CADTH Reimbursement Recommendation

Insulin Icodec (Awiqli)

Indication: For the once-weekly treatment of adults with diabetes mellitus to improve glycemic control

Sponsor: Novo Nordisk Canada Inc.

Final recommendation: Reimburse with conditions

Recommendation

What Is the CADTH Reimbursement Recommendation for Awiqli?

CADTH recommends that Awiqli be reimbursed by public drug plans for the once-weekly treatment of adults with type 2 diabetes mellitus (T2DM) to improve glycemic control if certain conditions are met.

Which Patients Are Eligible for Coverage?

Awiqli should only be covered to treat adults with T2DM whose glycated hemoglobin (hemoglobin A1C) is between 7.0% and 11.0% (inclusive).

What Are the Conditions for Reimbursement?

To ensure cost-effectiveness, the total drug cost of Awiqli should not exceed the total drug cost of the least costly long-acting basal insulin analogue.

Why Did CADTH Make This Recommendation?

• Evidence from 5 clinical trials demonstrated that Awiqli was noninferior to once-daily basal insulins (insulin degludec or insulin glargine) for change from baseline in hemoglobin A1C at week 26 or 52 of treatment, and likely results in little to no difference in this outcome.

• Treatment with Awiqli resulted in similar benefits to daily basal insulins in terms of time spent in the glycemic range and change in body weight.

• Awiqli is the first once-weekly basal insulin approved for the treatment of T2DM. Once-weekly injections may meet some patient needs or preferences compared to once-daily injections.

• Based on CADTH’s assessment of the health economic evidence, Awiqli does not represent good value to the health care system at the public list price. Awiqli should be negotiated so that it does not exceed the drug program cost of treatment with the least costly long-acting basal insulin reimbursed for the treatment of patients with T2DM who require insulin for glycemic control.

• Based on public list prices, Awiqli is estimated to cost the public drug plans approximately $41 million over the next 3 years.

Additional Information

What Is T2DM?

T2DM is a chronic health condition that develops when the body is no longer able to use insulin efficiently or produce enough insulin to keep blood glucose levels within a normal range. This persistent hyperglycemia results in a constellation of symptoms and downstream impacts on the body. The main goals of treatment for patients with T2DM are to reduce the risk of long-term complications through control of glycemia and blood pressure, and cardiovascular (CV) risk reduction. Management of T2DM combines lifestyle modifications (e.g., dietary modification, exercise, quitting smoking) with pharmacological interventions. Diabetes Canada estimates that more than 4 million people in Canada were living with diabetes mellitus in 2023. Approximately 90% of patients with diabetes specifically have T2DM. The prevalence of T2DM may be higher in racialized and minority groups such as Indigenous people and those who are South Asian or Black, compared to white people.

Unmet Needs in T2DM

Treatment with Awiqli is expected to meet similar needs for patients as treatment with daily basal insulin. Improvements that respondents wished to see in a new treatment that are not currently being achieved with available therapies included fewer side effects, blood flow improvement to extremities, weight control, and better hemoglobin A1C results.

How Much Does Awiqli Cost?

Treatment with Awiqli is expected to cost approximately $1,356 annually, assuming a maintenance dose of 50 units of insulin per day is required to achieve target fasting blood glucose.

Recommendation

The Canadian Drug Expert Committee (CDEC) recommends that insulin icodec be reimbursed for the once-weekly treatment of adults with T2DM to improve glycemic control only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

Five randomized controlled trials (RCTs) (ONWARDS 1 [n = 984], ONWARDS 2 [n = 582], ONWARDS 3 [n = 526], ONWARDS 4 [n = 1,085], and ONWARDS 5 [n = 588]) demonstrated that in patients with T2DM who were insulin naive or insulin experienced, treatment with once-weekly insulin icodec was noninferior in the outcome of change in hemoglobin A1C from baseline compared to daily basal insulins (insulin glargine or insulin degludec) at week 26 or week 52 of treatment. Secondary analyses of superiority showed that insulin icodec was statistically superior compared with the once-daily insulin analogues evaluated for this outcome, but the magnitude of the difference was not likely to be clinically important. Compared to daily basal insulins, treatment with insulin icodec resulted in similar clinical benefit in the secondary outcomes, such as time spent in glycemic range and change in body weight.

Patients indicated that there is a need for new treatments that reduce hyperglycemia events, provide better weight and hemoglobin A1C control, improve blood flow improvement to extremities, have fewer side effects, and improve health-related quality of life (HRQoL). CDEC concluded that insulin icodec may meet these needs in a similar manner to existing insulin analogue therapies for glycemic control in T2DM.

Using the sponsor-submitted price for insulin icodec and publicly listed prices for all other long-acting basal insulin comparators, insulin icodec was more costly than the lowest-cost comparator. Insufficient evidence was provided to demonstrate improved treatment efficacy with insulin icodec versus other long-acting basal insulin analogues. To ensure cost-effectiveness, the total drug cost of insulin icodec should not exceed the total drug cost of the least costly long-acting basal insulin analogue.

Table 1: Reimbursement Conditions and Reasons

hemoglobin A1C = glycated hemoglobin; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SGLT2i = sodium-glucose cotransporter-2 inhibitor; T2DM = type 2 diabetes mellites; vs. = versus.

Discussion Points

• The Health Canada indication supports the use of insulin icodec for the once-weekly treatment of adults with diabetes mellitus to improve glycemic control regardless of diabetes type. This recommendation only applies for the use of insulin icodec for the once-weekly treatment of adults with T2DM to improve glycemic control. The clinical expert noted to CDEC that insulin icodec fits within the existing treatment paradigm currently occupied by daily basal insulins such as insulin degludec and insulin glargine.

• Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment of the primary outcome of the ONWARDS trials concluded that insulin icodec was noninferior in change from baseline in hemoglobin A1C at week 26 or week 52, with moderate certainty in the insulin-naive population and high certainty in the insulin-experienced population. Secondary analyses of superiority suggested that, statistically, there may be a benefit associated with insulin icodec over the once-daily comparators for this outcome, but the clinical meaningfulness of this result is uncertain. The clinical expert consulted by CADTH indicated that the magnitude of difference in hemoglobin A1C between the treatment arms was unlikely to be clinically significant, given the reduction of 0.19% to 0.38% in patients who are insulin naive and 0.02% to 0.22% in patients who are insulin experienced when comparing insulin icodec to daily basal insulins. Additionally, GRADE assessment of the secondary outcomes in the ONWARDS studies concluded with moderate to high levels of certainty that insulin icodec results in little to no difference in the time spent in the glycemic range of 3.9 mmol/L to 10.0 mmol/L, below 3.0 mmol/L, and above 10.0 mmol/L.

• CDEC discussed that the ONWARDS trials did not include any comprehensive measures of HRQoL, so there is a lack of evidence to support the hypothesis that weekly injections would improve HRQoL compared to daily injections. The outcomes related to HRQoL evaluated in the ONWARDS trials included treatment satisfaction (using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), for which there was little to no difference between treatment groups, and treatment compliance (using the Treatment-Related Impact Measure for Diabetes [TRIM-D] compliance domain), which was increased among patients receiving insulin icodec compared to daily basal insulins, but the clinical importance of the increase was uncertain.

• The clinical expert noted to CDEC that the patients most likely to use insulin icodec in place of daily basal insulins are patients newly beginning basal insulin therapy due to the perceived advantages of a lower administration frequency. Insulin icodec may also be used by patients who are unable or unwilling to take daily injections.

• CDEC noted there is an absence of evidence for insulin icodec compared to daily basal insulins in the outcomes of CV mortality, other diabetes-related long-term microvascular or macrovascular complications, and long-term all-cause mortality beyond 1 year.

• CDEC discussed that although the proportion of patients with hypoglycemic events was similar across treatment arms in the insulin-naive populations and the results were inconclusive in the insulin-experienced populations, there were more level 2 hypoglycemic events among patients treated with insulin icodec than comparators in 4 of the 5 trials, although a few patients accounted for many events in the ONWARDS 1 and 3 trials.

