Combination insulin icodec and semaglutide cuts HbA1c and body weight in type 2 diabetes
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Key takeaways:
- A combination therapy of insulin icodec and semaglutide confers a similar HbA1c reduction as once-daily insulin glargine and insulin aspart.
- Most adverse events with the combination agent were gastrointestinal.
Once-weekly combination therapy of basal insulin icodec and semaglutide was noninferior to insulin glargine plus insulin aspart for lowering HbA1c among adults with type 2 diabetes, according to topline results from a phase 3a trial.
In the COMBINE 3 trial, 679 adults with type 2 diabetes inadequately controlled with basal insulin were randomly assigned to receive a fixed-ratio combination of basal insulin icodec and semaglutide (IcoSema, Novo Nordisk) or 100 units of once-daily insulin glargine plus insulin aspart injected 2 to 4 times a day at mealtimes for 52 weeks. Adults in the study had a baseline HbA1c of 8.3% and a baseline body weight of 85.8 kg.
At 52 weeks, the combination therapy demonstrated noninferiority. The group receiving combined insulin icodec and semaglutide had an HbA1c reduction of 1.47 percentage points compared with an HbA1c reduction of 1.4 percentage points for those receiving insulin glargine plus insulin aspart.
The combination therapy group lost 3.6 kg of body weight at 52 weeks, whereas those receiving insulin glargine and insulin aspart gained 3.2 kg. There were 0.26 hypoglycemia events per patient-year of exposure for those receiving the combination therapy compared with 2.18 events per patient-year of exposure with insulin glargine plus insulin aspart.
Adverse events were mostly gastrointestinal, which is consistent with other GLP-1 receptor agonist drugs. The majority of adverse events were mild to moderate in nature.
“We are very pleased to share the first phase 3a results for once-weekly IcoSema,” Martin Holst Lange, executive vice president for development at Novo Nordisk, said in a press release. “The results demonstrate the potential of IcoSema to simplify insulin intensification by reducing the injection burden to a single injection per week compared to around 28 injections per week for people with type 2 diabetes inadequately controlled on basal insulin while providing glycemic control as well as weight benefits and lower rates of hypoglycemia.”
The phase 3a COMBINE trial program includes three randomized trials, of which COMBINE 3 was the first to have topline results released. The COMBINE 1 trial, is comparing once-weekly IcoSema with insulin icodec. The COMBINE 2 trial, which compares IcoSema with semaglutide 1.0 mg, was initiated in the second quarter of 2022, and results are expected to be announced later in 2024, according to the press release.
Perspective
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Kevin M. Pantalone, DO, ECNU, FACE
The COMBINE 3 trial demonstrated that once-weekly IcoSema (700U/2 mg/mL) was non-inferior to insulin glargine U100 taken daily in combination with insulin aspart for people with type 2 diabetes inadequately controlled on daily basal insulin. These results highlight that non-inferior glycemic control can be obtained with far less treatment burden and/or complexity, and suggest that IcoSema will be helpful in negating or delaying the need to initiate prandial insulin.
In addition, IcoSema was found to be superior to insulin glargine U100 and insulin aspart in estimated rates of severe or clinically significant hypoglycemia (glucose below 54 mg/dL). This observation may be, in part, because utilization of the fixed-ratio combination likely results in lower overall basal insulin requirements and because it avoids the need for frequent daily injections of insulin aspart. The individual components of IcoSema work through complementary and synergistic mechanisms, with each component addressing one of the two key underlying drivers of inadequate glycemic control: The GLP-1 receptor agonist attenuates post-prandial hyperglycemia and basal insulin improves fasting glucose.
While these results are very promising, previously approved fixed-ratio combinations of GLP-1 receptor agonists and basal insulin, such as IDegLira (Xultophy, Novo Nordisk) and IGlarLixi (Suliqua, Sanofi) remain vastly underutilized in clinical practice. Many providers prefer to initiate and titrate each component independently to maximize the dose of the GLP-1 receptor agonist in the hopes of minimizing the basal insulin requirements. As always, access, coverage and provider/patient preferences will be strong drivers of its use in the real-world setting.
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