Noninvasive lipolysis modalities in aesthetic medicine

Adipose tissue is a vital metabolic organ that takes part in body homeostasis. However, an increase in fat tissue can be detrimental for one's health and lead to undesirable changes in body shape. Noninvasive lipolysis is becoming an increasingly popular method to destroy and remove excess body fat and improve one's satisfaction with their body appearance.

a significant storage of fat in the subcutaneous tissue of predominantly buttocks, thighs and hips, creating a "pear" shape. Men, however, have more lean mass and are more likely to store fat around the abdominal viscera. 3 The challenges associated with excessive adipose tissue created a niche for aesthetic medicine. There are multiple surgical procedures, such as liposuction, that help remove unwanted fatty deposits. Nevertheless, they carry significant health risks such as bleeding, contour irregularities, altered sensation, infections or fat embolism. 4 These adverse effects led to the development and introduction of noninvasive lipolysis treatments that induce rapid and long-lasting fat cell destruction.
Noninvasive lipolysis procedures can be classified by the energy source and its effect on the adipose tissue ( Figure 1). Cryolipolysis relies on the inherent sensitivity of adipocytes to cold temperatures. 5 On the other hand, radiofrequency technologies involve electromagnetic wave frequencies which generate electric fields in the skin causing an increase in temperature of the subcutaneous tissue. 6 Ultrasound delivers high-frequency sound waves across the skin to the subcutaneous fat and rapidly increases temperature in the target area. 7 The mechanism of laser treatment, however, is based on red and near-infrared photon absorption by chromophores in the mitochondria which stimulates a cascade of events. 8 In all these treatments, fat cells are destroyed to varying degrees by damaging the cell membrane which causes the contents of the lipid cells to be released into the extracellular space, triggering the innate immune response. They are then slowly absorbed by the macrophages over the course of several weeks and months. 9 Despite the increasing interest and growing demand for noninvasive lipolysis, the current state of research in this field has been inadequate and remains insufficient to provide definitive conclusions on its clinical efficacy and safety. There are still significant gaps in our understanding of the mechanisms, adverse effects, and optimal treatment protocols of various noninvasive lipolysis modalities. Therefore, conducting a thorough review of the available literature is necessary to fill these knowledge gaps and provide healthcare providers with up-to-date evidence-based recommendations for their patients.
The aim of this paper was to perform an evidence-based analysis of the clinical efficacy and safety of the abovementioned noninvasive modalities of lipolysis.

| MATERIAL S AND ME THODS
Three electronic databases were used to search for studies that investigate the different noninvasive modalities used in the management of excess fat tissue: PubMed, Scopus, and Embase.
The PICO (Population, Intervention, Comparator and Outcome) framework was used for structuring the clinical question. 10 Each electronic database was searched individually between February and May 2022 using search terms with Boolean Operators (AND, OR, and NOT). The search terms used were the following: "body contour*", "fat reduc*", "fat remov*", "*lipolysis", "non-invasive", "noninvasive", "non-surgical", "nonsurgical". Truncations were used to include the words that have different spelling or endings. Both American and British spelling were taken into consideration. Furthermore, MeSH terms were included to facilitate literature searching.
The inclusion criteria were randomized controlled trials and highquality observational studies performed on adult population in the last 20 years and reported in English that investigated the clinical outcomes of noninvasive lipolysis modalities in terms of efficacy and safety. Two independent reviewers screened the databases, selected studies for further analysis as per the above inclusion criteria and collected data on the clinical outcomes, including patient satisfaction, fat layer thickness or circumference reduction, as well as all reported short-term and long-term peri-procedural adverse effects. The extracted data have been meticulously presented in the evidence tables using a systematic approach. This facilitated a comprehensive analysis of the key findings and enhanced the ability to compare and synthesize the results across studies effectively.
The Critical Appraisal Skills Programme (CASP) tools were used to systematically assess the relevance, overall quality, and key results of the included studies. These checklists provided a structured framework for evaluating the current body of evidence and allowed smooth critical appraisal of various aspects, such as methodology and data analysis. By adhering to the standardized evaluation pathway, the authors were able to conduct a thorough assessment of the strengths and weaknesses of the included studies.
The level of evidence was graded according to the most recent guidance from Oxford Centre for Evidence-Based Medicine (OCEBM). 11 Level I was assigned to systematic reviews of randomized trials (RCTs) or n-of-1 trials. Individual RCTs or observational studies with dramatic effect were graded as level II. However, nonrandomized controlled cohort or follow-up studies were classified as level III. Last but not least, case series, case-control studies, or historically controlled studies were assigned level IV. Any disagreements were resolved through an open discussion between two reviewers.
F I G U R E 1 Mechanism of action of energy-based devices in nonsurgical lipolysis.
Strict exclusion criteria were also employed to ensure the highquality of evidence-based analysis of noninvasive methods of fat reduction. These criteria included studies reported in languages other than English or with a sample size of 10 or less participants, abstracts, case reports, letters to the editor, dissertations, literature reviews, conference proceedings, animal studies, systematic reviews, simulation studies, commercial experiences or comparisons of new applicators. Furthermore, papers not addressing modalities for lipolysis, for instance muscle toning or skin tightening, studies using invasive treatment methods or combination therapies, or investigating treatments for non-aesthetic purposes were also excluded from this evidence-based review.

