An LDL “cholesterol paradox” exists in patients with heart failure and raises doubt with regard to safe statin use in patients with HF without diabetes.

LDL cholesterol (LDL-C)—the most atherogenic cholesterol lipoprotein—is an established cardiovascular risk factor, and hypercholesterolemia is thought to contribute to incident HF. “Low total cholesterol levels have been consistently associated with increased mortality in patients with established HF,” explains Rita Gouveia, MD. This so-called “cholesterol paradox” has been primarily reported for total cholesterol, but little is known about whether an LDL-C paradox exists for HF. Dyslipidemia guidelines recommend a target LDL-C goal of 55 mg/dL in very-high-risk patients, but statin therapies have not been clearly associated with improved outcomes in HF.

Clear evidence on the benefits of applying stringent LDL-C limits to high-risk groups with established HF is lacking. Despite the anticipated effects of lowering cholesterol levels in HF, studies on treatment for hypercholesterolemia have had mixed results, and randomized controlled trials involving statin use in patients with HF have not shown a definite mortality benefit for this population. However, use of statins and aggressive lipid control—specifically LDL-C—is a common approach for treating hypercholesterolemia in patients with HF.

For a study published in the International Journal of Cardiology: Cardiovascular Risk Prevention, Dr. Gouveia and colleagues evaluated the prognostic impact of LDL-C in patients with HF with or without diabetes mellitus (DM). Investigators retrospectively analyzed 522 outpatients with chronic HF who had systolic dysfunction and were followed in an HF clinic for approximately 6.5 years. The average age of patients was 70, and two-thirds of the study population was men. The primary endpoint of the study was all-cause mortality. The data were also stratified according to the coexistence of DM.

Lower LDL-C Levels Associated With Higher All-Cause Mortality

Results from the study showed that 42.7% of patients with HF had severe systolic dysfunction, 30.5% had coronary heart disease, 60.5% had arterial hypertension, and 41.6% had DM. Approximately 92% of the study population was treated with beta-blockers, 87.5% received an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and 29.1% received an aldosterone receptor antagonist. During a median follow-up of 53 months, 45% of patients in the study died.

In patients with chronic HF, lower LDL-C levels correlated with an increased risk for all-cause mortality (Figure). When the analysis was stratified according to the coexistence of DM, patients with HF and no DM who had LDL-C levels less than 100 mg/dL had a 34% reduced mortality risk. However, among HF patients without DM, those with LDL-C levels of 100 mg/dL or lower had a 55% increased risk for all-cause mortality. This means a lower LDL-C level was not associated with a survival benefit in patients with established HF, regardless of cardiovascular risk factors and atherosclerotic disease, Dr. Gouveia says. Of note, this non-survival benefit does not appear to be attributable to nutritional status because LDL-C did not correlate with BMI, lymphocyte counts, or serum albumin.

Clarifying the Role of LDL-C in HF  

The study team noted it cannot be assumed that low LDL-C levels are causally implicated in the higher mortality rates that were seen among patients with HF in the study. “We cannot argue against using statins in HF patients without diabetes, but our findings question the use of statins in patients with HF, particularly for those who do not have diabetes,” says Dr. Gouveia. The results raise the possibility that a different LDL-C target or therapeutic approach might be reasonable when treating HF patients with or without diabetes.

In light of these results, HF patients with diabetes represent a subgroup in which clinicians should still consider using lipid-lowering therapies, such as statins. However, additional research is needed to explore whether statins should continue to be recommended in patients with HF without diabetes. “We need better clarity on the role of LDL-C in HF so that we can prescribe lipid-lowering therapy more safely in this growing patient population,” Dr. Gouveia says.