Hypercholesterolemia Management

Hypercholesterolemia Management: From Lifestyle Modification to Statins

Randomized clinical trials conducted over the past 20 years have consistently demonstrated that the aggressive reduction of low-density lipoprotein-cholesterol (LDL-C) with statin therapy reduces cardiovascular (CV) risk in the settings of secondary prevention and high-risk primary prevention.1 When used as an adjunct to lifestyle interventions, statin therapy can be expected to reduce the rates of major CV events (MACE) by 24% for each 1-mmol/L reduction in LDL-C (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.73–0.79), stroke by 15% (HR = 0.85; 95% CI, 0.80–0.89), and coronary revascularization by 24% (HR = 0.76; 95% CI, 0.73–0.79).2,3

Meta-analyses also demonstrate that relative risk reductions with statin therapy are not related to baseline levels of LDL-C. Rather, trial data as well as observational, ecologic, and genetic studies suggest that lower LDL-C levels are likely to confer CV benefits regardless of starting cholesterol levels for an individual patient.4-6 If anything, the greatest relative risk reductions observed with statin therapy accrue among those patients with lower rather than higher levels of absolute vascular risk. These data are consistent with the biologic view that aggressive reductions in circulating atherogenic lipids early in the disease process are likely to produce the greatest clinical benefits.7 LDL-C reduction with statin therapy has also proven highly effective for reducing vascular risk in those individuals with diabetes8 and, in some cases, can lead to regression of coronary atherosclerosis.9

However, variability in LDL-C response to statin therapy is exceptionally wide for individual patients.10 For example, in the JUPITER primary prevention trial in which all individuals received a high-intensity statin regimen, fewer than half of the subjects achieved LDL-C reductions greater than 50%; however, the magnitude of percentage change in LDL-C was directly related to subsequent event rates.11 Although the addition of ezetimibe to moderate-dose statin therapy further reduced LDL-C and clinical events in the contemporary secondary prevention IMPROVE-IT trial, the rate of recurrent vascular events in that study still exceeded 30% over the mean follow-up of 5.4 years.5 Finally, not all patients tolerate statin therapy. It is recognized that effective and safe treatments for residual cholesterol risk are needed, not only for those people with a history of CV events but also for primary prevention patients at high vascular risk.1 Significant reductions in CV events have been observed in individuals with diabetes mellitus treated with statins.12 However, real-world studies often report underutilization of statins and suboptimal dosing in high-risk patients.13,14

Additional lipid-lowering therapies that are used in conjunction with statins to address mixed dyslipidemia include ezetimibe, fibrates, nicotinic acid, and omega-3 fatty acids. Despite these treatment options, many individuals with diabetes continue to have persistent lipid abnormalities15-17 and are therefore exposed to residual CV risk.18-20


  1. Ridker PM, Amarenco P, Brunell R, et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes trials. Am Heart J. 2016;178:135-144.
  2. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.
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  12. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S103-S123.
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  14. Teramoto T, Uno K, Miyoshi I, et al. Low-density lipoprotein cholesterol levels and lipid-modifying therapy prescription patterns in the real world: an analysis of more than 33,000 high cardiovascular risk patients in Japan. Atherosclerosis. 2016;251:248-254.
  15. Wong ND, Chuang J, Zhao Y, Rosenblit PD. Residual dyslipidemia according to low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and Nutrition Examination Survey 2009–2010. J Clin Lipidol. 2015;9:525-532.
  16. Leiter LA, Lundman P, da Silva PM, et al. Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study. Diabet Med. 2011;28:1343-1351.
  17. Wong ND, Zhao Y, Patel R, et al. Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the Atherosclerosis Risk in Communities study, Multi-ethnic Study of Atherosclerosis, and Jackson Heart Study. Diabetes Care. 2016;39:668-676.
  18. Bramlage P, Lanzinger S, Rathmann W, et al. Dyslipidaemia and its treatment in patients with type 2 diabetes: a joint analysis of the German DIVE and DPV registries. Diabetes Obes Metab. 2017;19:61-69.
  19. Toth PP, Zarotsky V, Sullivan JM, Laitinen D. Dyslipidemia treatment of patients with diabetes mellitus in a US managed care plan: a retrospective database analysis. Cardiovasc Diabetol. 2009;8:26.
  20. Khavandi M, Duarte F, Ginsberg HN, Reyes-Soffer G. Treatment of dyslipidemias to prevent cardiovascular disease in patients with type 2 diabetes. Curr Cardiol Rep. 2017;19:7.
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