Compression therapy underrepresented: Critical assessment of interim LIPLEG results

Interim results of the LIPLEG study after 12 months

One year in, the evaluation reveals clear differences between surgery and conservative therapy:

• Pain reduction ≥ 2 NRS points: 68.3 % (liposuction) vs. 7.6 % (complex decongestive therapy, CDT); odds ratio 26.3; p < 0.001
• Improvement in mobility (LEFS): 70.0 % vs. 10.0 %
• Improvement in depressive symptoms (PHQ-9): 36.7 % vs. 5.0 %
• Improvement in quality of life (SF-36, especially physical component summary scale): 73.7 % vs. 13.4 %
• More adverse events: 196 vs. 32, of which 7.6 % vs. 4.5 % were serious.

These figures seem striking. However, their significance is limited by numerous methodological weaknesses, which even the G-BA points out (1).

Methodological criticisms

Compression therapy inadequately documented:

• Information on the implementation of CDT is largely missing: the type of compression device, compression class, wearing time, quality of fit and adherence were not systematically recorded.
• This raises the question of whether the control group was indeed treated in accordance with the guidelines.
• The secondary endpoint “scope of CDT” is not included in the interim analysis; robust compliance analyses are only expected in the final report.
• Prescription data alone do not provide meaningful information.

Asymmetrical observation periods:

• In the surgery arm: measurement 12 months after the last operation
• In the CDT arm: measurement 12 months after randomisation

Result

Extended observation time in the surgery arm, which may favour outcomes this group. No detailed information is provided regarding the duration of treatment and observation.

Since endpoints were assessed 12 months after randomisation in the CDT arm and after the last operation in the liposuction arm, it can be deduced that the duration of treatment in the liposuction arm was on average five months longer than in the CDT arm.

Handling of missing data

• Primary endpoint – pain: missing data was generally considered to be a “treatment failure”.
• This method is robust, but does not allow for a differentiated evaluation.
• Secondary endpoints: no imputation; sensitivity analyses will not be pub­lished until the final report.

Safety data

• Only the number of events is reported, not the number of patients affected.
• It remains unclear according to which criteria certain events were excluded from the analysis.
• Information on repeat procedures and long-term effects is currently lacking.
• Overall, more adverse events occurred in the surgery arm.

Study protocol and research question

The published study protocol (3) describes a multicentre, investigator-blind, randomised trial comparing liposuction with CDT. However, closer analysis reveals further points of criticism that go be­yond those documented by the G-BA and significantly limit the scientific validity and practical relevance of the results.

1. Unclear and inconsistent research question:

The wording of the research question in the study protocol is imprecise and inconsistent. No clear distinction is made between the primary investigation of the safety and efficacy of liposuction itself and the subsequent comparison of the superiority of liposuction over CDT. Take, for instance, the following wording: “safety and efficacy of liposuction and comparison of the effectiveness of liposuction vs. CDT”. The secondary outcomes aim to compare liposuction and CDT. This blending of two different research objectives compromises the scientific rigour of the study design. The assumption that liposuction is potentially superior to the established conservative form of treatment, compression therapy as part of CDT, is questionable without prior evidence and may prejudice the study results.

2. Concerns regarding the safety of liposuction

The safety of liposuction in lipoedema treatment is the subject of international debate. This is particularly evident in the report published by the National Institute for Health and Care Excellence (NICE) in the United Kingdom, which states (4): “Evidence on the safety ... is inadequate but raises concerns. Therefore, this procedure should only be used in the context of research.“ Risks mentioned include:

• Fluid imbalance
• Fat embolisms
• Deep vein thrombosis
• Toxicity caused by local anaesthetics

Therefore, not only is safety insufficiently proven, but there are also specific indications of potentially serious adverse events. For this reason, NICE currently recommends that liposuction only be performed as part of clinical trials.

By contrast, conservative treatment – in particular medical compression therapy (MCT/CDT) – has a well-documented and low-risk safety profile. It is well established and rightly considered the first-choice therapy.

