainly due to a difference in cardiovascular mortality – as well as advantages for endpoints relating to heart failure and for the endpoint of renal failure, there are disadvantages regarding diseases of the genital organs and the breast, particularly genital infections; however, after weighing up the respective clinical relevance of the events, this does not justify downgrading the extent of the additional benefit.
  • Overall, this therefore results in a considerable additional benefit of empagliflozin in patients with type 2 diabetes mellitus with established cardiovascular disease and previously inadequate blood glucose control, in addition to at least another blood glucose-lowering medicinal product and other medication for the treatment of cardiovascular risk factors, compared with the appropriate comparator therapy.

b2.1) In combination with another blood glucose-lowering medicinal product (other than insulin), if this does not adequately control blood glucose levels in conjunction with diet and exercise – In dual combination with another blood glucose-lowering medicinal product other than metformin and insulin – b2.1) in patients without manifest cardiovascular disease

• For combination therapy with empagliflozin and another blood glucose-lowering medicinal product other than metformin and insulin, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is considered unsuitable due to intolerance, the additional benefit is not proven in patients without manifest cardiovascular disease.
• No study has been submitted to assess the additional benefit of treatment with empagliflozin in combination with another blood glucose-lowering medicinal product other than metformin and insulin, where diet and exercise alone do not adequately control blood glucose and the use of metformin is deemed unsuitable due to intolerance, in patients without manifest cardiovascular disease, compared with the appropriate comparator therapy (metformin + sulphonylurea).

b2.2) In combination with another blood glucose-lowering medicinal product (other than insulin), if this, together with diet and exercise, does not adequately control blood glucose – In dual combination with another blood glucose-lowering medicinal product other than metformin and insulin – b2.2) in patients with manifest cardiovascular disease¹ in combination with other medication for the treatment of cardiovascular risk factors

• For the combination of empagliflozin with another blood glucose-lowering medicinal product other than metformin and insulin, where this medicinal product does not adequately control blood glucose levels in conjunction with diet and exercise, in patients with established cardiovascular disease in combination with further medication to treat cardiovascular risk factors, there is a hint of a considerable additional benefit.
• See the discussion on aspects common to all patient groups, page 8 ff.
• Morbidity – renal failure and long-term renal replacement therapy
  • For the endpoints of renal failure (HR 0.56, 95% CI [0.39; 0.79]; p < 0.001) and the initiation of long-term renal replacement therapy (HR 0.45, 95% CI [0.21; 0.97]; p = 0.041), a statistically significant advantage of empagliflozin was observed in each case.
• Morbidity – Non-fatal heart attacks and strokes
  • For non-fatal myocardial infarctions and when fatal and non-fatal myocardial infarctions are considered together, the result is not statistically significant.
  • For strokes, the trend was unfavourable to empagliflozin; the result was also not statistically significant.
• Health-related quality of life
  • Data on quality of life were not collected in the study.
• Side effects – diseases of the genital organs and mammary glands (genital infections)
  • For the SOC endpoints ‘Diseases of the genital organs and mammary glands’ (RR 1.60, 95% CI [1.33; 1.93]; p < 0.001), including ‘genital infections’ (RR 3.57; 95% CI [2.59; 4.91]; p < 0.001), a statistically significant result was observed in each case to the detriment of empagliflozin.
• Overall assessment
  • In the overall assessment of the results, an advantage of empagliflozin—particularly with regard to all-cause mortality, mainly due to a difference in cardiovascular mortality— as well as advantages for endpoints relating to heart failure and for the endpoint of renal failure, are offset by disadvantages regarding diseases of the genital organs and the breast, particularly genital infections; however, after weighing up the respective clinical relevance of the events, this does not justify downgrading the extent of the additional benefit.

c1) In combination with at least two other blood glucose-lowering medicinal products, if these do not adequately control blood glucose levels in addition to diet and exercise – c1) in patients without manifest cardiovascular disease

• For the combination of empagliflozin with at least two other blood glucose-lowering medicinal products, where these fail to adequately control blood glucose in addition to diet and exercise, in patients without manifest cardiovascular disease, the additional benefit is not proven.
• No study has been submitted that is suitable for assessing the additional benefit of treatment with empagliflozin in combination with at least two 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 in combination with further medication to treat cardiovascular risk factors, compared with the appropriate comparator therapy (metformin + human insulin).

