PriMera Scientific Medicine and Public Health (ISSN: 2833-5627)

Review Article

Volume 8 Issue 3

Heterogeneous Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Muscle Mass, Intramuscular Fat, and Functional Outcomes: A Systematic Review and Perspective Towards a Phenotype-Guided Framework

Tsu-Hsiang Kuo*

February 27, 2026

Abstract

Background: The therapeutic landscape for type 2 diabetes (T2D) and obesity has shifted from a glucocentric paradigm to one focused on organ protection and weight management. While Glucagon- like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now cornerstones of care, concerns regarding “iatrogenic sarcopenia” have emerged. Current evaluations often rely on Dual-energy X-ray Absorptiometry (DXA), which fails to capture muscle quality. This study aims to synthesize evidence from advanced imaging trials to clarify how these drugs remodel skeletal muscle and to propose a phenotype-guided prescribing framework.

Methods: We conducted a systematic review following PRISMA 2020 guidelines, searching PubMed, Embase, and Cochrane Library up to January 2026. We prioritized randomized controlled trials (RCTs) utilizing Magnetic Resonance Imaging (MRI) proton density fat fraction (PDFF) or Computed Tomography (CT) radiodensity (Hounsfield Units, HU) to assess myosteatosis and muscle quality, alongside functional outcomes (e.g., gait speed).

Results: Analysis of landmark trials (SURPASS-3 MRI, STEP 1, SLIM LIVER) reveals distinct remodeling patterns. Incretin-based therapies (e.g., Tirzepatide, Semaglutide) induce significant weight loss and absolute lean mass reduction. However, Tirzepatide significantly reduced muscle fat infiltration (-0.36%, p<0.0001) beyond what weight loss alone predicts, indicating a “quality optimization” effect. Despite muscle volume loss, functional metrics (gait speed) were preserved or improved, attributed to an enhanced power-to-weight ratio. Conversely, SGLT2 inhibitors (e.g., Dapagliflozin, Empagliflozin) demonstrated a “muscle-sparing” profile. Dapagliflozin increased paraspinal muscle radiodensity (+1.61 HU, p<0.01) without mass loss. Empagliflozin rapidly improved gait speed (+0.08 m/s, p<0.001) in frail older adults, suggesting bioenergetic enhancement.

Conclusions: GLP-1 RAs and SGLT2 inhibitors exert heterogeneous effects on the musculo-adipose unit. Incretins act as “Quality Optimizers” via deep lipid clearance, while SGLT2 inhibitors act as “Mass Preservers” and bioenergetic enhancers. We propose a “Cardiogeriatric Vulnerability Phenotype” framework to guide precision prescribing, ensuring metabolic benefits translate to long-term functional independence.

Keywords: Skeletal muscle quality; Myosteatosis; GLP-1 receptor agonists; SGLT2 inhibitors; Sarcopenia; Phenotype-guided therapy

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