Efficacy and safety of Once-Weekly Insulin Icodec

Introduction

Insulin icodec has a half-life of 196 hours (8.1 days) allowing its administration once weekly [01, 02]. After reaching a steady state 3-4 weeks following its initiation, insulin icodec exhibits an evenly distributed glucose-lowering activity throughout the 7 days of the week [01, 02]. The long duration of action of insu¬lin icodec is attributed to 2 main factors. First, binding to albu¬min through addition of a C20 fatty acid-containing side chain to form an albumin-binding depot from which icodec is slowly released in the circulation. Second, 3 amino acid substitutions that decreases affinity of icodec to insulin receptors leading to its decreased rate of clearance. Normally, insulin clearance occurs primarily through internalization following binding of insulin to its receptors at cell surface. Thus, reduced binding of insulin icodec to insulin receptors will lead to its reduced clearance and further prolongation of its action [01, 02]. Importantly, the re¬duced affinity of icodec to insulin receptor does not compromise its potency but slows its action [01, 02]. The concentration of formulation of insulin icodec is 7 times higher than that of the standard insulin U100 formulation. Consequently, the volume of insulin icodec administered once weekly is similar to other basal insulin dosing volumes given once daily [01, 02]. The ON¬WARDS Program consists of 6 phase 3 clinical trials to evaluate insulin icodec versus insulin degludec and gargine [01]. In a pre¬vious article, the author reviewed the pharmacologic properties of insulin icodec as well as its efficacy and safety in 5 of the 6 trials of the ONWARDS Program including patients with type 2 diabetes [01]. More recently, insulin icodec was evaluated in subjects with type 1 diabetes in the 6th and last trial of the ON¬WARDS Program [03-08]. The main objective of this article is to review the efficacy and safety of insulin icodec in patients with type 1 and type 2 diabetes.

Summary of the ONWARDS Studies

Table 1 summarizes the main features and results of the 6 ON¬WARDS trials [03-08]. The 6 trials were randomized, multina¬tional and treat-to target [03-08]. The primary endpoint was the change in HbA1c levels from baseline to the end of the study.

The target of fasting self-measured BG was 80-130 mg/dl. Thus, doses of insulin icodec, glargine and degludec were modified weekly based on 3 pre-breakfast BG readings to attain this gly-cemic target [01]. The process of titration was mentioned in de-tail in a previous article of the author [01]. Briefly, if the mean of the self-measured 3 BG values are > 130 mg/dl, insulin icodec dose is increased by 20 units weekly and doses of glargine or degludec are increased by 3 units daily. On the other hand, if the lowest of the 3 fasting BG values is < 80 mg/dl, doses of insulin icodec are decreased by 20 units/week and those of glargine or degludec by 3 units per day [03]. In terms of study duration, ONWARDS 1 trial is the longest-term trial of the ONWARDS Program lasting 78 weeks followed by 5-week follow-up peri¬od for safety monitoring [03]. The latter study that compared insulin icodec with insulin glargine in insulin-naïve patients with type 2 diabetes [03]. ONWARDS 2 trial compared insu¬lin icodec and degludec in subjects with type 2 diabetes already treated with a basal insulin [04]. ONWARDS 3 trial evaluated insulin icodec versus insulin degludec in insulin-naïve patients [05]. ONWARDS 4 trial compared insulin icodec with insulin glargine in subjects with type 2 diabetes already on basal-bolus insulin regimen [06]. The largest study was the ONWARDS 5 trial (n=1,805) that compared insulin icodec titrated with a dos-ing guide app with degludec, glargine U100, or glargine U300 titrated per standard practice in insulin naïve patients [07]. Fi-nally, the ONWARDS 6 trial, dedicated exclusively for patients with type 1 diabetes, compared insulin icodec with degludec, both in combination with meal-time insulin apart (≥2 injections/ day) [08].

