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Adding topical esmolol hydrochloride to standard of care (SOC) significantly improved healing of diabetic foot ulcers, a phase III randomized trial from India showed.

During a 12-week treatment phase, 60.3% of patients achieved target ulcer closure with esmolol plus SOC compared with 41.7% of those treated with SOC alone (OR 2.13, 95% CI 1.08-4.17, P=0.03), reported Ashu Rastogi, MD, DM, of the Post Graduate Institute of Medical Education and Research in Chandigarh, India, and colleagues.

By week 24 of the study, 77.2% of esmolol-treated patients achieved target ulcer closure versus 55.6% of the group who received only SOC (OR 2.71, 95% CI 1.22-5.99, P=0.01), which included wound cleaning with normal saline, maintenance of moist wound environment, and off-loading of the target ulcer, they noted in .

This is an area that is in desperate need of new therapeutics, as only about 30% of diabetes-related wounds heal, even with the best available therapies like moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative pressure wound therapy, Rastogi and team pointed out.

"Ulcer recurrence is a common problem with diabetic foot ulcers, with a rate of 40% to 70%," they added.

Overall, the median time for ulcer closure was 85 days among the esmolol-treated patients, and was not estimable for the SOC-alone group, since less than half of ulcers healed during the treatment period.

In a subgroup analysis, esmolol plus SOC was even more effective in patients who weighed more than 176 lb (OR 4.04, 95% CI 1.07-15.27, P=0.04), as well as patients with a body mass index over 25 (OR 2.72, 95% CI 1.08-6.79, P=0.03), compared with SOC only.

Adding esmolol to the treatment routine was also more effective when it came to healing plantar and non-plantar ulcers, as well as those <5 cm² and ≥5 cm².

About 19% of patients experienced adverse events, but 87.3% of these events were deemed unrelated to esmolol. After healing, reopening occurred in two ulcers treated with esmolol and one with SOC alone.

Acting as a β₁-selective adrenergic receptor-blocking agent, topical esmolol 14% gel was applied in a uniform layer over the ulcer twice daily. Rastogi's group noted that usually about 0.6 cm of gel was applied for every square cm of ulcer area.

"In preclinical studies, esmolol was shown to inhibit aldose reductase, formation of sorbitol in red blood cells, and advanced glycosylation end product generation, which might decrease cellular damage by reducing oxidative stress in wound tissues," they explained. "Esmolol inhibits Casp3, upregulates Bcl-2, and activates ERK1/2 mitogen-activated protein kinase, thereby facilitating wound repair."

For this double-blind, multicenter study conducted from December 2018 to August 2020, the researchers included 176 participants with type 1 or type 2 diabetes (69.3% men, mean age 56.4) from 27 referral centers across India. Mean HbA1c level was 8.6%.

Participants all had non-infected full-thickness diabetic foot ulcers of grade IA and IC on the University of Texas Diabetic Wound Classification system. Ulcers ranged in area from 2 to 15 cm², the majority of which were on the plantar metatarsus. Ulcers that showed a 30% area reduction between screening and baseline were excluded. A total of 140 patients were included in the efficacy analysis.

Necrotic, infected, or otherwise nonviable tissue was removed during visits by debridement. Investigators also managed infections if need be.

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