Cholesterol is an essential component of the human body. It is a constituent of cell membranes and necessary for synthesis of steroid hormones and bile acids.
In excess, some forms of cholesterol, such as low-density lipoprotein cholesterol (LDL), contribute to atherosclerosis and are major risk factors for atherosclerotic cardiovascular disease (ASCVD). ASCVD is a leading cause of morbidity and mortality in persons with diabetes.
Therapies are often utilized to target an LDL reduction of 30% to 50% to achieve a roughly equivalent decrease in risk for development of ASCVD.1 This LDL target continues to be a topic of interest in clinical practice. Due to possible increased incidence of intracerebral hemorrhage and cognitive decline, questions remain as to the minimum LDL needed to maintain structural integrity and sustain normal functions of cells.2-4
In 2006, the SPARCL trial highlighted the benefit of maximally tolerated 3-hydroxy-3-methyglutaryl-CoA reductase (statin; atorvastatin 80 mg) therapy after transient ischemic attack or stroke (ischemic or hemorrhagic) without known coronary artery disease compared to placebo. Incidence of recurrent stroke was significantly lower in the statin group versus placebo, with a hazard ratio (HR) of 0.84 (95% CI, 0.71-0.99, P = 0.03). Post hoc analyses revealed a difference among patients based on stroke type. When treated with statin compared to placebo, occurrence of ischemic stroke was significantly lower (HR 0.78; 95% CI, 0.66-0.94), but a potential increased risk of hemorrhagic stroke (HR 1.66, 95% CI, 1.08-2.55) was noted, which raised concern among clinicians.3
In 2015, the OSLER trials discussed possible concern regarding cognitive impairment associated with lowering of LDL with use of a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9-I). Neurocognitive events were reported in 27 patients in the PCSK9-I group compared to 4 patients in the “standard” therapy group. Upon further analysis, it was unclear if the higher incidence of neurocognitive events was related to LDL level because these events occurred in patients across the spectrum of LDL lowering. Due to these findings, additional trials focusing on cognitive impairment outcomes were undertaken.5
The American Heart Association (AHA) published a detailed summary of the data surrounding this topic in October 2023. The scientific statement reviews the literature associated with low LDL and the impact on different outcomes, including further analyses of risk associated with various lipid-lowering therapies. Several main concepts are addressed within the statement, as follows6:
ASCVD risk is reduced, especially in patients at high risk, by lowering LDL.
Cognitive impairment, including Alzheimer disease, is not associated with low LDL or lipid-lowering therapies.
Lowering LDL decreases risk of experiencing an ischemic stroke.
In patients without established cerebrovascular disease, the risk of hemorrhagic stroke is negligible, although it was noted that more data regarding LDL lowering in patients with a history of hemorrhagic stroke are needed.
A systematic review and meta-analysis of 11 active and placebo-controlled randomized controlled trials (RCTs) comprising over 20 000 patients also supported AHA’s findings and recommendations. Average follow-up for the 11 trials was 4 years, 67% of participants were men, average age was 64.9 years, and average LDL (weighted for trial size) was 79 mg/dL and 119 mg/dL in the more intensive versus less intensive LDL-lowering groups, respectively. Recurrent stroke risk was significantly lower in the more intensive LDL-lowering group in the pooled analysis of all 11 RCTs (relative risk [RR] 0.88; 95% CI, 0.8-0.96). Hemorrhagic stroke was increased in the pooled data of 8 trials comparing more intense versus less intense LDL lowering (RR 1.46; 95% CI, 0.52-0.87), with no association identified regarding type of lipid lowering therapy.7 Lee et al7 also evaluated cognitive impairment concerns as a secondary outcome, and 2 RCTs included in the analysis showed no association with intensity of LDL lowering with statin-based therapy (RR 0.99; 95% CI, 0.74-1.33).7
A large observational cohort study completed using electronic health record data from Kaiser Permanente Northern California (KPNC) evaluating the association of high-density lipoprotein (HDL) cholesterol and LDL with dementia supported AHA’s findings as well. Enrollees ages 55 or greater that had completed a baseline survey with KPNC, had an HDL and LDL measurement within 2 years of the survey, and had not been diagnosed with dementia, Parkinson’s, or amyotrophic lateral sclerosis prior to baseline (within 2 years of the survey) were included and were followed for an average of almost 9 years.
