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Metabolic syndrome (MetS) represents the concurrent manifestation of multiple cardiometabolic risk factors, including visceral obesity, hyperglycemia, hypertension, hypertriglyceridemia, and low HDL-cholesterol, cumulatively predisposing to accelerated atherosclerosis and type 2 diabetes mellitus (T2DM). Hypothyroidism frequently coexists with T2DM and further exacerbates insulin resistance (IR), lipid abnormalities, and systemic inflammation, increasing the prevalence and severity of MetS in this population. Oral semaglutide is a glucagon-like peptide-1 receptor agonist approved for T2DM management; however, its impact on MetS parameters in patients with coexisting hypothyroidism remains insufficiently explored. This study aimed to evaluate the effects of oral semaglutide on key MetS components in this high-risk subgroup. We conducted a single-center retrospective cohort study involving 51 adult patients with confirmed hypothyroidism and T2DM, on oral semaglutide (final dose = 14 mg daily) and monitored for 6 months. Clinical and biochemical parameters were analyzed, including glycated hemoglobin (HbA1c), body mass index (BMI), blood pressure, and lipid profile. At 6 months, mean HbA1c decreased by 6.7% (P < 0.001), BMI was reduced by 4.04% (P < 0.001), triglycerides decreased by 6.7% (P < 0.001), and HDL-C increased by 9% (P = 0.002). In this observational study, treatment with oral semaglutide was associated with improvements in several components of MetS among patients with coexisting hypothyroidism and T2DM. While these findings suggest a potential therapeutic role for semaglutide in complex metabolic profiles, they should be interpreted with caution due to the study's design limitations. Further prospective studies are warranted to confirm these observations and to explore the interaction between semaglutide and levothyroxine.