Glycaemic control: How effective are insulin/GLP-1 RA fixed-ratio combinations?

Fixed-ratio combinations of basal insulin and GLP-1 receptor agonists (GLP-1 RA) have shown robust results as a treatment intensification option for people with type 2 diabetes.

Examples include IDegLira (insulin degludec U100 + liraglutide) or iGlarLixi (insulin glargine U100 + lixisenatide). IcoSema, a once-weekly subcutaneous fixed-ratio combination of insulin icodec and semaglutide, is currently in phase III clinical development. “IcoSema is intended to combine the known benefits of the monocomponents with a reduced injection frequency,” say the authors of the COMBINE 2 trial, recently published in Diabetologia.

The study compared IcoSema with once-weekly semaglutide in people with insufficiently controlled type 2 diabetes who were receiving GLP-1 RA prior to enrolment. Now published, the efficacy and safety results show that IcoSema demonstrated superior glycaemic control compared with once-weekly semaglutide. While IcoSema achieved greater reductions in HbA1c, treatment with semaglutide resulted in significant weight loss. The safety profiles of the two treatment options were similar.

Study design and patient population

The COMBINE 2 trial is part of a broader clinical programme to evaluate IcoSema and was designed to assess its efficacy and safety compared to once-weekly semaglutide 1.0 mg. The study was a randomised, multicentre, open-label, parallel-group phase IIIa trial involving adults with inadequately controlled type 2 diabetes who were on stable doses of daily or weekly GLP-1 RA therapy (primarily subcutaneous or oral semaglutide and dulaglutide) with or without additional oral glucose-lowering medications, such as metformin, sodium-glucose cotransporter 2 inhibitors, and sulfonylureas. Patients on semaglutide doses > 1.0 mg were excluded from the trial.

A total of 683 participants were enrolled at 121 sites in 13 regions, all with a diagnosis of type 2 diabetes, with an HbA1c between 53 and 85.8 mmol/mol (7–10 %). Participants were randomised 1:1 to receive either IcoSema or semaglutide for 52 weeks, followed by a five-week follow-up period. IcoSema was administered with a starting dose of 40 dose steps (= 40 U of icodec and 0.114 mg of semaglutide) and adjusted according to self-measured blood glucose, while semaglutide treatments started at 0.25 mg and were escalated to 1 mg.

The primary endpoint was the mean change in HbA1c from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight, and the incidence of clinically significant or severe hypoglycaemia (level 2 [< 3.0 mmol/l] or level 3 [severe cognitive impairment]).

Improved glycaemic control, moderate weight gain

After 52 weeks of treatment, the mean HbA1c reduction was greater in the IcoSema group, with an estimated treatment difference (ETD) of –4.85 mmol/mol (–0.44 %-points; p < 0.0001). Overall, HbA1c was reduced by 14.7 mmol/mol (1.35 %-points) in the IcoSema group versus 9.88 mmol/mol (0.9 %-points) in the semaglutide group.

For the secondary endpoints, IcoSema significantly reduced fasting plasma glucose compared with semaglutide (–2.48 mmol/l vs. –1.43 mmol/l, respectively; ETD –1.05 mmol [95% CI: –1.36, –0.75]; p < 0.0001). However, participants in the IcoSema group gained 0.84 kg during the treatment, while in the semaglutide group weight was reduced by 3.7 kg (ETD 4.54 kg [95% CI: 3.84, 5.23]; p < 0.0001).

The rate of level 2 or 3 hypoglycaemia did not differ between the two study groups until the end of the follow-up period, with an observed rate of episodes per person-year of exposure [PYE] of 0.042 for IcoSema vs. 0.036 for semaglutide (estimated rate ratio 1.2 [95% CI: 0.53, 2.69]; p = 0.6646). “Notably, the proportion of participants achieving HbA1c < 53 mmol/mol (< 7 %) without clinically significant or severe hypoglycaemia after 52 weeks was statistically significantly larger in the IcoSema group than in the semaglutide group, suggesting that IcoSema provides an appropriate balance between efficacy and hypoglycaemia risk,” the authors add.

Importantly, gastrointestinal tolerability was comparable between the two groups, with 31.4 % of patients in the IcoSema group and 34.4 % in the semaglutide group experiencing gastrointestinal adverse events.

Points to consider from the study

The study results are consistent with previous findings on basal insulin and GLP-1 RA combinations. In particular, the authors note that one in five participants in the semaglutide group required additional non-randomised insulin or non-insulin glucose-lowering medication during the study. This was the case for only 3.8 % of the IcoSema group. “As such, the full impact of IcoSema on glycaemic management is greater than that illustrated by HbA1c alone,” the authors conclude.

Interestingly, the semaglutide group also showed a significant reduction in HbA1c, even though participants were already being treated with a GLP-1 RA prior to enrolment. This may reflect that the treatment was not adequately intensified or that the participants were not compliant prior to the study, the authors suggest. Another point of discussion was the weight gain associated with IcoSema, an effect usually seen with any insulin therapy. However, the weight gain associated with IcoSema treatment can be considered modest, suggesting that the semaglutide component of IcoSema mitigates the weight gain caused by insulin treatment.

Overall, the favourable results for glycaemic control suggest that IcoSema may add another option to the clinician’s repertoire when deciding between different treatment escalation options, with the potential to reduce the total number of injections per year. The overall verdict on IcoSema however, will depend not only on these results but also on the other studies in the COMBINE trial programme.

Read Professor Ildiko Lingvay’s original Diabetologia article here..

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.