Could a Repurposed Drug Improve Diabetic Wound Healing?

Liam Davenport

November 18, 2021

An oral medication that has been examined as a potential treatment for obesity and intracranial hypertension, among other indications, may improve wound healing in patients with type 2 diabetes, suggest results from a UK pilot study.

AZD4017 (AstraZeneca), which inhibits the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), was compared with placebo in almost 30 patients with type 2 diabetes but without active diabetic wounds.

Dr Ana Tiganescu, a research fellow in the Faculty of Medicine and Health at the University of Leeds, UK, and colleagues found that wound healing was substantially improved with the drug, reducing wound gaps following punch biopsy by almost 50% and increasing re-epithelialisation.

The research, presented at the Society for Endocrinology’s annual conference, SfE BES 2021, on November 8, also showed that there was no increase in adverse events with AZD4017 over placebo.

Dr Tiganescu told Medscape News UK that the team would next like to repeat the study in type 2 diabetes patients ‘with active diabetic foot ulcers’, and are currently looking for funding.

She believes that, if the drug is shown to be clinically effective, it could not only be beneficial to type 2 diabetes patients but also for wound healing in general.

“Wound healing isn’t an issue just for people with diabetes,” she said, emphasising that people have problems with skin healing and thinning as they get older, as well as having an increased risk of pressure ulcers.

The authors note that, although chronic wounds such as diabetic foot ulcers cause “substantial morbidity and mortality”, and are estimated to cost the NHS more than £1 billion every year, treatment options “remain limited”.

Over the years, a number of drugs targeting 11β-HSD1 have been developed for diabetes and metabolic syndrome, but they “failed to show sufficient improvement over and above current leading therapies”, Dr Tiganescu said.

However, glucocorticoids are known to impair wound healing, and preclinical research conducted by the team has shown that blocking glucocorticoid activation via 11β-HSD1 improves skin healing.

As AZD4017 was publicly available from AstraZeneca through their Open Innovation platform, Dr Tiganescu and team undertook the double-blind phase 2b Glucocorticoids and Skin Healing in Diabetes (GC-SHealD) trial.

For this, 28 patients with type 2 diabetes without active wounds were randomised 1:1 to oral AZD4017 400 mg or placebo twice daily for 35 days.   3 mm punch biopsies of the skin on the outer forearm were taken at baseline and on day 28.

The results showed that the 24-hour ex vivo skin activity of 11β-HSD1 was not inhibited by AZD4017 at day 28. However, systemic 11β-HSD1 activity was 87% lower at day 35 in patients taking the drug versus those given placebo.

The mean wound gap diameter on day 2 after baseline punch biopsy was 34% smaller in patients given AZD4017 than in the placebo group. After repeat wounding, the mean wound gap diameter was 48% smaller with AZD4017 on day 30.

Tape stripping to induce barrier disruption revealed that patients treated with AZD4017 had greater epidermal integrity, with 17 more tapes required to induce disruption than in those given placebo.

This, the team says, is the “equivalent to the greater epidermal integrity of young versus aged skin.”

Next, they developed a novel automated technique for the volumetric quantification of wound tissue types to validate the wound healing results.

This showed that AZD4017 was associated with a 42% increase in neo-epidermal volume and a 30% increase in re-epithelialisation versus placebo.

In addition to improvements in both cholesterol levels and systolic blood pressure, the results indicated that the drug was “well tolerated, with minimal side effects and adverse events comparable to placebo”, the researchers say.

The study is funded by the University of Leeds and the Medical Research Council.

Several of the study authors are employees of AstraZeneca.

No other relevant financial relationships declared.

Society for Endocrinology BES 2021: Abstract P40. Presented 8 November.

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