• CDEC discussed that the sponsor’s submitted network meta-analysis (NMA) had various limitations that precluded CADTH from being able to draw conclusions regarding the long-term comparative efficacy and safety of insulin icodec relative to long-acting basal insulin analogues. This uncertainty is propagated into the submitted economic model given that the mean reductions in change from baseline in hemoglobin A1C and the annual event rate of severe hypoglycemia were used to generate transition probabilities extrapolating disease progression across the 40-year lifetime horizon.

• The committee discussed the potential impact of insulin icodec weekly dosing compared to daily dosing with regards to cost-effectiveness. Due to inadequate evidence, the magnitude of this impact remains uncertain, resulting in considerable uncertainty regarding the cost-effectiveness of once-weekly injections.

• The committee noted concerns regarding the anticipated budget impact associated with the reimbursement of insulin icodec. This may result in an unknown proportion of patients with T2DM who are not currently on insulin for glycemic control to start once-weekly insulin injections given the improved dosing convenience. While there is insufficient evidence to suggest that once-weekly dosing may improve patient HRQoL, some patients with T2DM may express a preference for once-weekly over once-daily insulin injections.

Background

T2DM is a chronic health condition that develops when the body is no longer able to use insulin efficiently or produce enough insulin to manage blood glucose levels within a normal range. This persistent hyperglycemia results in a constellation of symptoms and downstream impacts on the body. Diabetes Canada estimates that more than 4 million people in Canada, representing around 10% of the population, were living with diabetes mellitus in 2023, and that this will increase to more than 5 million (12%) by 2033. Approximately 90% of patients with diabetes specifically have T2DM. The prevalence of T2DM may be higher in racialized and minority groups such as Indigenous people and those who are South Asian or Black, compared to white people. Indigenous Peoples are also at higher risk for diabetes-related complications.

The main goals of treatment for patients with T2DM are to reduce the risk of long-term complications through control of glycemia and blood pressure, and CV risk reduction through control of lipids and hypertension. Management of T2DM is individualized and ideally combines lifestyle modifications (e.g., dietary modification, exercise, quitting smoking) with pharmacological interventions, most commonly beginning with metformin. If metformin treatment alone is unable to lower or maintain a patient’s hemoglobin A1C or blood glucose levels, additional therapies may be combined with continued metformin therapy, such as sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and insulin.

According to Diabetes Canada treatment guidelines, insulin (in combination with metformin) should be initiated in the event of a patient in whom fasting glucose levels and/or hemoglobin A1C are not at target on current antihyperglycemic drugs, or those with symptomatic hyperglycemia and/or metabolic decompensation. Basal insulin should be initiated and titrated to achieve fasting glucose targets, and metformin should be continued unless contraindicated. Other antihyperglycemic drugs may also be used in combination with these therapies as needed, and therapy should be advanced if the patient’s hemoglobin A1C is not at target within 3 to 6 months despite adequate titration of basal insulin and supports for lifestyle and other pharmacotherapeutic interventions. Basal insulins for T2DM treatment can include long-acting or intermediate-acting insulins. Currently available long-acting insulins include insulin degludec (U100 or U200), insulin glargine (U100 or U300), and insulin detemir, while neutral protamine Hagedorn (NPH) insulin is an intermediate-acting insulin. Insulin and its analogues work to lower blood glucose by stimulating peripheral glucose uptake and by inhibiting hepatic glucose production.

Insulin icodec has been approved by Health Canada for the once-weekly treatment of adults with diabetes mellitus to improve glycemic control. Insulin icodec is a long-acting insulin that is administered subcutaneously on a once-weekly basis, in contrast to the currently available once-daily long-acting basal insulins. Like other insulins, the dose of insulin icodec is individualized and titrated based on the patient’s needs to achieve their glycemic control goal. The prefilled FlexTouch pen delivers doses in 10 unit increments up to 700 units in a single injection. The 1 mL of solution contains 700 units of insulin icodec (700 units/mL; equivalent to 26.8 mg of insulin icodec). Insulin icodec should not be taken in combination with other long-acting insulins, but may be used in combination with rapid-acting insulins, short-acting insulins, and/or noninsulin antidiabetic therapies.

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information:

• a review of 3 RCTs in patients with T2DM who are insulin naive, 2 RCTs in patients with T2DM who are insulin experienced, 1 long-term extension (LTE) study, and 1 indirect treatment comparison

• patient perspectives gathered by 1 patient group, Diabetes Canada

• input from the public drug plans that participate in the CADTH review process

• 1 clinical specialist with expertise diagnosing and treating patients with T2DM

• a review of the pharmacoeconomic model and report submitted by the sponsor.

Stakeholder Perspectives

Patient Input

Patient input was submitted for this CADTH review by Diabetes Canada, which fielded a self-directed questionnaire to people with T2DM and their caregivers across Canada between October 3 and 23, 2023, that inquired about respondents’ lived experiences with diabetes and with several questions pertaining to insulin icodec. Of the 21 respondents, 13 identified as living with T2DM and 1 identified as a caregiver, 93% (of 14 respondents for the question) were older than aged 55 years, 35% were 75 to 84 years of age, and 71% reported living with T2DM for more than 10 years (of which 29% reported living with T2DM for more than 20 years).

Most respondents indicated that living with T2DM was preoccupying, inconvenient, and burdensome, with constant management requiring foresight and planning. A total of 24% (out of 20 respondents) reported experiencing hyperglycemia more than once per day and 10% reported experiencing it more than once per week. A total of 43% (out of 20 respondents) indicated they did not experience hypoglycemia or experienced it in the past but not currently, while 14% experienced it more than once per week. No respondents reported experiencing hypoglycemia daily.

All respondents (n = 19; 100% of whom answered this question) reported taking antihyperglycemic medication, including long-, short-, and rapid-acting insulin; insulin icodec; and other noninsulin antihyperglycemic drugs, either as single-drug products or combined with metformin. A total of 5 of 18 respondents (28%) reported current insulin icodec use. A total of 61% respondents (out of 18) said they were very satisfied or satisfied with their medication; no respondents indicated dissatisfaction. The respondents indicated that ease of use, lack of side effects, and helping to lower hemoglobin A1C were aspects they liked about their medications.

When choosing a medication for diabetes management, several considerations were important to respondents, including avoiding hypoglycemia and hyperglycemia, reducing the risk of heart problems, reducing high blood pressure, maintaining satisfactory blood sugar levels throughout the day, and avoiding yeast infections, urinary tract infections, fluid retention, or weight gain. Affordability was also highlighted as an important consideration. Improvements that respondents wish to see in a new treatment that are not currently being achieved with available therapies included fewer side effects, blood flow improvement to extremities, weight control, and better hemoglobin A1C results.

Clinician Input

Input From Clinical Expert Consulted by CADTH

The clinical expert consulted by CADTH indicated that treatment of T2DM must be individualized, provided in a culturally appropriate manner, and equitably and affordably accessible across Canada. Treatment goals for patients with T2DM include reducing symptoms of hyperglycemia, reducing risks of long-term complications through control of glycemia and blood pressure, and reducing CV risk through control of lipids and hypertension, all through a combination of lifestyle modifications and pharmacotherapeutic approaches. The key unmet need highlighted by the clinical expert was a lack of widespread access to primary care and therefore lack of access to diabetes prevention, detection, and treatment. In particular, access to diabetes education and specialist care varies greatly across the country.

The clinical expert highlighted that insulin icodec would fit into the current paradigm for introduction of basal insulin in the management of T2DM. This includes patients who are not able to meet glycemic targets despite lifestyle modification, and use of, or intolerance or contraindication to, metformin, GLP-1 RAs, and/or SGLT2is. It may also be used as a first-line therapy in patients with T2DM who present with symptomatic hyperglycemia and/or metabolic decompensation with or without metformin. The clinical expert noted that insulin icodec may be preferred over daily basal insulins by some patients who are unable or unwilling to take daily basal insulin, or who would prefer a lower burden related to administration frequency.

