Noninvasive lipolysis modalities in aesthetic medicine

Abstract

Background

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.

Aim

The aim of this study was to perform an evidence‐based review of the clinical efficacy and safety of noninvasive lipolysis modalities in fat reduction.

Materials and Methods

An evidence‐based review was performed to evaluate the scientific evidence available on the subject. Three electronic databases (PubMed, Scopus, and Embase) were searched between February and May 2022 for randomized controlled trials and observational studies performed on adult population in the last 20 years investigating the clinical outcomes of noninvasive lipolysis modalities. The selected studies were divided by modality type (cryolipolysis, ultrasound therapy, radiofrequency, and laser therapy), and the data on the efficacy and safety were extracted.

Results

In total, the search identified 55 papers which met the inclusion criteria. All four energy‐based modalities, including cryolipolysis, ultrasound therapy, radiofrequency, and laser therapy, were shown to be clinically effective in terms of both objective body measurements, such as fat layer thickness or circumference reduction, and subjective patient satisfaction. Furthermore, the abovementioned methods were proven to have a low side effect profile.

Conclusion

In conclusion, although evidence supports safety and efficacy, further well‐designed trials are needed to strengthen confidence in long‐term effectiveness and safety of noninvasive lipolysis.

INTRODUCTION

Adipose tissue constitutes 20%–28% of the total body mass, and its distribution determines its function. It is a key metabolic organ that regulates body homeostasis and provides structural support, a central energy reservoir for internal organs and a lipid storage for adaptive thermogenesis. Men and women tend to store fat in different anatomical locations. Female sex hormones contribute to 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.

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. 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 ). Cryolipolysis relies on the inherent sensitivity of adipocytes to cold temperatures. 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. Ultrasound delivers high-frequency sound waves across the skin to the subcutaneous fat and rapidly increases temperature in the target area. 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. 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.

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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.

MATERIALS AND METHODS

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. 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 high-quality 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). 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, non-randomized 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.

Strict exclusion criteria were also employed to ensure the high-quality 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.

RESULTS

The above search identified 55 papers which met the inclusion criteria. Figure  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, which grades evidence based on the study design and quality of research methodology. Due to low numbers of high-quality articles investigating other lipolysis technologies, they were not included in further analysis.

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Cryolipolysis

The above-detailed search identified 20 studies investigating cryolipolysis (Table ). 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.

TABLE 1 Summary of available studies on safety and efficacy of cryolipolysis.

