Effects of GIP and GLP-1 Analogues in Lipoedema: Discussion of Different Medical Opinions

References

1. 1
   Viana Diogo Pinto da Costa, Invitti Adriana Luckow, Schor Eduardo (2025). Tirzepatide as a Potential Disease-Modifying Therapy in Lipedema: A Narrative Review on Bridging Metabolism, Inflammation, and Fibrosis.. International journal of molecular sciences. PubMed.https://doi.org/10.3390/ijms262110741

   ▼Abstract

   Lipedema is a chronic, progressive adipose tissue disorder that affects up to 10% of women and is characterized by disproportionate lower-limb fat accumulation, pain, edema, and resistance to conventional weight-loss approaches. Its pathophysiology involves a complex interplay of adipocyte hypertrophy, chronic inflammation, extracellular matrix fibrosis, mitochondrial dysfunction, and sex steroid imbalance, highlighting the need for disease-modifying therapies. This narrative review synthesizes mechanistic, translational, and clinical evidence linking metabolic, inflammatory, and fibrotic pathways to lipedema and tirzepatide's potential therapeutic relevance. Tirzepatide, a dual GLP-1 (Glucagon-Like Peptide-1)/GIP (Glucose-Dependent Insulinotropic Polypeptide) receptor agonist, has demonstrated unprecedented efficacy in obesity and diabetes, alongside pleiotropic actions on inflammation, fibrosis, and adipose remodeling. Mechanistic studies reveal favorable effects on macrophage polarization, cytokine signaling, extracellular matrix turnover, and thermogenesis, suggesting potential relevance to lipedema biology. Translational evidence from related fibro-inflammatory conditions such as steatohepatitis and heart failure further supports its antifibrotic and immunomodulatory plausibility. Although direct clinical evidence in lipedema is lacking, the convergence of mechanistic pathways provides a strong rationale to investigate tirzepatide as a disease-modifying candidate. If future clinical studies confirm these mechanisms, tirzepatide could represent a novel metabolic-hormonal therapy capable of modifying the natural course of lipedema.
2. 2
   Ravussin Eric, Sanchez-Delgado Guillermo, Martin Corby K, Beyl Robbie A, Greenway Frank L, O'Farrell Libbey S, Roell William C, Qian Hui-Rong, Li Jing, Nishiyama Hiroshi, Haupt Axel, Pratt Edward J, Urva Shweta, Milicevic Zvonko, Coskun Tamer (2025). Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.. Cell metabolism. PubMed.https://doi.org/10.1016/j.cmet.2025.03.011

   ▼Abstract

   Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.
3. 3
   Sørlie Vilde, De Soysa Ann Kristin, Hyldmo Åsne Ask, Retterstøl Kjetil, Martins Catia, Nymo Siren (2022). Effect of a ketogenic diet on pain and quality of life in patients with lipedema: The LIPODIET pilot study.. Obesity science & practice. PubMed.https://doi.org/10.1002/osp4.580

   ▼Abstract

   Lipedema is an underdiagnosed condition in women, characterized by a symmetrical increase in subcutaneous adipose tissue (SAT) in the lower extremities, sparing the trunk. The lipedema SAT has been found to be resistant to diet, exercise and bariatric surgery, in regard to both weight loss (WL) and symptom relief. Current experience indicates that a low carbohydrate and high fat (LCHF-diet) might have a beneficial effect on weight and symptom management in lipedema. To assess the impact of an eucaloric low carbohydrate, high fat (LCHF)-diet on pain and quality of life (QoL) in patients with lipedema. Women diagnosed with lipedema, including all types and stages affecting the legs, (age 18-75 years, BMI 30-45 kg/m) underwent 7 weeks of LCHF-diet and, thereafter 6 weeks of a diet following the Nordic nutrition recommendations. Pain (visual analog scale) and QoL (questionnaire for lymphedema of the limbs), weight and body composition were measured at baseline, week seven and 13. Nine women (BMI: 36.7 ± 4.5 kg/m and age: 46.9 ± 7 years) were recruited. The LCHF diet induced a significant WL -4.6 ± 0.7 kg (-4.5 ± 2.4%),  < 0.001 for both, and reduction in pain (-2.3 ± 0.4 cm,  = 0.020). No correlation was found between WL and changes in pain at week seven (r = 0.283,  = 0.460). WL was maintained between week seven and 13 (0.3 ± 0.7 kg,  = 0.430), but pain returned to baseline levels at week 13 (4.2 ± 0.7 cm,  = 0.690). A significant increase in general QoL was found between baseline and week seven (1.0 (95% CI (2.0, 0.001)),  = 0.050) and 13 (1.0 95% CI (2.0, 0.001)  = 0.050), respectively. A LCHF-diet is associated with reduction in perceived pain and improvement in QoL, in patients with lipedema. Larger randomized clinical trials are needed to confirm these findings.
4. 4
   How-Volkman Christiane, Bernal Carter, Kruayatidee Adira, Gulia Kanika, Kabutogi Sahya, Mohammed Hanifa, Wong Michael S (2026). Painful Adipose Tissue Disorder: A Systematic Review of Interventions for Dercum's Disease.. Annals of plastic surgery. PubMed.https://doi.org/10.1097/SAP.0000000000004665