3. Potential conflict of interest

One particular aspect concerns the authorship of the study protocol. Prof. Oliver Cornely (Cologne), one of the main authors alongside Prof. Maurizio Podda (Darmstadt), is the brother of Dr Manuel Cornely. Dr Cornely works as a surgeon, has been endorsing liposuction for many years, and also runs one of the participating study centres.

This close familial relationship between a key protocol author and a practising study physician carries the risk of a conflict of interest. Methodological decisions such as study design, selection of endpoints or recruitment could be influenced by this, at least indirectly. Influence on the sub­sequent interpretation of the results cannot be ruled out.

For a study with this kind of relevance for health policy, it is therefore essential to be transparent in disclosing these types of circumstances and to ensure neutrality through independent supervisory bodies, such as ethics committees or external monitoring boards. This is the only way to ensure that the results are interpreted in a scientifically sound manner and free from conflicts of interest.

4. Questionable investigator blinding

The protocol specifies an investigator-blind study design. In practice, however, it is questionable whether this blinding can be effectively maintained. The main problems are:

• Visible surgical scars
• Changes in body contours

Such characteristics may reveal group allocation even to inexperienced investigators. This is particularly critical in the case of subjective endpoints such as pain, quality of life or mobility, as even subtle distortions in perception can influence the results.

To reduce this risk, supplementary measures would be useful, such as standardised photo documentation with evaluation by independent, blinded experts or the use of objective measuring instruments such as movement analyses or digital activity trackers. Without such additional measures, investigator blinding remains methodologically questionable.

5. Methodological weaknesses in study design

Although the interim results provide clear signals, several methodological aspects limit their significance. The most important points are outlined below.

5.1 Randomisation

The 2:1 allocation in favour of surgery reduces the statistical power and precision of estimates in the CDT group. Although stratification was performed according to stage and centre, there is no stratification by pain level.

Consequences

• Lower statistical power in the CDT group
• Increased risk of bias due to lack of stratification by pain level

5.2 Recruitment

The predominantly online-based recruitment entails a risk of selection bias. It is plausible that the study predominantly enrolled patients who were highly motivated to undergo liposuction and actively sought this option.

Consequences

• Overrepresentation of women with a preference for surgery
• Limited external validity, as the study population is not representative of the overall population of patients with lipoedema

5.3 Prior treatment and inclusion criteria

The study protocol does not provide detailed information on previous conservative therapy. Neither the type nor the duration of the measures are described in detail, nor is the adherence of the patients.

In addition, patients who had been documented as experiencing insufficient symptom relief when undergoing conservative therapy were also explicitly included. Methodologically, this is problematic: on the one hand, it remains unclear whether the prior treatment was carried out in accordance with guidelines or whether it may have been suboptimal. On the other hand, this inclusion criterion creates a bias against CDT, as patients with negative experiences of conservative therapy were included in the study.

Consequences

• A lack of comparability between groups due to unclear documentation of the type and duration of and adherence to previous treatment
• Bias in favour of liposuction, as the control group is unilaterally disadvantaged
• It remains to be seen whether optimised conservative treatment could achieve similar effects to surgery

5.4 Definition of stages 

The study protocol uses classification according to lipoedema stages. While these stages have not become completely insignificant in the current guidelines (2), but they have clearly been relegated to the background. The reason for this is that they are often confused with severity classifications and are therefore not recommended as a primary criterion in practical care.

In addition, the clinical relevance of the stages is limited: patients with only slight disproportionate fat tissue growth can develop considerable pain, while patients with significant disproportionate fat tissue growth can sometimes be significantly less symptomatic. Pain and morphological appearance do not necessarily progress in parallel.

Consequences

• The use of stages in the study design complicates the clear interpretation of the results.
• It may give the impression of a severity classification, which is deliberately relativized in the current guidelines.
• Subgroup analyses based on stages are only of limited significance and may distort practical relevance.

5.5 Definition of conservative therapy 

The CDT described in the protocol is no longer consistent with current guidelines. Technically, this refers to “CDT” with its five well-known components (manual lymphatic drainage, compression, exercise, skin care, education). However, this therapy is the standard treatment for lymphoedema – not lipoedema.

