Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Type 2 diabetes mellitus (T2DM) substantially increases the risk of macrovascular complications, including coronary artery disease, cerebrovascular disease and peripheral arterial disease, which collectively represent the leading causes of morbidity and mortality among affected individuals. Evidence from clinical trials has demonstrated that intensive glycemic control alone provides limited protection against macrovascular outcomes, underscoring the need for comprehensive secondary prevention strategies. Objectives: This review aims to synthesize recent advances in integrated secondary prevention strategies for macrovascular complications in T2DM, with emphasis on pharmacological, lifestyle and personalized approaches that extend beyond glucose lowering. Methods: A narrative review of the literature published between 2015 and 2025 was conducted, including randomized controlled trials, meta-analyses, major cardiovascular outcome trials and international guideline updates. Evidence was evaluated across key domains: glycemic management, lipid lowering, blood pressure control, antithrombotic therapy, lifestyle interventions, emerging pharmacotherapies, biomarkers and digital health–based risk stratification tools. Results: Accumulating evidence supports a multifactorial approach to secondary prevention in T2DM. Sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists consistently reduce major adverse cardiovascular events, heart failure hospitalization and renal outcomes, independent of glycemic control. Optimized lipid management with statins, PCSK9 inhibitors and icosapent ethyl, along with strict blood pressure control and selective antiplatelet therapy, further lowers atherosclerotic risk. Emerging strategies targeting inflammation, endothelial dysfunction and the gut microbiota show promise. Biomarkers such as high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide and cystatin C, combined with artificial intelligence–driven risk prediction models, enable improved patient stratification and individualized therapy. Conclusion: Secondary prevention of macrovascular complications in T2DM requires an integrated, multidisciplinary strategy combining cardioprotective pharmacotherapy, lifestyle modification and personalized risk assessment. Advances in novel therapies, biomarkers and digital health technologies offer substantial potential to further improve long-term cardiovascular outcomes in this high-risk population