ONWARDS 2: Weekly insulin icodec superior to degludec in type 2 diabetes

medwireNews: The results of ONWARDS 2 show significantly improved glycemic control with weekly insulin icodec versus daily insulin degludec, without significantly increased hypoglycemia, in people with type 2 diabetes.

The randomized trial involved people with type 2 diabetes (average age 62.5 years, 57% men) who were already using basal but not prandial insulin and had a glycated hemoglobin (HbA1c) of 7.0–10.0% (53–86 mmol/mol). Their average diabetes duration was 16.7 years and they were using an average daily basal insulin dose of 26.5 units.

Other glucose-lowering medications were permitted, with the most common being metformin (84%). Participants taking sulfonylureas (22%) or glinides (4%) discontinued these medications to reduce the risk for hypoglycemia.

The average baseline HbA1c among the 263 people randomly assigned to take weekly insulin icodec was 8.17% (65.8 mmol/mol), and over 26 weeks of treatment this fell to an average of 7.20% (55.2 mmol/mol).

For the 263 people taking daily insulin degludec, average HbA1c fell from 8.10% to 7.42% (65.0 to 57.6 mmol/mol). The estimated treatment difference of 0.22 percentage points (2.4 mmol/mol) significantly favored icodec.

People taking icodec were significantly more likely to achieve HbA1c below 7.0% (53 mmol/mol) or 6.5% (48 mmol/mol) than those taking degludec. They also spent slightly more time within target blood glucose range during weeks 22–26 when this was measured, at 63.1% versus 59.5%, although the difference was not statistically significant.

The event rates for clinically significant or severe hypoglycemia were low overall and slightly but not significantly higher with icodec versus degludec, at 0.73 versus 0.27 events per person–year. There were no severe (level 3) events in the icodec group, and just one in the degludec group.

Hypersensitivity events and injection-site reactions were infrequent in both treatment groups, and “[o]verall, no new safety issues were identified in relation to icodec in this trial,” report Athena Philis-Tsimikas (Scripps Whittier Diabetes Institute, San Diego, California, USA) and colleagues in The Lancet Diabetes & Endocrinology.

Bodyweight increased by an average of 1.40 kg in the icodec group over the 26 weeks and decreased by an average of 0.30 kg in the degludec group.

In a linked commentary, Srikanth Bellary (Aston University, Birmingham, UK) and Anthony Barnett (University of Birmingham, UK) call the findings “encouraging” and suggest “one might predict that these findings could provide greater confidence to patients and health-care professionals to intensify insulin regimens and encourage insulin acceptance and improve adherence.”

But they stress that “much work still needs to be done in a real-world setting to prove that adherence rates and glycaemic control improve” with use of weekly insulins.

And they also highlight the numerically increased rate of hypoglycemia with icodec, saying this is a potential concern particularly in older, frailer people – especially if they have impaired awareness of hypoglycemia – and in people also taking a sulfonylurea, which they note is common in clinical practice.

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Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00093-1
Lancet Diabetes Endocrinol 2023; doi:10.1016/S2213-8587(23)00125-0