The clinical expert consulted by CADTH noted that the timing of assessments varies substantially between physicians and between patients, but ideally a patient would be supported through phone and email to adjust dosing over the first 2 to 3 months, followed by an assessment of treatment suitability after 3 to 6 months of therapy. Diabetes management is complex and individualized. As such, there are several factors a monitoring physician or nurse practitioner will assess with regards to insulin icodec, including treatment acceptance, treatment adherence, hemoglobin A1C target achievement, time in range with continuous glucose monitoring (CGM) of more than 70%, time below range of less than 4%, and no severe hypoglycemic episodes. A sign of positive response to insulin icodec would also be improved HRQoL, including but not limited to less diabetes distress and more treatment satisfaction. Factors that would influence a decision to discontinue insulin icodec include allergy, barriers to adherence, or diabetes remission or glycemic control improvement through weight loss or use of other antihyperglycemic drug or bariatric surgery. The clinical expert stated that diagnosis, prescribing of therapies, and management of treatment for patients with T2DM may occur in primary care. The diagnosis of T2DM and the use of insulin icodec were described by the clinical expert to be uncomplicated and not necessarily require specialist care. Additionally, there are limitations to access of specialist care because of the low number of endocrinologists in Canada and the high number of patients with T2DM.

Clinician Group Input

No clinician group feedback was received by the call for input deadline.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for insulin icodec:

• considerations for initiation of therapy

• considerations for prescribing of therapy

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Table 2: Responses to Questions From the Drug Programs

CDEC = Canadian Drug Expert Committee; T2DM = type 2 diabetes mellites; U = unit.

^aPieber TR, Arfelt KN, Cailleteau R, et al. 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 randomized crossover trial. Diabetologia. 2023;66(8):1413-1430.

Clinical Evidence

Systematic Review

Description of Studies

Five active-controlled, multicentre RCTs were included in this review, all of which compared once-weekly insulin icodec to once-daily basal insulins (insulin degludec and/or insulin glargine). Three of the included studies enrolled adults with T2DM who were insulin naive (the ONWARDS 1, 3, and 5 trials); of these, the ONWARDS 1 trial was 52 weeks in duration, while the ONWARDS 3 and 5 trials were 26 weeks in duration. The ONWARDS 5 trial additionally included the DoseGuide app to inform dosing choices in the insulin icodec arm. The remaining 2 included studies enrolled adults with T2DM who were insulin experienced. In the ONWARDS 2 trial, patients were experienced with basal insulin, and in the ONWARDS 4 trial, patients were experienced with basal and bolus insulin. Both of these studies were 26 weeks in duration. The ONWARDS 4 trial additionally included insulin aspart (bolus) administered 2 to 4 times per day before mealtimes. In all 5 studies, the primary outcome was an assessment of noninferiority of insulin icodec once-weekly compared to the once-daily comparator for the outcome of change in hemoglobin A1C from baseline. In all but the ONWARDS 4 trial, a secondary confirmatory analysis of superiority was also conducted for this outcome. Secondary outcomes varied between the studies and included percent time in range (3.9 mmol/L to 10.0 mmol/L blood glucose using CGM), time below range (< 3 mmol/L blood glucose using CGM), and time above range (> 10.0 mmol/L blood glucose using CGM) in the ONWARDS 1, 2, and 4 trials; change in body weight in all included studies; the number of clinically significant (level 2; < 3.0 mmol/L confirmed by blood glucose metre) or severe hypoglycemic episodes (level 3; any hypoglycemic event requiring active assistance of another person, for instance to administer corrective actions or receive medical care) in all studies; change in treatment satisfaction (measured via DTSQ, in which higher scores [ranging from 0 to 36] represent higher satisfaction with diabetes treatment) in the ONWARDS 5 and ONWARDS 2 trials (exploratory); and treatment compliance (measured via the TRIM-D compliance domain, in which higher scores [ranging from 4 to 20] represent higher compliance with treatment) in the ONWARDS 5 trial. All-cause mortality was a safety outcome in all trials. Additional outcomes of interest that were not reported include the long-term efficacy regarding CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and other microvascular or macrovascular complications of T2DM.

At baseline, patients in the ONWARDS study treatment arm had a mean age range of 58 to 62 years, and 53% to 63% were male. Across all studies, the majority of patients were white (60% to 90%) followed by Asian (4% to 42%), Black or African American (2% to 5%), other (< 1% to 4%), American Indian or Alaska Native (0 to < 1%), and Native Hawaiian or Other Pacific Islander (0 to < 1%). In the insulin-naive populations of the ONWARDS 1, 3, and 5 trials, the mean duration of diabetes was 11 to 12 years and the mean hemoglobin A1C was 8.44% to 8.88% at baseline. In the insulin-experienced populations of the ONWARDS 2 and 4 trials, the mean duration of diabetes was 16 to 18 years and the mean hemoglobin A1C was 8.17% to 8.31% at baseline. Approximately 90% of patients were receiving metformin at baseline, and other common antidiabetic background medications included sulfonylureas, SGLT2is, dipeptidyl peptidase 4 inhibitors, and GLP-1 RAs (> 15%). Uncommon antidiabetic background medications included thiazolidinediones, alpha-glucosidase inhibitor, and glinides. In the ONWARDS 2 and 4 trials, insulin glargine U100 (approximately 41% to 50%) followed by insulin degludec (approximately 23% to 29%) were the most common basal insulins in use at screening; most patients in the ONWARDS 4 trial were receiving basal insulin once daily and bolus insulin 3 times daily (approximately 75%).

Efficacy Results

Change in Hemoglobin A1C From Baseline

In the primary analyses for noninferiority among patients who were insulin naive (the ONWARDS 1, ONWARDS 3, and ONWARDS 5 trials), the between-group differences in mean change from baseline in hemoglobin A1C were –0.19% points (95% confidence interval [CI], –0.36 to –0.03; P < 0.0001) in the ONWARDS 1 trial at 52 weeks, –0.21% points (95% CI, –0.34 to –0.08; P < 0.0001) in the ONWARDS 3 trial at 26 weeks, and –0.38 (95% CI, –0.66 to –0.09; P < 0.0001) in the ONWARDS 5 trial at 52 weeks, indicating that insulin icodec once-weekly was noninferior to the once-daily comparator for the outcome of change in hemoglobin A1C from baseline in patients who were insulin naive. In the secondary analyses for superiority, the P values were 0.0210, 0.0016, and 0.0092, respectively, indicating that insulin icodec once-weekly was superior to the once-daily comparator for the outcome of change in hemoglobin A1C from baseline in patients who were insulin naive.

In the primary analyses for noninferiority among patients with insulin experience (the ONWARDS 2 and ONWARDS 4 trials), the between-group differences in mean change from baseline in hemoglobin A1C was –0.22% points (95% CI, –0.37 to –0.08; P < 0.0001) in the ONWARDS 2 trial and 0.02% points (95% CI, –0.11 to 0.15; P < 0.0001) for the ONWARDS 4 trial, indicating that insulin icodec once-weekly was noninferior to the once-daily comparator for the outcome of change in hemoglobin A1C from baseline in patients with insulin experience. In the ONWARDS 2 trial, a secondary analysis for superiority was also conducted (P = 0.0028), indicating that insulin icodec once-weekly was noninferior to once-daily insulin glargine for the outcome of change in hemoglobin A1C from baseline in patients with insulin experience. No superiority analysis was conducted in the ONWARDS 4 trial.

For each of the ONWARDS 1, 2, 3, 4, and 5 trials, a 2-dimensional tipping point sensitivity analysis was performed to evaluate the robustness of the assumptions regarding missing data; the results were consistent with the primary analysis for noninferiority of hemoglobin A1C.

