Lipid-lowering therapies are key to the prevention of cardiovascular (CV) events and CV-related mortality. In guidelines on cholesterol management formulated in 2018 by American Heart Association(AHA)/American College of Cardiology (ACC), it is recommended that low-density lipoprotein cholesterol (LDL-C) be reduced by 30% or more in moderate-risk patients and by 50% or more in high-risk patients.1 However, findings from population studies suggest that rates of CV events and mortality have not declined despite substantial growth in the use of statins (an estimated 80% increase in the United States between 2002 and 2013).2,3

The authors of an article published in BMJ Evidence-Based Medicine aimed to determine the effectiveness of the risk-based approach endorsed in the AHA/ACC guidelines. In this systematic review of randomized controlled trials (RCTs), the use of statins, ezetimibe, and PCSK9 inhibitors in reducing cholesterol in moderate- and high-risk patients was examined.2

“Our systematic review of 35 randomized trials of cholesterol reduction showed that trials that achieved the [LDL-C] targets recommended by the AHA/ACC reported clinical benefit less often than trials that did not achieve these targets,” noted the review authors. The target was met in 1 of 13 RCTs, in which there was an associated decrease in mortality, and a reduction in CV events was observed in 5 of these trials. Among 22 RCTs that did not meet the LDL-C target, a mortality benefit and reduction in CV events were reported in 4 and 14 studies, respectively.

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“Furthermore, risk-based [LDL-C] targets for most primary prevention patients may lead to unnecessary treatment of patients who are at extremely low risk while failing to identify and treat relatively young patients who experience heart attacks,” noted the authors. This lack of consistent CV and mortality benefit casts doubt on the validity of the concept that LDL-C reduction reduces CVD risk.2

To glean further insights regarding this topic, we interviewed Robert DuBroff, MD, clinical professor of medicine in the division of cardiology at the University of New Mexico School of Medicine in Albuquerque and first author of this review, as well as Luke J. Laffin, MD, preventive cardiologist and medical director of cardiac rehabilitation at Cleveland Clinic in Ohio, and Megan Kamath, MD, cardiologist at UCLA Health in Valencia, California.

What are your thoughts about the points made in the paper by DuBroff, et al?

Dr Laffin: I disagree with many points in the current paper, and there are definitely more well-designed studies and papers to address the authors’ question. Overall, if risk calculators and statins are applied or used appropriately by clinicians —  ie, not as “absolutes” but as they were intended as “guidelines” — patients and physicians should be having conversations about the many potential benefits and low risk for side effects associated with statins. The current paper highlights a number of investigations with quite disparate patient populations and makes some comparisons and conclusions that are not necessarily valid.

I agree that treatment based on risk may miss certain high-risk individuals — particularly younger individuals, but I do not agree with the statement that this approach “fails to identify many high-risk patients.” Additionally, I disagree with the statement that it “may lead to unnecessary treatment of low-risk individuals.” Again, if the clinician is having an informed discussion with the patient, we should be making them aware of the absolute and relative risk reduction. This is something that we as clinicians should be doing all the time, not just indiscriminately prescribing.

Dr Kamath: The points made in this paper emphasize the importance of using the established guidelines as a catalyst for conversation between clinicians and patients regarding prevention, risk reduction, and overall risk profile. These conversations should include shared decision-making and an evaluation of individualized patient-specific circumstances that should be taken into consideration when determining therapeutic interventions. In cases where the risk profile may be uncertain, we often will utilize additional tools to help further stratify the patient, including use of the coronary artery calcium score.

If you agree that the recommended targets miss the mark, what might be a more effective approach in clinical practice?

