Clinical Use of Once-Weekly Insulin Icodec: Translating Clinical Trial Data into Practical Guidance for Diabetes Management

Abstract

Insulin icodec (icodec) is a first-in-class once-weekly basal insulin approved for the treatment of adults with type 1 diabetes (T1D) and type 2 diabetes (T2D). Healthcare professionals (HCPs) may benefit from clear and practical guidance on translating the use of icodec from a controlled clinical trial setting into real-world clinical practice to ensure its appropriate implementation. Here, we primarily review the available evidence for icodec in T2D to provide evidence-based clinical recommendations and expert opinions to guide the use of icodec in a clinical setting. The pharmacology of icodec is summarized, along with an overview of the results from the ONWARDS 1–6 clinical trials (NCT04460885, NCT04770532, NCT04795531, NCT04880850, NCT04760626, NCT04848480). Key guidance on the practical use of icodec, including treatment initiation, switching to icodec from a once- or twice-daily basal insulin, switching from icodec back to a daily basal insulin, and dose titration, is provided. Icodec usage in special populations and practical situations (e.g., elderly and pediatric individuals, hepatic and renal impairment, hospitalized individuals, and those who are pregnant or planning pregnancy) is discussed. Considerations for glucose monitoring and management, as well as co-administration of icodec with other non-insulin glucose-lowering medications, are provided. Finally, we also briefly summarize the available evidence on icodec use in individuals with T1D, although the primary focus of this review is on its use in T2D. This review provides a comprehensive information resource for HCPs regarding the use of icodec in clinical practice.

Supplementary Information

The online version contains supplementary material including a slide deck, available at 10.1007/s40265-025-02201-0.

Key Points

The phase IIIa ONWARDS 1–6 clinical program demonstrated the efficacy and safety of once-weekly basal insulin icodec (icodec) in adults with diabetes, leading to its regulatory approval in the EU and several other countries.

This article provides expert guidance on initiating icodec for insulin-naïve individuals with type 2 diabetes (T2D), protocols for transitioning insulin-experienced individuals with T2D from daily basal insulin to icodec, and titration strategies for ongoing dose adjustments.

Recommendations are outlined for the clinical application of icodec across special populations and practical situations in T2D, supporting its implementation in diabetes management. A brief summary of the clinical use of icodec for the management of type 1 diabetes is included for completeness.

Introduction

Diabetes is a condition characterized by persistent hyperglycemia; in type 2 diabetes (T2D), the most common form (approximately 90% of all diabetes cases), hyperglycemia is primarily caused by insulin resistance and the progressive impairment of pancreatic beta-cell function [1, 2]. T2D affects over 500 million individuals globally, with this figure predicted to rise to 643 million people by 2030 and to 783 million people by 2045 [1, 2].

Insulin therapy is typically initiated in individuals with T2D when glycemic targets are no longer achieved with non-insulin glucose-lowering medications, when such medications are contraindicated or not tolerated, or in cases of severe hyperglycemia with metabolic decompensation [3]. Insulin treatment usually begins with basal insulin [3].

Despite the proven efficacy of basal insulins, the requirement for once-daily (OD) or twice-daily injections, regular blood-glucose monitoring, fear of hypoglycemia, needle phobia, perceived complexity of treatment regimens, and frequent dose titration can lead to delays in insulin initiation and reduced adherence and persistence [4]. Thus, once-weekly basal insulin formulations, which reduce injection frequency while providing similar or superior glucose-lowering efficacy and a low risk of hypoglycemia, offer flexible dosing schedules with lower perceived burden.

Advancements have led to the emergence of once-weekly basal insulin formulations, including insulin icodec (icodec) and efsitora alfa [5]. For icodec, five phase IIIa trials (ONWARDS 1–5 [NCT04460885, NCT04770532, NCT04795531, NCT04880850, NCT04760626]) have evaluated the efficacy and safety of icodec among adults with T2D (see Sects. 2.2 and 2.3), and one phase IIIa trial (ONWARDS 6 [NCT04848480]) assessed icodec in adults with T1D. Based on the ONWARDS program, icodec has received regulatory approval for the treatment of T1D and T2D in the EU and several other countries, such as Australia, Brazil, Canada, Japan, India, and South Korea, and is approved for the treatment of T2D in China.

In this review, we summarize key clinical data for icodec and provide evidence-based guidance and consolidated expert opinions on the use of icodec in clinical practice for the management of T2D. A brief summary of the clinical use of icodec for the management of T1D is included for completeness. Where clinical evidence is available, recommendations are based on published trial data; where evidence is limited or absent, expert opinion has been used and clearly indicated as such.

Icodec: Pharmacological Profile and a Summary of the Phase IIIa Clinical Data in Type 2 Diabetes (T2D)

Pharmacological Properties of Icodec in T2D

The unique structure of icodec, which includes three amino acid substitutions and a C20 icosane fatty diacid chain, prolongs its half-life to 196 h (approximately 8 days), making it suitable for once-weekly administration [13, 14].

The prolonged action of icodec results from its strong, reversible binding to human albumin, without forming subcutaneous depots [13, 14]. The three amino acid substitutions reduce the insulin receptor affinity and clearance, further prolonging the half-life of icodec [13, 14].

Following subcutaneous injection, the time to reach steady state in T2D is approximately 3–4 weeks; however, with a 50% one-time additional dose, steady state may be achieved within 2–3 weeks [15, 16]. The median time to reach the maximum plasma concentration is 16 h in T2D [15, 16]. At steady state, in T2D, the proportions of pharmacodynamic effect (glucose infusion rate) of icodec per day over 1 week were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0%, and 12.0% (days 1–7, respectively). Furthermore, no clinically meaningful difference in the overall exposure of icodec was observed across different injection sites (thigh, abdomen, or upper arm) [15].

Trial Designs of ONWARDS 1–5

ONWARDS 1–5 investigated the efficacy and safety of icodec versus OD comparators (degludec, insulin glargine U100 [glargine U100], or insulin glargine U300 [glargine U300]) in adults with T2D [6–10]. The trial designs, interventions, insulin-dosing and titration protocols, selection criteria, and results of the predefined outcomes have been published [11]. An overview of the respective trial design elements is provided in Table S1 in the Online Supplementary Material (OSM) and summarized below.

The ONWARDS 1–5 trials had a treatment period of 26 weeks (ONWARDS 2–4), 52 weeks (ONWARDS 5), or 78 weeks (ONWARDS 1; 52-week main phase and a 26-week extension phase). ONWARDS 1, 3, and 5 included 2,657 insulin-naïve participants. ONWARDS 2 and 4 included 1108 insulin-experienced participants with T2D switching from their existing basal insulin to icodec; in ONWARDS 4, participants received a basal-bolus regimen and were randomized to icodec or glargine U100, both in combination with two to four daily bolus insulin aspart injections. In ONWARDS 5, a trial with real-world elements, icodec was administered with a dosing guide app to facilitate titration; however, a dosing guide app was not used in the OD comparator arm, which should be considered when interpreting the findings from the trial.

