Metformin and Tirzepatide in Lipedema: Targeting Fibrosis and Inflammation Through Complementary Pathways. A Mechanistic, Translational and Therapeutic Perspective

1. Introduction

Lipedema is a chronic and progressive adipose tissue disorder characterized by a symmetrical and disproportionate accumulation of subcutaneous fat, predominantly affecting the extremities and sparing the hands and feet. The condition occurs almost exclusively in women and is frequently associated with pain, easy bruising, and functional impairment [1,2,3].

Although traditionally considered a hormonally driven disorder, emerging evidence suggests that lipedema is better understood as a complex disease involving genetic susceptibility, microvascular dysfunction, and adipose tissue dysregulation [4,5]. The condition remains significantly underdiagnosed and is often misclassified as obesity or lymphedema, delaying appropriate management [2,6]. Recent advances in molecular and genetic research have shifted the conceptual framework of lipedema from a purely endocrine-related condition toward a multifactorial disease involving alterations in vascular integrity, extracellular matrix remodeling, and genetically mediated adipogenesis [7,8]. This evolving perspective provides a more mechanistic basis for understanding disease progression and therapeutic targeting. This is a hypothesis-generating review aimed at providing mechanistic foundations to integrate the use of two pharmacological agents designed to interact and enhance their anti-inflammatory and antifibrotic effects in lipedema.

2. Literature Search Strategy

This narrative review was conducted using a structured literature search aimed at identifying relevant studies on lipedema pathophysiology and potential therapeutic mechanisms of metformin and incretin-based therapies. Searches were performed in PubMed/MEDLINE, Scopus, Web of Science, and Embase, including articles published up to March 2026.

The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to “lipedema”, “metformin”, “GLP-1 receptor agonists”, “tirzepatide”, “fibrosis”, “inflammation”, “microvascular dysfunction”, and “adipose tissue remodeling”. Boolean operators (AND, OR) were used to optimize search sensitivity.

Studies were selected based on their relevance to the biological mechanisms underlying lipedema and the pharmacological effects of the therapies discussed. Both experimental and clinical studies were considered. Additional relevant articles were identified through manual screening of reference lists.

Given the heterogeneity of available evidence and the limited number of studies specifically addressing lipedema, a qualitative and integrative approach was adopted. The selected literature was analyzed to support the development of a mechanistic and hypothesis-generating framework.

3. Current Therapeutic Limitations

Despite growing recognition of lipedema as a distinct clinical entity, current therapeutic strategies remain largely symptomatic and fail to address underlying pathophysiological mechanisms. Conservative treatments such as compression therapy, manual lymphatic drainage, and exercise may alleviate symptoms but do not modify disease progression [2,6]. Importantly, the resistance of lipedema adipose tissue to caloric restriction and weight loss highlights its biological distinction from obesity and suggests intrinsic alterations in adipocyte function and tissue remodeling [6,7]. Surgical approaches, particularly liposuction, have demonstrated sustained improvements in pain and quality of life. However, these interventions remain invasive and do not target the molecular drivers of the disease [9].

The absence of pharmacological therapies targeting genetic, microvascular, and inflammatory pathways underscores a critical unmet need and reinforces the importance of redefining lipedema within a mechanistic and translational framework.

4. Pathophysiology of Lipedema: An Integrated Model

Lipedema is increasingly understood as a disorder driven by the interplay between genetic predisposition, microvascular dysfunction, and aberrant adipose tissue remodeling. Rather than a primary disorder of fat accumulation, it represents a systemic dysregulation of adipose tissue biology influenced by vascular and molecular factors [4,5].

Genetic susceptibility plays a central role in disease development. Familial clustering and inheritance patterns consistent with autosomal dominant transmission have been widely reported, supporting a heritable component [3,5]. More recently, next-generation sequencing studies have identified multiple gene variants involved in lipid metabolism, adipogenesis, and endocrine signaling pathways, including PPARG, LIPE, INSR, and ALDH18A1 [7].