Study	Level of evidence	Sample size	Follow-up time	Main outcomes	Adverse effects
Boey et al., 2013, Canada	III	n = 11	16 weeks	Site: Thigh Outcome: 20% fat layer reduction (3.3 mm) in 83% of subjects Patient satisfaction: 91%	Numbness, tenderness
Dierickx et al., 2013, Belgium	IV	n = 518	3 months	Site: Various locations Outcome: 23% fat layer thickness reduction; 86% improvement as per investigator assessment Patient satisfaction: 73%	Erythema, decreased or increased sensitivity, nodular or diffuse infiltration
Garibyan et al., 2014, USA	III	n = 11	2 months	Site: Flank Outcome: 14.9% fat layer thickness reduction (volume loss of 56.2 cc, reduction from 45.6 mm to 38.6 mm) Patient satisfaction: 82%	Erythema, oedema, decreased sensation, pain
Bernstein et al., 2014, USA	III	n = 20	12 weeks	Site: Flank Outcome: 43% improvement Patient satisfaction: N/A	Erythema, oedema, bruising, numbness, tingling
Munavalli et al., 2015, USA	III	n = 21	120 days	Site: Pseudogynecomastia Outcome: 95% reported visual improvement of pseudogynecomastia Patient satisfaction: 89% reported reduced embarrassment post-procedure	Discomfort, paraesthesia, tenderness, paradoxical hyperplasia
Stevens et al., 2015, USA	III	n = 40	4 months	Site: Lateral thigh Outcome: 2.6 mm fat layer reduction Patient satisfaction: >80%	Erythema, swelling, numbness, numbness, discomfort
Wanitphakdeedecha et al., 2015, Thailand	III	n = 20	6 months	Site: Arms, inner thighs Outcome: 0.41 and 0.72 cm circumference reduction at 3-month and 6-month follow-up Patient satisfaction: Up to 25% improvement at 3 and 6 months	Pain, erythema, dysesthesia, purpura, pain
Zelickson et al., 2015, USA	III	n = 42	16 weeks	Site: Inner thigh Outcome: 2.8 mm fat layer reduction, 0.9 cm circumferential reduction Patient satisfaction: 93%, 84% noted visible fat reduction	Erythema, swelling, numbness
Kilmer et al., 2016, USA	III	n = 60	12 weeks	Site: Submental region Outcome: 2 mm fat layer reduction Patient satisfaction: 83%	Erythema, hyperpigmentation, fullness sensation
Adjadj et al., 2017, France	III	n = 53	6 months	Site: Thigh Outcome: 2.81 and 5.63 cm circumference reduction at 3 and 6 months; 0.95 and 1.31 cm fat layer thickness reduction at 3 and 6 months Patient satisfaction: approx. 90% would recommend cryolipolysis	Erythema, post-inflammatory hyperpigmentation
Bernstein et al., 2017, USA	III	n = 14	12 weeks	Site: Submental region Outcome: 2.3 mm fat thickness reduction according to caliper measurements; reduction in fat volume of 4.82 cm3, in skin surface area of 1.29 cm2, and in fat thickness of 3.77 mm according to 3D imaging Patient satisfaction: 93%	Numbness, tingling, erythema, oedema, sharp pain, tongue tingling
Carruthers et al., 2017, Canada	III	n = 30	12 weeks	Site: Arm Outcome: 3.2 mm fat layer reduction Patient satisfaction: N/A	Erythema, oedema, numbness, tingling
Savacini et al., 2018, Brazil	III	n = 21	90 days	Site: Abdomen, flanks Outcome: 21.6% and 14.5% fat reduction in abdomen and flanks Patient satisfaction: N/A	Not analyzed
De Gusmao et al., 2020, Brazil	III	n = 26	3 months	Site: Arms, submental region, breast Outcome: 19.1% reduction in all body parts except male breast in the region of left nipple or right axillary line Patient satisfaction: N/A	Not analyzed
Hwang et al., 2020, Korea	III	n = 15	12 weeks	Site: Abdomen Outcome: 9.9% (8.4 cm2) reduction of visceral adipose tissue and 0.6% (2.8 cm2) reduction overall after single cryolipolysis; 15.6% reduction in cross-section of abdominal adipose tissue after completed treatment Patient satisfaction: N/A	Not analyzed
Jain et al., 2020, Australia	IV	n = 35	12 weeks	Site: Submental region Outcome: 22.46 cm3 and 22.30 cm3 volume reduction at 6 and 12 weeks Patient satisfaction: 54.10 on FACE-Q	Numbness, erythema, oedema
Oh et al., 2020, Korea	IV	n = 231	12 weeks	Site: Various locations Outcome: 19.2% fat reduction via pinch test and 22.8% via ultrasonography Patient satisfaction: N/A	Erythema, oedema, bruising, numbness
Rodopoulou et al., 2020, Greece	III	n = 39	3 months	Site: Submental region, lateral neck Outcome: 35.3% (7.4 mm) submental fat layer reduction; 30.51%–32.1% (5.2–5.5 mm) lateral neck fat reduction Patient satisfaction: 85%	Pain, oedema, redness, numbness and tingling
McKeown et al., 2021, UK	III	n = 28	Minimum 12 weeks	Site: Various locations Outcome: 40% (13.7 mm) skinfold thickness reduction Patient satisfaction: 88%	Not analyzed
Nishikawa et al., 2021, Japan	IV	n = 4122	6 months	Site: Abdomen, upper arm Outcome: 2.7 cm abdomen circumference reduction; 1.3 cm upper arm reduction Patient satisfaction: 3.4 for abdomen and 4.0 for upper arms (on a 5-point grade scale)	Pain, swelling, bruising, hyperpigmentation, frostbite

Radiofrequency

A cumulative sum of nine studies that examined the radiofrequency devices in fat reduction were found (Table ). 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.

