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New evidence on icodec safety

17th August 2023

A clinical trial reported in Diabetologia compares once-weekly insulin icodec with once-daily insulin glargine U100 in type 2 diabetes with respect to hypoglycaemia. Dr Susan Aldridge reports.

Once-weekly insulins promise to simplify insulin therapy and could thereby address both therapeutic inertia and improve treatment adherence. However, there are potential concerns about hypoglycaemia with weekly administration, particularly if a dose is miscalculated because that would potentially expose the individual to a much larger amount of insulin than usual. 

In type 2 diabetes, longer duration of diabetes and increased time since initiation of insulin are both associated with diminishing hypoglycaemia awareness and blunted counterregulation. This may be why the risk of hypoglycaemia increases as type 2 diabetes progresses. It is therefore important that any new insulin, like the weekly insulins, be investigated to ensure that any hypoglycaemia it induces does elicit a robust symptomatic and counterregulatory response. 

Insulin icodec is a basal insulin under development for once-weekly administration. This is made possible because, on injection, insulin icodec binds strongly and reversibly to albumin, thereby creating a depot from which insulin is slowly and continuously released with a half-life that is suitable for once-weekly dosing. The action of insulin icodec is similar to that of native human insulin. Also, Phase 2 trials have shown similar reductions in HbA1c and fasting plasma glucose in type 2 diabetes as insulin glargine, and similar rates of level 2 and level 3 hypoglycaemia. 

However, given the novelty of insulin icodec, its characteristics with respect to hypoglycaemia require further investigation. Accordingly, Thomas Pieber at the Medical University of Graz, Austria, and colleagues elsewhere, carried out a randomised crossover trial of insulin icodec versus once-daily insulin glargine U100 in a group of participants with type 2 diabetes. They looked at the frequency of hypoglycaemia, time to hypoglycaemia and recovery time during a short period of exposure to double and triple doses of icodec and double and triple doses of glargine. In a subgroup analysis, they also investigated symptomatic and hormonal counterregulatory responses between these induced-hypoglycaemia experiments.  

Icodec versus glargine – hypoglycaemia profiles

The trial participants, aged between 18 and 72, were all on basal insulin with or without other glucose-lowering drugs and had no clinically significant diabetes complications or history of cardiovascular disease. They were considered reasonably representative of the type 2 diabetes population. As this was a crossover trial, they received insulin glargine or insulin icodec for either 11 days or six weeks, then swapped over after a washout period. 

While receiving each of the insulins, the hypoglycaemia-induction ‘challenges’ were carried out during short periods in which they received the double and triple doses. First, euglycaemia was achieved by allowing a glucose infusion to run to a glucose level of 5.5 mmol/l, at which point it was stopped and the glucose allowed to fall to no less than 2.5 mmol/l where it was maintained for 15 minutes. Then the euglycaemia was restored by the glucose infusion. During the hypoglycaemia window, various measurements and tests were carried out.

Hypoglycaemia was induced in 43 and 42 participants after a double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses. Clinically significant hypoglycaemia, defined as glucose less than 3.0 mmol/l or the presence of symptoms, occurred in comparable numbers after exposure to the double and triple doses of both insulins. 

There were no significant treatment differences in the time to hypoglycaemia, which varied from 2.9 to 4.5 hours for the double doses and 2.2 to 2.4 hours for the triple doses. And time to recovery from hypoglycaemia, via glucose infusion, took less than 30 minutes for all treatments. Outside these hypoglycaemia-induction periods, there were no severe hypoglycaemia episodes and the rate of clinically significant hypoglycaemia episodes was comparable for icodec and glargine U100 at around three episodes per participant-year of exposure. 

Counterregulatory responses

After the double doses of icodec and glargine U100, 20 and 19 participants experienced clinically significant hypoglycaemia, as did 20 and 29 participants after the triple doses. These individuals made up the subgroup for investigation of the physiological responses to hypoglycaemia. There was significant overlap in that 16 participants after double dose and 17 after triple dose experienced hypoglycaemia after both icodec and glargine U100.  