| RE SULTS
The above search identified 55 papers which met the inclusion criteria. Figure 2 shows a PRISMA flowchart which depicts the process of systematically identifying, screening, and selecting studies for this evidence-based review. The research papers were then divided into four energy-based modalities-cryolipolysis, ultrasound therapy, radiofrequency, and laser therapy. Data on the study design, level of evidence, sample size, follow-up time, and study outcomes with regards to the clinical efficacy and safety were extracted from the included papers. The level of evidence for the articles was determined based on the Oxford Centre for Evidence-Based Medicine's system, 11 which grades evidence based on the study design and quality of research methodology. Due to low numbers of highquality articles investigating other lipolysis technologies, they were not included in further analysis.

| Cryolipolysis
The above-detailed search identified 20 studies investigating cryolipolysis (Table 1). These studies encompass sample sizes ranging from 11 to 4122 patients. The minimum follow-up time in the included papers was 2 months, and the longest follow-up was 6 months.

| Radiofrequency
A cumulative sum of nine studies that examined the radiofrequency devices in fat reduction were found ( Table 2). The sample sizes within these studies varied from 13 to 30 participants, while the follow-up period implemented to monitor the treatment outcomes ranged from 1 month to 4 years.

| Ultrasound
A total of 16 studies investigating the ultrasound body sculpting devices were identified (Table 3). Across the included papers, the TA B L E 1 Summary of available studies on safety and efficacy of cryolipolysis.

| Laser
In the context of the reviewed literature, it was ascertained that there were 10 studies which focused on laser treatment in fat reduction ( Table 4). The sample sizes of the enrolled participants within these studies varied between 19 and 689 individuals. Furthermore, the follow-up time to monitor the outcomes of the interventions spanned a range of 1 week to 6 months.

| DISCUSS ION
Lipolysis, defined as the breakdown of triglycerides into their constituent molecules through hydrolysis, can be mimicked by various medical procedures that aim to reduce the volume of fatty tissue, which is the focus of noninvasive fat reduction techniques that use different technologies to target localized fat deposits in specific body areas, without surgery or prolonged recovery periods. Thus, the objective of this study was to assess the clinical efficacy and safety of noninvasive fat reduction methods based on available evidence.

| Clinical efficacy
Based on the review of evidence presented earlier, radiofrequency is most used in the abdominal region and results in a statistically significant decrease in abdominal fat thickness. 32,34,36,[38][39][40] These outcomes continue to improve with each treatment and persist until the last follow-up appointment. Additionally, this method has shown to successfully reduce fat volume in the lower face, both in terms of submental circumference and fat thickness. 35,37 The observed efficacy of this technique was found to be sustained in over 50% of patients at long-term follow-up. Only one article investigated the outcomes of radiofrequency in the treatment of thighs 33 -it showed an average circumference reduction of 3.86 cm. Interestingly, multiple articles reported that reduction in fat layer thickness was statistically independent of weight changes. 33,34,36 This suggests that there is no correlation between weight and body circumference following the abovementioned procedure.

| Safety
The main side effects of radiofrequency treatment were heat sensation, mild pain or discomfort and local skin irritation, that is, erythema, warmth, tingling or oedema. 32

| Clinical efficacy
Ultrasound therapy has many clinical uses but it is also increasingly utilized in lipolysis, mainly in abdomen, waist, and flanks. [41][42][43][45][46][47][48][50][51][52][53][54][55][56] Out of 16 selected studies, four investigated fat reduction using the above procedure in thigh 41,44,49,53 and only one analyzed the gluteal region. 44 Interestingly, one research group evaluated the clinical efficacy of ultrasound in cheek fat reduction 49 ; they showed a significant improvement of 96.9% at 4 weeks post-procedure. Unfortunately, this score reduced to 90.6% at 12-week follow-up. The lowest satisfaction rate of 58.3% was reported by Shek et al., 45 and the highest rate of 93% was presented by Verner et al. 56 Therefore, there is a relatively large discrepancy between patients' subjective assessments of the treatment outcomes.

