Mr Arturo Almeida presents an overview of fat-dissolving injections.
Injectable methods for non-surgical fat reduction, such as mesotherapy or Lipodissolve1 have been researched for over two decades. After initial enthusiasm, these fat-reduction therapies lost popularity due to lack of controlled studies and unwanted side effects.2 Recently, however, the availability of new formulations, most of them based on deoxycholic acid, has produced an increase in their demand, particularly following the US Food and Drug Administration’s (FDA) approval of one of them in 2015, ATX-101, for reduction of submental fat.3
At the end of the 1980s, an Italian doctor began to use a mesotherapy preparation containing phosphatidylcholine (PC) for the infiltration of xanthelasmas. He achieved satisfactory results and presented his method at the 5th International Mesotherapy Congress in Paris in 1988.4 In 1995, Brazilian dermatologist Dr Patricia Rittes treated her lower eye pads with injections of PC (although this is not advised, as she performed the treatment herself). The product Dr Rittes used was Lipostabil Endovena, which was marketed in Europe, South America and South Africa and was originally developed to treat fat embolism after trauma.2 The active principle was PC with a small percentage of sodium deoxycholate (SDC) to act as a detergent, as PC is not water soluble.7 She reported good results, so started to treat patients with unwanted fat deposits, publishing her results in a 2001 peer-reviewed journal.5 This was followed by articles in popular magazines in the US6 and other countries, focusing on people who succeeded in having fat deposits, such as cellulite, back rolls and lower eyelid fat herniation, eliminated with ‘miraculous’ injections. However, despite its rampant use in Brazil, Lipostabil was banned for cosmetic use in December 2002 by ANVISA, the Brazilian equivalent to the FDA in the US. The FDA and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK subsequently issued strong warnings against its cosmetic use as there were no clinical trials supporting its efficacy.8,9
The description by Rotunda et al.10 and other authors11-12 on the pharmacologic effect of SDC originated an increased interest in this substance, and subsequently, a range of products became available in the market. SDC is a secondary bile acid and therefore, its role in the bile is to emulsify the fat to ease its digestion. SDC acts as a detergent, resulting in compromising the phospholipid bilayer and leading to cell lysis. SDC behaves as an ionic detergent, disrupting the cellular membrane by introducing their polar hydroxyl groups into the hydrophobic core of the bilayer. This will lead to solubilisation of the membrane-associated proteins, and the cell membrane finally collapses into mixed micelles of phospholipids and detergent molecules.12 However, one of the main problems with SDC is the lack of specificity regarding the detergent activity. In the past, aqueous solutions of SDC were used through mesotherapy, and a number of cases of skin necrosis were reported.13 In vitro experiments revealed that mature adipocytes were more resistant to detergent-induced cellular lysis than other cell types, therefore raising concerns about the safety of using this substance in the fat compartment.14 Further studies showed that SDC is more effective if there is a lower protein content in the cell, as is the case for adipocytes (less than 5% protein content).15
One of the first SDC-containing products available in the EU market was a galactose-buffered, gelatinous substance known as Motolese’s solution or Aqualyx.16 It was released in 2008 and became available in the UK in 2014. Aqualyx was originally CE marked as a Class III medical device to be used as an adjuvant to ultrasound cavitation therapy;27 although, this CE mark is currently under review for non-medical reasons that are beyond the remit of this article, and therefore its use is regarded as off-label.
Other brands have also become available in the UK market, such as DesoBody/DesoFace or Celluform and Celluform Plus. They all have SDC in common, and differ in the concentration of SDC present per millilitre and/or the association with other substances.
The product that really has raised the awareness about these group of fat-dissolving agents is ATX-101, known as Kybella in the US Market and Belkyra in Canada and the EU.17 It was approved by the FDA as a first-in-class injectable drug for improvement in appearance of moderate to severe convexity or fullness associated with submental class.2 Its efficacy and clinical safety has been confirmed in four large Phase 3 trials, two conducted in Europe and two in the US and Canada.18-19 Although it is not yet available in the UK (at the time of publication), the experience in other European countries seems to be promising.