Notably, recent mechanistic evidence has suggested the presence of mutations in the PROC gene as a potentially associated factor in lipedema. Dysfunction of the Protein C–PROCR signaling axis impairs the regulation of adipogenesis through HIF-1α–mediated pathways, leading to increased adipocyte proliferation and expansion [8]. This finding represents one of the first reports suggesting a specific genetic mutation with potential association to lipedema pathogenesis.

In parallel, adipose tissue studies demonstrate hypertrophy, hyperplasia, increased macrophage infiltration, and fibrosis, along with distinct gene expression profiles, indicating a chronic inflammatory and remodeling process within the tissue [10].

Together, these findings support an integrated model in which genetic alterations drive adipocyte dysfunction, while microvascular abnormalities amplify tissue remodeling and inflammation, resulting in the progressive phenotype of lipedema, as illustrated in Figure 1.

Lipedema is conceptualized as a multifactorial disorder involving genetic predisposition, vascular and lymphatic dysfunction, chronic inflammation, and progressive adipose tissue remodeling. Genetic variants affecting adipogenesis and vascular regulation contribute to intrinsic adipose dysfunction, while endothelial alterations increase capillary permeability, leading to tissue hypoxia and inflammatory activation. This microenvironment promotes adipocyte hypertrophy, immune cell infiltration, and extracellular matrix remodeling, resulting in fibrosis. These processes form a self-perpetuating cycle linking vascular dysfunction, inflammation, and tissue remodeling, supporting lipedema as a systemic disease and providing a rationale for targeted antifibrotic and immunometabolic therapies.

5. Genetic Polymorphisms and Adipose Tissue Dysregulation

Genetic polymorphisms are increasingly recognized as key contributors to the pathogenesis of lipedema. Evidence suggests that the disease may arise from a polygenic background involving genes that regulate adipogenesis, lipid metabolism, vascular integrity, and extracellular matrix organization [4,7].

Large-scale sequencing approaches have identified deleterious variants in genes such as PLIN1, LIPE, PPARG, INSR, and PPARA, which are directly involved in adipocyte differentiation, lipid storage, and insulin signaling [7]. These findings indicate that lipedema may represent a disorder of dysregulated adipose tissue expansion driven by intrinsic molecular defects.

Additionally, polymorphisms affecting vascular and metabolic pathways may contribute to disease heterogeneity. For example, variations in genes related to estrogen receptors, such as ESR-1, have been associated with alterations in adipokine levels and inflammatory responses, although their role appears to be modulatory rather than causative [11].

Importantly, the identification of mutations in the PROC gene highlights the relevance of coagulation and endothelial signaling pathways in adipose tissue regulation. Impaired Protein C signaling disrupts adipocyte progenitor dynamics and promotes pathological adipogenesis, reinforcing the concept of lipedema as a genetically mediated disorder of tissue remodeling [8].

Ishaq et al., using large-scale gene expression profiling combined with pathway enrichment analysis, identified significant molecular alterations in lipedema-affected tissue. The resulting expression signature included genes such as ZIC1, UGT1A7, GREM1, TRIM67, BUB1, and HOTAIR, which are primarily involved in cell cycle control and cellular proliferation. These molecular changes are consistent with key pathological features of lipedema, including adipose tissue expansion, fibrosis, and chronic inflammation. Notably, BUB1 mRNA levels were markedly elevated both in lipedema tissue and in adipose-derived stem cells from individuals with lipedema. BUB1 overexpression has been widely associated with increased cellular proliferation and disruption of critical regulatory processes in various cancers. As a mitotic checkpoint kinase, BUB1 plays a central role in chromosome segregation, and its overactivation can lead to chromosomal instability, partly through enhanced histone H2A phosphorylation. The observed upregulation of BUB1 in adipose-derived stem cells from individuals with lipedema suggests that this gene may contribute to disease pathogenesis in a manner analogous to its role in oncogenesis, promoting excessive cellular proliferation and abnormal adipose tissue expansion. [12].

These findings collectively support a paradigm in which genetic polymorphisms appear to act as primary drivers of disease, influencing both adipose tissue biology and vascular function.

6. Microvascular Dysfunction and Lymphatic Impairment

Microvascular dysfunction represents a central component in the pathophysiology of lipedema and may precede adipose tissue expansion. Structural and functional abnormalities of capillaries and lymphatic vessels contribute to increased vascular permeability, interstitial fluid accumulation, and tissue hypoxia [1,4].