Efficacy and Safety of Icodec Versus Once-Daily Basal Insulin Comparators in ONWARDS 1–5

The primary endpoint for all five trials was the change in HbA_1c (glycated hemoglobin) from baseline to end of treatment (EOT; ONWARDS 2–4, week 26; ONWARDS 1 and 5, week 52) [6–11]. Additionally, continuous glucose monitoring (CGM) was used in ONWARDS 1, 2, and 4 to assess time in range (TIR; 70–180 mg/dL [3.9–10.0 mmol/L]), time above range (TAR; > 180 mg/dL [> 10.0 mmol/L]), and time below range (TBR; < 54 mg/dL [< 3.0 mmol/L]) during prespecified 4-week periods [6, 7, 9]. Select key outcomes from ONWARDS 1–5 are summarized in Fig. 1.

Fig. 1.

Key population characteristics and select outcomes from ONWARDS 1–5 among individuals with type 2 diabetes (T2D). ^a52-week main phase + 26-week extension phase; only data for the main phase are presented. Similar trends in the change in HbA_1c, rates of combined clinically significant or severe hypoglycemia, and CGM metrics were observed during the main phase and the extension phase. ^bAll trials also included a 5-week follow-up period. ^cDegludec, glargine U100, or glargine U300. ^dMean (ONWARDS 1, 2, 4, 5) and median (ONWARDS 3) duration of diabetes at baseline. ^eA statistically significant difference for icodec versus OD comparator (noninferiority confirmed). ^fA statistically significant difference for icodec versus OD comparator (superiority confirmed). ^gClinically significant (level 2) hypoglycemia defined as a blood glucose < 54 mg/dL (< 3.0 mmol/L), confirmed by a blood glucose meter. Severe (level 3) hypoglycemia was defined as hypoglycemia with severe cognitive impairment requiring external assistance. BL baseline, CGM continuous glucose monitoring, CI confidence interval, degludec insulin degludec, glargine U100 insulin glargine U100, glargine U300 insulin glargine U300, HbA_1c glycated hemoglobin, icodec insulin icodec, icodec with app icodec with a dosing guide app, ERR estimated rate ratio (icodec/OD comparator), ETD estimated treatment difference (icodec-OD comparator), OD once-daily, PYE patient-year of exposure

Glycated Hemoglobin (HbA_1c)

For the primary endpoint, compared with OD comparators, icodec demonstrated a noninferior (ONWARDS 1–5) and statistically superior (ONWARDS 1–3, 5) reduction in HbA_1c from baseline to EOT in insulin-naïve and insulin-experienced individuals with T2D [6–10].

Insulin Dose

During the last 2 weeks of treatment, no statistically significant differences in the mean weekly insulin dose were observed between icodec and OD comparators in ONWARDS 1 and 3. In ONWARDS 2 and 5, the estimated weekly insulin dose was statistically significantly greater with icodec than OD comparators. In ONWARDS 4, the estimated mean weekly total insulin dose was significantly lower with icodec than glargine U100, with a significantly higher basal insulin dose and a significantly lower bolus insulin dose for the icodec arm [6–10].

Body Weight

In ONWARDS 1, 3, 4, and 5, there were no statistically significant differences in the estimated mean change in body weight from baseline to EOT for icodec versus OD comparators. In ONWARDS 2, the change in body weight to EOT was statistically significantly greater with icodec than with degludec (estimated treatment difference [95% confidence interval]: 1.70 [0.76, 2.63] kg) [6–10].

Hypoglycemia

The rates of combined clinically significant or severe hypoglycemia remained below one episode per patient-year of exposure (PYE) with icodec and OD comparators in all trials except for ONWARDS 4 (basal-bolus trial), in which the rates were higher, as expected for a basal-bolus regimen. In ONWARDS 2–5 and the main phase of ONWARDS 1, these rates were numerically higher, but not statistically significantly different, for icodec than the OD comparator arms [6–10].

Composite Endpoint

The odds of achieving an HbA_1c target of < 7% at the end of treatment without combined clinically significant or severe hypoglycemia in the previous 12 weeks were significantly greater with icodec than with OD basal insulin comparators in all trials except ONWARDS 4, for which there was no statistically significant difference between treatment arms [6–10].

Continuous Glucose Monitoring (CGM) Metrics (ONWARDS 1, 2, and 4)

In insulin-naïve participants with T2D (ONWARDS 1), from week 48 to week 52, and week 74 to week 78, TIR was statistically significantly higher with icodec than glargine U100 (TIR was above the recommended target of > 70% for icodec but not glargine U100). From week 48 to week 52 and week 74 to week 78, TBR < 54 mg/dL (< 3.0 mmol/L) was low and remained below the internationally recommended target of < 1% for both icodec and glargine U100, with no significant differences between treatments. TAR was statistically significantly lower with icodec than glargine U100 from week 48 to week 52 and from week 74 to week 78 [6].

In insulin-experienced participants with T2D (ONWARDS 2 and 4), from week 22 to week 26 there were no statistically significant differences between icodec and OD comparators in TIR, TAR, or TBR < 54 mg/dL (< 3.0 mmol/L). In both trials, the mean percentage of TBR under 70 mg/dL (< 3.9 mmol/L) and TBR < 54 mg/dL (< 3.0 mmol/L) from week 22 to week 26 remained within the recommended targets (< 4% and < 1%, respectively) [17].

Adverse Events

The adverse event profile for icodec was generally similar to those of the OD comparators; no new safety signals were identified for icodec or OD comparators in ONWARDS 1–5 [6–10].

Clinical Use of Icodec for the Management of T2D

Treatment Initiation

Identification of Eligible Adults with T2D

The eligibility criteria for participants in ONWARDS 1–5 were broad and designed to closely mimic real-world clinical practice, reflecting the criteria used for daily basal insulins (e.g., degludec, glargine U100, and glargine U300) [6–11]. As a result, the eligibility criteria for icodec in clinical practice are similarly broad, covering insulin-naïve individuals and those transitioning from daily basal insulin [18].

ONWARDS 1–5 included insulin-naïve (ONWARDS 1, 3, 5) or insulin-experienced (ONWARDS 2, 4) adults (≥ 18 years of age) with T2D (HbA_1c 7.0–10.0% [ONWARDS 2, 4], 7.0–11.0% [ONWARDS 1, 3], or > 7.0% [ONWARDS 5]) and a body mass index (BMI) of 40.0 kg/m² or less (ONWARDS 1–4; no BMI restrictions in ONWARDS 5) [6–11].