Time in Range (3.9 mmol/L to 10.0 mmol/L)

In the ONWARDS 1 trial from week 48 to week 52, the least squares (LS) mean time in glycemic range was 71.27% (standard error [SE] = 0.85) for insulin icodec and 67.00% (SE = 0.85) for insulin glargine, representing an estimated treatment difference of 4.27% points (95% CI, 1.92 to 6.62; P = 0.0004). A 2-dimensional tipping point sensitivity analysis was conducted, which aligned with the primary analysis for time in range. This outcome was not assessed in the ONWARDS 3 or 5 trials.

In the ONWARDS 2 trial from week 22 to week 26, the LS mean time in the glycemic range of between 3.9 mmol/L and 10.0 mmol/L was 62.34% (SE = 1.16) for the insulin icodec group and 59.93% (SE = 1.16) for the insulin degludec group. The estimated treatment difference between insulin icodec and insulin degludec was 2.41% (95% CI, –0.84 to 5.56; P = 0.1461). In the ONWARDS 4 trial from week 22 to week 26, the LS mean time in the glycemic range of between 3.9 mmol/L and 10.0 mmol/L was 66.75% (SE = 1.00) for the insulin icodec group and 66.46% (SE = 1.02) for the insulin glargine group. The estimated treatment difference between insulin icodec and insulin glargine was 0.29% (95% CI, –2.52 to 3.09; P = 0.8406).

Time Spent (< 3.0 mmol/L)

In the ONWARDS 1 trial from week 48 to week 52, the LS mean time in a glycemic range below 3 mmol/L was 0.21% (SE not reported) for insulin icodec and 0.16% for insulin glargine (SE not reported), representing an estimated treatment ratio (insulin icodec divided by insulin glargine) of 1.27 (95% CI, 0.94 to 1.71; P = 0.1134). This outcome was not assessed in the ONWARDS 3 or 5 trials.

In the ONWARDS 2 trial from week 22 to week 26, the LS mean time in a glycemic range below 3.0 mmol/L was 0.33% in the insulin icodec group and 0.24% in the insulin degludec group. The estimated treatment ratio of insulin icodec and insulin degludec was 1.37 (95% CI, 0.92 to 2.04; P = 0.1180). In the ONWARDS 4 trial from week 22 to week 26, the LS mean time in a glycemic range below 3.0 mmol/L was 0.69% in the insulin icodec group and 0.58% in the insulin glargine group. The estimated treatment ratio of insulin icodec and insulin glargine was 1.20 (95% CI, 0.91 to 1.58; P = 0.2050).

Time Spent (> 10.0 mmol/L)

In the ONWARDS 1 trial from week 48 to week 52, the LS mean time in a glycemic range above 10 mmol/L was 27.56% for insulin icodec and 32.13% for insulin glargine, representing an estimated treatment difference of –4.58% (95% CI, –6.99 to –2.17; P = 0.0002). This outcome was not assessed in the ONWARDS 3 or 5 trials.

In the ONWARDS 2 trial from week 22 to week 26, the LS mean time in a glycemic range above 10 mmol/L was 36.34.52% SE 1.19) for insulin icodec and 39.28% (SE = 1.19) for insulin degludec, representing an estimated treatment difference of –2.93% (95% CI, –6.25 to 0.39; P = 0.0833). In the ONWARDS 4 trial from week 22 to week 26, the LS mean time in a glycemic range above 10 mmol/L was 30.64% (SE = 1.03) for insulin icodec and 31.24% (SE = 1.04) for insulin glargine, representing an estimated treatment difference of –0.60% (95% CI, –3.47 to 2.28; P = 0.6826).

Change in Body Weight

In the ONWARDS 1 (at 52 weeks), 3 (at 26 weeks), and 5 (at 52 weeks) trials, the between-group differences in change in body weight from baseline were 0.46 kg (95% CI, –0.12 kg to 1.04 kg; P = 0.1187), 0.46 kg (95% CI, –0.19 kg to 1.10 kg; P = 0.1657), and 0.83 kg (95% CI, –0.37 kg to 2.02 kg; P = 0.1747), respectively.

In the ONWARDS 2 (at 26 weeks) and 4 (at 26 weeks) trials, the between-group differences in change in body weight from baseline were 1.70 kg (95% CI, 0.76 kg to 2.63 kg; P = 0.0004) and 0.57 kg (95% CI, –0.39 kg to 1.54 kg; P = 0.2444), respectively.

Number of Clinically Significant Hypoglycemic Episodes (Level 2) (< 3.0 mmol/L [54 mg/dL] Confirmed by Blood Glucose Metre) or Severe Hypoglycemic Episodes (Level 3)

In the ONWARDS 1 trial, a similar number of patients experienced level 2 hypoglycemic events in the 2 groups, but there were numerically more level 2 events in the insulin icodec group. There were 143 events occurring in 48 patients (9.8%) in the insulin icodec group and 75 events occurring in 49 patients (10.0%) in the insulin glargine group. In the insulin icodec group, 3 of the 492 patients (0.6%) experienced 61 of the 143 clinically significant hypoglycemic events. The remaining patients in the insulin icodec group and all of the patients in the insulin glargine groups experienced between 1 and 5 episodes of level 2 hypoglycemic events. The estimated treatment ratio for level 2 events (insulin icodec divided by insulin glargine) was 1.67 (95% CI, 0.99 to 2.84; = 0.0561). Severe (level 3) hypoglycemic events occurred in 1 patient (0.2%) in the insulin icodec group and 3 patients (0.6%) in the insulin glargine group.

In the ONWARDS 3 trial, there were 53 clinically significant events of hypoglycemia (level 2) reported in 26 patients (8.9%) in the insulin icodec group and 23 events occurring in 17 patients (22.1%) in the insulin degludec group. In the insulin icodec group, 2 patients (0.7%) experienced 15 of the 53 clinically significant hypoglycemic events. The remaining patients in the insulin icodec group experienced between 1 and 4 episodes of level 2 hypoglycemic events. Patients in the insulin degludec group experienced between 1 and 3 episodes of level 2 hypoglycemic events. The estimated treatment ratio for level 2 events (insulin icodec divided by insulin degludec) was 2.09 (95% CI, 0.99 to 4.41; P = 0.0536). Severe hypoglycemic events occurred in no patients in the insulin icodec group and 2 patients (0.7%) in the insulin degludec group.

In the ONWARDS 5 trial, there were 104 clinically significant (level 2) hypoglycemic events that were reported in 64 patients (11.8%) in the insulin icodec group and 81 events occurring in 45 patients (8.4%) in the once-daily analogues group. The estimated treatment ratio for level 2 events (insulin icodec divided by once-daily analogues) was 1.23 (95% CI, 0.77 to 1.98; P = 0.3928). Severe (level 3) hypoglycemic events occurred in no patients in the insulin icodec group and 4 patients (0.7%) in the insulin glargine group.

In the ONWARDS 2 trial, there were 113 clinically significant events of hypoglycemia (level 2) reported in 37 patients (14.1%) in the insulin icodec group and 41 events occurring in 19 patients (7.2%) in the insulin degludec group. The estimated treatment ratio for level 2 events (insulin icodec divided by insulin degludec) was 1.98 (95% CI, 0.95 to 4.12; P = 0.067). Severe hypoglycemic events occurred in no patients in the insulin icodec group and 1 patient (0.4%) in the insulin degludec group.

In the ONWARDS 4 trial, clinically significant events of hypoglycemia (level 2) were reported in 148 patients (50.9%) in the insulin icodec group and 160 patients (55.0%) in the insulin glargine group. The estimated treatment ratio for level 2 events (insulin icodec divided by insulin glargine) was 0.99 (95% CI, 0.73 to 1.34; P = 0.93). Severe (level 3) hypoglycemic events occurred in 4 patients (1.4%) in the insulin icodec group and 2 patients (0.7%) in the insulin glargine group.

