Weekly Icodec versus Daily Glargine U100

in Type 2 Diabetes without Previous

Insulin

PRESENTER:
MODERATOR:
DR BALAJI PT DR SWIKRITA
TALUKDAR
2ND YEAR PGT ASSISTANT
PROFESSOR
DEPT OF GENERAL MEDICINE DEPT OF
GENERAL MEDICINE
FAAMCH FAAMCH
 Introduction
Diabetes mellitus

T2DM is characterised by insulin resistance, impaired insulin secretion,

increased hepatic glucose output due to glucagon dysregulation resulting in
chronic hyperglycaemia. The pathogenesis is not fully understood but seems
4

to be heterogeneous, involving environmental, lifestyle, and genetic factors

leading to chronic hyperglycaemia caused by peripheral tissue insulin
resistance, impaired insulin secretion due to abnormal beta-cell function and
abnormal glucose metabolism in the liver. The current treatment cascade
5

follows a stepwise approach comprising lifestyle changes in combination

with pharmacological intervention. In many countries, metformin is
recommended as initial pharmacological therapy, followed by combination
therapy with other oral anti-diabetic drugs, glucagon-like peptide 1 receptor
agonists (GLP-1 RA) and/or insulin as the disease progresses.
 Background

Basal insulin analogues (once/twice daily) are common in T2DM.

Daily injections reduce adherence → suboptimal glycemic control.
Insulin icodec: investigational once-weekly basal insulin analogue.
ONWARDS 1: Phase 3a trial comparing weekly icodec vs daily glargine
U100.
 Icodec

Insulin icodec is a novel long-acting insulin analogue which is developed to

safely cover the basal insulin requirements for a full week with a single
subcutaneous injection. Insulin icodec has a terminal elimination half-life of
approximately 196 hours. The molecule consists of a peptide backbone and
a fatty acid-containing side-chain. The peptide backbone is more resistant
towards proteolytical degradation compared to human insulin and the side
chain gives a strong binding to albumin. Both features contribute to the long
action of insulin icodec.
Onwards trial
 APPROVAL AND ETHICS

Approved by an independent ethics committee or institutional review

board.
All the participants provided written informed consent.
The trial was conducted in accordance with the principles of the
Declaration of Helsinki and the Good Clinical Practice guidelines of the
International Council for Harmonisation.
Funded by Novo Nordisk.
 Methods
Study design

Design - 78-week , randomised, open label, treat-to-target, phase 3a trial

Randomisation - 1:1 ratio
Setting - multiple centres, international-12countries
The first 52 weeks - the main phase, after which the primary and
confirmatory secondary endpoints are analysed.
Next 26 weeks - extension phase is to evaluate long term safety.
 Inclusion criteria
Informed consent provided before any trial-related activity.
Age ≥18 years
Diagnosed type 2 diabetes ≥180 days prior to the day of screening.
Glycated hemoglobin from 7.0–11.0% (53.0–96.7 mmol/mol)
Insulin naive. However, short-term insulin treatment for a maximum of 14 days prior to the day of screening was allowed, as is prior insulin
treatment for gestational diabetes.
Stable daily dose(s) ≥90 days prior to the day of screening of any of the following non-insulin glucose-lowering treatment(s) or combination
regimen(s).

a) Any metformin formulations ≥1500 mg or maximum tolerated or effective dose.

b) Any metformin combination formulations ≥1500 mg or maximum tolerated or effective dose.
c) Any of the following non-insulin glucose-lowering treatments, including combination products (≥ half of the maximum approved dose
according to local label or maximum tolerated or effective dose):

▪ sulfonylureas
▪ meglitinides (glinides)
▪ DPP-4 inhibitors
▪ SGLT2 inhibitors
▪ thiazolidinediones
▪ alpha-glucosidase inhibitors
▪ oral combination products (for the allowed individual oral non-insulin glucose-lowering treatments)
▪ oral or injectable GLP-1 RAs.
Body mass index ≤40.0kg/m 2
 Exclusion criteria

Known or suspected hypersensitivity to trial product(s) or related products.

Previous participation in this trial, where participation is defined as signed informed consent.
Woman who is pregnant, breastfeeding, or intends to become pregnant, or is of childbearing
potential and not using an adequate contraceptive method (adequate contraceptive
measures as required by local regulation or practice).
Participation in any clinical trial of an approved or non-approved investigational medicinal
product within 90 days before screening. Simultaneous participation in a trial with the
primary objective of evaluating an approved or non approved investigational medicinal
product for prevention or treatment of COVID-19 disease or post-infectious conditions is
allowed, if the last dose of the investigational medicinal product has been received more
than 30 days before screening.
Any disorder, except for conditions associated with type 2 diabetes, which in the
investigator’s opinion might jeopardise the participant’s safety or compliance with the
protocol.
Any episodes (as declared by the participant or in the medical records) of diabetic
ketoacidosis within 90 days prior to the day of screening.
Myocardial infarction, stroke, hospitalization for unstable angina pectoris, or transient ischemic attack within 180 days
prior to the day of screening.
Chronic heart failure classified as being in New York Heart Association Class IV at screening.
Planned coronary, carotid, or peripheral artery revascularization.
Renal impairment with estimated glomerular filtration rate value of <30 ml/min/1.73m at screening by central
2