Endothelial dysfunction and altered angiogenesis have been described in lipedema, leading to fragile, leaky capillaries and increased susceptibility to bruising—one of the hallmark clinical features of the disease [4,5]. These vascular abnormalities promote a chronic inflammatory microenvironment that perpetuates adipose tissue remodeling.

Lymphatic impairment further exacerbates this process. Although lipedema is distinct from lymphedema, subclinical lymphatic dysfunction is frequently observed and may contribute to fluid accumulation and progressive fibrosis [1,2].

Importantly, experimental models suggest that primary defects in lymphatic or vascular integrity may act as initiating events in lipedema. Increased capillary permeability and lymphatic leakage can trigger a cascade of inflammation, adipocyte proliferation, and extracellular matrix deposition, ultimately resulting in the characteristic tissue changes of the disease [4].

Thus, microvascular and lymphatic alterations are not merely secondary phenomena but likely play a fundamental role in disease initiation and progression, interacting closely with underlying genetic factors.

7. Metformin in Lipedema

Metformin, a widely used biguanide class drug, has emerged as a promising candidate for targeting key pathophysiological mechanisms involved in lipedema, particularly fibrosis, chronic inflammation, and adipose tissue dysfunction. Beyond its classical antihyperglycemic effects, metformin exerts pleiotropic actions mediated through energy sensing pathways, immune modulation, and extracellular matrix remodeling. These properties make it particularly relevant in diseases characterized by adipose tissue remodeling and microvascular dysfunction.

7.1. Mechanisms of Action: AMPK Activation

The central mechanism underlying metformin’s effects is the activation of AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. AMPK activation leads to downstream modulation of metabolic pathways, including inhibition of lipogenesis, increased fatty acid oxidation, and improved insulin sensitivity. In adipose tissue, AMPK activation plays a crucial role in maintaining extracellular matrix (ECM) homeostasis and preventing pathological remodeling. Experimental studies demonstrate that metformin suppresses excessive ECM deposition by inhibiting the TGF-β1/Smad3 signaling pathway, which is a major driver of fibrosis and tissue stiffening [13].

Additionally, AMPK activation influences mitochondrial function and cellular stress responses, contributing to improved metabolic efficiency and reduced oxidative stress. These effects are particularly relevant in lipedema, where hypoxia and metabolic dysregulation are key components of disease progression [14].

7.2. Anti-Fibrotic Effects: TGF-β Inhibition

Fibrosis is a hallmark of dysfunctional adipose tissue and is strongly implicated in lipedema progression. Metformin has demonstrated consistent antifibrotic effects across multiple tissues, including adipose tissue, by targeting central profibrotic pathways. One of the primary mechanisms involves inhibition of TGF-β signaling, which reduces fibroblast activation, collagen deposition, and extracellular matrix accumulation [15]. In adipose tissue models, metformin decreases collagen content, inhibits lysyl oxidase–mediated cross-linking, and restores ECM flexibility [13].

Furthermore, metformin modulates additional profibrotic pathways, including integrin/ERK signaling, and reduces the expression of matrix metalloproteinases and collagen VI, key mediators of adipose tissue fibrosis [16].

Experimental models of lymphatic dysfunction also demonstrate that metformin reduces dermal fibrosis and collagen deposition while promoting lymphangiogenesis, suggesting a direct link between antifibrotic and microvascular effects [17].

Collectively, these findings support a strong antifibrotic role for metformin, making it particularly relevant in lipedema, where fibrosis contributes to tissue rigidity, pain, and disease progression.

7.3. Anti-Inflammatory and Immunometabolic Effects

Chronic low-grade inflammation is a central feature of lipedema, driven by immune cell infiltration and dysregulated cytokine signaling. Metformin exerts significant anti-inflammatory effects through both AMPK-dependent and independent pathways.

At the molecular level, metformin inhibits NF-κB signaling, a key transcription factor regulating inflammatory responses, thereby reducing the expression of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α [18,19].

In adipose tissue, metformin modulates immune cell composition by promoting a shift in macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. This shift is associated with reduced cytokine production and improved tissue homeostasis [15].