Diabetes Treatment Satisfaction Questionnaire

This outcome was assessed only in the ONWARDS 5 and ONWARDS 2 trials.

In the ONWARDS 5 trial, the observed mean DTSQ total score at baseline was 26.15 in the insulin icodec plus DoseGuide group and 26.77 in the once-daily analogues group. The estimated LS mean DTSQ total score at week 52 was 31.13 (SE = 0.25) in the insulin icodec group and 30.35 (SE = 0.25) in the once-daily analogues group, representing an LS mean change from baseline in DTSQ total satisfaction score of 4.68 (SE = 0.25) and 3.90 (SE = 0.25), respectively. The LS mean difference between groups was 0.78 (95% CI, 0.10, 1.47; P = 0.0247).

In the ONWARDS 2 trial, the observed mean DTSQ total score at baseline was 26.76 in the insulin icodec group and 26.69 in the insulin degludec group. The estimated LS mean DTSQ total score at week 26 was 30.95 (SE = 0.30) in the insulin icodec group and 29.69 (SE = 0.31) in the insulin degludec group, representing an LS mean change from baseline in DTSQ total satisfaction score of 4.22 (SE = 0.30) and 2.96 (SE = 0.31), respectively. The estimated LS mean treatment difference between insulin icodec and insulin degludec was 1.25 (95% CI, 0.41 to 2.10, P = 0.0036).

Treatment-Related Impact Measure for Diabetes Compliance Domain

This outcome was assessed only in the ONWARDS 5 trial. The estimated treatment difference was 3.04 (95% CI, 1.28 to 4.81; P = 0.0007) at 52 weeks.

CV Death

CV death was not measured as an outcome in the included trials.

Nonfatal MI

Nonfatal MI was not measured as an outcome in the included trials.

Nonfatal Stroke

Nonfatal stroke was not measured as an outcome in the included trials.

Other Microvascular and Macrovascular Complications of T2DM

Other microvascular and macrovascular complications of T2DM were not measured as outcomes in the included trials.

Harms Results

Adverse Events

The proportion patients who had adverse events (AEs) was similar between the insulin icodec and once-daily insulin analogue comparator groups in all ONWARDS studies. The most common AEs were COVID-19, nasopharyngitis, diarrhea, and back pain. The majority of AEs were determined by the study investigators to be nonserious, mild to moderate in severity, unlikely related to trial products, and recovered or recovering by the end of the trial duration in each trial.

In the insulin-naive populations (the ONWARDS 1, 3, and 5 trials), 50% to 71% of patients across each treatment arm experienced at least 1 AE.

In the insulin-experienced populations (the ONWARDS 2 and 4 trials), 51% to 62% of patients across each treatment arm experienced at least 1 AE.

Serious Adverse Events

Serious adverse events (SAEs) occurred in similar proportions across both the insulin icodec groups and the once-daily analogues groups in each trial.

In the insulin-naive populations (the ONWARDS 1, 3, and 5 trials), among patients treated with insulin icodec, 5.1% to 10.4% had at least 1 SAE. In these same trials, among patients treated with the comparator once-daily analogues, 5.1% to 10.6% had at least 1 SAE.

In the insulin-experienced populations (the ONWARDS 2 and 4 trials), among patients treated with insulin icodec or once-daily analogues, 7.6% to 8.4% and 6.1% to 8.6% had at least 1 SAE, respectively.

Reported SAEs included cardiac disorders; infections and infestations; injury, poisoning, and procedural; vascular disorders; musculoskeletal and connective tissue disorders; neoplasms benign, malignant and unspecified nervous system disorders; eye disorders; reproductive system and breast disorders; respiratory, thoracic, and mediastinal disorders; blood and lymphatic system disorders; congenital, familial, and genetic disorders; gastrointestinal disorders; metabolism and nutrition disorders; and renal and urinary disorders. Each of these SAE categories occurred in 0 to fewer than 5% of patients. The most frequent category of SAEs observed was cardiac disorders, which ranged from approximately 3% to 4% of patients in the included studies, followed by infections and infestations (in approximately 2% to 3% of patients). There was no single most common event observed.

Withdrawals Due to Adverse Events

In the insulin-naive populations (the ONWARDS 1, 3, and 5 trials), permanent discontinuation of the study drug because of an AE occurred in 0.7% to 1.2% of patients treated with insulin icodec and 0.8% to 1.3% of patients treated with comparators (insulin glargine or insulin degludec). In the insulin-experienced populations (the ONWARDS 2 and 4 trials), permanent discontinuation of the study drug because of an AE occurred in 1.0% to 1.9% of patients treated with insulin icodec and 1.0% to 1.1% of patients treated with insulin degludec or insulin glargine. Temporary discontinuation was similarly uncommon, as were AEs leading to dose increases or dose decreases.

Mortality

In the ONWARDS 1 trial, there were 6 patients (0.6%) with fatal outcomes, of which 4 patients (0.8%) died in the insulin icodec treatment group and 2 patients (0.4%) died in the insulin glargine treatment group. The events (of which some patients may have had multiple) included infections and infestations (n = 2) and 1 each of COVID-19, cardiac disorders (angina pectoris), postoperative infection, pancreatic neoplasm, glioblastoma, unknown cause, and acute coronary syndrome. The death due to unknown cause in the insulin glargine treatment group was judged by investigators as “possibly” related to the trial product.

In the ONWARDS 3 trial, there were 2 patients (0.7%) in the insulin icodec group and 1 patient (0.3%) in the insulin degludec group with fatal outcomes. In the insulin icodec group, deaths were due to malignancy and an undetermined cause (n = 1 for each). In the insulin degludec group, death was due to acute MI (n = 1).

In the ONWARDS 5 trial, there were 3 patients (0.6%) who died in the insulin icodec plus DoseGuide group and 7 patients (1.3%) who died in the once-daily analogues group. In the insulin icodec plus DoseGuide group, deaths were due to an undetermined cause (n = 2) and malignancy (n = 1). In the once-daily analogues group, deaths were due to pulmonary causes (n = 2), undetermined causes (n = 2), malignancy, sudden cardiac death, and heart failure (n = 1 for each).

In the ONWARDS 2 trial, there were 2 patients (0.8%) who died in the insulin icodec group and 2 patients (0.8%) who died in the insulin degludec group. In the insulin icodec group, all deaths were due to infection (n = 2). In the insulin degludec group, deaths were due to CV procedures and malignancy (n = 1 for each).

In the ONWARDS 4 trial, there were 2 patients (0.7%) in the insulin icodec group and 1 patient (0.3%) in the insulin glargine group who died. In the insulin icodec group, deaths were due to other CV causes and infection (including sepsis) (n = 1 for each). In the insulin glargine group, there was 1 instance of gastrointestinal bleeding that resulted in death.

Notable Harms

Prespecified notable harms included hypersensitivity, injection-site reactions, hypoglycemia, and nocturnal hypoglycemia.

Events of hypersensitivity were reported among less than 7% of patients during all of the ONWARDS studies and were similar between treatment groups in each trial. Serious events were rare.

Injection-site reactions occurred among less than 9% of patients across all of the ONWARDS studies. In the ONWARDS 1 trial, 6 patients (1.2%) experienced 6 events in the insulin icodec group compared to 12 patients (2.4%) experiencing 12 events in the insulin glargine group. All events were considered mild or moderate in severity. In the ONWARDS 3 trial, 25 patients (8.5%) experienced 62 events in the insulin icodec group compared to 13 patients (4.4%) who experienced 22 events in the insulin degludec group. Of the 62 injection-site reactions reported in the insulin icodec group, 24 events were reported by only 2 patients. No events were considered serious. In the ONWARDS 5 trial, 5 patients (0.9%) experienced 6 events in the insulin icodec plus DoseGuide group compared to 7 patients (1.3%) who experienced 28 events in the once-daily insulin analogue group. No events of injection-site reactions were considered serious. In the ONWARDS 2 trial, 3 patients (1.1%) experienced 3 events in the insulin icodec group compared to 1 patient (0.4%) who experienced 1 event in the insulin degludec group. All events of injection-site reactions were considered mild or moderate in severity. In the ONWARDS 4 trial, 2 patients (0.7%) experienced 2 events in both the insulin icodec and insulin glargine groups. No events of injection-site reactions were considered serious, and all were mild in severity.