The new S2k guidelines make the following clarification (2): lipoedema is neither an oedema disorder nor a clinical condition involving venous or lymphatic dysfunction. The fact that the control group in the LIPLEG study is neverthe­less being treated with “decongestive therapy” is therefore fundamentally questionable. 

In addition, key conservative elements that are explicitly highlighted in the guidelines have not been consi­dered, including:

• Psychosocial therapy
• Weight management, including surgical options for obesity

Each of these two pillars is given its own separate chapter in the current guidelines. In other words: in the LIPLEG study, liposuction was not compared with a contemporary conservative therapy, but with a method that is considered outdated in essential aspects.

5.6 Standardisation of CDT

Binding specifications regarding the type, length and class of compression, duration of wear, fit quality, patient education and exercise therapy are missing. Adherence is not being recorded systematically either.

Consequences

• Unclear implementation quality
• Limited comparability of the groups

5.7 Treatment-experienced patients:

Another methodological problem is that the study included treatment-experienced patients, i.e. women who had previously received conservative treatment with CDT.

This has several consequences: on the one hand, these patients often have negative preconceptions about undergoing another course of CDT. Those who feel that they have already “tried everything” but are still experien­cing symptoms tend to be sceptical about conservative treatment and favour surgery. On the other hand, it remains unclear what the previous treatments actually looked like:

• Were the conservative measures carried out in accordance with guidelines?
• How long did they last and how intense were they?
• What was the situation regarding adherence?

Without precise documentation of these points, it is impossible to assess whether the patients actually received adequate conservative treatment or whether the previous treatments were in fact sub­optimal.

Consequences

• The inclusion of patients with pre­vious treatment experience creates a selection and expectation bias to the detriment of CDT.
• It is likely that these women consider surgery to be the only remaining solution.
• There is a risk that the superiority of liposuction appears exaggerated in the study results, even though part of the effect is due to inadequate or incomplete prior treatment.

6. Problematic definition and measurement of endpoints

The endpoint rationale of the LIPLEG study has several weaknesses. These relate to the primary endpoint, pain, and the selection and validity of the secon-dary endpoints, as well as the inclusion and exclusion criteria.

6.1 Primary endpoint “pain”

Pain was defined as the primary endpoint. How­ever, it remains unclear which type of pain should be recorded – pain at rest, pain on exertion or pressure pain. This lack of clarity weakens the significance. In addition, pain medication is not systematically documented. Analgesics can significantly influence the outcome and must therefore be considered.

Consequences

• Reduced clinical significance of the primary endpoint
• High risk of distortion due to failure to record analgesics.

6.2 Secondary endpoints 

Instruments such as SF-36, DLQI and WHOQOL-BREF/WHO-QOL-10 are used as secondary endpoints. These questionnaires are internationally established and measure general quality of life, which, however, is strongly affected by external appearance and body weight.

In lipoedema in particular, this results in a significant bias: many patients suffer greatly from the fact that their body proportions do not correspond to the common societal body ideal. The noticeable disproportionate distribution of fat is often stigmatised in society and leads to consider­able psychological pressure (2). If adipose tissue is surgically removed and a patient’s external appearance is brought closer to their ideal, this effect is inevitably reflected in the questionnaire results – even if the lipoedema-specific symptoms (e.g. pain, sensitivity to pressure) have barely im­proved or not at all.

Furthermore, important psychosocial factors such as anxiety, stress or depression are not adequately considered in the instruments used. In addition, according to the new S2k guidelines, the tendency to develop haematomas, which is mentioned as a criterion in the protocol, is no longer considered a valid diagnostic feature.