Additionally, metformin influences immune metabolism and cellular homeostasis by regulating mitochondrial function, autophagy, and oxidative stress, which are critical in controlling chronic inflammation [14].

These immunometabolic effects are particularly relevant in lipedema, where persistent inflammation contributes to adipose tissue remodeling and fibrosis.

7.4. Effects on Adipose Tissue Remodeling

Metformin plays a significant role in regulating adipose tissue structure and function, particularly in conditions characterized by hypertrophy, fibrosis, and metabolic dysfunction. Experimental evidence demonstrates that metformin reduces adipocyte hypertrophy, improves adipose tissue architecture, and enhances insulin sensitivity. These effects are largely mediated through AMPK activation and suppression of pathological ECM remodeling [13].

Metformin also reduces adipocyte apoptosis and necrosis, processes that contribute to inflammation and fibrosis in dysfunctional adipose tissue. By modulating integrin/ERK signaling and ECM dynamics, metformin restores adipose tissue plasticity and functional capacity [16].

Furthermore, its ability to reduce inflammation and fibrosis while promoting lymphatic function suggests a broader role in improving tissue perfusion and microenvironmental conditions [17].

Taken together, these findings indicate that metformin not only improves metabolic parameters but also directly targets structural abnormalities in adipose tissue, supporting its potential role as a disease-modifying therapy in lipedema.

8. Incretin-Based Therapies: GLP-1 / GIP, Tirzepatide

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GLP-1/GIP receptor agonists such as tirzepatide, have emerged as transformative agents in the treatment of metabolic diseases. Beyond their well-established effects on glycemic control and weight reduction, these agents exert pleiotropic actions on inflammation, endothelial function, and tissue remodeling, which are highly relevant to the pathophysiology of lipedema. Tirzepatide, a dual incretin receptor agonist, integrates the effects of both GLP-1 and glucose-dependent insulinotropic peptide (GIP), leading to enhanced metabolic regulation and potentially broader systemic effects compared to selective GLP-1 receptor agonists [20].

Recent evidence suggests that these therapies may act not only as metabolic regulators but also as modulators of inflammatory and fibrotic pathways, supporting their investigation as disease-modifying strategies in conditions characterized by adipose tissue dysfunction and microvascular impairment [21,22].

8.1. Metabolic Effects

Incretin-based therapies exert profound metabolic effects, including appetite suppression, delayed gastric emptying, improved insulin sensitivity, and enhanced glucose homeostasis. These mechanisms contribute to substantial and sustained weight loss, as demonstrated in large randomized clinical trials. In the SURMOUNT-1 trial, tirzepatide induced weight reductions of up to approximately 20% over 72 weeks, significantly outperforming placebo and demonstrating dose-dependent efficacy [20].

Importantly, the metabolic effects of incretin-based therapies extend beyond weight loss. Improvements in lipid metabolism, hepatic steatosis, and systemic insulin sensitivity have been consistently observed, indicating a broader role in restoring metabolic homeostasis [23].

These findings are particularly relevant in lipedema, where adipose tissue exhibits resistance to conventional weight loss strategies, suggesting that incretin-based therapies may overcome intrinsic metabolic dysfunction.

8.2. Anti-Inflammatory Effects

Chronic low-grade inflammation is a central feature of adipose tissue dysfunction, and incretin-based therapies have demonstrated significant anti-inflammatory effects through multiple mechanisms. A systematic review and meta-analysis showed that tirzepatide significantly reduces circulating inflammatory markers, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), across different populations and dosing regimens [24].

At the molecular level, GLP-1 receptor agonists modulate key inflammatory pathways, including inhibition of NF-κB signaling, reduction of oxidative stress, and suppression of pro-inflammatory cytokine production. Additionally, these agents influence immune cell function and mitochondrial activity, contributing to improved cellular homeostasis and attenuation of chronic inflammation [22].

These anti-inflammatory effects may play a critical role in lipedema, where persistent inflammation drives adipose tissue remodeling and disease progression.