TABLE 2 Summary of available studies on safety and efficacy of radiofrequency.

Study	Level of evidence	Sample size	Follow-up time	Main outcomes	Adverse effects
Boisnic et al., 2014, France	III	n = 21	3 months	Site: Abdomen Outcome: Circumference reduction from 113.4 to 111.5 cm immediately after treatment, to 111.1 cm at 1 month and to 110.7 cm at 3 months; 6 mm fat layer thickness reduction at 1 month; 1.5 kg weight loss at 3 months Patient satisfaction: N/A	“Shock”-like sensation, bruising, bloating, nausea, migraines, diarrhea, nerve spasms, stomach aches, urinary frequency
McDaniel et al., 2015, USA	III	n = 30	1 month	Site: Thigh Outcome: 3.86 cm circumference reduction Patient satisfaction: N/A	Heat sensation, erythema
Pumprla et al., 2015, Czech Republic	IV	n = 20	3 months	Site: Abdomen Outcome: 96.2–93.7 cm circumference reduction at 1 month, and to 93.3 cm at 3 months Patient satisfaction: N/A	Local skin irritation, abdominal discomfort, hyperesthesia
Park et al., 2016, Korea	III	n = 21	7 months	Site: Submental region Outcome: 1.4 and 0.9 cm circumference reduction at 1 and 6 months; 5.4 mm and 5.8 mm fat thickness reduction at 1 and 6 months Patient satisfaction: 100%	Not analyzed
Fritz et al., 2017, Germany	III	n = 13	4 years	Site: Waist Outcome: 5.88 cm circumference reduction at 1 month and 4.42 cm at 4 years Patient satisfaction: N/A	None
Sugawara et al., 2017, Japan	III	n = 14	2 months	Site: Lower face Outcome: 2.7 mL volumetric change in 92.9% of cases Patient satisfaction: 60%	Heat pain, redness
Choi et al., 2018, Korea	III	n = 24	8 weeks	Site: Abdomen Outcome: 3.48 and 5.12 cm circumference reduction at 4 and 8 weeks; 0.27 and 0.47 cm fat thickness reduction; 0.16 and 0.34 cm fat tissue depth reduction Patient satisfaction: N/A	Raised heat perception, pain
Qin et al., 2021, China	IV	n = 16	N/A	Site: Lower abdomen Outcome: 3.36, 3.01 and 2.46 cm circumference reduction after each treatment Patient satisfaction: N/A	Abdominal heat sensation, tingling, body sweating
Somenek et al., 2021, USA	III	n = 19	12 weeks	Site: Abdomen, flanks Outcome: 4.24 mm (23.8%) and 2.57 mm (22.3%) fat thickness reduction in abdomen and flanks Patient satisfaction: 64% were “extremely satisfied” and 29% were” satisfied”	Erythema, oedema, palpable nodules

Ultrasound

A total of 16 studies investigating the ultrasound body sculpting devices were identified (Table ). Across the included papers, the sample sizes of participants ranged from 12 to 180, and the follow-up periods varied between a minimum of 3 weeks to a maximum of 24 months.

TABLE 3 Summary of available studies on safety and efficacy of ultrasound.

