Empagliflozin (1) – Jardiance®

• Clinical trials
  • This two-arm, double-blind, multicentre, randomised clinical trial investigated the efficacy and safety of empagliflozin in combination with metformin compared with a combination of metformin and glimepiride over a period of 104 weeks.
  • Study 1275.1 is a five-arm, double-blind, multicentre, randomised clinical trial in which the efficacy and safety of empagliflozin in combination with metformin and/or linagliptin were investigated in comparison with a combination of metformin and linagliptin over a period of 52 weeks.

a) As monotherapy, when diet and exercise alone do not adequately control blood glucose levels and the use of metformin is considered unsuitable due to intolerance

• For monotherapy with empagliflozin, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is deemed unsuitable due to intolerance, the additional benefit is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of empagliflozin monotherapy, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride).

b1) In combination with another blood glucose-lowering medicinal product (other than insulin), where this medicinal product, together with diet and exercise, does not adequately control blood glucose – In dual combination with metformin

• In its summary assessment of the data submitted, the G-BA concludes that, for empagliflozin in dual combination with metformin – where metformin, together with diet and exercise, does not adequately control blood glucose – no additional benefit has been identified compared with the appropriate comparator therapy – metformin in combination with a sulphonylurea (glibenclamide or glimepiride).
• Mortality and morbidity
  • Results regarding overall mortality and cardiovascular or cerebrovascular events (MACE: major adverse cardiovascular events) could only be inferred from the data on adverse events (AE).
  • The study was not designed to provide proof of an advantage of empagliflozin in combination with metformin over glimepiride in combination with metformin with regard to these patient-relevant endpoints.
  • The results cannot be conclusively assessed, particularly in light of the fact that the above-mentioned endpoints were defined as safety endpoints (and were therefore not adjudicated by an independent endpoint committee), the low number of events, the lack of follow-up for patients who discontinued treatment, and the relatively short duration of follow-up.
  • Long-term data on overall survival, cardiovascular safety and the general safety profile are not yet available for empagliflozin (in combination with metformin).
  • Furthermore, weight loss (-3.12 kg vs. 1.34 kg, mean difference = 4.46, 95% CI [-4.81; -4.10], p < 0.001) was observed.
  • However, the significance or impact of the observed weight loss over the long term, particularly with regard to cardiovascular safety, remains unclear.
• quality of life
  • No usable data are available.
• Side effects
  • In the study, symptomatic hypoglycaemia (PG ≤ 54 mg/dl) occurred statistically significantly less frequently in the empagliflozin arm than in the glimepiride arm (5 (0.7%) vs. 62 (7.9%); RR = 0.08, 95% CI [0.03; 0.20], p < 0.001).
  • The same applies to symptomatic hypoglycaemia with a plasma glucose level between 54 and 70 mg/dl (8 (1.0 %) vs. 104 (13.3 %); RR = 0.08, 95% CI [0.04; 0.16], p < 0.001).
  • No relevant analysis was available regarding the occurrence of severe hypoglycaemia.
  • It should be borne in mind that the severity of hypoglycaemia correlates with the extent of the reduction in blood glucose levels.
  • In the empagliflozin arm, a minor initial reduction in HbA1c levels was observed.
  • In the glimepiride arm, a particularly high number of first events occurred during the titration period in the first 12 weeks; however, even after HbA1c levels had stabilised in both arms (around week 40), confirmed episodes of hypoglycaemia occurred more frequently with glimepiride than in the empagliflozin arm.
  • Regardless of the dose administered, a difference in the incidence of hypoglycaemia between the two treatment arms remained apparent as the study progressed.
  • However, the extent of the drug-specific effect in favour of empagliflozin on hypoglycaemia remains unclear.
  • For other endpoints relating to side effects investigated in the study, statistically significant differences were observed to the detriment of empagliflozin.
  • For example, the rate of serious adverse events differed significantly between the treatment arms to the detriment of empagliflozin (119 (15.6%) vs. 89 (11.4%); RR = 1.36, 95% CI [1.06; 1.76], p = 0.017).
  • Furthermore, the proportion of patients with non-serious adverse events was significantly higher in the empagliflozin arm.
  • This applies to renal and urinary tract disorders (112 (14.6%) vs. 55 (7.1%); RR = 2.02, 95% CI [1.50; 2.73], p < 0.001), disorders of the genital organs and mammary glands (91 (11.9%) vs. 46 (5.9%); RR = 1.95, 95% CI [1.40; 2.73], p < 0.001) and genital infections (90 (11.8%) vs. 17 (2.2%); RR = 5.40, 95% CI [3.25; 8.98], p < 0.001).
  • With regard to the endpoint ‘kidney and urinary tract diseases’, it should be noted that this endpoint includes relevant events, even if not all of them can be categorised as urinary tract infections.
  • With regard to the endpoint ‘diseases of the genital organs and the breast’, it should be noted that an overlap with the endpoint ‘genital infections’ cannot alone explain the observed difference, as the majority of events captured by the ‘diseases of the genital organs and mammary glands’ endpoint were not captured by the predefined ‘genital infections’ endpoint.
  • Thus, any advantage of empagliflozin in terms of non-serious hypoglycaemia is offset by disadvantages in terms of other non-serious adverse events (including, kidney and urinary tract disorders and genital infections), as well as serious adverse events (SAEs overall).
• Overall assessment
  • In the overall assessment of study 1245.28, due to the methodological shortcomings described, the results cannot be interpreted with sufficient certainty, particularly with regard to the hypoglycaemia rate, but also with regard to non-serious adverse events (including kidney and urinary tract disorders, as well as genital infections) and serious adverse events (total SAEs).
  • Long-term data for empagliflozin on patient-relevant endpoints and the general safety profile are not yet available.

b2) In combination with another blood glucose-lowering medicinal product (other than insulin), if this does not adequately control blood glucose in conjunction with diet and exercise – In dual combination with another blood glucose-lowering medicinal product other than metformin and insulin

• 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.
• 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, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + sulphonylurea).

c) 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

• For the combination of empagliflozin with at least two other blood glucose-lowering medicinal products, where these do not adequately control blood glucose in addition to diet and exercise, the additional benefit is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with empagliflozin in combination with at least two other blood glucose-lowering medicinal products, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + human insulin).

d) In combination with insulin (with or without an oral antidiabetic agent)

• For the combination of empagliflozin with insulin (with or without an oral antidiabetic agent), the additional benefit 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) compared with the appropriate comparator therapy (metformin + human insulin).

Courtesy translation only, please refer to the German original.