Cholesterol revisited

By Regina Druz

New developments and research in cardiology have changed our understanding of cholesterol and its role in vascular diseases. It is important for integrative practitioners to be familiar with the change in medical guidelines and find ways to offer their expertise in lifestyle focused interventions to traditional medical colleagues taking care of cardiovascular patients.

For decades, total serum level of blood cholesterol and its components-low-density lipoprotein (LDL), also known as “bad” cholesterol, and high-density lipoprotein (HDL), referred to as “good” cholesterol, were major determinants of cardiovascular risk. The data came from an observational study, the Framingham Heart Study, and guided cardiology practice for decades, focusing on reduction in plasma concentration of total cholesterol and LDL as major interventions that were evaluated in a multitude of trials.

These trials demonstrated a small reduction in absolute risk of major adverse cardiac events (MACE) that include non-fatal myocardial infarctions and cardiac death. The benefit was almost exclusively confined to secondary prevention—patients who previously had a cardiac event or procedure, or patients at high vascular risk due to age and other factors who did not experience a clinical event (primary prevention).

As is often the case with large scale, randomized clinical trials, the absolute risk reduction, while fairly small, translated into a sizable relative risk reduction. This fairly common statistical manipulation was used aggressively to promote lipid-lowering medications, initially statin drugs and subsequently others such as PCSK9 inhibitors. Based on a large meta-analysis of randomized controlled trials for statins, each 38. 67 mg/dl (1mmol/L) reduction in LDL cholesterol concentration was shown to reduce MACE by 23 percent. While ushering the era of aggressive use of statin medication, this “lower is better” mentality did not fully materialize in clinical practice, as many patients continued to have high residual risk despite lowered LDL-C, with clinical outcomes less favorable than was expected from the degree of LDL-C reduction.

Several factors contributed to the shift in thinking about role of cholesterol, including dietary cholesterol in vascular diseases. In the past decade, we saw emergence of undesirable side-effects, such as new-onset diabetes with statins and realization that an important clinical parameter, number needed to treat (NNT), was fairly high with these medications, especially if used in primary prevention. The concept of differential vulnerability emerged based on genetically-determined LDL concentrations in patients whose SNPs resulted in lower than average lifetime exposure to LDL, thus resulting in dramatically lower vascular event rates, 64 percent, based on a recent meta-analysis.

The focus on overall determinants of risk resulted in JUPITER, a major study in 2008 that demonstrated an impact of reduction in high-sensitivity C-reactive protein (hsCRP) of 2.0 miligrams or greater at baseline in patients with normal or near-normal lipid levels—LDL less than 130 mg/dl—on cardiovascular outcomes. This study was a major trial re-focusing practitioners on inflammation and its role in vascular diseases.

In 2017, the same researchers presented the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial using an orphan drug, Illaris, an interleukin-1 beta antibody injected every three months, to drastically lower hsCRP from baseline level of 2.0 mg or more in patients whose LDL levels were unchanged, demonstrating a sizable drop in vascular events with no change in LDL levels.

During the same year, development of PCSK9 inhibitors, the first genetically-guided molecular drug class for dyslipidemia once again focused on drastically lowering LDL as the ultimate path to risk reduction. However, the outcome trials such as FOURIER were disappointing, showing only modest event reduction in high-risk patients already receiving standard medical therapy.

Combined with steep price tags for these drugs and the need for pre-approval, their application was not widespread. While not all anti-inflammatory studies yielded successful results, and the risk of fatal infections was increased with interleukin-1 beta inhibition, it was clear that inflammation and not aggressive lipid lowering were the keys to vascular risk reduction.

In the past five years, the cardiovascular community has seen a rapid shift toward more personalized and risk-guided care, resulting in deeper understanding of the lifetime exposure to LDL and the role of inflammation in atherosclerosis. Understanding that optimal lipid levels and optimal inflammatory parameters bring dramatic reduction in vascular events if implemented early in life brings a renewed focus on lifestyle interventions. It is well-known that healthy lifestyle is anti-inflammatory, and, as an integrative cardiologist, I have seen patients drastically lower their hsCRP and LDL, both plasma concentrations and particle numbers as well as other ApoB-containing lipoproteins, using personalized holistic programs. 

In early November, the American Heart Association released a new set of cholesterol guidelines squarely putting lifestyle intervention as the first and most essential step in every patient group. While the guidelines call for statin therapy in patients who need secondary prevention, those with severe primary hypercholesterolemia (LDL >/= 190 mg/dl), and diabetes, the major emphasis is on risk assessment and clinician-patient risk discussion in other patient groups.

Cholesterol is complicated and complex, with many nuances. Shared clinician-patient decision making with individualized risk assessment allows room for lifestyle intervention and presents an opportunity for integrative practitioners to become valuable partners to traditional medical colleagues.

References

Ference, BA et al. Impact of Lipids on cardiovascular Health. JACC Health Promotion Series; 2018; 72 (10):1141-56.

Mahmood, SS, Levy, D, Vasan, RS, Wang, TJ. The Framingham Heart Study and the Epidemiology of Cardiovascular Diseases: A Historical Perspective. Lancet 2014, Mar 15:383 (9921):999-1008

Ridker, PM, Danielson E, Fonseca, FA et al for the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008: 359:2195-2207.

Ridker PM, Everett, BM et al for the CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017; 377:1119-1131

Sabatine, MS, Giugliano, RP et al for the FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-1722.