Statins are a very commonly prescribed drug in the world today, with many of our patients taking them on a regular basis to lower their cholesterol levels. High cholesterol, of course, being a significant risk factor in the development of cardiovascular diseases. In previous years, much discussion has focused on the negative side-effects particularly around muscle pain and myopathy. Yet, little is mentioned of their potentially positive benefits beyond cholesterol reduction. The drugs are known to have anti-coagulatory, anti-inflammatory, anti-microbial and immuno-modulatory effects [1].
A recent review published in Pharmacology & Therapeutics [2] has highlighted how this group of drugs have been shown to exhibit antifungal activity as well. Over the last decade, there have been a number of papers published which have examined aspects of the antifungal effects of the statin group of drugs and the authors have collated this work to give an overview of what is known and what may be the potential applications of this discovery.
From a podiatrist’s perspective, we think about our most common fungal pathogen group the dermatophytes and where this fits in. The story here starts in 2013 when a paper was published in the respected Medical Mycology journal [3] investigating the antifungal activities of statins against dermatophytes. The authors selected four dermatophytes (Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis and Microsporum gypseum) and exposed them to various statins (lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and pravastatin). The bottom line was that all of them showed some inhibitory effects against these dermatophytes with simvastatin and fluvastatin showing complete inhibitory effects even at low drug concentration levels. Interestingly, the authors went on to study the combined effects of common antifungal agents with statins and discovered a synergistic effect – the presence of the statin enhanced the antifungal drugs activity. This was particularly marked with azoles or terbinafine combined with simvastatin.
So how does this work? Fungal wall structure, and consequently fungal viability, depends on the manufacture of ergosterol. Statins have been shown to interfere with this enzymatic production pathway depleting farnesyl pyrophosphate, vital for ergosterol production [2]. This has been confirmed in experiments where supplementation of ergosterol has reduced the effects of the statins on fungal inhibition [4] although further research has suggested alternative mechanisms may be at play as well.
The next logical question, of course, is what is the clinical relevance here? Well, this as yet is unknown as this research is all laboratory-based. In real-life patients, it is unlikely that the statin serum levels required to have a significant antifungal effect can be achieved. Also, the use of azole antifungals (systemically) competes with statins as they both use the same P450 cytochrome pathway in the liver. Consequently, the azole is metabolised over the statin leading to increased levels of the latter in the blood which may risk side effects such as myositis. Consequently, this work is at a promising stage but opens the door to further research in developing new antifungal agents which may include the use of statins in some future formulation to improve efficacy. For the moment though, this is should be labelled as “work in progress”.
References
1. Blanco-Colio, L.M., et al., Anti-inflammatory and immunomodulatory effects of statins. Kidney International, 2003. 63(1): p. 12-23.
2. Tavakkoli, A., T.P. Johnston, and A. Sahebkar, Antifungal effects of statins. Pharmacology & therapeutics, 2020: p. early view.
3. Nyilasi, I., et al., Susceptibility of clinically important dermatophytes against statins and different statin-antifungal combinations. Medical Mycology, 2013. 52(2): p. 140-148.
4. Macreadie, I.G., et al., Growth inhibition of Candida species and Aspergillus fumigatus by statins. FEMS Microbiology Letters, 2006. 262(1): p. 9-13.