Insulin glargin / Lixisenatid (1) – Suliqua®

• Clinical trials
  • The benefit assessment is based on the three-arm trial EFC12404 (LixiLan-O). In this open-label, randomised, actively controlled, multicentre Phase III trial, 1,170 patients were randomised in a 2:2:1 ratio to receive treatment (in each case in combination with metformin) with the fixed-dose combination of insulin glargine/lixisenatide (469 patients), insulin glargine (467 patients) or lixisenatide (243 patients).
  • The pharmaceutical manufacturer is submitting the three-arm study EFC12626 (GetGoal-Duo 2) for the benefit assessment. This is an open-label, randomised, actively controlled, multicentre Phase III study designed to demonstrate the efficacy, safety and tolerability of a free combination of insulin glargine and lixisenatide compared with treatment with insulin glargine in combination with the short-acting insulin glulisine.

a) Adult patients with type 2 diabetes mellitus whose condition is not adequately controlled by treatment with at least two blood glucose-lowering medicinal products (exclusively oral, including metformin)

• For adult patients with type 2 diabetes mellitus whose condition is not adequately controlled by treatment with at least two blood glucose-lowering medicinal products (exclusively oral, including metformin), additional benefit is not proven.
• mortality
  • Overall mortality was not assessed as an independent endpoint in the LixiLan-O study. The results for the endpoint of overall mortality are based on the analyses of serious adverse events. Three deaths occurred during the observation period (insulin glargine/lixisenatide plus metformin: 1 death; control arm: 2 deaths). There was no statistically significant difference between the treatment arms.
• Morbidity – Cardiac and cerebrovascular morbidity
  • The results for the endpoints of cardiac and cerebrovascular morbidity are based on analyses of serious adverse events classified under the MEDRA SOCs ‘Cardiac disorders’ and ‘Nervous system disorders’. With regard to the cardiac morbidity endpoint, 5 events occurred (insulin glargine/lixisenatide plus metformin: 1 death; control arm: 4). For the endpoint of cerebral morbidity, there was 1 event in the insulin glargine/lixisenatide plus metformin arm. There was no statistically significant difference between the treatment arms.
• Morbidity – Health status (EQ-5D VAS, ‘Daily Life’ and ‘Mental Health’ domains of the TRIM-D)
  • Patients’ health status was assessed using both the visual analogue scale (VAS) of the EQ-5D questionnaire and the ‘daily life’ and ‘mental health’ domains of the TRIM-D.
  • On the EQ-5D VAS, patients rate their health status on a scale from 0 (the worst possible health status) to 100 (the best possible health status). Based on the analyses of the mean change in health status between the start and end of the study, there was no statistically significant difference between the treatment arms.
• Health-related quality of life
  • No relevant data for an assessment of health-related quality of life were collected in the LixiLan-O study.
  • The pharmaceutical manufacturer uses the IWQoL-Lite questionnaire to make statements regarding the endpoint category of health-related quality of life. However, this questionnaire is not suitable for assessing health-related quality of life in the present indication.
• Side effects – Serious adverse events (SAEs), therapy discontinuation due to AEs
  • Based on the overall rates, there are no statistically significant differences between the treatment arms for the endpoints SAE and therapy discontinuation due to AEs.
• Side effects – Non-severe symptomatic hypoglycaemia, severe hypoglycaemia
  • There is no statistically significant difference between the treatment arms either for non-severe symptomatic hypoglycaemia – defined as plasma glucose levels < 56 mg/dl and ≤ 70 mg/dl – or for severe hypoglycaemia.
• Side effects – Renal dysfunction
  • There was no statistically significant difference between the treatment arms for any of the endpoints.
• Side effects – gastrointestinal disorders
  • A statistically significant difference was observed between the treatment arms with regard to the endpoint ‘gastrointestinal disorders’ (SOC), to the detriment of the fixed-dose combination of insulin glargine/lixisenatide plus metformin. During treatment with the fixed-dose combination, gastrointestinal AEs occurred in 23.4% of patients. This compares with 11.5% in the control arm (relative risk 2.03; 95% CI [1.37; 3.02]; p < 0.001).
  • The gastrointestinal AEs diarrhoea, nausea and vomiting (Preferred Terms) occurred statistically significantly more frequently in patients treated with insulin glargine/lixisenatide plus metformin than in the control arm.
  • According to the summary of product characteristics (SmPC) for insulin glargine/lixisenatide, gastrointestinal side effects (nausea, vomiting and diarrhoea) were predominantly mild and of a transient nature.
• Overall assessment
  • For the benefit assessment of the fixed-dose combination of insulin glargin/lixisenatide in combination with metformin for the treatment of type 2 diabetes mellitus in adults, where metformin in combination with another oral antidiabetic medicinal product does not adequately control blood glucose levels, results are available for the endpoint categories of mortality, morbidity and side effects based on the LixiLan-O study.
  • In the LixiLan-O study, the fixed-dose combination of insulin glargine and lixisenatide in combination with metformin was compared, amongst other treatments, with insulin glargine in combination with metformin.
  • For the patient population relevant to the assessment, there are no advantages for insulin glargine/lixisenatide in combination with metformin compared with insulin glargine in combination with metformin in the endpoint categories of mortality and morbidity.
  • With regard to adverse effects, the overall rates of adverse events also show no disadvantages for insulin glargine/lixisenatide compared with the control therapy. However, negative effects were observed in specific adverse events relating to the occurrence of gastrointestinal side effects.
  • Overall, the interpretability of the present results in relation to the German healthcare context is subject to considerable uncertainty. For instance, contrary to guideline recommendations, the target values for fasting plasma glucose were not set on an individual patient basis in the LixiLan-O study.
  • On balance, there is no additional benefit for the fixed-dose combination of insulin glargine andlixisenatide in combination with metformin for the treatment of type 2 diabetes mellitus in adults – where metformin in combination with another oral hypoglycaemic medicinal product does not adequately control blood glucose levels – does not provide proof that it is superior to the appropriate comparator therapy.

b) Adult patients with type 2 diabetes mellitus whose condition is not adequately controlled by treatment with insulin (in combination with another blood glucose-lowering medicinal product, in this case metformin)

• For adult patients with type 2 diabetes mellitus who are not adequately controlled by treatment with insulin (in combination with another blood glucose-lowering medicinal product, in this case metformin), additional benefit is not proven.
• No data were submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.