Effects of Iinsulin Icodec on Glycemic Control

In ONWARDS 1, 2, 3, and 5 insulin icodec was shown to be slightly but statistically superior to both glargine glargine and degludec in reducing HbA1c values, with estimated treatment difference (ETD) of approximately 0.19 to 0.38 percentage points (table 1) [03-05, 07]. In ONWARDS 4 and 6, insulin ico¬dec was not inferior than degludec with respect to HbA1c reduc¬tion (table 1) [06, 08]. In the 5 studies including patients with type 2 diabetes, reductions in HbA1c levels were evident 10-13 weeks after starting insulin in all treatment groups, then attained a trough at week 26 followed by a plateau [03-07]. Meanwhile, in type 1 diabetes, HbA1c levels reached a trough earlier after 10 weeks followed by gradual rebound [08]. Information from CGM was used for a duration of 4 weeks in ONWARDS 1, 2 and 6 trials to identify the diurnal glycemic trajectory [03, 04, 08]. In general, no significant differences in time spent in range (70-180 /dl) was recorded between icodec groups and glargine or degludec [03, 04, 08]. Meanwhile, in ONWARDS 1 trial, the percentage of time spent with BG levels above the range (ie. > 180 mg/dl) was approximately 1 hour less with insulin icodec than with insulin glargine [03]. While insulin efficacy depends largely on its doses, there was no consistent trend with respect to differences in insulin doses between insulin icodec and other basal insulins (table 1).

*The primary outcome in all trials was reduction of HbA1c with insulin icodec versus comparator. Values are means. Abbreviations in the table: OD: once daily, ETD: estimated treatment difference, ERR: estimated rate ratio, HbA1c: glycated hemoglobin, CGM: continuous glucose monitoring, PYE: hypoglycemic event per person-year of exposure. DTSQ: Diabetes Treatment Satisfaction Questionnaire. TRIM-D: Treatment Related Impact Measure for Diabetes compliance domain score.

Table 1. *Summary of phase 3a trials of once-weekly insulin icodec

Patient Satisfaction with Insulin Icodec

Patient satisfaction with insulin icodec versus degludec was as-sessed in ONWARDS 2, 5,6 and 8 studies using the validated “Diabetes Treatment Satisfaction Questionnaire” (DTSQ) with higher score indicating greater satisfaction [04, 07, 08]. In ON-WARDS 2, at week 26, the DTSQ score was slightly but sig-nificantly higher in patients randomized to insulin icodec than insulin degludec 4.22 and 2.96, respectively; ETD 1.25 (95% CI, 0.41 to 2.10, P=0.003) (table 1) [04]. In ONWARDS 5, the corresponding ETD was smaller, but still statistically significant; ETR 0.78 (95% CI, 0.10 to 1.47) (table 1) [07]. On the contrary, in type 1 diabetes, total satisfaction score was significantly lower with insulin icodec compared with insulin degludec; ETD at 52 weeks -1.59 (95% CI, -2.5 to -0.67) (table 1) [08]. Compliance with insulin administration, evaluated by the Treatment Related Impact Measure for Diabetes [TRIMP-D] compliance domain score, was conducted in only 1 of the 6 studies, the ONWARDS 5 trial. The latter trial showed that compliance score was sig- nificantly higher with insulin icodec vs once-daily insulin ana¬logues, ETD 3.04 (95% CI, 1.28 to 4.81) [07].