Concentrations of all five counterregulatory hormones – glucagon, adrenaline, noradrenaline, cortisol, growth hormone – appeared to increase from baseline during hypoglycaemia induction for both insulin products following double dose and triple dose. Following a triple dose of insulin, the hormone response was greater with icodec for adrenaline and cortisol. However, there were no statistically significant differences in other counterregulatory hormone concentrations between icodec and glargine after the double or triple doses. 

Study backs once-weekly icodec on safety

So, in summary, this study shows that the risk of hypoglycaemia was comparable for icodec and glargine U100 following experiments with double and triple doses. The duration of decline in plasma glucose towards clinically significant hypoglycaemia was similar for both insulins, as was the recovery time of around 30 minutes. There was also a robust endocrine and symptomatic response among participants with clinically significant hypoglycaemia.

Phase 2 clinical trials of up to 26 weeks in people with type 2 diabetes show low rates of level 2 and level 3 hypoglycaemia for weekly icodec that are comparable to once-daily glargine U100. The results of this new study support these findings. They also suggest that even if there were a substantial mismatch between the insulin dose administered and that required, there would still not be an increased risk of hypoglycaemia with icodec compared with once-daily glargine U100. 

Avoiding hypoglycaemia is important for people with diabetes. If an episode does occur, it is important to be able to rapidly correct the fall in plasma glucose. Given the longer dosing interval and longer duration of action of once-weekly insulin, prolonged hypoglycaemia, slow recovery and recurrent events might be a big concern. However, results from this study and from Phase 2 trials are reassuring. An analysis of continuous glucose monitor (CGM) data from two Phase 2 trials showed similar duration of hypoglycaemic episodes with icodec versus glargine U100 in type 2 diabetes. And, in the current trial, recovery from hypoglycaemia via constant intravenous glucose infusion took less than 30 minutes for all treatments. Furthermore, no severe hypoglycaemia episodes were observed following the hypoglycaemia-induction episode. 

The present findings apply where an unintentionally high insulin dose is administered by either forgetting a dose has been taken and taking another one or by miscalculation. They may also apply where the usual dose is too high for current needs. This could occur during and after exercise, during intercurrent illness or during hospitalisation, if fasting is required before tests or operations. 

Double and triple doses of once-weekly icodec used in this study are actually equivalent to 14 and 21 times the regular daily dose of insulin. Despite this vast amount, when the next weekly dose was omitted in this trial, the risk of hypoglycaemia was not higher in comparison with double or triple doses of once-daily glargine U100 followed by omission of the next daily dose. And recovery from hypoglycaemia did not require more glucose for icodec versus glargine U100 after a triple dose, and only slightly more after the double dose. 

Previous studies have looked into the symptomatic and endocrine responses to hypoglycaemia for insulin detemir, insulin degludec and glargine U100 in healthy individuals and in type 1 diabetes. There have also been studies investigating the response to hypoglycaemia induced by human soluble insulin under clamp conditions in people with type 2 diabetes, but this is the first study to look at the physiological response to hypoglycaemia induced by a basal insulin analogue in type 2 diabetes. It was reassuring to discover that the physiological response to hypoglycaemia was as large for icodec as for the widely used basal insulin analogue glargine U100.

A strength of this trial was the recruitment of people with type 2 diabetes. They may have the most to gain from a weekly insulin as they – and maybe their healthcare provider – may be reluctant to intensify their treatment by starting on daily insulin injections.  

In conclusion, then, it is reassuring to learn that double and triple doses of once-weekly icodec do not lead to increased risk of hypoglycaemia compared with once-daily glargine U100. Furthermore, the time taken to develop and recover from hypoglycaemia is comparable for the two insulins. The study also suggests that hypoglycaemia induced by icodec is accompanied by symptomatic and counterregulatory responses at least as robust as those seen for glargine U100. This new study therefore provides further reassurance about the safety of once-weekly icodec, bringing it one step closer to mainstream diabetes care.

To read this study, go to: Pieber TR, Arfelt KN, Cailleteau R, Hart M, Kar S, Mursic I, Svehlikova M, Urschitz M, Haahr H. Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial. Diabetologia 13 June 2023.

To learn more, enrol on the EASD e-Learning course ‘Hypoglycaemia’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.