8.3. Endothelial and Adipose Tissue Modulation

Endothelial dysfunction and microvascular abnormalities are key components of lipedema pathophysiology. Incretin-based therapies have demonstrated beneficial effects on vascular function, including improved endothelial nitric oxide production, reduced oxidative stress, and enhanced microvascular integrity [22].

These vascular effects are complemented by improvements in adipose tissue function. Incretin receptor agonists influence adipocyte metabolism, reduce lipotoxicity, and improve insulin signaling, contributing to a more favorable adipose tissue phenotype [23].

Furthermore, emerging evidence indicates that incretin-based therapies may exert antifibrotic effects by modulating key signaling pathways such as TGF-β/Smad and AMPK, reducing extracellular matrix deposition and fibroblast activation [21]. Incretin agonists act across multiple organ systems by simultaneously reducing inflammation, inhibiting fibrosis, and improving metabolic signaling, reinforcing their potential role in diseases characterized by fibro-inflammatory remodeling.

8.4. Potential Role Beyond Weight Loss

While weight reduction is a major therapeutic benefit of incretin-based therapies, growing evidence indicates that their clinical impact extends far beyond adiposity reduction. Cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events, improvements in renal function, and stabilization of metabolic disease, often independent of the magnitude of weight loss. This paradigm shift—from weight-centric treatment to systemic disease modulation—positions incretin-based therapies as potential disease-modifying agents rather than simple anti-obesity drugs [23].

In the context of lipedema, this distinction is particularly important. The disease is characterized not only by excess adipose tissue but also by inflammation, fibrosis, and microvascular dysfunction. Therefore, therapies that target these underlying mechanisms may offer greater clinical benefit than those focused solely on weight reduction. Although direct clinical evidence in lipedema remains limited, current data support the biological plausibility of tirzepatide as a therapeutic option. Narrative reviews highlight its potential to modulate inflammatory and metabolic pathways relevant to lipedema, although dedicated clinical trials are still lacking [25].

9. Metformin vs Incretin-Based Therapies: Complementary Mechanisms

The pathophysiology of lipedema involves a complex interplay between adipose tissue dysfunction, chronic inflammation, fibrosis, and microvascular impairment. In this context, both metformin and incretin-based therapies target key but distinct components of this pathological network, supporting a complementary rather than competitive therapeutic role. While metformin primarily acts at the level of cellular energy sensing and tissue remodeling, incretin-based therapies exert broader systemic effects involving metabolic regulation, inflammation, and vascular function. The integration of these mechanisms provides a rationale for a multimodal therapeutic strategy.

9.1. Distinct Mechanistic Targets

Metformin exerts its effects predominantly through activation of AMPK, a central regulator of cellular metabolism and energy balance. This leads to inhibition of lipogenesis, improvement in insulin sensitivity, and suppression of profibrotic signaling pathways such as TGF-β/Smad [13]. Additionally, metformin directly modulates extracellular matrix remodeling and reduces collagen deposition, positioning it as a key agent in targeting structural alterations in adipose tissue [16].

In contrast, incretin-based therapies act through receptor-mediated signaling involving GLP-1 and GIP pathways. These pathways regulate appetite, glucose homeostasis, and systemic metabolism, while also influencing intracellular signaling cascades such as cAMP, PI3K/Akt, and AMPK [21].

Thus, while metformin primarily targets intracellular metabolic and fibrotic pathways, incretin therapies act at both central (neuroendocrine) and peripheral levels, modulating systemic metabolic and inflammatory responses.

9.2. Inflammation and Immune Modulation

Both metformin and incretin-based therapies exert significant anti-inflammatory effects, but through partially distinct mechanisms. Metformin reduces inflammation by inhibiting NF-κB signaling and promoting macrophage polarization toward an anti-inflammatory M2 phenotype, leading to decreased production of pro-inflammatory cytokines such as IL-6 and TNF-α [15,19]. These effects are closely linked to AMPK activation and improved cellular energy homeostasis [14].

Incretin-based therapies also reduce systemic inflammation, as demonstrated by significant reductions in hsCRP and IL-6 levels in clinical studies involving tirzepatide [24]. Additionally, GLP-1 receptor agonists modulate immune responses by reducing oxidative stress, inhibiting inflammatory signaling pathways, and improving mitochondrial function [22]. Importantly, while metformin appears to exert stronger effects at the level of adipose tissue immune remodeling, incretin therapies may have broader systemic anti-inflammatory effects.