Study	Level of evidence	Sample size	Follow-up time	Main outcomes	Adverse effects
Teitelbaum et al., 2007, USA/UK/Japan	II	n = 164	12 weeks	Site: Abdomen, flanks, thighs Outcome: 1.9 cm circumference reduction at 12 weeks (2.3 cm for abdomen, 1.8 cm for flanks and 1.6 cm for thighs); fat thickness reduction by 2.6 mm on day 14 and by 2.9 mm on day 28 Patient satisfaction: N/A	Tingling, erythema, blisters, purpuric lesions
Ascher et al., 2010, France	III	n = 25	112 days	Site: Abdomen Outcome: 2.47, 3.52, and 3.58 cm circumference reduction on day 14, 56 and 112 Patient satisfaction: 63% reported positive body change	Pain
Jewell et al., 2012, USA	II	n = 180	24 weeks	Not analyzed	Discomfort, ecchymosis, oedema
Milanese et al., 2014, Italy	III	n = 28	N/A	Site: Thighs, gluteal region, trunk Outcome: reduction of 2.03% in right gluteus, 1.86% in left gluteus, 2.79% in right thigh and 2.78% in left thigh; whole body fat mass reduction of 3.48%, trunk 3.97%, 3.86% left leg and 2.62% right leg Patient satisfaction: N/A	Rubor
Shek et al., 2014, China	III	n = 12	12 weeks	Site: Waist Outcome: 2.1 cm circumference reduction at 12 weeks Patient satisfaction: 8.3%	Pain 5.7/10
Tonucci et al., 2014, Brazil	III	n = 20	2 months	Site: Waist, abdomen, umbilical region Outcome: 1.5 cm reduction in waist circumference, 2.1 cm in abdominal circumference and 1.9 cm in umbilical circumference Patient satisfaction: Moderate	Burning, discomfort, pain, tingling, blisters
Moravvej et al., 2015, Iran	III	n = 28	3 weeks	Site: Abdomen Outcome: 1.89 cm circumference reduction for each session and 8.21 total reduction Patient satisfaction: 76.2%	None
Coleman et al., 2017, USA	II	n = 126	12 weeks	Site: Midline region Outcome: 2.5 cm circumference reduction (treatments at 2-week intervals) and 3.5 cm (immediate treatment). Patient satisfaction: 3.2/5	Erythema, abdominal pain, heat sensation, bruising
Ko et al., 2017, Korea	III	n = 32	12 weeks	Site: Cheek, abdomen, thigh Outcome: 96.9%, 84.4%, and 78.1% improvement on cheek, abdomen, and thigh at 4 weeks; cheek score reduced to 90.6% at 12 weeks. Patient satisfaction: High SGAIS scores	Pain, erythema, ecchymosis
Dhillon et al., 2018, UK	III	n = 20	3 months	Site: Umbilical area, under ribs, ASIS Outcome: 2.14 cm circumference reduction at umbilicus, ASIS 1.83 cm and under ribs 2.19 cm Patient satisfaction: 89.5%	Erythema
Ferrando et al., 2018, UK	III	n = 17	90 days	Not analyzed	Erythema
Guth et al., 2018, Brazil	III	n = 24	N/A	Site: Infraumbilical region Outcome: 0.6% infraumbilical circumference reduction Patient satisfaction: N/A	N/A
Wilkerson et al., 2018, USA	III	n = 14	16 weeks	Site: Thigh Outcome: 1.6, 2.9, and 2.8 cm circumference reduction at 4, 8 and 16 weeks; fat thickness reduction of 18.49%, 20.58% and 19.23% Patient satisfaction: >90%	Erythema
Gold et al., 2019, USA	II	n = 46	16 weeks	Site: Flanks Outcome: 2.2 mm flank fat reduction of 2.2 mm at 16 weeks Patient satisfaction: N/A, but 70% investigator satisfaction at 4 weeks	Discomfort, erythema, oedema
Hong et al., 2020, Korea	III	n = 20	16 weeks	Site: Waist Outcome: 3.43 cm circumference reduction at week 8; fat reduction of 30.26 mm at week 8 and 29.32 mm at week 16 Patient satisfaction: N/A	Bruising, pain
Verner et al., 2021, Italy	III	n = 18	3 months	Site: Abdomen Outcome: 5.4 cm circumference reduction at 1 week; 5.8 cm at 1 month and 5.2 cm at 3 months Patient satisfaction: 93%	Erythema, pain

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 ). 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.

TABLE 4 Summary of studies on safety and efficacy of laser.