Of the 184 367 participants included in the analyses, 55.1% were female, most participants were White (72.6%), average HDL was 53.7 mg/dL, average LDL was 108 mg/dL, and average age was 69.5 years. More than half had the diagnosis of hypertension and were taking or had taken a statin. The investigators controlled for confounders such as age, gender, education level, and many risk factors associated with the development of dementia and cardiovascular disease. Risk of dementia was associated with both high (>65 mg/dL) and low (11 mg/dL to 41 mg/dL) HDL quintiles. No association with dementia was seen across any LDL quintile. When evaluated based on statin use history, higher LDL was associated with higher risk of dementia in participants with a history of statin use but lower in those without. The authors note this should be interpreted carefully due to the potential for confounding variables.8
Based on available literature, there does not seem to be an association with intensive LDL lowering and cognitive impairment. Overall, additional data are needed to truly understand the risk of hemorrhagic stroke with low LDL.
There are several national guidelines that discuss cholesterol targets and lipid-lowering therapies. The American Diabetes Association (ADA) recommends assessing cardiovascular risk and lipids upon diagnosis of diabetes and then annually. Lipid-lowering therapy, specifically statins, are recommended for most persons with diabetes. Clinicians should initiate statin therapy associated with a 50% reduction in LDL from baseline (high intensity) and target LDL of less than 70 mg/dL in ages 40 to 79 for primary prevention and less than 55 mg/dL for secondary prevention. The ADA notes that concerns regarding lipid-lowering therapies and neurocognitive dysfunction are not currently supported by the literature and highlights the importance of their use in persons with diabetes at high risk for ASCVD.9
Diabetes care and education specialists (DCESs) can encourage persons with diabetes to maintain healthy lifestyle habits and take medications as prescribed. They need to also be prepared to answer questions presented regarding cholesterol levels and the potential health benefits of achieving recommended cholesterol goals.
As seen in the literature, no specific LDL is too low. DCESs can assuage patient fears regarding potential links of LDL and neurocognitive effects. A patient-centered approach is always needed when deciding on the use and intensity of lipid-lowering therapy but is especially important in patients at risk for hemorrhagic stroke without ASCVD.
Amanda M. Stahnke, PharmD, BCACP, is with the University of Missouri-Kansas City. Maci Foerderer, PharmD, is with Kansas City Veterans Affairs Medical Center. Kathryn M. Holt, PharmD, BCPS, is with the University of Missouri-Kansas City. All are in Kansas City, MO.
The authors declare having no professional or financial association or interest in an entity, product, or service related to the content or development of this article.
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360(9326):7-22. doi:10.1016/S0140-6736(02)09327-3
Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. doi:10.1056/NEJMoa061894
Bandyopadhyay D, Quereshi A, Ghosh S, et al. Safety and efficacy of extremely low LDL-cholesterol levels and its prospects in hyperlipidemia management. J Lipids. 2018:8598054. doi:10.1155/2018/8598054
Sabatine MS, Giuliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509. doi:10.1056/NEJMoa1500858
Goldstein LB, Toth PP, Dearborn-Tomazos, et al. Aggressive LDL-C lowering and the brain: impact on risk for dementia and hemorrhagic stroke: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2023;43:e404-e442. doi:10.1161/ATV.0000000000000164
Lee M, Cheng CY, Wu YL, Lee JD, Hsu CY, Ovbiagele B. Association between intensity of low-density lipoprotein cholesterol reduction with statin-based therapies and secondary stroke prevention: a meta-analysis of randomized clinical trials. JAMA Neurol. 2022;79(4):349-358. doi:10.1001/jamaneurol.2021.5578
Ferguson EL, Zimmerman SC, Jiang C, et al. Low- and high-density lipoprotein cholesterol and dementia risk over 17 years of follow-up among members of a large health care plan. Neurology. 2023;101:e2127-e2184. doi:10.1212/WNL.0000000000207876
American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(suppl 1):S179-S218.