Consequences

• Risk of pro-surgical bias, as cosmetic improvements may exaggerate the results of quality-of-life questionnaires
• Limited specificity of these endpoints for symptoms typical of lipoedema
• Inadequate assessment of psycho­social stress factors that are central to patients’ daily lives

6.3 Inclusion and exclusion criteria 

Some of the inclusion and exclusion criteria are contradictory or problematic:

• The criterion “average pain over four weeks” is retrospectively prone to error and somewhat imprecise.
• Inclusion in cases of “inadequate conservative therapy” reinforces negative expectations of CDT.
• The phrase “willingness and ability to take conservative measures...” favours the selection of patients who intend to undergo surgery.
• Contradiction: other oedema diseases are excluded, yet “prevalence of oedemas” is recorded as an endpoint. By definition, lipoedema does not involve fluid accumulation. The requirement “no oedema” mentioned in the flowchart (p. 7 of the study protocol) reinforces this inconsistency.
• Secondary endpoints such as body fat percentage or leg circumference can only be influenced to a limited extent by CDT, which puts the control group at a disadvantage.
• The exclusion of simultaneous arm and leg lipoedema limits the representativeness of the results.

Eating disorders should be explicitly defined as exclusion criteria, as they can significantly influence both conservative and surgical measures.

6.4 Cosmetic motivation 

Annother methodological problem concerns the question of whether the patients’ participation was actually motivated by medical complaints or whether cosmetic reasons played a significant role.

Many women with lipoedema suffer greatly from the fact that their body proportions do not correspond to the common societal body ideals. As already mentioned in section 6.2, fat distributions perceived as being disproportionate can often lead to considerable psychological distress and social stigmatisation. For many patients, this psychological strain can be at least as severe as the physical symptoms.

The study protocol stipulates that patients with primarily cosmetic motivations should be excluded. However, it remains unclear how reliably this has been verified in practice. The proposed crossover design in particular – with the option of switching from the CDT group to the surgical arm after 12 months – makes it even more 
appealing to patients who are primarily interested in liposuction.

Consequences

• Risk of patients participating whose main motivation is to conform to societal body ideals rather than to receive medical treatment for their condition
• Possible distortion of results, as improvements in quality of life may be cosmetic rather than medical in nature
• Increased expectations in favour of surgery, which affects the balance of the study

6.5 Weight criterion 

The exclusion criterion “weight ≥ 120 kg” is vague and methodologically problematic, as it is not set in relation to height or BMI. A simple weight limit can lead to incorrect inclu­sions or exclusions.

Example: a patient weighing 120 kg and measuring 165 cm in height has a BMI of approximately 44. According to current guidelines, bariatric surgery should always be considered for patients with a BMI ≥ 40, as obesity treatment takes priority in this area. Obesity surgery may be considered for individuals with a BMI of just 35 or higher if they have relevant comorbidities. 

This clear differential therapeutic recommendation is not taken into account by the simple weight criterion in the study protocol. Furthermore, liposuction is not a treatment for obesity. In fact, there is evidence to suggest that liposuction can lead to fat redistribution towards the abdominal region — an area that is particularly associated with metabolic and cardiovascular risks (5).

Consequences

• A fixed weight limit of 120 kg is not in line with guidelines and distorts patient selection.
• Patients who would normally be eligible for bariatric surgery under the guidelines are included in the study and undergo liposuction instead.
• There is a risk that this will blur the boundaries between obesity treatment and the treatment of lipoedema.

6.6 Duration of therapy

Another problem arises with regard to the different treatment durations in the two study arms:

• CDT: 12 months
• Surgery: 12–17 months (possible with multiple procedures)

The longer observation time in the surgery arm makes it difficult to fairly attribute the effects and may distort comparability.

6.7 Supplementary medications 

The protocol refers to “supplementary medications” without specifying precisely which preparations are meant by this. Accurate documentation is essential, particularly for analgesics, as they have a direct in­fluence on the primary endpoint pain.

6.8 Continued CDT after surgery

The study protocol stipulates that CDT therapy is continued even after liposuction (“CDT therapy is continued ... for progression prophylaxis”).

This is problematic in several respects:

• If both groups continue to be treated conservatively, the isolated effect of surgery is no longer distinctly measurable. It is therefore not possible to draw a clear distinction between surgical and conservative benefits.
• The justification that CDT can prevent the progression of lipoedema after liposuction is not scientifically proven.
• According to current guidelines on lipoedema and the International
• Consensus (6), obesity is a key factor in the progression of the condition – not whether compression garments are worn in addition.

