Letter to the Editor: androgenetic alopecia; drug safety and therapeutic strategies

In their article, Motofei et al. [1] concluded that finasteride should be preferred to dutasteride for the treatment of male androgenetic alopecia (AGA) as it preserves (at least in part) important physiological roles of dihydrotestosterone (DHT) owing to its partial suppression of DHT, its adverse events (AEs) seem to be largely predictable and the primary (mental and sexual) AEs induced by finasteride are in some cases questionable and difficult to quantify.

Dutasteride 0.5 mg once daily has been shown to be an effective treatment for men with AGA, with an acceptable and well-established safety profile. Dutasteride has been approved in Korea for AGA since 2009, Japan since 2015, Taiwan since 2016 and Singapore since 2017. There is also much experience of dutasteride 0.5 mg once daily for the management of Benign Prostatic Hyperplasia (BPH).

Dutasteride has shown a superior efficacy to finasteride in treating AGA in a head to head Phase III study. The mechanism of this improved effect is believed to be due to dutasteride exerting a stronger inhibition of 5a-reductase enzymes, resulting in a greater suppression of testosterone conversion to DHT, a more potent androgen. However, the important data from efficacy data of dutasteride 0.5 mg once daily compared to finasteride 1 mg once daily in the treatment of male AGA patients were not clearly outlined in the paper. The 24-week, double blind, placebo- and finasteride-controlled Phase III study [2] demonstrated that dutasteride 0.5 mg once daily was well tolerated and had a safety profile comparable to finasteride 1.0 mg once daily but with superior clinical efficacy in terms of:

• Hair count (primary endpoint): Dutasteride 0.5 mg was associated with significantly greater improvements in vertex hair count vs finasteride 1.0 mg at Week 12 (82.3 vs 50.9 within a 2.54 cm diameter; p = 0.003) and Week 24 (89.6 vs 56.5 within a 2.54 cm diameter; p = 0.003).

• Vertex hair width: Significant improvement in vertex hair width with dutasteride 0.5mg vs finasteride 1.0 mg at Week 24 (5.8 μm vs 4.0 μm × 1e−3; p = 0.004).

• Panel global photographic assessment: Dutasteride 0.5 mg significantly improved visual appearance of hair growth in the frontal but not vertex region vs finasteride 1.0 mg, according to a panel assessment at Week 24 (median score 0.58 vs 0.34).

These results have also been replicated in a small, independent randomized controlled open-label, evaluator-blinded study of dutasteride vs finasteride conducted in a single center in India [3].

In addition, it is important to review the comparative data on treatment-related sexual side effects (SEs) as investigated in the head to head Phase III study where the AEs profile between dutasteride and finasteride were comparable. This was not clearly presented in the paper to provide the reader with a complete picture of dutasteride as a therapeutic option for AGA. Despite greater suppression of DHT and better efficacy profile, incidence of sexually-related AEs with dutasteride has been comparable to those reported with finasteride in the clinical trials, meta-analysis of RCTs and in post-marketing surveillance studies.

Administration of dutasteride 0.5 mg daily over 12 months in an open-label, prospective outpatient study in men with AGA [4] was associated with a safety profile comparable with that in Phase III trials with no new safety signals reported. The incidence of AEs and treatment-related AEs was 53% and 17%, respectively. The most common AE reported was nasopharyngitis (15%) followed by erectile dysfunction (ED) (12%) and decreased libido (8%). Sexual function AEs were the most frequently reported drug-related AE.

The incidence of sexual dysfunction AEs in this study was higher than in other controlled studies, possibly related to the open-label study design, i.e., subjects being more likely to report AEs if they are aware of taking active treatment. Incidence of AE was higher in the first 6 months than the second 6-month period. Up to 50% of the sexual function AEs resolved at the end of the study (decreased libido, 50%; ED, 43%; ejaculation disorder, 33%) and all sexual dysfunction AEs resolved during treatment or within 6 months of treatment cessation.

In comparison, in an open label, multicenter, non-interventional, regulatory requirement, post-marketing observational Phase IV study of dutasteride reported AEs in 712 Korean men with AGA (average treatment duration: 204.7 ± 161.5 days), treatment-related AEs were reported by 66 subjects (9.3%); the most frequent (>1%) were decreased libido (1.3%), dyspepsia (1.1%), and ED (1.0%) [5]. No deaths, treatment-related SAEs, AEs leading to treatment discontinuation or study withdrawal were reported. No sexual AEs or gynecomastia were found to be severe. Most of the AEs occurred in subjects less than 1 year of treatment (85.9% vs 14.1%).

Sexual AEs of ED, decreased libido, and ejaculation disorders were mild or moderate, expected, tolerable, and most resolved while on treatment.

Trost et al. carried out a meta-analysis of 27 randomized controlled studies of 5-alpha reductase inhibitors (5ARIs). The meta-analysis included studies across multiple indications, including AGA, with a treatment duration of up to 4 years for dutasteride and 7 years for finasteride. The incidence of sexual dysfunction-related AEs was found to be similar for dutasteride and finasteride compared with placebo. Rates of sexual AEs decreased over time; the highest rates occurred between 6 and 12 months of starting therapy. Many studies in the meta-analysis reported improvements in libido, ED, and ejaculatory dysfunction over time (years 1–4). Only one study reported increased rates of ED over 5 years [6]. Amory et al. demonstrated that the DHT decrease induced by 5ARIs is associated with mild reversible decreases in semen parameters [7].

Finally, it was mentioned that finasteride should be preferred to dutasteride because some plasmatic degree of DHT is maintained. This was suggested to be important because DHT plays important physiological roles in the organism and, therefore, strong suppression of DHT might not be optimal for some men due to other physiological roles for DHT. During clinical studies of dutasteride for AGA or BPH, there was no indication of dutasteride causing metabolic changes based on either laboratory measures or AE reporting. Clinical pharmacology studies have also shown that dutasteride had no clinically significant effect on other androgens, hormones, thyroid stimulating hormone, thyroxine, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, bone metabolism, or bone density after 52 weeks of treatment. Furthermore, clinical study data show no clinically significant correlation of dutasteride and metabolic/physiologic changes in the human body [8]. Amory reported no significant differences in total, HDL or LDL cholesterol at any time during treatment or the 26-week follow-up period in his study of 5-ARIs impact on bone metabolism, fasting serum lipoproteins, hemoglobin, and sexual function. Serum triglyceride concentrations were normal at baseline and during treatment in all subjects. Absence of elevated triglyceride levels in 5ARI-treated patients suggests that 5ARI treatment is not associated with a clinically significant increase in insulin resistance. Furthermore, as treatment with 5ARIs had no significant effect on total or HDL cholesterol in this study, the authors suggested that androgens effects on lipoprotein metabolism are likely mediated by testosterone or its active metabolite rather than by DHT [8]. The Korean phase IV AGA study with dutasteride also reported very low rates (0.1%) of hypertriglyceridemia or weight increase and no reports of prostate cancer, breast cancer, or heart failure [5].

Safety of dutasteride 0.5 mg for treatment of AGA in men is further supported by the large clinical study and post-marketing database for dutasteride 0.5 mg for the treatment of BPH. Safety data were obtained from clinical studies in more than 16,357 subjects exposed to dutasteride or dutasteride + tamsulosin in BPH. Worldwide post-marketing data are available for over 16.2 million patient-years of dutasteride exposure and the risk benefit profile for dutasteride in both AGA and BPH remains favorable.

Declaration of interest

The authors G.O., M.M. and Z.L. were employed by GlaxoSmithKline at the time of writing of this letter.