Safety of Insulin Icodec

Hypoglycemia

Type 2 diabetes: The main concern related to safety of insulin icodec is hypoglycemia. This concern is justified given the pro¬longed duration of action of insulin icodec that could potentially lead to intractable hypoglycemia and recurrence of hypogly¬cemic episodes. Results of one short-term (7 weeks) study in¬cluding 43 patients with type 2 diabetes did not show significant differences between insulin icodec and insulin glargine in terms of symptoms and hormonal response to induced hypoglycemia [09]. Despite these preliminary reassuring findings, results de¬rived from the ONWARDS Program clearly showed increased risk of hypoglycemia with insulin icodec versus either insulin glargine or degludec. Thus, in ONWARDS 1 trial, at week 83, the rates of combined clinically significant (level 2) or severe hypoglycemia (level 3) were significantly greater with insulin icodec compared with glargine, 0.30 and 0.15 hypoglycemic events per person-year of exposure (PYE), respectively, ERR 1.71 (95% CI, 1.06 to 2.76) [03]. Moreover, the gap of hypo-glycemia between insulin icodec and glargine widened with the duration of insulin use [03]. In ONWARDS 3 trial, combined level 2 and 3 hypoglycemia from baseline to week 26 was ap-proximately 3-fold higher with insulin icodec compared with insulin degludec; ERR 3.12 (95% 1.30 to 7.51, P=0.01) [05]. In addition, in ONWARDS 2, 3 and 5 trials, there was increased risk of hypoglycemia (level 1, and combined level 2 and 3) with insulin icodec compared with insulin degludec or glargine (table 1) [04, 05, 07]. However, frequency of level 3 hypoglycemia and nocturnal hypoglycemia, when reported separately, was not increased with insulin icodec in the ONWARDS 1,3-5 trials [03-05, 07].

Type 1 diabetes: In type 1 diabetes, results of ONWARDS 6 trial showed that rates of level 2 and 3 hypoglycemia with insu-lin icodec were approximately double the rates with degludec at 57 weeks, 17.0 versus 9.2 events per PYE [08]. Furthermore, percentage of time below 54 mg/dl measured by CGM was sig-nificantly higher with icodec than degludec, 1.0% and 0.7%, re-spectively; ETR 1.46 (95% CI, 1.16 to 1.85, P=0.0014) [08]. It should be emphasized that, irrespective of insulin regimen, frequency of hypoglycemia in general is much higher in patients with type 1 diabetes compared with those with type 2 diabetes. Therefore, when expressed in absolute values, the increase in number of hypoglycemic episodes related to insulin icodec was substantially greater in patients with type 1 diabetes compared with those with type 2 diabetes (table 1) [04-08].

Weight Gain: Overall, no significant differences in weight gain were observed between patients treated with insulin icodec ver-sus degludec or glargine except in ONWARDS 2 trial where patients randomized to insulin icodec had a mean weight gain of 1.4 kg compared to 0.3 kg weight loss in subjects receiving insulin degludec, ETD 1.7 kg (95% CI, 0.76 to 2.63, P=0.0004) (table 1) [04].

Allergic Reactions: Frequency of allergic events and injection site skin reactions were not increased with the use of insulin ico-dec compared with insulin degludec or glargine [03-08].

Medication Errors: Medication errors were defined as misuse or abuse of insulin that had the potential to harm the participant (e.g. overdosing insulin to maximize its effects or with the inten¬tion to cause harm) [07]. In general, no increase in medication errors was recorded with insulin icodec in patients with type 2 diabetes. Meanwhile, in patients with type 1 diabetes, 18 events of medication errors were reported in 6% of patients randomized to icodec compared with 7 such events in 2% of patients ran¬domized to insulin degludec [08]. The causes of the latter finding were unclear but could have contributed to the increase rates of hypoglycemia in patients with type 1 diabetes who received insulin icodec in the ONWARDS 6 trial [08].

Advantages of Insulin Icodec: The main advantage of insulin icodec resides in its once-weekly administration. Moreover, there is some flexibility in timing of injection such that the day of administration may be changed by up to 3 days ensuring a minimum of 4 days between injections [06, 07]. Additionally, a single dose-study showed that pharmacokinetics and pharmaco-dynamics of insulin icodec did not change significantly whether injected in the thigh, abdomen or upper arm [10]. It was not sur¬prising therefore that in patients with type 2 diabetes satisfaction was higher with insulin icodec compared to one-daily insulin analogues. However, in type 1 diabetes, for unclear reasons, sat¬isfaction with insulin icodec was lower than other basal insu¬lin analogues [08]. As far as efficacy is concerned, data suggest that insulin icodec is at least as effective as once-daily insulin glargine and degludec. It is reassuring that current information suggests that insulin icodec is no more immunogenic than other basal insulins. This was reflected by the low number of allergic and injection site reactions that were generally similar to insulin glargine and degludec [03-07].