In its early days, PC was thought to be the active fat-melting agent present in Lipostabil; however, its role on PC is currently unclear.
PC is the most important phospholipid in the human body, and between 40-50% of cell membranes are composed of PC so it provides the main structural support.20 It is a dipolar ion with both lipophilic and hydrophilic properties, which makes it a natural emulsifier with the ability to emulsify blood lipids. It can reduce cholesterol levels to some extent, and its intravenous usage may prevent fat embolism in trauma patients or after major orthopaedic surgery.21 Although there have been several hypotheses of how PC acts as a fat dissolvent (one being that due to its emulsifying properties it can dissolve triglycerides and transport them), none of them actually explains it.12 It has also been hypothesised that the presence of PC within SDC-containing injectables help to control the detergent action of SDC.9 Another study suggests that the association of PC and SDC may regulate the expression of lipolysis-related factors, and therefore, stimulate lipolysis.22 One of the products currently available has PC in the formulation (Celluform).
Other active ingredients have been also described as fat-dissolving agents or as adjuvants to the action of SDC. L-carnitine is known to promote the transportation of fatty acids into the mitochondrial matrix of the adipocyte during the breakdown of lipids. It is available as a nutritional supplement but is present in some SDC-containing products (Sagoni Melt, which is not currently available in the UK) and mesotherapy formulations.23 Caffeine helps in the hydrolysation of triglycerides within the adipocytes. Readily available in different beverages and supplements, it is frequently used in combination within mesotherapy preparations.24
Lipolysis is the biological process for which the triglycerides (TG) are broken down into free fatty acids (FFA) and glycerol. This process can occur at both intracellular or extracellular levels. Intra-adipocyte lipolysis is carried out by hormone-dependant lipases and its goal is to use the lipid storage at the intracytoplasmic vacuole as a source for energy. The lipolytic cascade is triggered at the β-receptors by catecholamines or cortisol, and requires a second-messenger, mainly cAMP. However, at the extracellular level, lipolysis is mediated by lipoprotein lipases, both from muscular and adipocyte origin, and is responsible for the breakdown of circulating TG (in the form of chylomicrons or very-low density lipoproteins or VLDL) to FFA. This could be used as a form of energy or subsequently re-esterified as TG within the adipocyte.25 Adipocytolysis, on the contrary, is the destruction of the adipocyte cell, with the subsequent release of cell debris and TG that may, subsequently, be hydrolysed and eliminated via the lymphatic system or renal excretion.20
As mentioned above, at initial stages, the fat-dissolving properties were incorrectly attributed to PC – the main component of Lipostabil – but the research performed by Rotunda et al.10 in 2004 indicated that the real agent that actually produced the fat-dissolving effect was deoxycholic acid, the detergent used to solubilise PC.
Therefore, in light of the mechanism of action described above, what we are in fact doing when using fat injection agents (SDC) is adipocytolysis, which is the basis behind these treatments.
