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Abstract

Background: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder marked by insulin resistance, β-cell dysfunction, and progressive organ damage. The global burden of T2DM continues to rise, with over 537 million individuals affected as of 2021. Given the limitations of traditional antidiabetic therapies, there is an urgent need to explore newer agents that target underlying pathophysiological mechanisms and offer additional organ-protective benefits.
Objective: To systematically evaluate the pathophysiological mechanisms of T2DM and assess the clinical effectiveness and safety of GLP-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in its management.
Methods: A systematic review was conducted using PubMed and Google Scholar databases to retrieve relevant literature published from 2015 to 2025. A total of 143 articles were initially identified using keywords such as "GLP-1 receptor agonist," "SGLT2 inhibitor," and "T2DM pathophysiology." After applying inclusion and exclusion criteria, 42 full-text articles were selected for detailed analysis. Studies included randomized controlled trials, cohort studies, and meta-analyses evaluating therapeutic outcomes of GLP-1 RAs and SGLT2 inhibitors in adult T2DM patients.
Results: GLP-1 RAs demonstrated an average HbA1c reduction of 0.8% to 1.8% and body weight reduction of 2.5 to 6.5 kg. Tirzepatide outperformed semaglutide with an additional 6.56 kg mean weight loss. SGLT2 inhibitors lowered HbA1c by 0.5% to 1.0%, reduced systolic blood pressure by 3–6 mmHg, and body weight by 2–3 kg. Both drug classes showed significant cardiovascular and renal protective effects in patients with established comorbidities. Combination therapy further improved glycemic outcomes without increasing hypoglycemia risk.
Conclusion: GLP-1 RAs and SGLT2 inhibitors offer multifaceted benefits in T2DM by addressing core metabolic dysfunctions and reducing long-term complications. Their integration into clinical practice supports a more personalized and organ-protective approach to diabetes care.