9.3. Fibrosis and Tissue Remodeling

Fibrosis is a central feature of lipedema progression and represents a critical therapeutic target. Metformin has well-documented antifibrotic effects, including inhibition of TGF-β signaling, reduction of collagen synthesis, and modulation of extracellular matrix turnover. It also reduces apoptosis and necrosis in hypertrophied adipocytes, contributing to improved tissue architecture [13,16]. Incretin-based therapies, although traditionally viewed as metabolic agents, have demonstrated emerging antifibrotic properties. These include inhibition of fibroblast activation, suppression of TGF-β/Smad signaling, and reduction of extracellular matrix deposition across multiple organ systems [21]. However, current evidence suggests that the antifibrotic effects of incretin therapies are more indirect and mediated through improvements in inflammation, metabolism, and oxidative stress, whereas metformin exerts more direct effects on fibrotic pathways.

9.4. Microvascular and Endothelial Effects

Microvascular dysfunction is increasingly recognized as a key driver of lipedema pathophysiology. Incretin-based therapies demonstrate significant benefits in endothelial function, including improved nitric oxide bioavailability, reduced oxidative stress, and enhanced vascular reactivity [22]. These effects contribute to improved microvascular integrity and may reduce capillary permeability and tissue edema. Metformin also exerts vascular effects, including improved endothelial function and reduced vascular inflammation, but these effects are generally secondary to its metabolic and anti-inflammatory actions [14].

Thus, incretin-based therapies may play a more prominent role in targeting the vascular component of lipedema, complementing the structural effects of metformin.

10. Integrated Therapeutic Model

Taken together, the mechanisms of metformin and incretin-based therapies can be viewed as complementary components of a unified therapeutic strategy. Metformin primarily targets fibrosis, extracellular matrix remodeling, adipose tissue dysfunction and cellular energy metabolism. Incretin-based therapies (e.g., tirzepatide) primarily target systemic metabolism and energy balance, chronic inflammation and endothelial and microvascular dysfunction.

This complementary profile suggests that combination therapy may provide synergistic benefits by simultaneously targeting structural and systemic components of lipedema. Furthermore, while incretin-based therapies may rapidly improve metabolic and inflammatory parameters, metformin may contribute to longer-term structural remodeling of adipose tissue, as illustrated in Figure 2.

This figure illustrates the complementary mechanisms of metformin and tirzepatide in lipedema. Metformin primarily acts at the adipose tissue level through AMPK activation, inhibiting TGF-β signaling, reducing extracellular matrix deposition, and suppressing local inflammation, thereby attenuating fibrosis and improving adipocyte function. In contrast, tirzepatide exerts systemic effects via GLP-1/GIP receptor signaling, enhancing metabolic regulation, reducing systemic inflammation, and improving endothelial function and vascular integrity. The convergence of these pathways supports reduced inflammation and fibrosis, improved microcirculation, and preservation of adipose tissue function. Together, these agents represent a complementary therapeutic strategy targeting both local and systemic drivers of lipedema, supporting a disease-modifying approach.

11. Clinical Implications

The integration of metformin and incretin-based therapies represents a shift toward a mechanism-based treatment paradigm in lipedema. Rather than focusing solely on symptom control or weight reduction, this approach targets the underlying biological drivers of the disease.

Although direct clinical evidence in lipedema remains limited, the convergence of mechanistic data supports the exploration of combined metabolic and antifibrotic strategies. Future clinical trials should evaluate not only changes in body composition but also biomarkers of inflammation, fibrosis, and microvascular function to better assess therapeutic efficacy.

12. Proposed Therapeutic Model

Based on the integration of current pathophysiological and pharmacological evidence, lipedema can be conceptualized as a disease driven by the interaction between genetic susceptibility, microvascular dysfunction, chronic inflammation, and progressive fibrosis [4,5,7]. This multifactorial nature supports the development of a multimodal therapeutic model targeting distinct but interconnected biological pathways.