Fat-dissolving injections are mainly indicated to reduce and sometimes eliminate localised fat depots, which are defined as fatty areas present in normal-weight individuals that don’t go away despite intensive exercise and/or diet measures.26 Therefore, this is not a weight loss treatment, and this point should be clearly addressed to patients considering this kind of intervention. Almost any area with localised fat can be treated – in my experience the most popular are back rolls, saddle bags, ‘bra-roll’ and double chins. Another indication is for patients who present with small lumps of adipose tissue after undergoing liposuction or other surgical fat-reducing procedures.27
Fat-dissolving treatments have also been successfully used to treat lipomas; although in such cases, patients must be advised about lipoma recurrence, as the capsule cannot be eliminated.28 Undoubtedly, the occurrence of a number of scars, particularly in cases with multiple lipomatosis, is avoided. Such treatments have also been used to treat the so-called ‘buffalo hump deformity’ behind the shoulder, which may be often seen as a result of HIV-related lipodystrophy.29 The most common side effects are swelling and bruising at the treated areas. Pain or discomfort is sometimes observed, but this rarely needs treatment. Swelling must be properly addressed with patients, as it may last up to three weeks. Less commonly seen side effects are inflammatory nodules and numbness that sometimes last up to six weeks.27 Numbness has been reported more often when treating the submental area.30
Besides the normal contraindications for cosmetic treatments (such as pregnancy, lactation, acute infectious or autoimmune diseases), obesity – as mentioned earlier – is not an indication in itself. However, a bespoke treatment plan for such patients, which would include commitment to a dietary plan and exercise, can be offered and can have fantastic results, as the addition of fat-dissolving injections will speed up the volume reduction and increase their motivation to carry on with diet and exercise.
Patients without enough thickness of fat layer are not candidates for these treatments as this may increase the incidence of side effects. A minimum of 1.5cm thickness is desired,27 and this can be easily assessed by using a ‘pinch test’ (Figure 1).
Caution must be taken when treating delicate areas such as the submental, jowls and inner knee, and extensive anatomy knowledge and mastery of the technique is key to achieve the desired results and minimise unwanted side effects.31 Fat-dissolving injections are no longer indicated to treat eye fat pads. Practitioners using these treatments have to be particularly careful with patients with body dysmorphic disorder. As we all know, many of these patients have not yet been diagnosed and we should be mindful during a medical consultation to identify alert signs that may be evident.
As mentioned, in the early stages of fat-dissolving treatments, the only available technique was mesotherapy, which involves multiple intradermal or subdermal injections of small aliquots of substances. Some of the products currently available still use this method of injection but are always administered subdermally32 (Figure 2).
With the advent of new SDC-containing formulations, and in particular with Aqualyx, a technique called intralipotherapy was developed.27 The main advantage is the use of only two or three opposite injection sites per treated area (Figure 3) versus numerous injection sites with mesotherapy. As well as this, there is the possibility of releasing the adipocytolytic agent directly into the fatty tissue homogenously and at different levels, therefore reducing the occurrence of nodules or irregularities of the skin. Patients are marked and photographed in a standing position, and preferably measured, to properly document the results of the treatment. A specially-designed needle that is between 70mm and 100mm long is then inserted and a retrograde fan technique is used to treat the entire surface of tissue. A small dose of 2% lidocaine is recommended to reduce discomfort during the injection, which is almost pain-free.27,33 ATX-101 is delivered with a very specific and standardised technique at the submental level.34 Key anatomical landmarks in this area are the inferior mandibular border, the antegonial notch (a bony landmark at the anterior masseter that approximates the location of the marginal mandibular nerve) and the thyroid cartilage.31 After the submental area is marked, a 1cm injection grid is used to mark the injection sites (Figure 4). A volume of 0.2ml of product is delivered at each site, using a 30 gauge 13mm needle. A similar approach is used by other formulations, such as Celluform Plus. In all cases, several sessions are required, spaced between three to four weeks apart to allow the normal inflammatory response, which occurs as a consequence of adipocytolysis, to subsidise. Approximately three sessions are usually required. An important point to address is the mandatory need of specific training before using any of these deoxycholate-containing products. This is to ensure the proper understanding of its mechanism of action and to make sure that the treatment is accurately delivered.
