Insulin icodec (2) – Awiqli®

• Clinical trials
  • The randomised, open-label, multicentre ONWARDS 6 trial investigated the use of insulin icodec versus insulin degludec, each in combination with insulin aspart, in 582 adults with type 1 diabetes mellitus.

Adults with type 1 diabetes mellitus

• mortality
  • In the ONWARDS 6 study, one death occurred in the intervention arm.
  • For the endpoint of all-cause mortality, the ONWARDS 6 study showed no statistically significant difference between the treatment arms.
• morbidity
  • For the change in HbA1c levels compared with baseline, there was a statistically significant difference in favor of insulin degludec compared with insulin icodec (both in combination with insulin aspart). However, this effect is not considered relevant, as the 95% confidence interval for the effect, with a lower limit of 0.02%, is close to zero.
  • To assess the non-inferiority of insulin icodec compared with insulin degludec, the European Medicines Agency (EMA) applied a threshold of 0.3 percentage points for the HbA1c level. Non-inferiority was demonstrated for insulin icodec at week 26; at week 52, this was not demonstrated.
  • For the endpoints of acute coronary syndrome, cerebrovascular events and heart failure, the ONWARDS 6 study showed no statistically significant difference between the treatment arms in each case.
  • For the endpoints of diabetic retinopathy and end-stage kidney disease, no analyses are available regarding suitable operationalisation.
• quality of life
  • Health-related quality of life was not assessed in the ONWARDS 6 study.
• Side effects
  • For the endpoints of SAE and AEs, the ONWARDS 6 study showed no statistically significant differences between the treatment arms.
  • For the endpoints of non-severe symptomatic, confirmed hypoglycaemia (PG < 54 mg/dl or PG < 70 mg/dl), the pharmaceutical manufacturer submitted post-hoc analyses in the dossier and in its statement. However, according to the pharmaceutical manufacturer, the symptoms may not have been fully recorded by all study participants or investigators during the study, although this was required under the CRF. However, as only symptomatic hypoglycaemia is taken into account for the benefit assessment, and no systematic recording of symptoms took place in this instance, there are therefore no suitable data available for non-severe symptomatic, confirmed hypoglycaemia.
  • Post-hoc analyses are available for the endpoint of severe hypoglycaemia. Severe hypoglycaemia was defined as follows: it required the assistance of healthcare professionals for treatment with glucagon or intravenous glucose; were life-threatening; led to hospitalisation; or were characterised by severe neuroglycopaenic symptoms. In the ONWARDS 6 study, no statistically significant differences between the treatment arms were observed for the endpoint of severe hypoglycaemia.
  • With regard to the endpoint of serious hypoglycaemia (PT hypoglycaemia), the ONWARDS 6 study shows a statistically significant disadvantage compared with insulin degludec for insulin icodec (each in combination with insulin aspart).
  • The pharmaceutical manufacturer also submits a post hoc analysis of hypoglycaemia in the dossier, which comprises a collection of PTs based on SUEs. This analysis is not used for the benefit assessment, as the post hoc selection of PTs means it cannot be ruled out that the compilation was outcome-driven.
  • For the endpoint of diabetic ketoacidosis, the ONWARDS 6 study shows no statistically significant difference between the treatment arms.
• Overall assessment
  • For the endpoint of all-cause mortality, the study shows no statistically significant difference between the treatment arms.
  • With regard to morbidity, there is a statistically significant disadvantage for insulin icodec compared with insulin degludec in terms of the change in HbA1c levels from baseline (in each case in combination with insulin aspart); however, it cannot be assumed with sufficient certainty that this represents a clinically relevant effect. For the remaining endpoints in the morbidity category, no statistically significant differences were observed (acute coronary syndrome, cerebrovascular events and heart failure), or no analyses are available regarding appropriate operationalisation (diabetic retinopathy, end-stage renal disease).
  • Endpoints relating to health-related quality of life were not assessed in the ONWARDS 6 study.
  • With regard to side effects, there were no statistically significant differences between the treatment arms in the overall rates of serious adverse events (SAEs) or in therapy discontinuations due to AEs. In detail, however, there was a negative effect for the specific AEs of serious hypoglycaemia; the proportion of patients with serious hypoglycaemia was in the low single-digit percentage range. With regard to non-severe symptomatic, confirmed hypoglycaemia (blood glucose threshold of ≤ 54 mg/dl or ≤ 70 mg/dl), no analyses are available regarding a suitable operationalisation. No statistically significant differences were observed between the treatment groups with regard to severe hypoglycaemia. Overall, based on the data from the ONWARDS 6 study, a disadvantage of insulin icodec compared with insulin degludec is identified in the ‘side effects’ category, as the negative effect on one of the endpoints—serious hypoglycaemia—can be potentially fatal is of particular relevance to patients with type 1 diabetes mellitus.
  • Overall, in the endpoint categories of mortality and morbidity, there are neither advantages nor disadvantages for insulin icodec compared with insulin degludec. Health-related quality of life was not assessed in the ONWARDS 6 study. With regard to side effects, however, a disadvantage is evident with insulin icodec, specifically in relation to the AE of serious hypoglycaemia, which can be life-threatening. Taking the study results as a whole, however, it does not appear justified to conclude that insulin icodec offers less benefit. Taken together, it is therefore concluded that, based on the results of the ONWARDS 6 study, the additional benefit of insulin icodec over insulin degludec – in each case in combination with insulin aspart as part of intensified insulin therapy – is not proven.

Courtesy translation only, please refer to the German original.