Contemporary non-statin therapies for dyslipidemia management: achieving current lipid targets

Current Trends in Lipid-Lowering Target Therapy

Evaluation of relative safety and therapeutic efficacy of antihyperlipidemic drug regimens used alone or in combination in cardiovascular disease: randomized controlled study

Statin monotherapy is a cornerstone of lipid-lowering therapy for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk in patients with dyslipidemia. However, many patients at moderate-to-high cardiovascular risk fail to achieve recommended LDL-C targets with statin therapy alone, prompting interest in combination lipid-lowering strategies. Ezetimibe inhibits intestinal cholesterol absorption through Niemann–Pick C1-like 1 (NPC1L1) protein inhibition and may enhance LDL-C reduction while allowing lower statin doses, potentially improving tolerability. To compare the efficacy and short-term safety of moderate-intensity rosuvastatin (10 mg) combined with ezetimibe (10 mg) versus high-intensity rosuvastatin (20 mg) monotherapy in patients with dyslipidemia. This prospective randomized controlled study included 60 patients who completed 24 weeks of follow-up after random allocation to either rosuvastatin/ezetimibe (10/10 mg) combination therapy or rosuvastatin 20 mg monotherapy. Lipid profile, liver enzymes (AST and ALT), and creatine kinase (CK) were measured at baseline and at week 24. Continuous variables were analyzed using repeated-measures general linear modeling and mixed-model ANOVA after assessment of data normality. Safety evaluation included biochemical monitoring and clinical assessment for adverse events. Both treatment groups demonstrated significant reductions in total cholesterol and LDL-C from baseline (both p < 0.001). Post-treatment LDL-C was significantly lower in the combination group than in the monotherapy group (71.83 ± 12.14 vs. 86.30 ± 23.87 mg/dL; p = 0.004), whereas reductions in total cholesterol, triglycerides, and HDL-C changes were comparable between groups. Absolute post-treatment AST and ALT values did not differ significantly between treatment groups. However, percentage increases from baseline were significantly smaller in the combination group for AST (15.38% vs. 35.71%; p = 0.015) and ALT (14.28% vs. 21.11%; p = 0.018). Importantly, mean liver enzyme values in both groups remained well below clinically significant hepatotoxicity thresholds throughout follow-up. No major adverse cardiovascular events occurred during the 24-week study period. Moderate-intensity rosuvastatin combined with ezetimibe achieved lipid-lowering efficacy comparable to high-intensity rosuvastatin while producing lower relative increases in liver enzymes over 24 weeks. These findings suggest that combination therapy represents a reasonable therapeutic alternative for selected patients requiring intensive LDL-C reduction; however, larger multicenter studies with longer follow-up are needed to establish comparative cardiovascular outcomes and overall safety. https://clinicaltrials.gov/study/NCT07313124.

NOVEL DIRECTIONS IN LIPID-LOWERING THERAPY FOR THE PREVENTION OF CARDIOVASCULAR DISEASES

Cardiovascular diseases remain the leading cause of mortality worldwide despite significant advances in preventive cardiology. Dyslipidemia is one of the most important modifiable risk factors contributing to the development and progression of atherosclerotic cardiovascular disease. While statins continue to represent the cornerstone of lipid-lowering therapy, a substantial proportion of high-risk patients fail to achieve recommended low-density lipoprotein cholesterol targets or experience recurrent cardiovascular events despite optimal treatment. Recent years have witnessed remarkable progress in the development of novel lipid-lowering agents that target different pathways of lipoprotein metabolism, offering improved efficacy and longterm cardiovascular protection. Emerging therapeutic strategies include proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, small interfering RNA (siRNA)-based therapies such as inclisiran, adenosine triphosphate citrate lyase inhibitors represented by bempedoic acid, and innovative approaches targeting lipoprotein(a), angiopoietinlike protein 3, and apolipoprotein C-III. These therapies not only achieve profound reductions in LDL-C but also address residual cardiovascular risk that persists despite intensive statin therapy. Furthermore, advances in precision medicine, genetic profiling, and artificial intelligence have facilitated individualized lipid management strategies, improving patient adherence and optimizing clinical outcomes. This review summarizes current evidence regarding novel lipid-lowering therapies, their mechanisms of action, clinical efficacy, safety profiles, and future perspectives in the prevention of cardiovascular diseases.

Beyond the Pill – The Future of LipidLowering Therapy: A 2026 Review of Novel Lipid-Lowering Agents

These agents have expanded treatment options for patients with familial dyslipidaemia, severe hypertriglyceridaemia, and persistent residual cardiovascular risk while paving the way for precision medicine.