Patients’ overall satisfaction is very good, although sometimes the degree of success is perceived differently by patients and practitioners. Besides the fact that practitioners have access to different evaluators such as photography, measurements and even ultrasound scans, another reason for this discrepancy is that patients often don’t remember the extent of their original concern, leading them to underestimate the results. Also, as with any aesthetic treatment, careful patient selection and proper management of expectations is key.33 In a multicentre study published on Aqualyx experience, the best results were seen on the hips, double chin and buffalo humps, and the worst results were observed on the arms and inner thighs.27 Android fat-type (abdomen and hips) shows increase responsiveness to treatment; therefore, a smaller number of sessions are required than gynoid fat-type depots (saddle bags, inner thighs and inner knee).33 In a recently published, single-centre study on the effectiveness of ATX-101 for the contouring of the neck, a statistically-significant improvement was seen in 88% of patients.35
There is enough scientific data proving the effectiveness of adipocytolytic injections to reduce unwanted fat depots. These treatments are safe, with minimum side effects and almost no interference with our patients’ daily activities. However, accurate knowledge of the mechanisms of action and proper training and certification, together with careful patient selection, are mandatory to achieve the desired outcome.
Disclosure: Mr Arturo Almeida is a UK trainer for Aqualyx and Celluform/Celluform Plus, as well as an international trainer for Sagoni Melt.
1. Mahmud K, Crutchfield III CE, Lipodissolve for body sculpting: Safety, effectiveness and patient satisfaction. J Clin Aesth Dermatol 2012; 5(10):16-19
2. Young VL. Lipostabil. The effects of phosphatidylcholine in subcutaneous fat. Aesth Surg J 2003;23(5):413-417
3. Kybella prescribing information. (Westlake CA, USA:2015) <www.accessdata.fda.gov/drugsatfda_ docs/label/2015/206333orig1s000lbl.pdf>
4. Maggiori S. Traitment mésotérapique des xanthelasmas à la phosphatidylcholine polyinsturèe (EPL). V Congrès International de Mésothérapie, Paris, 1988. Dermatologie. p. 364
5. Rittes PG. The use of phosphatidylcholine for correction of lower lid bulging due to prominent fat pads. Dermatol Surg 2001; 27: 391–2.
6. Neal, R. Burn fat away with an injection? (New York City, NY: CBS 2003) <https://www.cbsnews.com/ news/burn-fat-away-with-an-injection>
7. Lichtenberg d, Robson rj, Dennis EA. Solubilization of phospholipids by detergents: Structural and kinetic aspects. Biochem Biophys Acta 1983; 737:285-304
8. Medicine Health Regulatory Agency (MHRA). Questions and answers about Lipostabil, also markete as Flabjab; Lipomelt and Fat Away, which is being illegally promoted as a cosmetic in the UK. 14th April 2004. <webarchive.nationalarchives.gov.uk/20150110163657/http://www.mhra.gov. uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/ CON1004243>
9. Kamalpour s, Leblanc K. Injection adipolysis: Mechanisms, agents and future directions. J Clin Aesth Dermatol 2016;9(12):44-50
10. Rotunda AM, Suzuki H, Moy RL, Kolodney MS. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg 2004 July; 30: 1001–8
11. Yagima Odo ME, Cucé LC, Odo LM, Natrielli A. Action of sodium deoxicholate on subcutaneous human tissue. Local and systemics effects. Dermatolog Surg 2007;33:178-179
12. Motolese P. Phospholipids do not have lipolytic activity: A critical review. J Cosm Laser Therap 2008;10: 114-118
13. Yagima Odo ME, Cucé Lc, Odo LM et al. Action of sodium deoxycholate on subcutaneous human tissue: local and systemic effects. Dermatol Surg 2007;33:178-188
