1. Introduction

The ideal shape of the youthful female face has been described as an upside-down triangle with a full and wide mid-face narrowing toward the chin. In addition, the shape and contour of the chin and neck play an important role in facial esthetics. Furthermore, a strong chin has been associated with self-confidence, authority, and trustworthiness, whereas submental convexity or fullness can make an individual appear overweight and older. One common cause of submental fullness is accumulation of submental fat (SMF), which often presents as a double chin. Although weight gain, secondary to diet and lifestyle, can contribute to accumulation of SMF, aging, and genetics play a major role. For some individuals (both males and females), fat deposited in the submental area is disproportionate to their overall fat profile and diet and exercise are not sufficient to reduce SMF in these individuals. According to data from a blinded online consumer survey conducted by the American Society for Dermatologic Surgery in 2015, 67% of the 7 315 respondents indicated that they were somewhat to extremely bothered by excess fat under their chin/neck. In addition, the number of chin augmentation procedures increased by 71% between 2010 and 2011 based on statistics from the American Society of Plastic Surgeons.

The neck is divided by the sternocleidomastoid muscle into the anterior and posterior triangles, with the submental area being part of the anterior triangle. Within the submental area, fat is separated into two distinct compartments by the platysma, which is composed of two broad muscles located on either side of the neck. Preplatysmal (supraplatysmal) fat is located between the dermis and platysma, while postplatysmal (subplatysmal) fat is located between the platysma and submental musculature.

Current treatment options for submental contouring often target preplatysmal fat, as extensive removal of postplatysmal fat can result in a concave and distorted neck shape and can include invasive procedures such as surgical rejuvenation and targeted liposuction. Although energy devices (lasers, radiofrequency, and ultrasound) offer a noninvasive option for submental contouring, these treatments focus on tightening the skin within the submental area versus reducing SMF. Cryolipolysis was recently cleared in the United States for use in the submental area and may offer a less invasive alternative to surgery or liposuction for reduction of SMF. Injectable therapy with phosphatidylcholine/ deoxycholate also offers a less invasive option for reduction of SMF; however, these products are produced by chemical compounding and are not regulated by the US FDA, Health Canada, or the CE commission. In contrast, ATX-101 (deoxycholic acid [DCA] injection) is the first injectable drug approved by the FDA and Health Canada for improvement in the appearance of moderate-to-severe convexity or fullness associated with SMF.

2. Mechanism of action of ATX-101 for reduction of SMF

Endogenous DCA is a secondary bile acid that serves to emulsify and solubilize dietary fat, thereby aiding in its breakdown and absorption within the gastrointestinal tract. The initial mechanism of action proposed for ATX-101 was that administration of exogenous DCA to subcutaneous fat (adipose tissue) within the submental area would lead to adipocyte lysis, the targeted destruction of fat cells, and ultimately a reduction in SMF. DCA has been shown to mediate dipocyte lysis via disruption of the cell membrane leading to cell death. As DCA destroys adipocytes, administration of exogenous DCA would be expected to result in a reduction in the overall number of adipocytes within the treatment area (preplatysmal fat) and a durable treatment response over time.

In this open-label study, a BA-preserved formulation of ATX-101 was administered subcutaneously into the abdominal fat of healthy subjects (n = 14) aged 25–65 years who were planning to undergo abdominoplasty and had 3–6 cm (thickness) of abdominal fat for excision. The abdominal fat was divided into predefined segments and subjects were assigned to one of two ATX-101 dosing groups: group 1 received two injections per segment administered at least 1.5 cm apart, while group 2 received four injections per segment administered in a grid pattern. Varying concentrations of ATX-101 (1, 2, 4, and 8 mg/cm2) were administered to each subject. At 1, 3, 7, or 28 days post-ATX-101 administration, abdominoplasty was performed with the resected abdominal fat preserved for histology. Tissue samples were stained with hematoxylin and eosin (for cellular, vascular, and inflammation assessment) and Masson’s trichrome stain (for collagen assessment).

Consistent with the proposed mechanism of action for ATX- 101, adipocyte lysis was noted as early as 1 day post ATX-101 administration, and was followed by local tissue response and septal thickening. Neutrophilic infiltration was observed on days 1 and 3, with lipid-laden macrophages and mild septal inflammation of the adipocyte layer noted on day 7. By day 28, inflammation was nearly resolved while neovascularization, thickening of fibrous septae indicative of collagen production (neocollagenesis), and fat lobule atrophy were noted. The effects of ATX-101 were dose dependent and confined to the subcutaneous fat layer across all doses evaluated with no changes observed in either the dermis or epidermis. Overall, the results of this study supported the proposed mechanism of action of ATX-101 for reduction of localized fat and established the 28-day interval between ATX-101 treatment sessions used in the Phase II/III clinical trials.

3. Expert commentary and 5-year view

The scientific and clinical study of DCA and ATX-101 has taken over a decade for final objective proof of efficacy and safety. The results were so overwhelming that the Dermatologic and Ophthalmic Drugs Advisory Committee gave a 100% agreement to recommend approval of ATX-101. Overall, the clinical development program for ATX-101 has been an exciting evolution from experimental drug to well-developed treatment for reduction of SMF.

Injectables have been well established for facial treatment with both neuromodulators and injectable facial fillers. Extending injectable treatment into the neck is a major advance for nonsurgical cosmetic correction. Up to this point, only invasive surgical modalities have been effective to correct SMF and contour the aging neck. The use of ATX-101 as an injectable adipocytolytic agent has resulted in removal of unwanted SMF and, used correctly, can recontour the shape of the chin and neck to deliver a more youthful and pleasing appearance. ATX-101 represents a safe, nonaggressive treatment for reduction of SMF that will provide a major tool for the esthetic physician.

4. Conclusion

The submental area is a region of increasing focus among patients and within the field of facial esthetics. However, treatment options for submental contouring have been limited with invasive procedures such as surgical rejuvenation and targeted liposuction being the standard of care. The recent approval of ATX-101, a first-in-class injectable drug for reduction of SMF, offers a minimally invasive treatment alternative for patients.