Nocturnal Hypoglycemia

In the ONWARDS 1 trial, level 1 nocturnal hypoglycemic events occurred in 67 patients (13.6%) in the insulin icodec group and 58 patients (11.8%) in the insulin glargine group. Clinically significant (level 2) nocturnal hypoglycemic events occurred in 9 patients (1.8%) in the insulin icodec group and 10 patients (2.0%) in the insulin glargine group, and severe (level 3) nocturnal hypoglycemic events occurred in 0 patients and 1 patient (0.2%) in the insulin icodec and insulin glargine groups, respectively. The estimated treatment ratio between insulin icodec and insulin glargine for clinically significant (level 2) nocturnal hypoglycemic events was 0.92 (95% CI, 0.29 to 2.86; P = 0.8816). The estimated treatment ratio between insulin icodec and insulin glargine for clinically significant (level 2) or severe (level 3) nocturnal hypoglycemic events was 0.88 (95% CI, 0.29 to 2.64; P = 0.8189).

In the ONWARDS 3 trial, level 1 nocturnal hypoglycemic events occurred in 24 patients (8.2%) in the insulin icodec group and 23 patients (7.8%) in the insulin degludec group. Clinically significant (level 2) nocturnal hypoglycemic events occurred in 1 patient (0.3%) in the insulin icodec group and 4 patients (1.4%) in the insulin degludec group. There were no severe (level 3) nocturnal hypoglycemic events in either treatment group. The estimated treatment ratio between insulin icodec and insulin degludec for clinically significant (level 2) nocturnal hypoglycemic events was 2.09 (95% CI, 0.99 to 4.41; P = 0.0536). The estimated treatment ratio between insulin icodec and insulin degludec for clinically significant (level 2) or severe (level 3) nocturnal hypoglycemic events was 1.82 (95% CI, 0.87 to 3.80; P = 0.1091).

In the ONWARDS 5 trial, level 1 nocturnal hypoglycemic events occurred in 48 patients (8.9%) in the insulin icodec group and 46 patients (8.6%) in the once-daily analogues group. Clinically significant (level 2) nocturnal hypoglycemic events occurred in 11 patients (2.0%) in both treatment groups and severe (level 3) nocturnal hypoglycemic events occurred in no patients in the insulin icodec group and 1 patient (0.2%) in the once-daily analogues groups. The estimated treatment ratio between insulin icodec and once-daily analogues for clinically significant (level 2) or severe (level 3) nocturnal hypoglycemic events was 1.36 (95% CI, 0.82 to 2.27; P = 0.02396).

In the ONWARDS 2 trial, level 1 nocturnal hypoglycemic events occurred in 60 patients (22.9%) in the insulin icodec group and 35 patients (13.3%) in the insulin degludec group. Clinically significant (level 2) nocturnal hypoglycemic events occurred in 16 patients (6.1%) in the insulin icodec group and 9 patients (3.4%) in the insulin degludec group. Severe (level 3) nocturnal hypoglycemic events occurred in no patients in either treatment group. The estimated treatment ratio between insulin icodec and insulin degludec for clinically significant (level 2) nocturnal hypoglycemic events was 1.98 (95% CI, 0.95 to 4.12; P = 0.0677). The estimated treatment ratio between insulin icodec and insulin degludec for clinically significant (level 2) or severe (level 3) nocturnal hypoglycemic events was 1.93 (95% CI, 0.93 to 4.02; P = 0.0782).

In the ONWARDS 4 trial, level 1 nocturnal hypoglycemic events occurred in 108 patients (37.1%) in the insulin icodec group and 132 patients (45.4%) in the insulin glargine group. Clinically significant (level 2) nocturnal hypoglycemic events occurred in 54 patients (18.6%) in the insulin icodec group and 71 patients (24.4%) in the insulin glargine group, and severe (level 3) nocturnal hypoglycemic events occurred in no patients and 1 patient (0.3%) in the insulin icodec and insulin glargine groups, respectively. The estimated treatment ratio between insulin icodec and insulin glargine for clinically significant (level 2) nocturnal hypoglycemic events was 0.74 (95% CI, 0.47 to 1.15; P = 0.1818). The estimated treatment ratio between insulin icodec and insulin glargine for clinically significant (level 2) or severe (level 3) nocturnal hypoglycemic events was 0.73 (95% CI, 0.47 to 1.14; P = 0.1694).

Critical Appraisal

All of the ONWARDS trials were randomized, active-controlled trials with adequate methodologies related to randomization and allocation concealment, and there were no concerning between-arm imbalances in patient characteristics at baseline, nor in diabetes-related background medications. As such, the risk of bias arising from the randomization process is low in all trials. Each trial was adequately powered for the purpose of its primary hypotheses. ONWARDS 1, 2, 4, and 5 were open-label trials, which is associated with a risk of bias in subjective and self-report outcomes, while the ONWARDS 3 trial was double blinded, with adequate blinding and concealment procedures, including placebos matched in visual quality and administration methods to the active trial products.

The primary outcome in each trial was the change in hemoglobin A1C from baseline, and the noninferiority margin of 0.3% points was chosen based on established FDA guidance and previous trials of insulin products in the treatment of T2DM. Change in hemoglobin A1C from baseline was considered a clinically relevant outcome by the clinical expert consulted by CADTH. This outcome is considered acceptable by the FDA for trials of new antihyperglycemic therapies seeking a glycemic control indication, the rationale being that it is a validated surrogate of microvascular disease risk reduction and it is currently recognized as the key surrogate marker for the development of long-term diabetes complications in people with type 1 or 2 diabetes. The selection of this noninferiority margin was determined based on FDA guidance as previously described, and was considered clinically relevant as a threshold of minimal important difference, according to the clinical expert consulted by CADTH. However, hemoglobin A1C is ultimately a surrogate biomarker, and there is evidence to suggest that hemoglobin A1C may not be appropriate as a surrogate outcome for downstream complications in diabetes trials because of poor associations with mortality, CV mortality, MI, heart failure, kidney injury, and stroke. Other limitations of hemoglobin A1C include a lack of information about acute glycemic events (i.e., hypoglycemia or hyperglycemia) and insensitivity regarding day-to-day variations of glucose, and measurement of hemoglobin A1C can be confounded by other conditions such as anemia, hemoglobinopathies, iron deficiency, and pregnancy.

Use of CGM allows for observation of time in and outside of range and daily glycemic variability, and the clinical expert consulted by CADTH indicated that this is of growing importance in clinical trials of glycemic control in patients with T2DM in addition to hemoglobin A1C. Time in range as measured by CGM is a useful measure of short-term glycemic control and there is good correlation between time in range and hemoglobin A1C. Time in range has been demonstrated to be associated with diabetic retinopathy and microalbuminuria but publications assessing this outcome as a surrogate for other diabetes-related complications (e.g., mortality, MI, and other major CV or renal events) were not identified.

The primary outcome in all trials was adjusted for multiple comparisons. Additionally, in the ONWARDS 1 trial, the outcome of time in range (3.9 mmol/L to 10 mmol/L) was also adjusted for multiple comparisons. As the remaining outcomes were not adjusted for multiplicity, there is an increased risk of type I error (i.e., false-positive results) for statistically significant results for those outcomes.

Multiple imputation was used for all outcomes to account for missing data. Multiple imputation methods will not remove or reduce bias that occurs when missingness is not random, but the proportion of missing data in each case was low, so this was not considered cause for concern. Additionally, sensitivity analyses were conducted for the primary outcome, which bolstered confidence in the primary analyses.