c2) In combination with at least two other blood glucose-lowering medicinal products, where these fail to adequately control blood glucose levels despite diet and exercise – in patients with manifest cardiovascular disease, in combination with further medication to treat cardiovascular risk factors

• There is a hint of considerable additional benefit for the combination of empagliflozin with at least two other blood glucose-lowering medicinal products, where these do not adequately control blood glucose levels in addition to diet and exercise, in patients with established cardiovascular disease.
• See the discussion on aspects common to all patient groups, page 8 ff.
• Morbidity – renal failure and long-term renal replacement therapy
  • For the endpoints of renal failure (HR 0.56, 95% CI [0.39; 0.79]; p < 0.001) and the initiation of long-term renal replacement therapy (HR 0.45, 95% CI [0.21; 0.97]; p = 0.041), a statistically significant advantage of empagliflozin was observed in each case.
• Health-related quality of life
  • Data on quality of life were not collected in the study.
• Side effects – diseases of the genital organs and breast (genital infections)
  • For the SOC endpoints ‘Diseases of the genital organs and mammary glands’ (RR 1.60, 95% CI [1.33; 1.93]; p < 0.001), including ‘genital infections’ (RR 3.57; 95% CI [2.59; 4.91]; p < 0.001), a statistically significant result was observed in each case to the detriment of empagliflozin.
• Overall assessment
  • In the overall assessment of the results, an advantage of empagliflozin—particularly with regard to all-cause mortality, mainly due to a difference in cardiovascular mortality— as well as advantages for endpoints relating to heart failure and for the endpoint of renal failure, are offset by disadvantages regarding diseases of the genital organs and the breast, particularly genital infections; however, after weighing up the respective clinical relevance of the events, this does not justify downgrading the extent of the additional benefit.

d1) In combination with insulin (with or without an oral antidiabetic agent) – d1) in patients without manifest cardiovascular disease

• The additional benefit of the combination of empagliflozin with insulin (with or without an oral antidiabetic agent) in patients without manifest cardiovascular disease is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with empagliflozin in combination with insulin (with or without an oral antidiabetic agent) in patients without manifest cardiovascular disease, compared with the appropriate comparator therapy (metformin + human insulin).

d2) In combination with insulin (with or without an oral antidiabetic agent) – d2) in patients with manifest cardiovascular disease¹ in combination with further medication for the treatment of cardiovascular risk factors

• There is a hint of considerable additional benefit for the combination of empagliflozin with insulin (with or without an oral antidiabetic agent) in patients with manifest cardiovascular disease, in combination with further medication to treat cardiovascular risk factors.
• See the discussion on aspects common to all patient groups, page 8 ff.
• Morbidity – renal failure and long-term renal replacement therapy
  • For the endpoints of renal failure (HR 0.56, 95% CI [0.39; 0.79]; p < 0.001) and the initiation of long-term renal replacement therapy (HR 0.45, 95% CI [0.21; 0.97]; p = 0.041), a statistically significant advantage of empagliflozin was observed in each case.
• Health-related quality of life
  • Data on quality of life were not collected in the study.
• Side effects – diseases of the genital organs and breast (genital infections)
  • For the SOC endpoints ‘Diseases of the genital organs and mammary glands’ (RR 1.60, 95% CI [1.33; 1.93]; p < 0.001), including ‘genital infections’ (RR 3.57; 95% CI [2.59; 4.91]; p < 0.001), a statistically significant result was observed in each case to the detriment of empagliflozin.
• Overall assessment
  • In the overall assessment of the results, an advantage of empagliflozin—particularly with regard to all-cause mortality, mainly due to a difference in cardiovascular mortality— as well as advantages for endpoints relating to heart failure and for the endpoint of renal failure, are offset by disadvantages regarding diseases of the genital organs and the breast, particularly genital infections; however, after weighing up the respective clinical relevance of the events, this does not justify downgrading the extent of the additional benefit.

Courtesy translation only, please refer to the German original.