laboratory analysis.2

Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 mmHg at screening.
Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within
90 days prior to the day of screening. However, short-term insulin treatment for a maximum of 14 days and prior insulin
treatment for gestational diabetes are allowed.
Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) known to affect weight
or glucose metabolism (e.g., treatment with orlistat, thyroid hormones, or corticosteroids).
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed
within the past 90 days prior to screening or in the period between screening and randomization. Pharmacological pupil-
dilation was a requirement unless using a digital fundus photography camera specified for non-dilated examination.
Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, in situ carcinomas of the
cervix, or in situ prostate cancer) within 5 years prior to the day of screening.
Anticipated change in lifestyle affecting glucose control.
 Randomisation and intervention

Total subjects-1293
Total subjects after screening-970
Subjects will be randomised (1:1) into two groups with 492 subjects in
each group
Icodec group - to receive once weekly sc insulin icodec.Starting dose
70U/week.
Glargine U100 - once daily sc insulin glargine.starting dose 10U/day
Dose adjusted to target fasting blood glucose t0 80-130 mg/dl
Pretrial noninsulin glucose-lowering treatments were continued after
randomization, except for sulfonylureas and glinides, which were
discontinued.
 Outcomes
Primary end points

to demonstrate the non inferiority of once weekly insulin icodec(in

combination with non-insulin anti-diabetic drugs) versus once daily insulin
glargine U100, in insulin naïve subjects with T2DM.
By comparing the difference, in change in HbA1c from baseline after 52
weeks of treatment.
 Outcomes
Secondary endpoints

Confirmatory secondary end point - percentage of time spent in glycemic range (70-180mg/dl) from
week 48-52
Supportive secondary endpoint

Secondary efficacy end point - change in fasting plasma glucose from baseline to week 52
Secondary safety end point -

number of hypoglycaemic episodes;

time spent in glucose range between <54mg/dl and >180mg/dl;
the mean weekly insulin dose from week 48 to 52; change in body weight from
baseline to week 52.
To evaluate treatment satisfaction and adherence
 Statistical analysis

Continuous endpoints using baseline data (including the primary endpoint)

were analyzed using a standard analysis of covariance, with treatment and
region as fixed factors, and the baseline value of the response as
covariate.
 Safety analysis

Hypoglycemia alert value (level 1) - glucose level 54 to <70 mg/dL (3.0–

<3.9 mmol/L)
Clinically significant (level 2) hypoglycemia - glucose level below 54mg/dL
(3 mmol/L)
Severe (level 3) hypoglycemia - had no specific glucose threshold, but was
associated with severe cognitive impairment that required external
assistance for recovery.
Adverse events
 Results
Efficacy

984 participants (492 in each arm); baseline HbA1c ~8.5%.

Week 52 HbA1c change: from 8.50% to 6.93% with icodec [mean change, −1.55
percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, −1.35
percentage points]
estimated between-group difference (−0.19 percentage points; 95% confidence interval
[CI], −0.36 to −0.03)
confirmed the noninferiority (P<0.001) and superiority (P=0.02) of icodec.
time in range - 71.9% (icodec) vs 66.9% (glargine) ;(P<0.001).
estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62];
P<0.001), which confirmed superiority.
Rates of combined clinically significant or severe hypoglycemia were 0.30 events per
person-year of exposure with icodec and 0.16 events per person-year of exposure with
glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75)
incidences of adverse events were similar in the two groups.
 Results
Safety

Clinically significant/severe hypoglycemia: 0.30(icodec) vs 0.16(glargine)

events/person-year.
Rate ratio: 1.64 (95% CI 0.98–2.75) – NS at Week 52.
Body weight gain: +2.29 kg (icodec) vs +1.83 kg (glargine).
No new safety signals; AE rates similar between groups.
 Limitations

Open label design - potential to subjective bias

Blinded glucose monitoring - not used for dose titration
Low proportion of black and latino participants
Done in selected population- cannot be generalised to all T2DM patients.
Long term safety and efficacy data is needed
Cost effectiveness - data pending
Conflict of interest
 Conclusion

In a phase 3a trial involving adults with type 2 diabetes who had not
previously received insulin, glycemic control was better with once-weekly
insulin icodec than with once-daily insulin glargine U100.
Superior time in glycemic range (71.9 to 66.9%)
Acceptable safety profile with low hypoglycaemia rates
Significant convenience advantage with once-weekly dosing
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