Individuals who had hypersensitivity to trial products, cardiovascular events in the 180 days before screening, chronic heart failure, or severe renal impairment were excluded from the trials, except ONWARDS 5, in which severe renal impairment was permitted. In ONWARDS 2 and 4, individuals who had hypoglycemia unawareness, recurrent severe hypoglycemia episodes, and/or uncontrolled blood pressure were also excluded [6–11]. In clinical practice, caution should be exercised for similar individuals, particularly those with a history of severe hypoglycemia or hypoglycemia unawareness [expert opinion].

Although most adults with T2D would be eligible for icodec, practical considerations such as cost, coverage, and access may affect icodec initiation in real-world practice [expert opinion].

Initiation of Icodec Treatment in Insulin-Naïve Individuals with T2D

In ONWARDS 1, 3, and 5 (insulin-naïve individuals with T2D), icodec was initiated at 70 U/week (equivalent to 10 U of daily basal insulin), maintaining the same injection volume as a 100 U/mL daily basal insulin owing to its seven-times concentration (700 U/mL) [6, 8, 10]. The recommended starting dosage of icodec in clinical practice is 70 U/week, followed by individual once-weekly dose adjustments [18]. However, according to expert opinion, as is common practice with OD basal insulin, icodec may be started at a different dose depending on the individual and the clinical situation (Fig. 2; Step 1). For certain individuals with T2D, such as those who also have chronic kidney disease with a reduced glomerular filtration rate or low BMI, a lower starting dosage (e.g., 50 U/week) may be appropriate [expert opinion], similar to what is commonly given when initiating daily basal insulin in such individuals (e.g., initiating at 6 U/day instead of 10 U/day).

Fig. 2.

Treatment algorithm used for individuals with type 2 diabetes (T2D) in ONWARDS 1–5. Weekly dose adjustment is based on three prebreakfast SMBG values, measured 2 days prior to and on the day of titration. If any of the three prebreakfast SMBG values are below the lower limit of the target range, titration is based on the lowest recorded value. If all three SMBG values are above the lower limit of the target range, titration is based on the mean of the three measurements. ^aWhen switching individuals from OD or twice-daily basal insulin, the recommended once-weekly icodec dose is the total daily basal dose multiplied by seven. When switching individuals from OD or twice-daily basal insulin, for the first injection only (week 1 dose), a 50% one-time additional icodec dose is recommended (for the first injection only) if seeking faster achievement of glycemic control in individuals with type 2 diabetes; however, this one-time additional dose is not mandatory. If the 50% one-time additional icodec dose is administered, the week 1 dose should be the total daily basal insulin dose multiplied by seven and then multiplied by one and a half, rounded to the nearest 10 U. The 50% one-time additional dose must not be added for the second injection. ^bExpert opinions regarding the initiation and titration of icodec. ^cFor individuals with T2D and low body mass index or chronic kidney disease, a lower starting dose (e.g., 50 U/week) may be appropriate, while higher doses may suit those with high insulin resistance or HbA_1c [expert opinion]. For Asian individuals, 30–70 U/week may be considered, per local labels in China (70 U/week) and Japan (30–70 U/week). ^dClinicians may decide to titrate less aggressively for individuals who are at greater risk of hypoglycemia, such as those with preserved insulin sensitivity, hepatic or renal impairment, or elderly individuals [expert opinion]. The prefilled insulin pen injector used to administer icodec can be dosed either up or down by a minimum of 10 U, so clinicians may also consider fine tuning in increments or decrements of 10 U for dose optimization or in special situations once a stable dose has been established [expert opinion]. In some situations, such as during prolonged hospital admission and pregnancy, it may be preferable to switch from icodec to daily insulin. Icodec insulin icodec, OD once-daily, SMBG self-measured blood glucose, U units.

For Asian individuals, a starting dosage ranging 30–70 U/week could be considered [expert opinion]. According to the approved labels, the recommended weekly starting dosage in China is 70 U, with individual adjustments based on the individual’s condition; in Japan, treatment may be initiated with 30–70 U, adjusted according to the individual’s condition [19, 20] (corresponding to approximately 4–10 U/day) [20].

Occasionally, as is true in clinical practice for other insulins, higher starting doses of icodec might be preferred, particularly among individuals with high levels of insulin resistance or a high HbA_1c [expert opinion]. However, icodec may not be the most suitable option when rapid glycemic control is required [expert opinion].

Switching from Daily Basal Insulin to Icodec in Insulin-Experienced Individuals with T2D

In ONWARDS 2 and 4, to prevent a potential transient increase in fasting plasma glucose levels that may occur until steady state of icodec is achieved, the weekly icodec dose, calculated as the pretrial total daily dose multiplied by seven, was increased by 50% for the first injection only. From week 2 (second injection), participants received the calculated once-weekly icodec dose [7, 9].

In an open-label, phase I trial (NCT04582435) of 46 adults (≥ 18 years) with T2D, a pharmacokinetic modeling analysis demonstrated that clinical steady state was reached 2–4 weeks after subcutaneous injection when initiating icodec without a one-time additional dose, and 2–3 weeks after subcutaneous injection when initiating icodec with a 50% one-time additional dose [16]. Additionally, in a phase II trial (NCT03922750), switching from daily insulin to icodec with a 100% one-time additional dose reduced the transient increase of fasting plasma glucose and TAR in the first 4 weeks following the initial icodec injection when compared with icodec administered without an additional dose [21]. A pharmacokinetic/pharmacodynamic modeling analysis using data from ONWARDS 2 and 4 investigated efficacy outcomes and hypoglycemia rates when switching from daily basal insulin to icodec with or without a 50% one-time additional dose. The model predicted a mild, transient (1–2 weeks) increase in prebreakfast self-measured blood glucose (SMBG) after initiation without sustained differences in HbA_1c, clinically significant hypoglycemia, or weekly insulin dose at week 26, suggesting no sustained difference from omitting the 50% one-time additional dose [22]. A clinical trial is ongoing currently exploring the switch from daily basal insulin to icodec without a one-time additional dose (NCT0634085; results have not yet been posted at the time of writing), thus providing further evidence to support tailoring of clinician decisions to suit the needs of individuals.

Therefore, in clinical practice, if seeking faster achievement of glycemic control when switching to icodec, the first (week 1) icodec dose should be the total daily basal insulin dose multiplied by seven and then by one and a half (i.e. the 50% one-time additional dose) (Fig. 2; Step 1); for practical purposes, this can also be calculated by multiplying the daily basal insulin dose by 10.5, rounded to the nearest 10 U [18]. Based on the clinician’s judgment, the 50% one-time additional dose may be omitted, including if the individual tends to miss daily basal insulin injections because this may lead to an overestimation of the actual insulin need [expert opinion]. From the second week onwards, the calculated weekly basal insulin dose will be reduced to the daily basal insulin dose multiplied by seven [18]. Care should be given to avoid dosing errors, such as overdosing or forgetting to remove the one-time additional dose after the first injection, which could lead to hypoglycemia. Subsequent insulin titration (see Sect. 3.2) requires a minimum of three prebreakfast SMBG measurements per week, from week 2 if not using a one-time additional dose, and from week 3 if using a one-time additional dose (Fig. 2; Step 1). Individuals should be instructed to consult their physician if they are uncertain about the correct dose.

