Targeting Inflammation in Obesity and the Cardiovascular–Kidney–Metabolic (CKM) Syndrome Spectrum: A Narrative Review

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome refers to a multi-systemic condition with established pathophysiological connections between obesity, diabetes mellitus, chronic kidney disease (CKD), and cardiovascular disease (CVD). Chronic low-grade inflammation has been recognized as a common pathophysiological theme linking metabolic dysfunction to multisystem damage of the heart, kidneys, and vasculature. The aim of this narrative review is to summarize the major pharmacologic strategies that target inflammatory pathways in obesity and across the cardiovascular-kidney-metabolic (CKM) disease spectrum, including metabolic therapies with indirect anti-inflammatory effects and targeted immunomodulatory agents. SUMMARY: New therapies have markedly changed the obesity and the CKM treatment paradigm, with evidence that currently available metabolic medications confer cardiovascular and renal benefits in addition to glycemic control or weight improvement. Nutrient-Stimulated Hormone (NuSH) therapies, and sodium-glucose cotransporter-2 inhibitors (SGLT2i), work synergistically to positively modulate systemic inflammation while maintaining cardiovascular health and cardiometabolic function throughout therapy. Additionally, emerging clinical data for direct anti-inflammatory treatments, such as interleukin-1β/interleukin-6 inhibition and low-dose colchicine, have established inflammation as a modifiable cardiovascular risk factor. Furthermore, therapies that target the liver such as resmetirom, fibroblast growth factor-21 (FGF21) analogues, and peroxisome proliferator-activated receptors (pan-PPAR) agonists, have highlighted the role of the liver-adipose axis in metabolic inflammation and CKM progression. Together, both metabolic and direct anti-inflammatory therapies represent the most recent evolution of a combined approach to treating metabolic dysfunction and inflammation. This type of approach has the potential to revolutionize the prevention and treatment of CKM across the spectrum of diseases and usher in personalized medicine for obesity-related cardiometabolic diseases. However, further studies are needed to determine when these therapies should be initiated, which patients are most likely to benefit, and whether combination approaches can alter disease progression beyond the current standard of care.