Within this framework, metformin and incretin-based therapies occupy complementary roles. Metformin acts primarily at the tissue level, targeting adipose dysfunction and fibrosis through AMPK activation and inhibition of TGF-β–mediated signaling. These effects contribute to reduced extracellular matrix deposition, improved adipocyte function, and attenuation of structural tissue remodeling [13,16].

In contrast, incretin-based therapies exert systemic effects, including regulation of energy balance, reduction of chronic inflammation, and improvement of endothelial function. Dual incretin agonists such as tirzepatide enhance metabolic homeostasis while also modulating inflammatory and vascular pathways, which are central to lipedema pathophysiology [20,22].

This dual approach allows simultaneous targeting of structural alterations (fibrosis, ECM remodeling) — predominantly influenced by metformin and systemic dysregulation (inflammation, metabolism, endothelial dysfunction) — predominantly influenced by incretin therapies.

Importantly, microvascular dysfunction may represent a key intersection between these pathways. Incretin-based therapies improve endothelial integrity and vascular signaling, while metformin contributes indirectly through reduction of inflammation and oxidative stress [14,22]. Thus, a combined therapeutic model may interrupt the self-perpetuating cycle of adipose expansion → hypoxia → inflammation → fibrosis → vascular dysfunction, which underlies disease progression [4]. This integrated model supports the hypothesis that lipedema should be treated not as a localized fat disorder but as a systemic adipose tissue disease requiring multimodal intervention.

13. Clinical Implications and Future Directions

The shift toward a mechanism-based understanding of lipedema has important implications for clinical practice. Current therapeutic strategies remain largely symptomatic and fail to address the underlying biological drivers of the disease [2,6].

The incorporation of pharmacological approaches targeting inflammation, fibrosis, and microvascular dysfunction represents a potential paradigm shift. Metformin, through its antifibrotic and immunometabolic effects, may contribute to modifying tissue architecture and slowing disease progression [13,19].

Incretin-based therapies, particularly tirzepatide, offer systemic benefits that extend beyond weight reduction. Clinical trials have demonstrated substantial improvements in metabolic parameters, cardiovascular risk, and inflammatory markers, many of which occur independently of weight loss [20,23].

This is particularly relevant in lipedema, where adipose tissue is resistant to conventional weight loss strategies and disease burden is driven by inflammation and vascular dysfunction rather than adiposity alone [2].

Despite strong mechanistic rationale, direct clinical evidence in lipedema remains limited. Most available data are extrapolated from studies in obesity, diabetes, and fibrotic diseases. Preliminary reports suggest potential benefits of incretin-based therapies, but robust clinical trials specifically targeting lipedema are lacking [25].

Future research should focus on the following:

• Randomized controlled trials...
• Identification of biomarkers...
• Patient stratification...
• Evaluation of combination therapies...

14. Conclusion

Lipedema is increasingly recognized as a complex, multifactorial disorder involving genetic predisposition, microvascular dysfunction, chronic inflammation, and progressive fibrosis. This evolving understanding challenges traditional paradigms that classify the disease primarily as a disorder of fat accumulation [4,5].

The evidence presented supports a shift toward a mechanistic and integrated therapeutic approach. Metformin and incretin-based therapies target complementary aspects of lipedema pathophysiology, with metformin acting predominantly on tissue remodeling and fibrosis, and incretin-based therapies modulating systemic metabolism, inflammation, and vascular function [13,20,21].

This dual strategy provides a biologically plausible framework for disease modification, addressing both structural and systemic components of the disease.

Although clinical evidence remains limited, the convergence of molecular, experimental, and clinical data strongly supports further investigation of these therapies in lipedema. These findings should be interpreted as hypothesis-generating rather than confirmatory. Ultimately, advancing from symptomatic management to mechanism-based intervention may represent a critical step toward improving outcomes and quality of life in patients with lipedema. This framework should be interpreted as a conceptual and hypothesis-generating model requiring clinical validation.

Author: Contributions: Conceptualization: M.F.L. and M.P.R.L.; Writing—original draft: M.F.L. and M.P.R.L.; Writing—review and editing: M.F.L. and M.P.R.L. All authors have read and agreed to the published version of the manuscript.