Consequences

• The planned continuation of CDT after surgery obscures the results and makes it difficult to analyse the effect of the surgery accurately.
• It suggests a benefit (“progression prophylaxis”) for which there is currently no evidence.
• It therefore remains unclear what actual contribution the surgery itself makes to improvement.

6.9 Statistical analysis 

The planned analysis does not take into account any correction procedure for multiple testing in secondary or exploratory endpoints.

Consequences

• Increased risk of false-positive results
• Appropriate methods would include hierarchical testing strategies, Bonferroni correction or FDR adjustment.

7. Outstanding issues requiring further clarification 

In addition to the methodological weaknesses already outlined, there are further points that must be taken into account in the final report. They concern both the implementation of the study and its classification within the broader healthcare context.

7.1 Representativeness of the study centres 

The selection of participating study centres could influence the results. It must be examined whether the centres actually provide a representative picture of care in Germany in terms of their patient groups, their experience with conservative therapies and their surgical expertise.

7.2 Long-term effects of liposuction 

The evidence collected to date on the long-term effects of liposuction for lipoedema is weak. In order for a reliable assessment to be made, at least medium- to long-term follow-up data are required. This would include:

• Sustainability of pain reduction
• Development of quality of life
• Possible long-term effects (e.g. sensitivity disorders, fat redistribution, re-growth of adipose tissue)

7.3 Impact of obesity 

Obesity is the main factor in the progression of lipoedema. The final report should clearly outline how the study addresses this aspect and whether patients with obesity were adequately considered or assessed in a differentiated manner.

7.4 Documentation of adverse events

The recording and reporting of adverse events (AEs) and serious adverse events (SAEs) is of central importance. This is essential to properly assess the safety of liposuction. Transparent information on the frequency, severity and management of such events is essential.

7.5 Health economic evaluation

As liposuction for lipoedema incurs considerable costs, a health economic analysis is essential. This addresses issues such as:

• The costs of the surgeries (including follow-up procedures)
• The costs of conservative therapies
• Potential savings through reduced use of conservative measures after surgery
• Societal aspects such as ability to work and participation

7.6 Comparison with international recommendations

Finally, the final report should place the results in the context of international recommendations – in particular the assessments of NICE (UK) and other professional associations. This is essential to ensure that the German findings can be integrated into the international discourse.

Conclusion

The LIPLEG study was unable to provide any robust or reliable data for comparing liposuction and conservative therapy for lipoedema. On the contrary: numerous methodological weaknesses limit the significance of the findings to such an extent that the results must be interpreted with the utmost caution.

What is particularly problematic is that even the title of the study is misleading: conservative treatment – in this case CDT – was not implemented in a representative manner or in accordance with guidelines. Key components such as psychosocial therapy or structured weight management were not taken into account. This meant that, ultimately, liposuction was not compared with a modern conservative therapy, but with an outdated and inadequate concept.

The main points of criticism of the LIPLEG study are:

• Unclear definition of the primary endpoint pain and a lack of documentation of pain medication
• Secondary endpoints that are strongly influenced by external appearance and thus favour a pro-surgical bias
• Problematic inclusion and exclusion criteria that compromise represen­tativeness and comparability
• Inadequate definition and standardisation of conservative therapy (CDT), which is exaggerated in the title
• Questionable continuation of CDT after surgery without scientific evidence
• Potential conflicts of interest in authorship
• Insufficient consideration of obesity as a key influencing factor

For healthcare practice, this means:

• Liposuction should not currently be considered an established standard treatment.
• Implementation is only justified within the framework of clinical studies with high methodological quality.
• Despite its limitations, conservative treatment remains the treatment of choice, as its benefits and safety are well documented.
• Future studies must be structured more in line with guidelines, record adverse events transparently, take psychosocial factors into account and demonstrate long-term benefits.

In terms of health policy, the final report should classify the results with appro­priate caution and clearly distinguish between proven medical benefits and purely cosmetic effects. This is the only way to make an appropriate and evidence-based decision about the future role of liposuction for lipoedema.

The translation was kindly supported by eurocom e. V.