Diabetes Distilled: Once-weekly insulins – ONWARDS and upwards?

It has been suggested that once-weekly insulin could improve acceptability and adherence compared with daily or twice-daily injections (Peyrot et al, 2012), and this is supported by studies of once-weekly versus daily GLP-1 receptor agonist treatments (Weeda et al, 2021). In the present phase 3, open-label randomised controlled trial, ONWARDS 2, the authors sought to explore the efficacy and safety of insulin icodec, an ultra-long-acting basal insulin analogue with a half-life of 196 hours. The half-life is due to lower affinity for the insulin receptor and strong, reversible binding to albumin, which provides a depot from which the insulin is slowly released, providing near-even glucose lowering and allowing once-weekly subcutaneous dosing.

A total of 526 people with type 2 diabetes poorly controlled on once- or twice-daily insulin regimens were randomised to switch to appropriate doses of once-weekly icodec or daily degludec (including an initial, additional 50% dose of icodec). Doses were then titrated weekly in both groups, aiming for fasting glucose of 4.4–7.2 mmol/L. Stable doses of oral glucose-lowering drugs were continued during the study, except for sulfonylureas and glinides, which were stopped at randomisation. People with an HbA_1c of 53–86 mmol/mol were included, and the mean HbA_1c values at baseline were around 65 mmol/mol in the two groups. Participants were followed for 26 weeks.

The primary outcome was change in HbA_1c from baseline to 26 weeks. Secondary and additional prespecified outcomes included:

• Clinically significant hypoglycaemia (level 2: <3 mmol/L), severe hypoglycaemia (level 3: cognitive impairment and third-party intervention needed) and a combination of the two.
• Changes in body weight.
• Time in Range (3.9–10.0 mmol/L), time below 3 mmol/L and time above 10 mmol/L were assessed via CGM during weeks 22–26 (CGM readings were not available to patients or clinicians to titrate insulin or to identify hypoglycaemia).
• Numbers achieving HbA_1c <53 mmol/mol or ≤48 mmol/mol, with and without level 2 or 3 hypoglycaemia.
• All adverse events were documented and collated.

Results

Although the study was designed to confirm whether weekly icodec treatment would be non-inferior to daily degludec in achieving the primary outcome, at 26 weeks, those treated with icodec achieved both non-inferior and statistically superior reductions in HbA_1c; mean HbA_1c fell from 65.8 to 55.2 mmol/mol on icodec, versus a reduction from 65.0 to 57.6 mmol/mol in those treated with degludec (estimated treatment difference –2.4 mmol/mol; P<0.001 for non-inferiority and P=0.003 for superiority). Mean body weight increased by 1.4 kg in the icodec group versus a reduction of 0.30 kg in the degludec group.

Level 1 hypoglycaemic events (measured glucose <3.9 mmol/L) were significantly more common in those treated with icodec than degludec (7.79 versus 3.86 events per person-year of exposure). Combined level 2 and 3 hypoglycaemic event rates were low (and lower than in previous trials of degludec and glargine), and were identified in 14% versus 7% of icodec and degludec recipients, respectively (a non-significant difference). There were no severe hypoglycaemic events in those treated with icodec and only one in those treated with degludec. Overall, 61% of those receiving icodec and 50% of those receiving degludec experienced an adverse event, with 8% and 6% suffering a serious adverse event, respectively; however, rates of withdrawal from the study were low.

No new safety issues were identified with icodec. However, any increased level of hypoglycaemia may be important, especially when considering elderly people and those with decreased hypoglycaemia awareness.

There were no significant differences between groups in terms of CGM measurements, with both groups achieving around 60% Time in Range and similar proportions of time above and below range.

Sulfonylureas were stopped at randomisation (used by just under a quarter of participants), yet in clinical practice they are commonly continued with a 50% dose reduction when insulin is initiated, so it will be important in future studies, such as ONWARDS 3 and 5, to clarify the potential impact of combination sulfonylurea and icodec treatment on hypoglycaemia.

After 100 years of insulin use, and many failed attempts to improve insulin acceptability and to improve clinical inertia around insulin initiation, ongoing studies with once-weekly basal insulins (both icodec and others in development) suggest these may finally reach the market and represent a significant advance (Rosenstock and Del Prato, 2022). However, as the authors of an accompanying comment in Lancet Diabetes & Endocrinology discuss, whether once-weekly dosing will prove to be safe and translate into greater adherence and efficacy still requires further study (Bellary and Barnett, 2023).

Readers seeking to learn more about weekly insulins are directed to an open access review by Rosenstock and Del Prato (2022).

Basal insulin icodec and other once-weekly basal insulins are not yet licensed in the UK or Europe.