Beta Blocker Gel Shows Potential for Treating Diabetic Foot Ulcers

According to Indian experts, using esmolol hydrochloride gel twice a day (Galnobax, NovaLead) appears to considerably enhance the closure of diabetic foot ulcers, especially in individuals who have risk factors for impaired wound healing.

The US Food and Drug Administration has just approved the short-acting beta-adrenergic receptor blocker esmolol for use in cardiac indications, including the short-term treatment of supraventricular tachycardia. Esmolol hydrochloride is applied topically as a gel to promote wound healing by processes like endothelium, fibroblast, and keratinocyte migration into wound tissue.

Among 140 patients in the current experiment, all with type 1 or type 2 diabetes, it was shown that the group randomized to esmolol gel + standard of care had a greater than twofold higher chance of achieving target ulcer closure within 12 weeks compared to the group receiving standard care alone. For patients who weighed more than 80 kg (176 lb) or had a body mass index (BMI) of more than 25 kg/m2, the addition of esmolol gel to conventional therapy had an even higher effect.

According to Ashu Rastogi, MD, DM, of the Department of Endocrinology at the Post Graduate Institute of Medical Education and Research in Chandigarh, India, and colleagues, "the use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers" was recently published in JAMA Network Open.

At the 2022 Annual Meeting of the European Association for the Study of Diabetes, Rastogi initially presented the results. The results, as published by Medscape Medical News, were highly received; one doctor called them "astounding."

Though the final published statistics are "interesting," according to Andrew Boulton, MD, PhD, Medscape Medical News "needs further confirmation" because "there are one or two unusual features" about the study. Boulton teaches medicine at the University of Manchester in the United Kingdom, namely in the Division of Diabetes, Endocrinology, and Gastroenterology.

The study, he emphasized, concerned "basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy." Furthermore, according to Boulton, the inclusion criteria allow the ulcers to be either below or 5 cm above the malleoli, which is "very unusual and would therefore include some atypical and not truly diabetic 'foot' ulcers."

There are concerns with the study methodology, according to Frances Game, MBBCh, Department of Diabetes and Endocrinology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK. Despite being a "fascinating study," she informed Medscape Medical News that the major comparison group did not get vehicle gel (also known as a placebo) in addition to standard of care. She questioned, "How were they blinded [to treatment]?"

The "biggest problem" with the study, however, is that instead of reporting the primary outcome as a standard intention-to-treat analysis, the researchers reported it as a per protocol endpoint. This permitted them to remove patients whose ulcers had grown larger than 30% on two separate visits. "That kind of makes [esmolol gel] look better than it is because they've taken out the ones who got worse," Game said. She did, however, come to the conclusion that more research on esmolol gel was necessary despite the results not being definitive.

The authors point out that diabetic foot ulcers are a serious side effect of diabetes, with a frequency ranging from 1.3% to 12.0% in different nations. The complication raises patient risk factors and death rates, with a 5-year mortality rate significantly greater than that of several cancers.

Furthermore, just 30% of wounds associated with diabetes heal "even with the best therapy," which includes sophisticated moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth hormones, electric stimulation, and negative pressure wound therapy. Recurrence rates might reach 70%.

In light of these findings, a phase 1/2 research comparing standard of care with a control vehicle gel to topical esmolol 14% gel shown an association with ulcer area reduction and an earlier time for wound healing.

Participants in the current phase 3 randomized controlled trial ranged in age from 18 to 75 years, had either type 1 or type 2 diabetes, and had noninfected diabetic foot ulcers with an area of 2 to 25 cm2 that were classified as grade 1A or 1C on the University of Texas Wound Classification System after they had been open for at least six weeks.

From 2018 to 2020, patients from 27 tertiary care facilities in India were enrolled. Three groups were randomly assigned to them in a 3:3:1 ratio: Normal of care plus 14% esmolol gel, only the standard of care, automobile plus the required level of care. A 1-week screening phase, where all patients got conventional care, a 12-week therapy phase, and a 12-week follow-up phase comprised the 25-week study. The latter comprised an eight-week observation period and a four-week closure confirmation period.

During the therapy phase, patients were evaluated once a week, and then at weeks 14, 16, 20, and 24. A total of 176 patients were signed up. With a mean age of 56.4 years, 69.3% of the participants were male. The A1c average was 8.6%. The average size of diabetic foot ulcers was 4.7 cm2, and they typically lasted 49.8 weeks.

The main result, which was evaluated for 140 patients, was the percentage of patients who closed their target ulcers over the 12-week treatment period. With an odds ratio (OR) of 2.13 (P =.03), patients treated with esmolol gel in addition to standard of treatment generally achieved target ulcer closure, compared to 41.7% of patients in the standard of care alone group.

The secondary result, which was evaluated in 120 participants, was the percentage of patients who had achieved the goal of ulcer closure by the end of the research. With an OR of 1.72 (P =.01), 77.2% of patients in the esmolol gel plus standard of care group ultimately fulfilled the secondary objective, compared to 55.6% of patients receiving standard of care alone.

Subsequent investigation revealed that individuals with a weight over 80 kg and a BMI over 25 kg/m2 benefited more from esmolol gel + standard of care compared to standard of care alone (OR, 4.04; P =.04). Thirty-three (18.8%) individuals reported treatment-emergent adverse events, of which twelve were considered significant. The researchers state, "However, none of the serious adverse events were considered as drug-related by the investigators."

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India.

Also Read: Special Considerations in Diabetes Mellitus

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