Icodec Dose Titration in Insulin-Naïve and Insulin-Experienced Individuals with T2D

The titration strategy used in the phase IIIa ONWARD 1–5 trials is summarized in Fig. 2; Step 2. In insulin-naïve individuals with T2D, the titration was ± 20 U weekly (or no change) if prebreakfast SMBG was above or below the target range of 80–130 mg/dL [4.4–7.2 mmol/L] on the 2 days prior to and on the day of the next injection.

Clinicians may decide to titrate less aggressively for individuals who are at greater risk of hypoglycemia, such as those with preserved insulin sensitivity, or hepatic or renal impairment, or elderly individuals (aged ≥ 65 years) [expert opinion]. The prefilled insulin pen injector used to administer icodec can be dialed either up or down by a minimum of 10 U, so clinicians may also consider fine-tuning in increments or decrements of 10 U for dose optimization or in special situations once a stable dose has been established [expert opinion].

With the advancement of digital health technologies, insulin titration tools are being explored to potentially support healthcare professionals and individuals with diabetes [23]. In ONWARDS 5, icodec titration was guided by an app providing weekly dose recommendations based on SMBG levels [10]. A post hoc analysis investigated clinical outcomes for icodec according to adherence to the app guidance, and categorized participants into three adherence subgroups: low (≤ 1 week adherent per 4 weeks), medium (> 1 to ≤ 3 weeks), and high (> 3 weeks) [24, 25]. Modeling analyses assessed associations between app adherence, estimated prebreakfast SMBG, and weekly insulin dose. In the modeling analyses, higher adherence was linked to statistically significantly lower SMBG levels compared with low adherence, and there were trends toward higher weekly insulin doses in high- versus low-adherence subgroups [24, 25]. The observed rate of clinically significant hypoglycemia was lower in the high- versus low-adherence subgroups [24, 25]. The results of this study support the use of app-based titration strategies for icodec in real-world clinical practice, where available.

Factors to Consider when Administering Icodec and its Use in Special Populations

Ethnicity and Race

A post hoc analysis of ONWARDS 1–5 assessed the effects of ethnicity (Hispanic/Latino and nonHispanic/Latino) and race (Asian, Black/African American, White, and 'Other' (American Indian or Alaska native, and native Hawaiian or other Pacific islander)) on the efficacy and hypoglycemia outcomes of icodec versus OD comparators [26].

Overall, efficacy and hypoglycemia outcomes were consistent for icodec versus OD comparators across ethnicity and race subgroups. The estimated change in HbA_1c from baseline to EOT generally favored icodec, with no statistically significant treatment by subgroup interactions. Rates of combined clinically significant or severe hypoglycemia were also consistent among these subgroups [26].

Based on these data, no blanket dose adjustments would be required for icodec based solely on ethnicity or race; however, specific considerations, such as the potential for lower starting doses in some Asian individuals, as discussed is Sect. 3.1.2, may still apply [18].

Age: Elderly Individuals

Most people with T2D are elderly adults (≥ 65 years), which can make diabetes management challenging owing to comorbidities and potential cognitive decline. As the global population ages, the prevalence of T2D among elderly adults is expected to rise, further emphasizing the need for individualized treatments across age groups [27–29].

A post hoc analysis of ONWARDS 1–5 demonstrated that the efficacy and hypoglycemia outcomes were consistent for icodec versus OD comparators across all age groups (< 55, 55–64, and ≥ 65 years) [26]. The estimated change in HbA_1c from baseline to EOT was generally higher for icodec than OD comparators, with no statistically significant treatment by subgroup interactions. Rates of combined clinically significant or severe hypoglycemia were low and consistent across age groups [26]. Based on these data, no blanket dose adjustments are required for icodec with older users [18], and no excess risk of hypoglycemia is expected with icodec in older users.

Icodec may be particularly appropriate for those with frailty who have high perceived pill burden or do not tolerate non-insulin glucose-lowering medications, those who are recommended relaxed glycemic targets that are not being achieved with their current non-insulin antihyperglycemic regimen, those who have difficulty remembering daily injections, people in nursing homes, or those who are dependent on caregivers/family members for insulin administration [expert opinion].

Pediatric Populations

Preliminary data from a phase 1 trial (NCT05790681) of icodec use in an insulin-experienced pediatric population (< 18 years) with T2D demonstrated that icodec was well tolerated, with a pharmacokinetic profile that was similar to that in adults with T2D [30]. Further trial data are expected to become available in the future.

Hepatic Impairment

Hepatic impairment can affect insulin clearance and glucose regulation, potentially necessitating adjustments in insulin dosing to avoid hypoglycemia or suboptimal glycemic control [31, 32]. A phase I trial (NCT04597697) found no clinically relevant differences in icodec pharmacokinetics after a single 1.5 U/kg dose in adults with normal or impaired hepatic function [33]. Owing to the relatively few numbers of individuals with hepatic impairment included in the ONWARDS trials, there are no additional efficacy and safety data for icodec in these individuals. Based on the available data, no specific icodec dose adjustments are required in individuals with hepatic impairment. However, the increased icodec exposure due to reduced clearance in individuals with mild and moderate hepatic impairment suggests more frequent glycemic monitoring may be needed, as recommended for daily insulin preparations [18, 33].

Renal Impairment

Reduced kidney function can decrease insulin elimination, thereby prolonging insulin activity and potentially increasing the risk of hypoglycemia [34].

In a phase I trial (NCT03723785), icodec exposure was slightly higher in adults with renal impairment or end-stage renal disease (ESRD) than in those with normal renal function after a single subcutaneous icodec dose (1.5 U/kg) [33]. Furthermore, a post hoc analysis of ONWARDS 1–5 examined efficacy and hypoglycemia outcomes by renal function category (excluding ESRD and severe renal impairment (in ONWARDS 1–4)], per trial eligibility criteria). Outcomes with icodec versus OD comparators were generally consistent regardless of kidney function, with no statistically significant treatment interactions by kidney function subgroup for HbA_1c change, and no consistent trend by kidney function subgroup for overall rates of combined clinically significant or severe hypoglycemia or weekly basal insulin dose during the last 2 weeks of treatment [35].

Based on these data, no specific dose adjustments are required among individuals with renal impairment because icodec should be dosed according to individual needs. However, the increased icodec exposure associated with reduced insulin clearance in individuals with, versus without, renal impairment [33] suggests that more frequent glycemic monitoring may be required, as with other insulin preparations [expert opinion].

