Sublingual Minoxidil 5 mg versus Oral Minoxidil 5 mg for male androgenetic alopecia: A double‐blind randomized clinical trial

Low-dose oral minoxidil (OM) is effective for male androgenetic alopecia (AGA).1, 2 Sublingual minoxidil (SM) was proposed as an alternative to minimize adverse systemic cardiovascular effects and increase clinical response by bypassing the hepatic first-pass metabolism and improving bioavailability.3 Bypassing hepatic first-pass metabolism would reduce the rate of rise of the circulating activated drug and its systemic vascular effect. However, its efficacy and tolerability have yet to be compared to OM.4 This double-blind, randomized clinical trial compares the efficacy, safety and tolerability of SM 5 mg per day versus OM 5 mg daily for 24 weeks in patients with male AGA. Men with AGA (Norwood-Hamilton 3 V, 4 V and 5 V) were randomized (1:1) into two groups: SM 5 mg and oral placebo once a day or OM 5 mg and sublingual placebo once a day for 24 weeks. The primary outcome was the change in total hair density in the vertex region (TrichoLab® H2H-matching technology).5 Secondary outcomes included changes in non-vellus hair density and photographic evaluations. One hundred ten participants were enrolled in a specialized clinic in Brazil (Table 1). Eighty-five participants completed the study; 43 were in the SL group, and 42 were in the OM group. The total hair density increased 24.5 hairs/cm2 (95% CI: 18.8–30.2) in the sublingual group and 21.8 hairs/cm2 (95% CI: 14.9–29.0) in the oral group. Non-vellus hair density increased by 7.8 hairs/cm2 (95% CI: 4.2–11.4) in the sublingual group and by 7.4 hairs/cm2 (95%CI: 4.2–11.4) in the oral group. The mean changes from baseline in total and non-vellus hair density were greater in the SL group, but this difference was not statistically significant (p > 0.5). According to the consensus of the three treatment-blind dermatologists, 42% of the sublingual group and 40% of the oral group showed clinical improvement in the vertex, with no significant difference between the groups (p = 0.69) (Table 2). Hypertrichosis was the main adverse event reported. Palpitation was less frequent in the sublingual group compared to the oral group (0% vs. 9%; p = 0.048). Minoxidil is a pro-drug, and in order to act, it must be bio-activated into minoxidil sulfate.6 Considerable inter-individual variation in both hepatic and follicular sulfotransferase activity may explain the difference in clinical response among patients.7-9 In a previous clinical trial of 40 participants with AGA, SM was proven safe and effective at doses of 0.45, 1.35 and 4.05 mg per day.4 No adverse effects were described. In this study, the different administration methods did not impact the increase in hair density or clinical improvement. However, there was a significant difference between the groups in the frequency of palpitations. The vasodilation caused by minoxidil can lead to reflex tachycardia, commonly reported a few hours after ingestion. In patients using low-dose OM (0.25–5 mg daily) for hair loss, palpitations have been described in up to 4% of cases.10 In this study, the absence of reported palpitations in the SM group could be explained by the escaping of immediate minoxidil liver activation. Maybe the frequency of the other adverse events like hypertrichosis, oedema and dizziness were not different between the groups because they depend on the drug's long-term effect. So, they would not be impacted by short metabolism differences. The limitations of our study include its single-centre design, the absence of blood pressure and heart rate monitoring, and the small sample size. In conclusion, SM 5 mg per day did not demonstrate superiority over OM 5 mg per day in the treatment of male AGA after 24 weeks. Both treatments were well tolerated, with less frequent palpitation in the SM group. The principal investigator had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. None. BS, CC, PMR and HAM: None. RS: patents: oral minoxidil for hair loss (telogen effluvium); sublingual minoxidil to treat excessive hair shedding; US10226462, us16344288, us201990269684, us162522107; Stock owner: Samson Clinical Pty Ltd. This protocol was approved by the Ethics Committee of the Anhaguera—UNIDERP (# 5.936.863). Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and included at the time of article submission to the journal, stating that all patients gave consent with the understanding that this information may be publicly available. RBR-7wsgdm8. The data that support the findings of this study are available from the corresponding author upon reasonable request.