Study	Level of evidence	Sample size	Follow-up time	Main outcomes	Adverse effects
Maloney et al., 2009, USA	II	n = 67	2 weeks	Site: Waist, hip, thighs Outcome: 3.521 in. total circumferential reduction; reduction of 0.98 in. across the waist, 1.05 in. across the hip, and 0.85 in. and −0.65 in. across the right and left thighs at 2 weeks Patient satisfaction: N/A	Not analyzed
Caruso-Davis et al., 2011, USA	II	n = 40	4 weeks	Site: Waist Outcome: 0.4–0.5 cm loss in waist girth with each treatment; 2.15 cm cumulative girth loss after 4 weeks Patient satisfaction: N/A	Not analyzed
Jackson et al., 2012, USA	IV	n = 689	1 week	Site: Waist, hips, thighs Outcome: 1.14 in. circumferential reduction in waist (3.16%), 0.95 in. in hips (2.34%), 0.57 in. in right thigh (2.33%) and 0.61 in. in left thigh (2.53%); mean total circumferential loss 5.17 in. Patient satisfaction: N/A	Not analyzed
McRae et al., 2013, USA	IV	n = 86	1 week	Site: Waist, hips, and thighs Outcome: 2.99 in. (7.59 cm) mean loss; waist, hips, and thighs reported a reduction of −1.12, −0.769, and −1.17 Patient satisfaction: N/A	Not analyzed
Hexsel et al., 2016, USA	III	n = 25	12 weeks	Site: Abdomen Outcome: 2–3 cm circumference reduction Patient satisfaction: 80% of the participants reported treatment improved their body contour	None
Katz et al., 2017, USA	III	n = 49	12 weeks	Site: Flank Outcome: 9% at 6 weeks and 13% at 12 weeks fat reduction Patient satisfaction: 96%	Discomfort, oedema, blistering, erythema, pain, bruising, hardness
Bass et al., 2018, USA	III	n = 35	12 weeks	Site: Abdomen Outcome: 1.5 mm at 6 weeks and 2.65 mm at 12 weeks fat layer thickness reduction Patient satisfaction: 91%	Tenderness, erythema, ecchymosis, firmness
Fiala et al., 2021, USA	III	n = 26	12 weeks	Site: Abdomen Outcome: 11.8% fat reduction at 6 weeks and 21.6% at 12 weeks; over 50% of participants achieved >20% fat reduction; 6.3 mm reduction in abdominal fat thickness and 4.1 cm in abdominal circumference Patient satisfaction: 84.6%	Erythema, subcutaneous firmness
Kislevitz et al., 2021, USA	III	n = 29	12 weeks	Site: Abdomen Outcome: 4.92% (0.80 mm) fat reduction at 6 weeks and 8.55% (1.28 mm) at 12 weeks. Patient satisfaction: 2.6/4.0%–72% were “satisfied” or “very satisfied” with outcome	Pain, erythema, oedema, purpura, nodules
Yan et al., 2022, Thailand	III	n = 19	6 months	Site: Knee Outcome: 42.7, 41.9, and 41.3 cm circumference reduction at 1, 3 and 6 months; reduction to 2.0 cm at 1 month and 1.5–1.6 cm at 6 months (from 2.4 to 2.5 cm) Patient satisfaction: 17.7% at 3 months and 47.1% at 6 months rated greater than 75% improvement and were satisfied	Pain, erythema, and tenderness

Figures  and illustrate different aspects of the research outcomes, with Figure  providing a breakdown of the article distribution by level of evidence and Figure  displaying the number of articles published by country. Based on the research outcomes presented in the figures below, it can be observed that level III evidence was the most prevalent level of evidence reported in the research articles. Furthermore, the data displayed in Figure  highlights that the majority of research studies were conducted in the United States, which may reflect the dominance of American institutions in the field.

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DISCUSSION

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.

Cryolipolysis

Clinical efficacy

According to the evidence-based review above, cryolipolysis can be used in fat reduction of multiple body areas—thighs, flanks, upper arms, abdomen, lateral neck, and submental region. It was also reported to be effective in the management of pseudogynecomastia in men. Patient satisfaction was rated as high in the majority of included studies and ranged between 73% and 93%. Regrettably, comparing the objective changes observed in the selected studies is challenging because of the use of varying measurement techniques, including circumference, fat layer thickness, volume loss, cross-section of body adipose tissue, skinfold thickness, pinch test, or ultrasonography.