The study designs with respect to patient eligibility criteria and characteristics at baseline were appropriately reflective of the target population in Canada, with the exception that there is a notable lack of inclusion of Indigenous people, who are at higher risk of T2DM and its complications. The selected comparators, medications at baseline among included patients and concomitant mediations used during the trials, were considered by the consulted clinical expert to be appropriate and to reflect clinical practice in Canada.

The impact of insulin icodec on patients’ HRQoL was not measured in the ONWARDS trials. Although the DTSQ and TRIM-D compliance domains provide information about treatment satisfaction and compliance, they are not comprehensive measures of HRQoL. As such, the influence of insulin icodec on HRQoL as compared with insulin or insulin glargine is not known. Additionally, there were no compliance data reported for the insulin-experienced populations.

There is a data gap regarding the long-term effect of insulin icodec versus daily insulins on outcomes such as CV death, nonfatal MI, nonfatal stroke, and long-term all-cause mortality beyond the duration of the included clinical trials. Additionally, the clinical trials did not evaluate any global HRQoL measures.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with the expert committee members:

• outcomes related to blood glucose (i.e., percent change in hemoglobin A1C from baseline, percent time in range [3.9 mmol/L to 10.0 mmol/L], percent time spent below range, percent time spent above range)

• mortality and morbidity (i.e., all-cause mortality, CV death, nonfatal MI, nonfatal stroke, and microvascular and macrovascular complications of T2DM)

• change in body weight from baseline

• treatment satisfaction (i.e., DTSQ) and compliance (i.e., TRIM-D compliance domain)

• proportion of patients with clinically significant or severe hypoglycemic events.

Table 3: Summary of Findings for Insulin Icodec vs. Daily Basal Insulins^a for Patients With T2DM — Patients Who Were Insulin Naive

CI = confidence interval; DTSQ = Diabetes Satisfaction Treatment Questionnaire; hemoglobin A1C = glycated hemoglobin; LS = least squares; MI = myocardial infarction; NA = not applicable; NR = not reported; RCT = randomized controlled trial; T2DM = type 2 diabetes mellites; TRIM-D = Treatment-Related Impact Measure for Diabetes; vs. = versus.

Note: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.

^aThe comparator for the ONWARDS 1 trial was insulin glargine, the comparator for the ONWARDS 3 trial was insulin degludec, and the comparators for the ONWARDS 5 trial were insulin glargine and insulin degludec.

^bAdditional information was requested from the sponsor to obtain 95% CIs for the LS mean estimates in each treatment group within the trials, and to obtain between-group differences with 95% CIs for hypoglycemia outcomes. This information was not necessarily part of the sponsor’s statistical analysis plan and is considered exploratory evidence.

^cRated down 1 level for serious imprecision. The target of the certainty appraisal is little to no difference based on a threshold of 0.3% points for a clinically important between-group difference (the noninferiority margin). The 95% CI for all trials includes the potential for important benefit. There is high certainty that insulin icodec is noninferior to insulin glargine or insulin degludec with respect to change from baseline in hemoglobin A1C.

^dRated down 1 level for serious imprecision. The CI for the percent time in range (3.9 mmol/L to 10.0 mmol/L) included a potential benefit (based on a threshold of importance of 5% provided by the clinical expert).

^eIn the trial, statistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^fRated down 1 level for serious imprecision. The CI for the percent time above 10.0 mmol/L included a potential benefit (based on a threshold of importance of 5% provided by the clinical expert).

^gRated down 1 level for serious indirectness due to the short follow-up length in the trials and down 2 levels for very serious imprecision because of the small number of events.

^hRated down 1 level for serious study limitations. The open-label design may bias reporting of subjective measures because patients were aware of the treatment they were receiving.

ⁱRated down 1 level for serious imprecision. The CI for difference between groups in all trials included a potentially important increase (based on a threshold of importance of 3% provided by the clinical expert).

^jRated down 1 level for serious imprecision. The CI for the proportion of patients experiencing level 2 or 3 hypoglycemia included potential harm (based on a threshold of importance of 3% provided by the clinical expert).

Source: ONWARDS 1 Clinical Study Report, ONWARDS 2 Clinical Study Report, ONWARDS 3 Clinical Study Report, ONWARDS 4 Clinical Study Report, ONWARDS 5 Clinical Study Report, and additional information provided by the sponsor at CADTH’s request.

LTE Studies

Description of Studies

The sponsor submitted the LTE phase of the ONWARDS 1 trial, which extended the original open-label trial design an additional 26 weeks to provide 78 weeks of data. Patients originally randomized to either insulin icodec or insulin glargine continued their treatment per the protocol of the ONWARDS 1 trial until the end of the LTE phase. The patient population, interventions, comparators, and trial design elements remained the same. The same efficacy and safety outcomes were also assessed using the same statistical methods, with some exceptions — the efficacy outcomes were not controlled for multiplicity and there was no hierarchical testing procedure for the primary outcome.

The efficacy outcomes summarized by CADTH included change in hemoglobin A1C from baseline, change in body weight from baseline, proportion of patients with level 2 or 3 hypoglycemic events, time spent in range (3.9 mmol/L to 10.0 mmol/L), time spent under 3.0 mmol/L, and time spent over 10.0 mmol/L, all between weeks 74 and 78.

Efficacy Results

Briefly, similar to the 52-week mark of the ONWARDS 1 trial, there was little to no difference between insulin icodec and insulin glargine in terms of change in hemoglobin A1C from baseline to week 78, change in body weight from baseline to week 78, or time spent under 3.0 mmol/L. Similar to the 52-week mark of the ONWARDS 1 trial, insulin icodec was statistically favoured for time spent in the range of 3.9 mmol/L to 10.0 mmol/L (treatment difference = 4.41; 95 % CI, 1.92 to 6.90; P = 0.0005) and time spent > 10.0mmol/L (treatment difference = –4.65; 95 % CI, –7.20 to –2.10; P = 0.0004) between weeks 74 and 78. The treatment ratio for level 2 or 3 hypoglycemic in the LTE phase was 1.63 (95% CI, 1.02 to 2.61).

Table 4: Summary of Findings for Insulin Icodec vs. Daily Basal Insulins for Patients With T2DM — Patients With Insulin Experience^a

CI = confidence interval; DTSQ = Diabetes Satisfaction Treatment Questionnaire; hemoglobin A1C = glycated hemoglobin; LS = least square; MI = myocardial infarction; NA = not applicable; NR = not reported; RCT = randomized controlled trial; T2DM = type 2 diabetes mellites; vs. = versus.

Note: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.

^aThe patient population for the ONWARDS 2 trial was patients experienced with basal insulin and the patient population for the ONWARDS 4 trial was patients experienced with basal and bolus insulin.

^bAdditional information was requested from the sponsor to obtain 95% CIs for the LS mean estimates in each treatment group within the trials, and to obtain between-group differences with 95% CIs for hypoglycemia outcomes. This information was not necessarily part of the sponsor’s statistical analysis plan and is considered exploratory evidence.

^cRated down 1 level for serious imprecision. The target of the certainty appraisal is little to no difference based on a threshold of 0.3% points for a clinically important between-group difference (the noninferiority margin). The 95% CI for all trials includes the potential for important benefit. There is high certainty that insulin icodec is noninferior to insulin glargine or insulin degludec with respect to change from baseline in hemoglobin A1C.

^dRated down 1 level for serious indirectness as the short follow-up length in the trials is insufficient to fully capture this outcome. Rated down 2 levels for very serious imprecision as there is a very small number of events captured.

^eIn the trial, statistical testing for this outcome was not adjusted for multiplicity. The results are considered supportive evidence.

^fRated down 1 level for serious study limitations. The open-label design may bias reporting of subjective measures because patients were aware of the treatment they were receiving.

