Weekly insulin icodec offers better glycemic control than daily insulin glargine U100 in type 2 diabetes

Current treatment guidelines for type 2 diabetes recommend a stepwise strategy with incretin-based therapies used as first-line injectable treatments. However, the initiation of once- or twice-daily basal insulin analogues to assist glycemic control remains a common treatment strategy.

Insulin icodec, an investigational once-weekly basal insulin analogue for diabetes management, provides basal insulin coverage over a week following a single subcutaneous injection. A short-term, proof-of-concept, phase 2 trial comprising patients with type 2 diabetes who had not previously received insulin compared once-weekly insulin icodec with once-daily insulin glargine U100. It revealed low hypoglycemia rates and similar glycemic control in the two trial groups.

In the ONWARDS 1 (78-week randomized, open-label, treat-to-target phase 3a trial), Julio Rosenstock, Velocity Clinical Research at Medical City, Dallas, TX, and colleagues investigated the long-term safety and efficacy of once-weekly insulin icodec as compared with once-daily insulin glargine U100, both in combination with noninsulin glucose-lowering treatments (sodium–glucose cotransporter 2 inhibitors and GLP-1 receptor agonists), in patients with type 2 diabetes who had not previously received insulin.

The 78-week ONWARDS 1 trial included a 52-week main phase and a 26-week extension phase, plus a follow-up period of 5 weeks. It included adults with type 2 diabetes (HbA1c level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a ratio of 1:1 to receive once-weekly insulin icodec (n=492) or once-daily insulin glargine U100 (n=492).

The primary endpoint was measured as the change in the glycated haemoglobin level from baseline to week 52; the confirmatory secondary endpoint was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter in 48 to 52 weeks. Hypoglycemic episodes were recorded from baseline to weeks 52 and 83.

The study revealed the following findings:

• Baseline characteristics were similar in the two groups. The mean reduction in the glycated haemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec and from 8.44% to 7.12% with glargine U100); the estimated between-group difference (−0.19 percentage points) confirmed the noninferiority and superiority of icodec.
• The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% versus 66.9%; estimated between-group difference, 4.27 percentage points), 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) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63).
• No new safety signals were identified, and incidences of adverse events were similar in the two groups.

"The findings of the current trial highlight the totality of evidence for glycemic control with icodec," the researchers wrote.

They found that among patients with long-standing diabetes taking noninsulin glucose-lowering agents including SGLT-2 inhibitors and GLP-1 receptor agonists, those who received icodec were more likely to reach an HbA1c level below 7% than those who received glargine U100, and they spent more time in the target glycemic range and were more likely to reach an HbA1c level below 7% without clinically significant or severe hypoglycemia.

"In this phase 3a trial, we found that once-weekly insulin icodec offered better glycemic control than once-daily insulin glargine U100 in type 2 diabetes patients who had not previously received insulin," they concluded.

Reference:

Rosenstock J, Bain SC, Gowda A, Jódar E, Liang B, Lingvay I, Nishida T, Trevisan R, Mosenzon O; ONWARDS 1 Trial Investigators. Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin. N Engl J Med. 2023 Jul 27;389(4):297-308. doi: 10.1056/NEJMoa2303208. Epub 2023 Jun 24. PMID: 37356066.