Safety

Due to its mechanism of action, cryolipolysis is bound to cause certain side effects. Fortunately, all adverse effects reported in the selected papers were relatively mild. The main side effects included transient erythema with oedema, numbness or tingling, and mild pain or discomfort at treatment site. No serious or delayed adverse events were described in any of the studies. Several research articles reported cases of post-inflammatory hyperpigmentation, sensory abnormalities and nodular or hyperplastic changes, some of them being prolonged. Paradoxical adipose hyperplasia (PAH) has been widely described in scientific literature and has been frequently reported as a side effect after cryolipolysis. The etiology of this phenomenon remains unknown but one theory suggests decreased adipocyte organization and increased vascularity of PAH tissue. In this evidence-based review, only one patient could not tolerate the treatment due to pain, therefore it was not completed, and one required oral analgesia. One case of frostbite was reported.

Radiofrequency

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. 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. 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—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. 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. Two cases required interruption of treatment and one participant developed a palpable nodule. All adverse reactions were transient and resolved without intervention. No serious or long-term complications were reported. In addition, there were no cases of PAH documented in any of the included studies.

Ultrasound

Clinical efficacy

Ultrasound therapy has many clinical uses but it is also increasingly utilized in lipolysis, mainly in abdomen, waist, and flanks. Out of 16 selected studies, four investigated fat reduction using the above procedure in thigh and only one analyzed the gluteal region. Interestingly, one research group evaluated the clinical efficacy of ultrasound in cheek fat reduction; 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., and the highest rate of 93% was presented by Verner et al. Therefore, there is a relatively large discrepancy between patients' subjective assessments of the treatment outcomes.

Safety

The most common side effect of ultrasound therapy was transient localized skin changes, mainly erythema, with complete self-resolution at follow-up visits. Little to no pain was also described, and no significant adverse effects were reported in selected articles. Three papers had incidences of heat sensation, mild burning or blistering, and five articles reported cases of post-procedure bruising, also known as ecchymosis. Furthermore, several studies on ultrasound lipolysis measured any elevations in blood markers—the blood results of all participants who had their blood checked remained stable; and therefore, they proved that noninvasive modalities of lipolysis have no significant impact on blood tests.

Laser

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. The outcomes were also objectively assessed and revealed a statistically significant fat reduction in abdomen, waist, flanks, hips, thighs, and—surprisingly—knees. In five studies, the results of the above treatment were maintained or even improved at 12-week follow-up. One study investigated the efficacy of laser in medial knee fat reduction. 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 and erythema. The lesser reported side effects were ecchymosis and subcutaneous firmness or nodule formation. They all denied any occurrence of serious adverse events. Disappointingly, 4 of 10 articles did not analyze the incidence of adverse effects. 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. 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 to significant heterogeneity of included studies and non-uniform measurement techniques, statistical comparison of their clinical outcomes is challenging. A randomized controlled trial by Mostafa et al. demonstrated that cryolipolysis produces a better improvement than laser treatment in the reduction of waist-hip ratio, suprailiac skin folds, and subcutaneous adipose tissue. However, another study by Eldesoky et al. showed there were no statistical differences between ultrasound and cryolipolysis with regards to waist circumference and suprailiac skinfold.

Limitations

This study relied on a relatively limited number of databases and the above evidence-based review was performed by reviewers who had to rely on self-proclaimed results, increasing the risk of consequent replication, and reproduction of findings which might have been measured inaccurately.

Due to clinical and statistical heterogeneity of the included studies, the authors were also prevented from conducting a meta-analysis. The differences in the participants or outcome measures across studies made it challenging to pool data from the included studies. Combining results would not provide a reliable overall estimate of the treatment effect. Additionally, different available devices have been used to deliver these procedures and the impact of specific devices on treatment outcomes was not considered in the analysis.

Furthermore, the vast majority of included studies were observational in design and therefore, another limitation of the methodology used in this paper included the inherent risk of bias. Even though a formal risk of bias analysis has not been performed, the reliance on observational studies limits the ability to establish causal relationships between variables, as these types of studies cannot control for all potential confounding factors. Additionally, the potential bias in the methodology might raise concerns about the accuracy and validity of the findings. This highlights the need for further research utilizing rigorous study designs.

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.

CONCLUSION

Noninvasive methods of lipolysis present an interesting alternative to the surgical management of fat excess. The most well-researched 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.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to declare.

DATA AVAILABILITY STATEMENT

Data openly available in a public repository that issues datasets with DOIs

ETHICS STATEMENT

None required.

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