^gRated down 1 level for serious imprecision. The target of the certainty appraisal is an increase based on a threshold for a clinically important between-group difference of 3% as informed by the clinical expert. The 95% CI includes the possibility of little to no difference.

^hRated down 2 levels for very serious imprecision. The target of the certainty appraisal is a decrease based on a threshold for a clinically important between-group difference of 3% as informed by the clinical expert. The 95% CI includes the possibility of little to no difference and an increase.

Source: Details included in the table are from the sponsor’s summary of clinical evidence, the ONWARDS 2 Clinical Study Report, the ONWARDS 4 Clinical Study Report, and additional information provided by the sponsor.

Harms Results

Harms in the 2 study arms were broadly similar during the LTE phase of the study, with some exceptions. Patients in the insulin glargine arm had a numerically higher incidence of AEs requiring temporary discontinuation, although the proportion was low in each group (< 5%). There was a numerically higher proportion of patients in the insulin icodec arm who experienced level 1 hypoglycemic events (55.9% versus 48.2%). Level 2 events occurred in the same proportion of patients (12.4% in both arms) and level 3 hypoglycemic events were rare in both arms (1 patient [0.2%] in the insulin icodec arm and 5 patients [1.0%] in the insulin glargine arm). All-cause mortality was similar between the treatment arms, with 5 patients (1.0%) in the insulin icodec arm and 3 patients (0.6%) in the insulin glargine arm (1 additional death per group relative to the 52-week mark of the ONWARDS 1 trial).

Critical Appraisal

All appraisal points pertaining to the main phase of the ONWARDS 1 trial also pertain here as this LTE was a continuation of the same study design, patients, and outcomes. In addition to those, an additional internal validity limitation is that all efficacy outcomes are exploratory and not adjusted for multiplicity, resulting in an increased risk of type I error (i.e., false-positive conclusions) for statistically significant results. Regarding external validity, the LTE results are only applicable to patients who are insulin naive as this was the only patient population included in the ONWARDS 1 trial, leaving a knowledge gap for these outcomes in patients with insulin experience. Data on all-cause mortality are only provided during the LTE phase; thus, information on mortality beyond 78 weeks is lacking. The comparison was also based on a small number of events, limiting a conclusion as to which treatment may be favoured. Lastly, results on long-term treatment adherence or satisfaction and clinical outcomes such as microvascular and macrovascular complications (e.g., nonfatal MI, stroke) were not assessed.

Indirect Comparisons

A NMA was submitted with the objectives of assessing the relative efficacy and safety of insulin icodec compared to other basal insulin analogues used by patients in Canada. Analyses were conducted for patients who were insulin naive, basal insulin experienced, and basal and bolus insulin experienced. The outcomes of interest appraised by CADTH were change in hemoglobin A1C, overall hypoglycemia, level 2 and 3 hypoglycemia, and nocturnal hypoglycemia. Relevant comparators were insulin glargine U100 and U300, insulin degludec U100 and U200, and insulin detemir.

Description of Studies

The literature search yielded a total of 8,760 citations that were screened at the title and abstract phase. Of these, 22 studies were considered for data extraction for the feasibility assessment of the NMA. For patients who were insulin naive, the NMAs contained 14 studies (11 phase III/IV studies, 1 phase II trial, and 2 studies with unreported trial phases). The trials were either open label (n = 13) or double blinded (n = 1). For patients with basal insulin experience, there were a total of 5 unique trials contributing to the NMA. All trials were multicentre, open-label phase III trials. For patients with basal and bolus experience, a total of 3 unique trials contributed to the NMA. Two studies were multicentre, multinational, open-label trials. One trial was a phase III study and the phase was not reported for the other.

Efficacy Results

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Harms Results

No safety analysis was run beyond the NMAs for hypoglycemia outcomes.

Critical Appraisal

The systematic literature review that informed the NMA did not specify which comorbidities were used for the exclusion criteria of “patients with comorbidities.” This could impact the generalizability of the NMA results and affect confidence in the transitivity assumption if patient populations with different comorbidities are included.

With regards to the feasibility assessment in the NMA, the risk of bias appraisals were undertaken at the level of the trial, rather than at the level of the reported result (within each trial), ignoring that risk of bias can differ across outcomes within the same trial. Furthermore, the methods for appraising risk of bias were not reported and there was no discussion of how the treatment effect modifiers were chosen for the feasibility assessment or how the assessment ensured that the list of treatment effect modifiers was comprehensive. There are also concerns with unmeasured treatment effect modifiers and heterogeneity across the trials in treatment effect modifiers (e.g., a paucity of studies reported ethnicity and the ranges reported were wide). Overall, there remains uncertainty in the plausibility of the transitivity assumption underpinning the NMA.

Small treatment networks, particularly for the hypoglycemia outcomes and patients who were insulin experienced, necessitated the selection of fixed-effect models for most comparison outcomes as the standard error was unstable to estimate with such a small network; however, these models do not account for between-study variances and this adds some uncertainty to the results. Furthermore, the submission did not contain any consistency assessments for the instances where there were closed loops in the network, which limits assessing the consistency of the results in the NMA with the results from the individual trials.

In addition, in several analyses, the proportion of patients experiencing hypoglycemic events was much lower in the insulin icodec studies (the ONWARDS trials) than in the comparator studies. The submission raised the question of whether the comparison was appropriate but did not adjust for these differences in any way or explore them in sensitivity analyses. For nearly all hypoglycemia outcome comparisons, the effect estimates were also affected by imprecision due to wide credible intervals, precluding any conclusions regarding which treatment in the comparison may be favoured.

Furthermore, the NMA is subject to some limitations in clinical meaningfulness. The clinical expert consulted by CADTH noted that while the results for hemoglobin A1C change from baseline across study populations may attain statistical significance, they overall do not provide an important clinical benefit. In addition, while the rationale for the NMA was to include insulin detemir and provide data for insulin icodec compared to insulin detemir, a lack of available results limited the outcomes for which insulin icodec could be compared to insulin detemir. Finally, the NMA is limited in its generalizability; participants who were other races than white and/or those over the age 70 with poorly-controlled diabetes would not be represented in this analysis and the impact of insulin icodec on the long-term control of blood glucose and the long-term safety relative to daily insulin comparators remains unknown.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies were submitted that address gaps in the evidence.

Economic Evidence

Cost and Cost-Effectiveness

Table 5: Summary of Economic Evaluation

CFB = change from baseline; hemoglobin A1C = glycated hemoglobin; ICER = incremental cost-effectiveness ratio; LY = life-year; NMA = network meta-analysis; QALY = quality-adjusted life-year; T2DM = type 2 diabetes mellites; U = unit; vs. = versus.

Budget Impact

CADTH identified the following limitations in the sponsor’s base case: the estimated basal insulin dose for insulin icodec and long-acting basal insulin analogues is uncertain, the proportion of claims assumed to originate from patients with type 1 diabetes mellites is overestimated, and the projected market uptake of insulin icodec is uncertain. CADTH conducted reanalyses of the budget impact analysis by adopting average daily doses calculated from real-world evidence and using published estimates to inform the proportion of claims that are likely to be generated by patients with type 1 diabetes. Based on the CADTH base case, the estimated budget impact associated with the reimbursement of insulin icodec as treatment for adults with T2DM who require glycemic control is expected to be $650,056 in year 1, $4,288,283 in year 2, and $10,317,977 in year 3, for a 3-year budgetary impact of $15,256,316. CADTH conducted a scenario analysis to address the remaining uncertainty. If the projected market share of insulin icodec is assumed to be 10%, 20%, and 30% in years 1, 2, and 3, respectively, the 3-year budget impact associated with reimbursing insulin icodec is expected to be $41,043,671.

CDEC Information

Members of the Committee

Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Edward Xie, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Trudy Huyghebaert, Dr. Danyaal Raza, and Dr. Peter Zed

Meeting date: March 28, 2024

Regrets: Three expert committee members did not attend.

Conflicts of interest: None