| Clinical efficacy
Laser is a modality used in lipolysis to target and break down adipose tissue through the use of thermal energy. Based on the above evidence-based analysis, between 72% and 96% of participants reported improved satisfaction with their body contour following the laser treatment. [57][58][59][60][61][62][63][64][65] The outcomes were also objectively assessed and revealed a statistically significant fat reduction in abdomen, waist, flanks, hips, thighs, 57-65 and-surprisingly-knees. 66 In five studies, the results of the above treatment were maintained or even improved at 12-week follow-up. [61][62][63][64][65] One study investigated the efficacy of laser in medial knee fat reduction. 66 They reported a reduction in knee circumference and fat layer thickness in both axial and sagittal planes. Nevertheless, despite clinically significant results, less than 50% showed greater than 75% improvement. Furthermore, this study reported the highest average pain score of 6.1 compared to the rest of the included studies.

| Safety
The majority of studies analyzing the side effect profile of laser treatment report self-resolving mild-to-moderate pain 62,63,65,66 and erythema. [62][63][64][65][66] The lesser reported side effects were ecchymosis 63,65 and subcutaneous firmness or nodule formation. [62][63][64][65] They all denied any occurrence of serious adverse events. [61][62][63][64][65] Disappointingly, 4 of 10 articles did not analyze the incidence of adverse effects. [57][58][59][60] One study reported that none of their patients experienced any short-or long-term adverse effects at all which is undoubtedly rare after medical or aesthetic treatments. 61 Nevertheless, the evidence base for safety of the above procedure in lipolysis is poor, compared to other modalities, and should be explored further in future studies.

| Comparison between different modalities
The appraisal of the current literature shows that all four modalities are safe and effective when used appropriately. Nonetheless, due

| Future considerations
The findings of this study provide valuable insights into the clinical efficacy and safety of noninvasive lipolysis modalities in fat reduction. The papers included in this evidence-based review suggest that the abovementioned methods are effective in fat reduction, as well as improving patient satisfaction with their body appearance.
Additionally, these modalities have demonstrated a relatively low side effect profile which further highlights their potential as viable and effective alternative options to invasive procedures. However, due to the observational design of most included papers, this study also emphasizes the need for additional well-designed randomized controlled trials to enhance the body of evidence supporting the use of noninvasive lipolysis. Studies of larger sizes and with longer follow-up periods should be conducted to provide research papers at a higher evidence level and to further explore the long-term effectiveness and safety of these modalities. Furthermore, future research should introduce uniform validated tools of outcome measurement to enable the conduction of meta-analysis or high-quality comparison studies.
Some studies suggest a possible role for combination therapies to increase the clinical effects of the treatment. Surgical procedures, such as liposuction, or weight loss undoubtedly lead to a significant reduction in fat layer. However, they do not address the subsequent issue of excessive loose skin and striae. The analyzed noninvasive methods not only reduce body circumference, but they also enhance skin tightening and improve skin laxity due to fibroblast activation and neo-collagen production. Therefore, they could be used as adjuncts to surgical treatment to improve the overall clinical outcome. Nevertheless, the introduction of multiple modalities might also increase the risk of adverse events.
Therefore, future studies should investigate the efficacy and safety of combination therapies.
The results of this evidence-based review pose a philosophical question whether these modalities will ever replace the traditional ways of fat reduction such as exercise, diet etc. The discussed modalities might be considered a short cut to a leaner body. However, it is vital to remember that their use in the treatment of large areas of fat remains debatable as they produce relatively small changes in body circumference. Furthermore, they do not cause weight loss or address abnormalities in blood results. Therefore, these methods are more suitable for non-overweight and non-obese patients.

| CON CLUS ION
Noninvasive methods of lipolysis present an interesting alternative to the surgical management of fat excess. The most wellresearched modalities include cryolipolysis, radiofrequency, laser, and ultrasound therapy. The demand for these procedures has been increasing in the recent years due to less post-treatment recovery time and a relatively low risk of adverse events. These procedures do not require complicated pre-procedure preparation and patients can return to their normal activities almost immediately after treatment. Their efficacy has been reported to be high and patients' body satisfaction appear to be improving following the above-discussed procedures. However, in order to be fully effective, multiple treatments over the course of weeks or months are often required. Therefore, further research should be undertaken to enhance their clinical outcomes.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no conflict of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data openly available in a public repository that issues datasets with DOIs