Hypoalbuminemia

At steady state, in individuals with a normal serum albumin level (approximately 4.0 mg/dL [0.6 mmol/L]), the maximum serum concentration of icodec is lower than that of albumin. The ratio of albumin to icodec is approximately 2000:1 meaning that icodec occupies < 0.05% of all available albumin molecules in circulation. Additionally, each albumin molecule has at least four high-affinity binding sites for icodec, resulting in an excess of binding capacity even at relatively high concentration of icodec [14]. Consequently, displacement of icodec from albumin due to reduced levels of albumin (e.g., from hypoalbuminemia) or the presence of other medications such as GLP-1 RAs that bind to albumin is likely minimal, with no clinically relevant effect on icodec activity [14]. In vitro data show no clinically relevant displacement of icodec by fatty acids or anionic protein-bound medicinal products [18].

Across the ONWARDS 1–5 trials, only three participants of the 1,881 who received icodec reported hypoalbuminemia [35]. These individuals experienced HbA_1c reductions from baseline to planned EOT ranging from − 1.1% points to − 2.1% points, with one participant reporting two episodes of clinically significant hypoglycemia. Current data does not show any correlation between serum albumin levels and icodec exposure, suggesting that increased icodec exposure due to hypoalbuminemia is unlikely [35].

Pregnancy

Treatment guidelines stipulate that insulin should be administered alongside medical nutrition therapy to control pre-existing T2D among pregnant individuals [36]. Although animal reproduction studies with icodec have not revealed any effects regarding embryotoxicity and teratogenicity, there are no clinical data regarding the use of icodec during pregnancy available, and there are no registered clinical trials (ClinicalTrials.gov, accessed 14 January 2025). Therefore, women of childbearing potential should be advised to discontinue icodec if they become pregnant or wish to become pregnant [18], and, if indicated, switch to another insulin regimen approved for use during pregnancy [expert opinion].

Coadministration of Icodec with GLP-1 RAs and SGLT2is

A post hoc analysis of ONWARDS 1–5 showed that icodec had consistent efficacy and hypoglycemia outcomes versus OD comparators among adults with T2D regardless of baseline GLP-1 RA or SGLT2i use [37] (Fig. S1 and S2, OSM). Overall, across GLP-1 RA and SGLT2i subgroups, there were no statistically significant treatment by subgroup interactions with respect to change in HbA_1c from baseline to EOT, change in body weight from baseline to EOT (except for SGLT2i use in ONWARDS 5), mean weekly basal insulin dose during the last two weeks of treatment (except for SGLT2i use in ONWARDS 5), and the proportions of participants who achieved an HbA_1c < 7% without combined clinically significant or severe hypoglycemia. Irrespective of baseline GLP-1 RA and SGLT2i use, the rates of combined clinically significant or severe hypoglycemia were low (less than one episode per PYE) across the treatment arms of ONWARDS 1, 2, 3, and 5. The weekly basal insulin dose during the last two weeks of treatment was similar or higher with icodec than OD comparators, irrespective of baseline GLP-1 RA and SGLT2i use, but the treatment difference was generally equivalent to approximately 1–3 U/day, corresponding to typical daily basal insulin adjustments in clinical practice [38].

Based on these post hoc data, the efficacy and hypoglycemia profile of icodec appeared generally consistent regardless of concomitant GLP-1 RA or SGLT2i use.

In addition to GLP-1 RAs and SGLT2is, other non-insulin glucose-lowering medications, such as sulfonylureas and glinides, may affect insulin requirements and need consideration when co-administered with basal insulin [expert opinion]. As noted in the European product label, certain medicinal products may increase (e.g., corticosteroids, oral contraceptives) or decrease (e.g., sulfonylureas, GLP-1 RAs) insulin needs [18]. Pretrial sulfonylureas and glinides were discontinued in ONWARDS 1, 2, and 4, and reduced by 50% in ONWARDS 3 and 5 (changes to other background non-insulin glucose-lowering medications in ONWARDS 5 were allowed at the investigator’s discretion) to minimize the risk of hypoglycemia. This highlights the importance of adjusting these medications when combined with insulin therapy to reduce the hypoglycemia risk while maintaining optimal glycemic control [6–11].

Treatment Monitoring and Management of Icodec Use During Practical Situations

Hypoglycemia Monitoring

Given the risk of hypoglycemia with insulin therapy, regular glucose monitoring is imperative to improve treatment outcomes. CGM is advisable, particularly for individuals with impaired hypoglycemia awareness [39, 40].

CGM was used in insulin-naïve individuals (ONWARDS 1) and insulin-experienced individuals with T2D (ONWARDS 2 and 4) at treatment initiation/switch (from week 0 to week 4), during/at the EOT (from week 22 to week 26, and week 48 to week 52, and week 74 to week 78 for ONWARDS 1), and follow-up (from week 27 to week 31 for ONWARDS 2 and 4; week 78 to week 83 for ONWARDS 1) [6, 41].

In an exploratory analysis of ONWARDS 1, during/at the EOT, TIR was statistically significantly greater, whereas TAR was lower, with icodec than with glargine U100 [41]. TBR < 54 mg/dL (< 3.0 mmol/L) and TBR < 70 mg/dL (< 3.9 mmol/L) remained below recommended targets (< 1% and < 4%, respectively) [42, 43] across time periods and treatment arms; TBR < 54 mg/dL (< 3.0 mmol/L) was slightly higher on days 1–2 versus other days of the week after icodec injection [41]. In a post hoc analysis of ONWARDS 2 and 4, there were no statistically significant differences in TIR, TAR, or TBR < 54 mg/dL (< 3.0 mmol/L) for icodec versus OD comparators [17]. TBR < 54 mg/dL (< 3.0 mmol/L) and TBR < 70 mg/dL (< 3.9 mmol/L) remained within recommended target levels [42, 43] across time periods and treatment arms; TBR < 70 mg/dL (< 3.9 mmol/L) was slightly higher on days 2–4 than on other days of the week in the icodec arms [17].

The approaches to the prevention and management of hypoglycemia for icodec are generally the same as those for daily insulins, although additional care should be given for monitoring hypoglycemia with icodec on days 2–4 after the icodec injection [expert opinion]. Hypoglycemia history should be reviewed at every clinical encounter for individuals at risk, and regular glucose monitoring is crucial, especially during the initial weeks of transitioning to icodec, dose adjustments, changes in physical activity, or illness [18]. Regular use of CGM during titration and maintenance phases can help minimize the risk of hypoglycemia. As with other insulins, glucose (15 g) can be administered to treat hypoglycemic alert value episodes (blood glucose < 70 mg/dL [< 3.9 mmol/L]), which can be repeated after 15 min if hypoglycemia persists. For severe hypoglycemic events, glucagon can be prescribed [18].

