Upfront Combination or Stepwise Escalation: Personalising LDL-C Reduction in Clinical Practice

PURPOSE OF REVIEW: Low-density lipoprotein cholesterol (LDL-C) reduction is central to the prevention of atherosclerotic cardiovascular disease. This review examines the evolving shift from goal-oriented lipid management toward an approach that prioritises the magnitude and timing of LDL-C reduction, focusing on the comparative roles of stepwise escalation and upfront combination therapy. RECENT FINDINGS: Evidence from randomised clinical trials confirms that incremental LDL-C reductions lead to proportional reductions in cardiovascular events, supporting the principles that “lower is better” and “earlier is better.” The concept of cumulative LDL-C burden further highlights the importance of early and sustained LDL-C lowering. Upfront combination therapy, typically combining statins with ezetimibe, bempedoic acid, and, when indicated, proprotein convertase subtilisin/kexin type 9 inhibitors, achieves faster and greater LDL-C reductions than statin monotherapy and improves attainment of guideline-recommended goals, particularly in very high-risk patients. Conversely, while guideline-endorsed, the traditional stepwise approach may delay optimal LDL-C reduction due to reassessment intervals and therapeutic inertia, prolonging exposure to atherogenic lipoproteins in high-risk patients. Stepwise escalation remains appropriate for patients at low to moderate cardiovascular risk, those with modest LDL-C elevations, concerns about tolerability, or where cost and access limit early use of non-statin agents. Upfront combination therapy is an effective strategy for rapid LDL-C reduction in patients at high or very high cardiovascular risk, whereas a stepwise approach remains suitable for lower-risk individuals. Optimal lipid management requires an individualised strategy that integrates cardiovascular risk, baseline LDL-C, safety, adherence, and health system considerations, rather than rigid adherence to a single therapeutic goal.