A familiar beta-blocker has found itself in an unfamiliar place: not in an IV line, but on a diabetic foot wound.
Esmolol is best known as an ultra-short-acting beta-1 blocker—a drug we use when we want the heart to slow down, and we want that effect to be rapidly controllable.
So here is a wonderfully counterintuitive question:
Can a drug that slows the heart speed wound healing?
When esmolol is reformulated as a topical 14% gel, the answer may be yes.
An old drug with a new job
Diabetic wounds do not simply lack time. They can become biologically stalled. Excess glucose drives sorbitol accumulation and advanced glycation end products. Nitric oxide signaling is impaired. Fibroblasts, keratinocytes, and endothelial cells—the construction crews of repair—do not migrate as effectively into the wound.
Preclinical work suggests that topical esmolol may push on several of these pathways at once. It inhibited aldose reductase activity and advanced glycation end-product formation, increased nitric oxide, and encouraged the migration of key wound-healing cells. In other words, it may do considerably more locally than its cardiac résumé would suggest.
That is mechanistic and preclinical evidence, of course. Interesting biology is not the same thing as a healed human wound. Fortunately, this idea has also been put through a serious clinical test.
The Phase 3 signal
In a randomized, double-blind Phase 3 trial conducted at 27 centers in India, 176 people with noninfected diabetic foot ulcers were assigned to topical esmolol 14% gel plus standard care, standard care alone, or vehicle gel plus standard care.
The efficacy analysis comparing esmolol plus standard care with standard care alone found:
- At 12 weeks: complete closure in 60.3% (41/68) with esmolol plus standard care versus 41.7% (30/72) with standard care alone (odds ratio 2.13; 95% CI, 1.08–4.17; P=.03).
- At 24 weeks: complete closure in 77.2% (44/57) versus 55.6% (35/63), respectively (odds ratio 2.71; 95% CI, 1.22–5.99; P=.01).
This was not esmolol instead of good wound care. It was esmolol added to standard care. Offloading, debridement, infection control, perfusion assessment, and metabolic care remain the orchestra. A topical therapy—however promising—is one instrument.
What about the wounds already telling us they are slow?
This may be the most clinically provocative part of the study.
Early area reduction is one of our most useful wound-healing vital signs. When a diabetic foot ulcer has reduced by less than 50% after four weeks, it is warning us that closure is unlikely without a change in course.
In a post hoc subgroup analysis of these slower-healing wounds, closure at 12 weeks occurred in 39.3% of those receiving esmolol plus standard care compared with 8.3% receiving standard care alone—an approximately fivefold difference.
That result is compelling, but it deserves the correct label: it was post hoc and therefore hypothesis-generating. It should be validated prospectively. Still, it raises a useful possibility—that an adjunct such as topical esmolol may prove especially valuable when the wound trajectory tells us, early on, that standard care is not enough.
And safety?
Across all 176 randomized participants, 18.8% experienced a treatment-emergent adverse event. Investigators judged most of those events—87.3%—unrelated to the study drug, and no serious adverse event was considered drug-related.
A smaller open-label randomized study published in 2025 added an encouraging, if much less definitive, signal: among 30 participants, the group receiving topical esmolol plus standard care had greater mean wound-area reduction at 12 weeks (89.7% versus 61.5%) and more complete healing (40.0% versus 13.3%). The study was small and open-label, so it supports the conversation rather than settles it.
The take-home
Can a drug that slows the heart speed wound healing?
Perhaps—when it is applied locally and given an entirely different job.
Topical esmolol is a fascinating example of drug repurposing: a familiar molecule, an unexpected target, plausible biology, and a positive randomized trial. It is not a replacement for excellent standard care, and the slow-healer finding needs prospective confirmation. But it is exactly the sort of idea worth pursuing when too many diabetic foot wounds still stall, recur, and threaten limbs.
Sometimes innovation is a brand-new molecule. Sometimes it is looking at an old molecule sideways.
References
- Rastogi A, Kulkarni SA, Agarwal S, et al. Topical esmolol hydrochloride for diabetic foot ulcer healing: a phase 3 randomized clinical trial. JAMA Netw Open. 2023;6(5):e2311509. doi:10.1001/jamanetworkopen.2023.11509
- Kulkarni SA, Deshpande SK, Rastogi A. Novel topical esmolol hydrochloride improves wound healing in diabetes by inhibiting aldose reductase, generation of advanced glycation end products, and facilitating the migration of fibroblasts. Front Endocrinol (Lausanne). 2022;13:926129. doi:10.3389/fendo.2022.926129
- Chowdary CS, et al. Efficacy and safety of topical esmolol cream as an adjunctive therapy in diabetic foot ulcers: a randomized controlled study. Int J Life Sci Biotechnol Pharma Res. 2025;14(8):397–400. Full text (PDF)
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