Management of Icodec Use on Sick Days

Currently, there are no clinical data for icodec use with respect to sick days. As with daily insulins, frequent monitoring of blood glucose is recommended, and dose adjustments based on the titration regimen (which may include adjustments in either basal or bolus insulin) may be required during sick days to maintain euglycemia [expert opinion]. However, if an individual is receiving icodec treatment only and experiences rapid deterioration in glycemic control, adjusting the icodec dose may not be timely, depending on when it was last administered, and the introduction of short-term rapid-acting insulin to control rises in glucose may be necessary [expert opinion]. Notably, while the administration of icodec should not be stopped, stress hyperglycemia during sick days may require temporary short-acting insulin to manage rapid rises in glucose. Therefore, as with other long-acting basal insulins, a similar strategy to that used during hospitalizations (see Sect. 3.4.3) could be considered, with bolus insulin doses supplemented (basal-only regimen) or increased (basal-bolus regimen) to control hyperglycemia during sick days. Frequent monitoring is crucial, and if required, the introduction of rapid-acting insulin should be considered for the duration of the sick days to manage hyperglycemia [expert opinion]. Monitoring and dose adjustments should continue until the sickness has resolved.

Management of Icodec Use During Hospitalization

Hospitalizations are common among individuals with diabetes and effective insulin management during hospitalization is critical because poor glycemic control (both hyperglycemia and hypoglycemia) is linked to increased morbidity, mortality, and healthcare costs. A post hoc analysis of ONWARDS 1–6 found similar rates and durations of hospitalization among participants with T2D receiving icodec or OD comparators, with most participants continuing trial treatments after discharge [44]. Mean HbA_1c levels remained stable across treatment groups, with low rates of clinically significant or severe hypoglycemia. However, as hospitalizations rarely coincided with scheduled icodec dosing, few participants received icodec while hospitalized, limiting the conclusions that can be drawn regarding inpatient use. Although the post hoc analysis suggests minimal differences between icodec and OD basal inulin analogs during hospitalization, their findings should be interpreted cautiously [expert opinion]. In individuals treated with weekly basal insulin, further doses of daily basal insulin should be avoided during the initial hospitalization, with bolus insulin doses supplemented (basal-only regimen) or increased (basal-bolus regimen) to maintain glycemic targets until discharge [expert opinion]. Depending on the clinical situation, a switch to an OD basal insulin at one-seventh of the individual’s weekly icodec dosage may be made starting 2 weeks after the last icodec injection [expert opinion]. Note that a similar timeline and calculation for the switch to OD insulin from icodec treatment was recommended in ONWARDS 2 and 4 at the end of the trial [7, 9].

Management of a Missed Icodec Dose

The protocols for missed icodec doses were specified in the ONWARDS 1–5 trials. If a dose of icodec is missed, it is recommended that it is administered as soon as possible. If it is injected within 3 days after the missed dose, the original once-weekly dosing schedule can be resumed for subsequent injections, although monitoring of fasting blood glucose should be performed [18]. If more than 3 days have passed, the missed dose should still be administered as soon as possible; the once-weekly dosing schedule will then be changed to the day of the week when the missed dose was administered [18]. If there is a wish to return to the original day of once-weekly dosing schedule, the individual can extend their subsequent dosing by 1–3 days each week until they reach their original administration day [18].

Management of an Icodec Accidental Extra Dose

Accidental extra doses of insulin can result in hypoglycemia and may occur from a dosing error during the switch from daily basal insulin to icodec, especially if the one-time additional dose, against recommendation, continues to be administered after the first injection. Accidental extra dosing can also occur due to erroneous transfer of dosing habits from other once-weekly injectable glucose-lowering medications such as GLP-1 RAs [expert opinion].

A phase II, randomized, open-label, two-period crossover trial (NCT03945656) in 43 adults with T2D receiving basal insulin (with or without oral glucose-lowering medications) found that double or triple doses of icodec did not increase hypoglycemia risk or significantly alter counter-regulatory hormone responses compared with glargine U100 [45]. Follow-up in this phase 2 trial was limited to a fairly short period (1–2 weeks following triple and double doses, respectively), hence delayed effects were not assessed [45]. Additionally, this phase 2 trial did not assess the insulin secretory capacity of trial participants, thus the observed hypoglycemia outcomes should be interpreted with caution, especially for individuals with T2D with advanced beta-cell dysfunction, or for individuals with T1D.

To avoid dosing errors and accidental overdoses, individuals and caregivers should double-check that the correct dose is being administered and ensure that icodec is only used as supplied in its prefilled pen [expert opinion]. Instructions should be given to strictly adhere to dosing instructions as prescribed by the healthcare provider, checking that they select and inject the correct dose, especially for the first and second injections. Instructions should also be given to always check the prefilled pen label before each injection to avoid accidental mix-ups with other injectable products, and to always use the dose counter and the dose pointer on the prefilled pen (and not pen clicks) to select the dose [18]. If accidental overdosing occurs, the individual should closely monitor their blood glucose levels to detect and manage hypoglycemia [18].

Management of Icodec Use Around Exercise

Periods of increased physical activity (such as during exercise) can increase glucose utilization and insulin sensitivity, potentially leading to hypoglycemia in individuals with diabetes [46–48]. Because the therapeutic levels of icodec cannot be reduced in anticipation of increased physical activity during the course of the week, further investigation is warranted [49].

A post hoc analysis of ONWARDS 1–5 examined physical activity-attributed hypoglycemia for icodec versus OD comparators among insulin-naïve and insulin-experienced adults with T2D and found no statistically significant differences in the odds of experiencing physical activity-attributed combined clinically significant or severe hypoglycemia between arms [50] (Table 1). These findings suggest that icodec does not increase the risk of physical activity-attributed hypoglycemia compared with OD comparators in adults with T2D. Routine recommendations regarding the use of CGM or frequent monitoring of glucose values during exercise, and having additional carbohydrate snacks available in case of need, should be followed by all insulin users, irrespective of insulin duration of action [expert opinion].

Table 1.

Proportion of physical activity-attributed hypoglycemic episodes and observed incidence of physical activity-attributed combined clinically significant or severe hypoglycemia with icodec versus once-daily (OD) comparators in individuals with type 2 diabetes (T2D; ONWARDS 1–5)

Triala	Incidence of physical activity-attributed combined clinically significant or severe hypoglycemiab
	Number of participants		Observed incidence, %		OR (95% CI)	p-value for interactionc
	Icodec	OD comparator	Icodec	OD comparator
ONWARDS 1 (basal initiation)	492	492	3.0	1.6	1.86 (0.78, 4.44)	0.1607
ONWARDS 3 (basal initiation)	294	294	2.4	0.7	3.65 (0.74, 17.89)	0.1103
ONWARDS 5 (basal initiation)	542	543	1.7	1.1	1.47 (0.52, 4.17)	0.4640
ONWARDS 2 (basal switch)	263	263	2.7	2.3	1.10 (0.36, 3.37)	0.8621
ONWARDS 4 (basal-bolus)	291	291	18.6	17.9	1.08 (0.70, 1.66)	0.7250

