Beta-blocker shows potential for diabetic foot ulcers

A novel, topical formulation of esmolol, a cardio-selective beta-1 adrenergic blocker, may just have landed a spot in the diabetes treatment landscape, as it shows promise as treatment alternative for diabetic foot ulcers (DFUs).

“Standalone treatments … do not treat DFUs effectively,” said Dr Ashu Rastogi from the Postgraduate Institute of Medical Education and Research, Chandigarh, India, at EASD 2022.

Approved for supraventricular tachycardia and heart failure with fast ventricular rate, esmolol has a pleiotropic mechanism of action that could account for its potential as a DFU treatment alternative. For one, its anti-inflammatory action and aldose reductase inhibition can help reduce tissue damage. [Front Endocrinol 2022;13:926129]

“[Furthermore,] we believe that esmolol [may] induce nitric oxide generation, which can lead to fibroblast migration and EPC* mobilization. It can also improve collagen turnover, which can help in crosslinking and wound healing,” he added.

The study included 176 type 2 diabetes patients (mean age 56.6 years, 68 percent male) with uninfected, grade A1 full-thickness DFUs (area 2–15 cm²), which have been present for at least 6 weeks. After a 1-week run-in phase, participants entered the 12-week treatment phase wherein they were randomized 3:3:1 to esmolol 14% gel + SoC**, SoC only, or vehicle-SoC. The ensuing 12 weeks comprised the follow-up phase wherein wound closure was evaluated at 4 weeks and observed for the remaining 8 weeks. [EASD 2022, abstract 22]

At week 12, more participants on esmolol-SoC achieved complete wound closure than those on SoC only (60 percent vs 42 percent; odds ratio [OR], 2.13; p=0.028). This effect was sustained by week 24 (77 percent vs 56 percent; OR, 2.71; p=0.013).

Esmolol-SoC continued to prevail over SoC only regardless of wound site (59 percent vs 43 percent [plantar] and 64 percent vs 38 percent [non-plantar]) and size (66 percent vs 50 percent [<5 cm²] and 48 percent vs 27 percent [>5 cm²]).

On subgroup analysis, esmolol-SoC remained better than SoC only among those with BMI >25 kg/m² (OR, 2.72; p=0.0309), ulcer age >12 weeks (OR, 3.07; p=0.0066), HbA_1c >8 percent (OR, 3.43; p=0.0067), Hb <11 g/dL (OR, 5.00; p=0.0179), eGFR*** <90 mL/min (OR, 2.80; p=0.0269), and hypertension history (OR, 14.00; p=0.0006).

“Esmolol remained significantly better than SoC in ‘real-life’ situations,” noted Rastogi, as seen in subgroups of patients with <15-percent reduction at screening (OR, 2.43; p=0.0194), <50-percent reduction in 4 weeks (OR, 7.12; p=0.0102), hypertension during study (OR, 4.29; p=0.0223), and abnormal echocardiogram (OR, 4.00; p=0.0269).

Ulcer area reduction post-treatment

From end-of-treatment (EOT) to end-of-study (EOS), ulcer area reduction with esmolol-SoC was markedly higher than the ‘negligible’ reduction seen with SoC only (61 percent vs 3 percent; p=0.021).

When comparing against baseline, percent area reduction from EOT to EOS with esmolol-SoC was 23 percent. “There was some kind of legacy effect of topical esmolol on the migration of … fibroblasts or keratinocytes … Esmolol triggered wound healing, further reducing the ulcer size during follow-up,” explained Rastogi. Conversely, with SoC, there was a 7.5-percent increase in ulcer size.

Effect on exudates, AEs

In nonhealing DFUs, the ongoing inflammatory processes produce exudates for long durations, thereby increasing the chances of open wound infections. With esmolol-SoC, participants were able to reach the no-exudate status after a median 5 weeks, whereas with SoC only, it took 8 weeks (hazard ratio, 2.0; p=0.024). “[These findings] demonstrate early reduction of inflammation with esmolol-SoC,” explained Rastogi.

All serious adverse events (AEs) and most AEs were unrelated to the study drug, suggesting the safety of esmolol for use in this patient setting.

A novel treatment alternative

“This is the first randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase III study [evaluating] the efficacy of topical esmolol gel for uninfected DFUs,” said Rastogi.

“[Our findings show that] esmolol 14% topical gel significantly improves wound healing for predominantly neuropathic grade 1 DFUs [and] is safe to apply over DFUs,” he continued. “[As such,] topical esmolol may be a novel treatment option for DFUs.”