Insulin Therapy De-Escalation to Fixed-Ratio Combo Safe

MADRID — The de-escalation of a multiple daily injection regimen of insulin for type 2 diabetes to a once-daily fixed-ratio combination of insulin glargine U100 and glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) provides similar glucose control, with added benefits including weight reduction, without increasing the risk for hypoglycemia, new research showed.

“This is the first prospective randomized trial to explore whether it is possible to de-escalate intensive insulin therapy of four injections per day to once-daily injection of fixed-ratio combination insulin glargine/lixisenatide,” first author Martin Haluzík, MD, PhD, of the Institute for Clinical and Experimental Medicine, Prague, Czech Republic, told Medscape Medical News.

“We found that insulin therapy de-intensification from a multiple daily injection regimen to iGlarLixi is an efficient and safe treatment option for patients with type 2 diabetes that provides comparable glucose control with the reduction of body weight, a decrease in total insulin dose, lower number of insulin injections, and also a lower risk of hypoglycemia,” he said.

Haluzik presented the findings at the annual meeting of the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

Multiple daily injection insulin therapy, often necessary in poorly controlled type 2 diabetes, comes with the known drawbacks of potential weight gain, an increased risk for hypoglycemia leading to lower quality of life, and ultimately challenges in adherence.

iGlarLixi is typically used either for intensification of insulin therapy from basal insulin once daily or as the first injectable in poorly controlled patients with type 2 diabetes, with data showing the combination to provide greater A1c reductions in type 2 diabetes than lixisenatide or insulin glargine alone.

However, “the idea of de-escalation [from multiple day injection] is relatively new, and these data are the first to test this treatment option in a prospective randomized manner, [with] only observational data with another fixed-ratio combination, insulin degludec/liraglutide,” Haluzik explained.

For the five-center, open-label Insulin therapy DE-intensificAtion with iGlarLixi trial, 91 participants with type 2 diabetes were enrolled who were on a multiple daily injection regimen, with background therapy of metformin with or without sodium-glucose co-transporter 2 inhibitor therapy.

Patients were randomized 1:1 to receive either once-daily iGlarLixi (n = 45) or to continue with their multiple daily injection regimen (n = 44). Both groups were titrated to fasting plasma glucose of ≤ 6 mmol/L (108 mg/dL).

Overall, the patients had a mean age of 66 years; 22% of patients were women, the mean diabetes duration was 17 years, and their mean body mass index was 33.5.

For the primary endpoint, the mean change in A1c over 24 months in the iGlarLixi group was noninferior to the multiple daily injection group, with a reduction of −0.47% vs −0.37% (P = .01 for noninferiority; P = .25 for superiority).

The iGlarLixi group had a significantly higher mean reduction in body weight from baseline to week 24, with a reduction of 4.8 kg vs 0.5 kg in the multiple injection group (P < .001).

The mean reduction in the total daily dose of insulin in the iGlarLixi group from baseline to 24 weeks was from 63 units to 37 units (P < .0001), whereas levels remained unchanged in the multiple daily injection group (58 units vs 61 units; P = .233).

Importantly, there were fewer reports of hypoglycemia in the iGlarLixi vs multiple daily injection group (5.5% vs 9.6%; P = .029).

There were no significant differences between the groups in terms of fasting plasma glucose or postprandial glycemia outcomes.

The results were further supported by data from continuous glucose monitoring (CGM; Freestyle Libre Pro iQ), which was used by approximately 80% of patients in the study and reported in a separate abstract.

The CGM results from 2 weeks before baseline and for the last 2 weeks of the 24-week treatment period showed significant improvements in the median time in range in the iGlarLixi group over the 24 weeks vs baseline (P = .039) but not in the multiple injection dose group (P = .728).

And the CGM data also showed significant reductions in the iGlarLixi group in terms of measures of time above range, time in level 2 hyperglycemia, mean sensor glucose, and glycemia risk index (all P < .05), without increasing the time spent in hypoglycemia.

Haluzik noted that, with little experience so far, “there were concerns that the glucose control may significantly worsen after de-intensification. Our study has shown that this isn’t the case at all.”

He urges clinicians: “Consider whether all your patients on multiple daily injection regimens really need such an intensive treatment and try to de-intensify them if possible.”

The findings underscore that “the efficacy is similar, and it makes patients’ lives much easier.”

The study was an investigator-initiated trial supported by Sanofi. Haluzik has previously consulted and given lectures for Sanofi, Eli Lilly and Company, Novo Nordisk, AstraZeneca, Boehringer Ingelheim, and Novartis.