   ▼Abstract

   Dercum's disease (DD) is a rare connective tissue disorder characterized by multiple painful progressive adipose deposits. No definitive treatment for DD exists; therefore, the purpose of this study was to aggregate the current treatment options and outcomes in the literature to guide clinical decision-making regarding intervention. A comprehensive search was conducted across the selected databases, PubMed, Web of Science, and clinicaltrials.gov , for studies including at least 3 patients with DD without concurrent lipedema. Given the rarity of the pathology, descriptive analysis was primarily utilized if there were no homogenous endpoints. A total of 837 studies were extracted from the databases, of which 10 met the inclusion criteria. The majority of studied interventions included liposuction (4 studies), followed by dermolipectomy, transcutaneous electrical stimulation, cyclic pneumatic compression, and injections with either Tapencarium (RZL-012) or deoxycholic acid, and prostigmine and aminoacetic acid. One hundred ninety patients underwent these intervention types, of which 95.3% were female, with a mean age of 51.7 years and an average body mass index of 34.0 kg/m 2 . Four intervention types (liposuction, pneumatic compression, dermolipectomy, and electrical stimulation) included pain assessments utilizing a visual analog scale. All interventions demonstrated a decrease in pain scores, although the effect of electrical stimulation did not reach significance. Of the 2 studies assessing liposuction, there were significantly decreased visual analog scale scores at the following time points: 3 and 6 months, and 3 and 5 years, with nonsignificant reductions at 1 and 2 years. Dercum's disease is a rare pathology that continues to cause pain and distress in a primarily middle-aged, obese female population. Our systematic review calls for further investigation for optimal management of an often debilitating disease.
5. 5
   Atan Tuğba, Bahar-Özdemir Yeliz (2021). The Effects of Complete Decongestive Therapy or Intermittent Pneumatic Compression Therapy or Exercise Only in the Treatment of Severe Lipedema: A Randomized Controlled Trial.. Lymphatic research and biology. PubMed.https://doi.org/10.1089/lrb.2020.0019

   ▼Abstract

   Lack of diagnostic awareness of lipedema and frequent confusion with obesity or lymphedema may be an obstacle for treatment. The clinical effects of conservative treatment methods are not clearly known. This study investigated the effects of exercise-based rehabilitation combined with complete decongestive therapy (CDT) or intermittent pneumatic compression therapy (IPCT) or alone in patients with severe lipedema. Thirty-three women with severe (type 3, stage III or IV) lipedema diagnosed according to the revised-Wold criteria were randomized into three groups: Group 1 (CDT plus exercises), Group 2 (IPCT plus exercises), and Group 3 (control-exercises alone). All groups received 30 sessions of combined (aerobic, strengthening, and stretching) exercise program. In addition, there were CDT in Group 1 and IPCT in Group 2 five times a week for 6 weeks. The primary outcome measure was the limb volume measurements. The secondary outcome measures were anthropometric measurements (body weight, body mass index, waist-to-height ratio, waist-to-hip ratio), 6-minute walk test, visual analog scale for pain, fatigue severity scale, Beck Depression Inventory, and Short Form Health Survey-36 (SF-36). Thirty-one participants completed the interventions. Limb volumes ( = 0.017, ηp = 0.562 for right;  < 0.001, ηp = 0.775 for left), pain ( = 0.045, ηp = 0.199), and physical functioning subscore of SF-36 ( = 0.040, ηp = 0.465) differed significantly between treatments originating from Group 1. All programs improved outcome measurements after the intervention. However, when the difference between treatments was investigated, CDT administered in addition to the exercises has been shown to provide significant improvements in reducing limb volumes, pain, and physical function. The study was registered at the US National Institutes of Health (ClinicalTrials.gov) (NCT03924999) and available at https://clinicaltrials.gov/ct2/show/NCT03924999?term=lipedema&draw=2&rank=6.
6. 6
   Podda Maurizio, Kovacs Maximilian, Hellmich Martin, Roth Rebecca, Zarrouk Marouan, Kraus Daria, Prinz-Langenohl Reinhild, Cornely Oliver A (2021). A randomised controlled multicentre investigator-blinded clinical trial comparing efficacy and safety of surgery versus complex physical decongestive therapy for lipedema (LIPLEG).. Trials. PubMed.https://doi.org/10.1186/s13063-021-05727-2