14. Janke J, Engeli S, Gorzelniak K, Luft FC, Jordan J. Compounds used for “injection lipolysis” destroy adipocytes and other cells found in adipose tissue. Obes Facts 2009;2 (1) : 36-39
15. Thuangtong R, Bentow JJ, Knopp K, et al. Tissue-selective effects of injected deoxycholate. Dermatol Surg 2010;36(6): 899-908
16. Salti G, Motolese P. Cavitational adipocitolysis with a new microgelatinous injectable for subcutaneous adipose tissue reduction: ex-vivo histological findings. Eur. J. Aesth Medicine and Dermatology 2012;2(2): 94-97
17. Dayan SH, Humphrey S, Jones DH, Lizzul PF, Gross TM et al. Overview of ATX-101 (deoxycholic acid): A non surgical approach for reduction of submental fat. Dermatol Surg 2016; 42:115S: S263-S270
18. Dayan SH, Jone DH, Carruthers J et al. A pooled analysis of the Safety and and Efficay results of a Multicenter, double-blind, randomized, placebo-controlled phase 3 REFINE-1 and REFINE-2 Trials of ATX-101, a submental contouring injectable drug for the reduction of submental fat. Plast Reconstr Surg 2014; 134 (4 Suppl 1):123
19. Jones DH, Carruthers J, Joseph JH et al. REFINE-1, a multicentre , randomized, double-blind, placebo-controlled , phase 3 trial with ATX-101, an injectable drug for submental fat reduction. Dermatol Surg 2016;42(1):38-49
20. Kramp G. Cellular and molecular biology. NY: John Wiley; 2002
21. Shepherd j. Lipids in health and disease. Biochem Soc Trans 2004;32:1051-6
22. Won TJ, Nam y, Lee HS, Chung S, et al. Injection of phosphatidylcholine and deoxycholic acid regulates gene expression of lipolysis-related factors, pro-inflammatory cytokines and hormones on mouse fat tissue. Food Chem Toxicol 2013;60:236-268
23. Hoppel C. The role of carnitine in normal and altered fatty acid metabolism. Am J Kidney Dis 2003; 41 (4 suppl 4):S4-12
24. Acheson KJ, Gremaud G, Meirim I, et al. Metabolic effects of caffeine in humans: lipid oxidation or futile cycling?. Am J Clin Nutr 2004;79:40-46
25. Santamaria-Fojo S, Dugi KA. Structure, function and role of of lipoprotein lipase in lipoprotein mechanism. Curr Opin Lipidol 1994;5:117-25
26. Pinto H. Local fat treatments: classification proposal. Adipocyte 2016;5:22-26
27. Amore R, Pinto H, Gritzalas K, Hernandez C, Skwara-Guzikowska K, Amuso D et al. Intralipotherapy: the state of the art. Plast ReconstrSurg Glob Open 2016;4:e1085
28. Rotunda AM, Ablon G, Kolodnet MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol 2005;53:973-8
29. Rausso R, Non surgical reduction of buffalo hump deformity: Case report and literature review. Eur J Aesth Medicine and Dermatology 2011;1(1): 29-34
30. Asher B, Hoffmann k, Walter p, et al. Efficacy, patient-reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for the reduction of unwanted submental fat. Results from a phase III, randomized, placebo-controlled study. J Eur Acad Dermatol Veneorol 2014;28:1707-15
31. Anatomical and clinical implications of the deep and superficial fat compartments of the neck. Plastic Reconstr Surg 2017;140:405e
32. Duncan D, Rubin JP, Golitz L, et al. Refinement of technique in injection lipolysis based on scientific studies and clinical evaluation. Clin Plast Surg 2009;36(2):195-209
33. Amore R, Amuso D, Leonardi V, Leva F, Carnovale Sibaud A, Guida A, Costa E et al. Evaluation of safe and effectiveness of an injectable solution acid deoxycholic based for reduction of localized adiposities. Plast Reconstr Surg Glob Open 2018;6:e1794
34. Jones DH, Kenkel JM, Fagien S, Glasser DA, Monheit GD, Stauffer K et al. Proper technique administration of ATX-101 (Deoxicholic acid injection): Insights from an injection practicum and roundtable discussion. Dermatolog Surg 2016; 42 (115S): S275-S281
35. Shridharani SM. Early experience in 100 consecutive patients with injection adipocytolysis for neck contouring with ATX-101 (deoxycholic acid). Dermatol Surg 2017;43:950-958