CI confidence interval, degludec insulin degludec, glargine U100 insulin glargine U100, glargine U300 insulin glargine U300, icodec insulin icodec, OR odds ratio (icodec/OD comparators)

^aONWARDS 1 (78-week trial): icodec vs. glargine U100; ONWARDS 3 (26-week trial): icodec vs. degludec; ONWARDS 5 (52-week trial): icodec with a dosing guide app vs. OD analogs (degludec, glargine U100 or glargine U300); ONWARDS 2 (26-week trial): icodec vs. degludec; ONWARDS 4 (26-week trial): icodec vs. degludec, both + 2–4 daily insulin aspart injections

^bClinically significant hypoglycemia: blood glucose < 3.0 mmol/L (< 54 mg/dL), confirmed by blood glucose meter. Severe hypoglycemia: episodes of severe cognitive impairment requiring external assistance for recovery

^cTwo-sided p-value for the test of no treatment difference (no correction for multiplicity)

The pharmacological properties of icodec during exercise are being assessed among adults with T2D in an ongoing phase I trial (NCT06288412; results have not yet been posted at the time of writing).

Fasting Management

Currently, there are no clinical data for icodec use with respect to fasting. However, the pharmacological properties of icodec are being assessed during prolonged fasting among adults with T2D in an ongoing phase I trial (NCT06288412; results have not yet been posted at the time of writing). As with other insulin preparations, more frequent glucose testing should be conducted during the period of fasting, and glucose provided if blood glucose values fall below range [expert opinion].

Stopping Icodec Treatment and Transitioning to Other Basal Insulins

In some situations, such as during prolonged hospital admission, pregnancy, and religious observances (e.g., fasting during Ramadan), it may be preferable to switch from icodec to daily insulin (Fig. 1; Step 3).

According to the ONWARDS 2 and 4 trial protocols, at the end of trial treatment participants who received icodec were recommended to switch to a daily basal insulin; the new daily basal insulin dose was calculated by dividing the latest icodec dose by seven, and the transition was typically initiated 2 weeks after the last icodec dose or sooner if their prebreakfast SMBG was over 180 mg/dL (> 10 mmol/L) [7, 9]. Daily monitoring of prebreakfast SMBG was recommended during the follow-up period, with earlier initiation of the daily basal insulin dose if needed, based on glycemic control. Titration of the daily basal insulin was advised once or twice weekly, based on prebreakfast SMBG values and the local label of the chosen daily insulin [7, 9]. Similar CGM-based metrics (TIR, TAR, TBR) were observed between participants transitioning from icodec and OD comparator arms to daily basal insulins across both trials during the follow-up periods, indicating that the transition from icodec to daily basal insulin can be achieved with minimal disruption to glycemic control [17].

Clinical Use of Icodec for the Management of Type 1 Diabetes (T1D)

When administered specifically as part of a basal-bolus regimen, icodec is indicated as a treatment for adults with T1D in several countries, particularly in cases in which a clear benefit from a once-weekly dosing regimen is expected [18]. The pharmacological properties and the efficacy and safety of icodec versus degludec have been investigated in individuals with T1D in only one phase IIIa trial (ONWARDS 6); hence, to date, there are fewer data available than for T2D (ONWARDS 1–5).

In a pharmacokinetic/pharmacodynamic study, following subcutaneous injection, icodec reached pharmacokinetic steady state on average within 2–3 weeks in T1D [51], which is slightly sooner than the 3–4 weeks needed to reach steady state in T2D [16]. At steady state, the proportions of pharmacodynamic effect (glucose infusion rate) of icodec per day over a 1-week period were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6%, and 8.4% (days 1–7, respectively). The largest daily effect occurred on day 2, and the smallest effect occurred on day 7 [51].

The efficacy and safety of icodec versus degludec as part of a basal-bolus regimen (≥ 2 daily insulin aspart injections) among adults with T1D was assessed in a 52-week (26-week main phase; 26-week extension phase) phase IIIa trial (ONWARDS 6) [12]. For the first injection, the icodec starting dose was the pretrial daily basal insulin dose multiplied by seven and increased by a one-time additional dose (50% for individuals with screening HbA_1c < 8% or 100% for individuals with screening HbA_1c ≥ 8%). For the second injection, participants received the calculated once-weekly dose (their pretrial basal insulin dose multiplied by seven). The icodec dose was adjusted weekly according to a prespecified titration algorithm to attain a prebreakfast SMBG of 80–130 mg/dL (4.4–7.2 mmol/L). In ONWARDS 6, icodec showed noninferiority to degludec in HbA_1c reduction at week 26, meeting the primary endpoint of the trial. From baseline to week 26 and from baseline to week 57, there were statistically significantly higher rates of combined clinically significant or severe hypoglycemia with icodec versus degludec (week 26: 19.9 vs. 10.4 episodes per PYE, p < 0.0001; week 57: 17.0 vs. 9.16 episodes per PYE, p < 0.0001); the incidence of severe hypoglycemia was numerically similar with icodec versus degludec from baseline to week 26 and from baseline to week 57. The higher rate of combined clinically significant or severe hypoglycemia with icodec may be attributed to the weekly profile of icodec in T1D, which might not allow for as precise adjustments to daily variations in insulin needs, particularly for individuals who are used to the flexibility of daily insulin dosing [12].

A post hoc analysis of ONWARDS 6 assessed CGM metrics and CGM-based hypoglycemia duration from week 0 to week 4, week 22 to week 26, and week 48 to week 52 [52]. Although rates of CGM-based clinically significant hypoglycemia (< 54 mg/dL [< 3.0 mmol/L] for ≥ 15 consecutive min) were statistically significantly higher with icodec than degludec, estimated rate ratios (icodec/degludec) for CGM-based clinically significant hypoglycemic episodes were lower than those estimated from SMBG data. Across the trial period, percentage of TIR was highest on days 2–4 after icodec injection, with a concomitant reduction in TAR and an increase in TBR; the median duration of CGM-based hypoglycemia was comparable between treatment arms [52].

Another post hoc analysis of ONWARDS 6 investigated the effects of icodec according to glycemic variability (low variability, coefficient of variation [CV%] ≤ 36%; high variability, CV% > 36%) using CGM data from week 0 to week 2 [53]. When used as part of a basal-bolus regimen in T1D, icodec may offer a lower risk of hypoglycemia for individuals with low glycemic variability than those with high glycemic variability. The proportion of participants achieving HbA_1c targets and percentage of TIR were higher in the low glycemic variability subgroup than in the high glycemic variability subgroup [53].

A third post hoc analysis of ONWARDS 6 found no increased odds of physical activity-attributed hypoglycemic episodes with icodec than with degludec [54]. Most episodes were hypoglycemia alert values or clinically significant level, with few severe episodes. Baseline physical activity level did not affect the rate of combined clinically significant or severe hypoglycemic episodes in either treatment group. TBR < 54 mg/dL (< 3.0 mmol/L) was similar within the icodec treatment group regardless of baseline physical activity levels [54].