   ▼Abstract

   Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT. LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0-10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction. The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher's exact test in a hierarchical test strategy. LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema. ClinicalTrials.gov NCT04272827. Registered on February 14, 2020. Protocol version is 02_0, December 17, 2019.
7. 7
   Lundanes Julianne, Storliløkken Gunnhild Eggen, Solem Marte Siwsdotter, Dankel Simon N, Tangvik Randi J, Ødegård Rønnaug, Holst Jens Juul, Rehfeld Jens Frederik, Martins Catia, Nymo Siren (2025). Gastrointestinal hormones and subjective ratings of appetite after low-carbohydrate vs low-fat low-energy diets in females with lipedema - A randomized controlled trial.. Clinical nutrition ESPEN. PubMed.https://doi.org/10.1016/j.clnesp.2024.11.018

   ▼Abstract

   Ketosis seems to attenuate, or prevent, the rise in both ghrelin concentrations and subjective hunger ratings that follow weight loss. However, most of the previous studies have employed very-low energy diets (VLED) and are therefore limited in terms of generalizability. To compare changes in ghrelin plasma concentrations after a low-carbohydrate (LCD) versus an isocaloric low-fat low energy diet (LED) in females with lipedema. Secondary objectives were to determine potential differences between diets in changes in satiety hormones, and subjective ratings of appetite. Females with obesity and lipedema were randomized to either an LCD (75 g carbohydrates) or low-fat diet (180 g carbohydrates) for 8 weeks. Plasma concentrations of ghrelin, peptide YY, cholecystokinin (CCK), and glucagon-like peptide 1 (GLP-1), and subjective ratings of appetite were measured in the fasting and postprandial states, pre and post intervention. 55 females (30 in LCD) were included (age 47.9 ± 11.3 years, BMI 36.8 ± 5.1 kg/m). Both LCD and low-fat groups lost weight (10.3 %, P < 0.001 and 7.3 %, P < 0.001, respectively), but the LCD lost significantly more. No within or between groups differences were found for ghrelin in the fasting state. A reduction in postprandial (tAUC) ghrelin was seen only in the LCD group (P = 0.002), and this change was significantly different from the low-fat group (P = 0.046). The LCD group also reported an increase in postprandial (both iAUC and tAUC) fullness ratings (P = 0.035 and P = 0.005, respectively), but this was not significantly different from the low-fat group (P = 0.703 and P = 0.365, respectively), despite the latter experiencing no change (P = 0.127 and P = 0.152, respectively). Conversely, only the low-fat group reported increased hunger in fasting (P = 0.046), but changes were not significantly different from the LCD group (P = 0.711). A decrease in postprandial (both tAUC and iAUC) CCK was observed in both LCD and low-fat diet groups (P ≤ 0.005 for all). Despite no changes in fasting ghrelin concentrations in either of the diet groups, a reduction in postprandial ghrelin and increased fullness was seen in the LCD group. These favorable changes in appetite in the LCD group might have contributed to the greater weight loss observed in this group. NCT04632810, Effect of Ketosis on Pain and Quality of Life in Patients With Lipedema (Lipodiet).