Dr Dubroff: Following a healthy lifestyle remains the best preventive strategy. This includes no smoking, maintaining an ideal body weight, following a Mediterranean diet, and regular exercise. By focusing almost exclusively on LDL reduction, patients and clinicians may inadvertently ignore the benefits of a healthy lifestyle. In fact, there are some reports that individuals who take statin drugs often develop unhealthy dietary habits in part because they think they are protected by their statin drugs.4

Dr Laffin: I do not agree that recommended targets miss the mark. There is very high-quality evidence showing that LDL reduction results in lower risk for future atherosclerotic cardiovascular disease (ASCVD) when studied in appropriately sized and powered studies. The current paper includes some studies that were not powered to detect changes in ASCVD or mortality.

What are additional relevant treatment considerations for clinicians?

Dr Dubroff: By emphasizing the relative risk reductions of statin drugs, the clinical benefits may have been overstated. In our paper, we provide examples of the discordance between relative risk reduction and absolute risk reduction, and we encourage clinicians to use the number needed to treat calculation to facilitate informed decision-making with their patients.

Dr Laffin: One important issue not discussed or differentiated in the paper is the competing risk for comorbid conditions such as end-stage renal disease (as studied in the AURORA and 4D trials) or heart failure (as studied in the CORONA AND GISSI-HF trials).5,6 These trials were conducted in sick patients and do not demonstrate benefit with statin therapy in these populations. It may not be appropriate in these individuals to start statin therapy if they have other severe competing comorbidities (consistent with statements in the guidelines). For example, certain patients with advanced heart failure are not going to benefit from statins; this is similar for patients with end-stage renal disease. The decision must be based on a discussion between patient and physician.

Dr Kamath: One of the most important things that we can do as clinicians is to educate our patients early about the benefits of a heart-healthy lifestyle including diet, exercise, and lifestyle modifications at an early age, and to place emphasis on this concept of prevention throughout the lifespan. Utilizing a multidisciplinary team approach to engage the patient — including the patient’s primary care physician, cardiovascular specialists, and family — is often key to maintaining success.

What should be the focus of future research in this area?

Dr Dubroff: Our focus on LDL may have distracted us from researching other causes of cardiovascular disease. There is growing evidence that diets high in processed foods and high-glycemic index foods are atherogenic, as is insulin resistance. Consider that diabetics, who are at high risk for cardiovascular disease, typically have normal cholesterol levels.

Dr Laffin: Future research is ongoing to better identify young individuals at more elevated lifetime risk for ASCVD, who may not reach the 10-year pooled cohort equations  threshold for statin treatment initiation, but may derive benefit long-term and should start taking statins at an earlier age (primordial prevention).

Dr Kamath: One important area for ongoing research involves further characterizing LDL and its subtypes in order to help clinicians identify the patients who may be at the highest risk of developing CVD and stroke.

From a women’s health perspective, there is ongoing research examining the connection between pre-eclampsia and hypercholesterolemia. Research in this arena will have a key role in the ongoing efforts toward preventing cardiovascular disease in women.


  1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 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. J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003
  2. DuBroff R, Malhotra A, de Lorgeril M. Hit or miss: the new cholesterol targets. BMJ Evid Based Med. Published online August 31, 2020. doi:10.1136/bmjebm-2020-111413
  3. Salami JA, Warraich H, Valero-Elizondo J, et al. National trends in statin use and expenditures in the US adult population from 2002 to 2013: insights from the medical expenditure panel surveyJAMA Cardiol. 2017;2(1):56-65. doi:10.1001/jamacardio.2016.4700
  4. Korhonen MJ, Pentti J, Hartikainen J, et al. Lifestyle changes in relation to initiation of antihypertensive and lipid-lowering medication: a cohort studyJ Am Heart Assoc. 2020;9(4):e014168. doi:10.1161/JAHA.119.014168
  5. Nemerovski CW, Lekura J, Cefaretti M, Mehta PT, Moore CL. Safety and efficacy of statins in patients with end-stage renal disease. Ann Pharmacother. 2013;47(10):1321-1329. doi:10.1177/1060028013501997
  6. Feinstein MJ, Jhund P, Kang J, et al. Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual-level reanalysis of CORONA and GISSI-HFEur J Heart Fail. 2015;17(4):434-441. doi:10.1002/ejhf.247