Limitations of Insulin Icodec

Despite the above advantages, insulin icodec suffers from the following limitations. First, the increased risk of hypoglycemia. Indeed, in patients with type 1 diabetes, the absolute difference in hypoglycemic events between insulin icodec and degludec was unacceptably high (table 1) [08]. Hence, it is unsafe at present to recommend insulin icodec for patients with type 1 diabetes. Second, insulin icodec was not studied in patients with end-stage kidney disease and those with baseline HbA1c levels > 11.0% in type 2 diabetes and HbA1c ≥ 10% in type 1 diabetes because these patients were excluded from the ONWARDS pro¬gram [03-08]. Third, insulin icodec may not be convenient for use in the hospital setting where rapid variations in BG levels are expected. For instance, patients already on insulin icodec before hospital admission should be monitored closely for hypoglyce¬mia for 7 days from the day of last icodec injection. Fourth, all available trials of insulin icodec are sponsored by the manufac¬turer and all ONWARDS trials, except ONWARDS 3, are open label (table 1) [03-08]. Therefore, these investigations might be virtually prone for several bias in favor of insulin icodec. Panel 1 depicts advantages and limitations of insulin icodec.

Conclusions and Current Directions

Insulin icodec is a new basal insulin formulation that can be given once-weekly. Whereas data derived from the ONWARDS Program suggests that insulin icodec may have similar or slight¬ly superior efficacy than once-daily insulin glargine or degludec, its use may be associated with increased risk of hypoglycemia, particularly in patients with type 1 diabetes. The increased pro¬pensity for hypoglycemia with the use of insulin icodec may be attributed to its long duration and possibly inappropriate dose titration. Indeed, the up-titration schedule of icodec doses by 20 units per week, as suggested by the investigation conducted by Lingvay et al [11] and adopted in the ONWARDS Program, may be too aggressive [03-08]. Thus, less aggressive titration of in¬sulin icodec, e.g. an increase of its dose by 10 units per week instead of 20 units, might result in less frequency of hypoglyce¬mia. Several clinical trials are underway to assess the combina¬tion of once-weekly icodec with the once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) Semaglutide in one sin¬gle formulation [12, 13]. The latter combination may be an at¬tractive therapeutic strategy that potentially lowers icodec doses and therefore incidence of hypoglycemia. Moreover, the weight reduction effect of the GLP-1 RA may help lessening or even re-versing the weight gain induced by insulin icodec. Importantly, large randomized trials with adequate power are required to ex-amine the long-term effects of insulin icodec on cardiovascular events and mortality.

Conflict of interest

The author does not have a conflict of interest to declare.

Panel 1. Advantages and limitations of insulin icodec

Advantages

• Once-weekly dosing.

• Higher patient satisfaction when compared with insulin de-gludec in patients with type 2 diabetes.

• Increased compliance when compared with once-daily insu¬lin analogues (degludec, glargine U100 and glargine U300) in patients with type 2 diabetes.

• May be injected in abdomen, thigh or upper arm.

• No increase in allergic reactions compared with insulin glargine or degludec.

• Administration with once-weekly glucagon-like 1 receptor agonists in one formulation may be potentially effective and convenient.

Limitations

• Increased risk of hypoglycemia compared with insulin glargine and degludec, particularly in patients with type 1 diabetes.

• Lower patient satisfaction when compared with insulin de-gludec in patients with type 1 diabetes.

• Unknown long-term effects (safety was studied up to 83 weeks).

• Propensity for hypoglycemia in cases of hospital admis-sions and intermittent sickness

• Limited flexibility in dose-adjustment during days of exer-cise or variable lifestyle.

• Not studied in patients with glycated hemoglobin levels > 11.0% in type 2 diabetes and ≥10.0% in type 1 diabetes.

• Not studied in patients with end-stage kidney disease.

• Most clinical trials were open-label prone for bias.

References

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