Based on these data and clinical practice experience, it should be noted that the mean baseline HbA_1c reported in ONWARDS 6 (7.6%) may not represent glycemic levels seen among T1D populations in clinical practice; therefore, careful consideration is needed when selecting suitable individuals with T1D for icodec treatment [expert opinion].

Until further research, icodec may not be considered to be the preferred insulin in all individuals with T1D, unlike in individuals with T2D. Individuals with T1D who may be suitable for icodec treatment include those who are frequently hospitalized with diabetic ketoacidosis owing to missed basal and missed bolus insulin doses, individuals in nursing homes or other long-term care facilities where managing multiple daily injections can be challenging (these individuals may also have relaxed glycemic targets, making the administration of once-weekly dosing advantageous), and individuals receiving high-dose insulin-pump therapy (icodec could serve as partial background basal insulin so that the insulin pump reservoir can last longer and simplify the insulin regimen) [expert opinion].

When switching individuals with T1D from daily basal insulin to icodec, the recommended icodec dose is the total daily basal insulin dose multiplied by seven [18]. A one-time additional 50% dose is recommended for the first injection only for all individuals with T1D [18]. Owing to the pharmacological profile of icodec, the bolus insulin dose may need to be adjusted downwards slightly (e.g., by approximately 10–30%) on days 2–4 after the icodec injection, based on blood glucose measurements; however, such adjustments are optional and should be considered on a case-by-case basis [expert opinion].

Conclusion

In this review we have summarized the key practical recommendations for icodec use in a clinical setting. As with other basal insulin preparations, icodec can be used to treat a broad range of individuals with T2D without any specific considerations with respect to special populations, although, as with any other insulin treatment, an individualized approach to diabetes care should always be applied. Recommendations should, therefore, be tailored to each individual’s needs. Given the potential benefits of icodec, efforts should be made to offer icodec to those who may benefit most from its use [expert opinion]. Clinical evidence from the ONWARDS phase IIIa clinical trial program in individuals with T2D demonstrated that icodec provides effective glycemic control compared with OD comparators, without an excess risk of hypoglycemia. Once-weekly basal insulins like icodec represent an important step toward simpler, more convenient treatments for people living with T2D, requiring fewer injections with similar or better efficacy and similar safety profiles to available daily basal insulins.

The recommended starting dosage for insulin-naïve individuals with T2D is 70 U/week, followed by once-weekly dose adjustments. In insulin-treated individuals with T2D, when switching from OD or twice-daily basal insulin, the recommended icodec dose is the total daily basal insulin dose multiplied by seven. For the first injection only, a 50% one-time additional dose of icodec is recommended if seeking faster achievement of glycemic control (i.e., week 1 dose should be the total basal insulin dose multiplied by seven and then multiplied by one and a half, rounded to the nearest 10 U). Clear instructions should be offered to individuals and/or caregivers, to avoid dosing errors and accidental overdoses. No dose adjustments are required for elderly individuals, and those with renal or hepatic impairment. Co-administration of icodec with other non-insulin glucose-lowering medications is possible, but dose reduction or discontinuation of insulin secretagogues should be considered. For dose titration guidance, fasting plasma glucose measurements should also be performed frequently to ensure accurate dose adjustments. CGM use is recommended for the monitoring of hyperglycemia and hypoglycemia, especially during the initial weeks of transitioning to icodec, changes in physical activity, or illness.

Future research efforts should focus on icodec use in special situations (such as during prolonged fasting, sickness, exercise, and pregnancy), alternative dose titration algorithms, its use in nursing home settings, and its application among individuals with T1D.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

Medical writing support, provided by Oxford PharmaGenesis, Oxford, UK, was funded by Novo Nordisk.

Conflicts of Interests

AP-T performs research and serves as an adviser on behalf of their employer for Abbvie, Corcept, Dexcom, Eli Lilly, Genentech, Medtronic, Novo Nordisk, Regeneron, and Roche; there has been no direct or indirect transfer of funds. JA has acted as consultant, advisory board member, and speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. HB reports trial fees paid to his institution by Novo Nordisk during ONWARDS 3 and ONWARDS 5; he also reports trial fees paid to his institution by Amgen, Anji, AstraZeneca, Biomea, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Ionis, Kowa, Novartis, Novo Nordisk, and Pfizer, outside the submitted work. IL has received research funding (paid to the institution they are affiliated with) from Boehringer Ingelheim, Merck, Mylan, Novo Nordisk, Pfizer, and Sanofi, and has received advisory/consulting fees and/or other support from AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GI Dynamics, Intarcia Therapeutics, Intercept Pharmaceuticals, Johnson & Johnson, MannKind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, Target Pharma, Valeritas, and Zealand Pharma. YM has received speaking fees from Boehringer Ingelheim, and honoraria and personal fees from Lilly, Novo Nordisk, and Sanofi outside of the submitted work. SS has served as an advisory board member/has carried out speaker activities for Abbott Diabetes Care, AstraZeneca, Cipla, Medtronics, Novo Nordisk, Sun Pharmaceutical Industries, and Torrent Pharmaceuticals. AV has received fees for activities as an advisory board member for Abbott Diabetes Care, AstraZeneca, Eli Lilly, Medtronic, and Novo Nordisk; has carried out speaker activities for Abbott Diabetes Care, AstraZeneca, Eli Lilly, Medtronic, Novo Nordisk, and Roche; and has received research grants from, Eli Lilly, Sanofi, and Novo Nordisk. HW has received research support from Kowa Company, Ltd, Nippon Boehringer Ingelheim Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., SBI Pharma CO., Ltd., and Sumitomo Pharma Co., Ltd.; and has acted as a speaker for Abbott Japan LLC, Bayer Yakuhin, Ltd., Daiichi Sankyo Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., Nippon Boehringer Ingelheim Co., Novo Nordisk Pharma Ltd., Roche DC Japan, MSD K.K., Sanwa Kagaku Kenkyusho Co., Ltd., and Sumitomo Pharma Co., Ltd. SDP served as president of the European Association for the Study of Diabetes (EASD)/European Foundation for the Study of Diabetes (EFSD) from 2020 to 2022; is currently President of Fondazione Menarini; has served as an advisor for Abbott, Amarin Corporation, Amplitude, Applied Therapeutics, AstraZeneca, Biomea Fusion, Eli Lilly & Co., EvaPharma, Menarini International, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Novo Nordisk, and Sanofi.

Availability of Data and Material

Not applicable.

Ethics Approval

Not applicable.

Consent for Publication

Not applicable.

Consent to Participate

Not applicable.

Code Availability

Not applicable.

Author Contributions

All authors contributed equally to the conception, drafting, and revision of the manuscript. All authors approved the final version of the manuscript.