The addition of evolocumab vs ezetimibe to statin therapy for coronary plaque regression and sd-LDL reduction in patients with ultrahigh-risk ASCVD.

BACKGROUND Despite achieving target low-density lipoprotein cholesterol (LDL-C) levels, patients with ultrahigh-risk atherosclerotic cardiovascular disease (ASCVD) continue to experience substantial residual cardiovascular risk. Small dense LDL (sd-LDL) is increasingly recognized as a key atherogenic factor. OBJECTIVE To compare the efficacy of adding evolocumab vs ezetimibe to statin therapy in promoting coronary plaque regression, and to evaluate the predictive value of sd-LDL reduction in patients with ultrahigh-risk ASCVD. METHODS In this prospective, randomized, open-label, single-center trial, 422 patients with ultrahigh-risk ASCVD and LDL-C levels ≥1.4 mmol/L despite moderate-intensity statin therapy were enrolled. Participants were randomly assigned (1:1) to receive either ezetimibe (10 mg daily) or evolocumab (140 mg every 2 weeks) in addition to statins. The primary endpoints were changes in percent diameter stenosis and the rate of plaque regression over 12 months, assessed by coronary angiography or coronary computed tomography angiography. RESULTS After 12 months, the evolocumab group showed significantly greater reductions in both LDL-C and sd-LDL compared to the ezetimibe group (P < .001). Coronary plaque regression occurred in 35.6% of patients in the evolocumab group vs 10.5% in the ezetimibe group (P < .001). Multivariable logistic regression identified the percentage reductions in both sd-LDL (adjusted odds ratio [OR]: 0.54; 95% CI: 0.32-0.86; P = .014) and LDL-C (OR: 0.63; 95% CI: 0.47-0.85; P = .002) as independent predictors of plaque regression. Discordance analysis revealed that achieving sd-LDL targets was associated with higher regression rates, regardless of LDL-C levels. A nomogram combining sd-LDL changes and baseline clinical variables demonstrated moderate predictive accuracy (area under the curve = 0.669). CONCLUSION In patients with ultrahigh-risk ASCVD, evolocumab was more effective than ezetimibe in promoting coronary plaque regression. Moreover, reductions in sd-LDL were strongly associated with plaque regression alongside reductions in LDL-C. These findings underscore the importance of targeting sd-LDL to reduce residual cardiovascular risk.

Renal Outcomes of Triglyceride-Targeting Lipid-Lowering Therapies versus Statins in Patients with CKD.

BACKGROUND Dyslipidemia, distinctly characterized by hypertriglyceridemia and impaired high-density lipoprotein cholesterol (HDL-C) metabolism in patients with chronic kidney disease (CKD), is associated with kidney disease progression. However, evidence on the renal outcomes of Triglyceride (TG)-targeting lipid-lowering therapies (LLTs), such as fibrates and niacin, often prescribed to patients with non-dialysis-dependent (NDD) CKD, is insufficient and equivocal. METHODS We designed this retrospective cohort study using a target trial emulation framework and leveraged data from a nationwide cohort of 3,562,882 US Veterans to identify incident CKD patients initiating de novo LLTs. We compared eGFR decline from baseline and the odds of rapid eGFR decline in fibrate and niacin initiators versus statin initiators using the mixed-effects model-predicted 1-year, 3-year, and 10-year eGFR slopes, adjusted for baseline covariates. We also compared the risk of major adverse kidney events [MAKE] (composite of a sustained ≥57% decrease in eGFR from baseline, sustained eGFR<15 mL/min/1.73 m2, incident end-stage renal disease, and all-cause death) using Cox proportional hazards models adjusted for baseline covariates during follow-up of up to 10 years. RESULTS Among 68,073 patients with incident CKD, 62,866 initiated de novo statin, 3,202 fibrate, or 2,005 niacin therapy. Compared to statin use, de novo fibrate initiators had slower eGFR decline (difference in 10-year slope: 0.26 mL/min/1.73 m2/year [95% CI, 0.11, 0.40], P<0.001), whereas the eGFR decline was not statistically significant in the niacin vs. statin comparison. The risk of MAKE was not significantly different in fibrate (hazard ratio, 0.94 [95% CI, 0.88, 1.01], P=0.09) or niacin (0.96 [0.89, 1.04], P=0.31) users after a median follow-up of 3.69 years. CONCLUSIONS Among patients with NDD-CKD, unlike niacin, long-term fibrate use (compared to statin use) was associated with slower eGFR decline, suggesting renoprotective effects of fibrates. Further studies are warranted to investigate whether fibrate use is beneficial for preventing other outcomes, such as adverse cardiovascular events.