Head-to-head comparison of 4 hyaluronic acid dermal fillers for lip augmentation: A multicenter randomized, quadruple-blind, controlled clinical trial

Abstract

To the Editor: Currently, no superiority of hyaluronic acid filler products over others has been shown.1Alam M. Tung R. Injection technique in neurotoxins and fillers: indications, products, and outcomes.J Am Acad Dermatol. 2018; 79 (J Am Acad Dermatol. 2019;80(6):1814. https://doi.org/10.1016/j.jaad.2018.01.037): 423-435Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,2Stojanovič L. Majdič N. Effectiveness and safety of hyaluronic acid fillers used to enhance overall lip fullness: a systematic review of clinical studies.J Cosmet Dermatol. 2019; 18: 436-443https://doi.org/10.1111/jocd.12861Crossref PubMed Scopus (31) Google Scholar Trials have been plagued by poor methodological quality, conflicts of interest, and industry sponsoring.2Stojanovič L. Majdič N. Effectiveness and safety of hyaluronic acid fillers used to enhance overall lip fullness: a systematic review of clinical studies.J Cosmet Dermatol. 2019; 18: 436-443https://doi.org/10.1111/jocd.12861Crossref PubMed Scopus (31) Google Scholar Our trial assesses whether superiority in effect durability, improvement of appearance appraisal, quality of life, and safety can be shown among the 4 most frequently used hyaluronic acid dermal filler brands in the Netherlands. We performed a multicenter, randomized, controlled, parallel, quadruple-blind clinical trial of 143 adult women who requested lip augmentation (NCT04362891). Participants (Supplementary Tables I and II, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb) were randomized (physician and product stratified) in a 1:1:1:1 ratio to receive 1.2 mL of either of the 4 hyaluronic acid dermal filler brands: Juvéderm Ultra 3, Belotero Intense, Restylane Kysse, or Stylage M (Fig 1; Supplementary Table III, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb). Between July 2021 and January 2022, they were injected by 5 board-certified cosmetic physicians at 5 locations of Faceland Clinics in the Netherlands. We used a unique blinding method in which hyaluronic acid products were transferred into blinded study syringes in a sterile operating theater (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb).3Bellew S.G. Carroll K.C. Weiss M.A. Weiss R.A. Sterility of stored nonanimal, stabilized hyaluronic acid gel syringes after patient injection.J Am Acad Dermatol. 2005; 52: 988-990https://doi.org/10.1016/j.jaad.2005.01.131Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Outcomes were evaluated at baseline, day 14 (ie, “check-up”), and week 13 (ie, “follow-up”) (Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb). As a result (Fig 2; Supplementary Table IV, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb), the linear mixed model analysis findings showed an overall increase in lip height (Supplementary Figs 3 and 4, available via Mendeley at https://data.mendeley.com/datasets/gpxrsnf7pb) from baseline to follow-up (+2.1 mm [+18.9%], P < .01); with Stylage (+2.8 mm [+26.3%]), lip height increased more than with Juvéderm (+1.2 mm [+10.9%], d = 0.73). Overall, appearance appraisal increased from baseline to follow-up (+9.4 points on a 10–40 point scale [+40,7%], P < .01), and increased more with Juvéderm (+10.9 points [+50.7%]) than with Belotero (+7.2 points [+29.8%], d = 0.50). No serious adverse events were recorded.4Steenen S.A. Bauland C.G. de Lange J. van der Lei B. Complications after botulinum neurotoxin type A and dermal filler injections: data from a large retrospective cohort study.Aesthet Surg J. 2022; (Published online August 12, 2022. https://doi.org/10.1093/ASJ/SJAC228)Crossref PubMed Scopus (1) Google Scholar Overall, social function (+2.4 points on a 8–32 point scale [+9.8%], P < .01) and psychological well-being (+2.7 points on a 10–40 point scale [+8.7%], P < .01) scores increased from baseline to follow-up. Social function increased more with Stylage (+4.6 points [+20.1%]) than with Belotero (+1.6 points [+6.3%]; d = 0.64). Overall, lip height increased from baseline to check-up (+3.8 mm [+34.4%], P < .01). Belotero (+4.7 mm [+41.3%]) resulted in a greater increase than both Juvéderm (+3.1 mm [+27.7%], d = 1.21) and Stylage (+3.4 mm [+31.1%], d = 0.58). Juvéderm was associated with higher side effect scores (13.0 points on a 8–32 point scale) 25.3% than Stylage (12.0 points; d = 0.85). Not all statistically significant differences between the products observed may be clinically relevant. A successful lip filler treatment is the result of the combination of a visually volumizing effect, satisfaction with anatomical shape, function, recovery, and psychosocial effects. At follow-up, no between-group difference was found for any of these outcomes. We showed that side-effect profiles were low, and, at month 3, lip appraisal, treatment satisfaction, and quality of life were high in all groups. Nonetheless, the absolute difference in lip volume increase from baseline to follow-up between Juvéderm versus Stylage was 1.6 mm (15.4%) in this sample of women with relatively small lips (an average of 10.9 mm at baseline), suggesting a clinically relevant longer duration of Stylage. Last, the absolute difference in the lip appraisal score increase between Juvéderm versus Belotero was 20.9%, suggesting a clinically relevant better appraisal of Juvéderm over time. In conclusion, statistically significant but clinically arguably relevant superiority was found in duration, patient satisfaction, and quality of life. No product was superior in all categories. Safety profiles were equal. Future dermal filler trials would benefit from the use of stereophotogrammetry for accurate volume quantification.5Sawyer A.R. See M. Nduka C. 3D stereophotogrammetry quantitative lip analysis.Aesthetic Plast Surg. 2009; 33: 497-504https://doi.org/10.1007/s00266-008-9191-1Crossref PubMed Scopus (59) Google Scholar None disclosed. The authors thank Jacqueline de Vries, L.LM. (VvAA) for advice on legal context. We thank Dr. Nienke Vulink (psychiatrist, AUMC–location AMC) for suggesting instruments to exclude body dysmorphic disorder. We like to thank Aarent R.T. Brand Kanters for his thoughtful comments in choosing an adequate timeframe for the follow-up period. We also thank Ruud van den Handel, Ronald de Gier, Tamika Jobse, Britt Verdonck–Oude Nijhuis, Nicoline L. Nijman, Albert Oostdijk, Zuwena Koeiman, Sanne Kruidhof, Melisa Sencan, Nikita van Keulen, Iman Wasch, Samra Zarify, Anna Hobsebyan, and all clients for their help and participation in this study.

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