This article was written in collaboration with Dr. Steven Nissen, MD.
Chief Academic Officer of the Heart and Vascular Institute at the Cleveland Clinic and Professor of Medicine at the Lerner College of Medicine.
With the high prevalence of risk factors and cardiovascular disease in the US, looking at Statin vs Supplements for high cholesterol appears well-timed. As physicians, we face the hurdle that overall patients are reluctant to take medicine and would rather take dietary supplements. Reasons for this include statin misinformation and patients’ reluctance to start a medication that could give them side effects such as liver problems, muscle cramps, and memory issues. This nocebo effect plays a major role in statin intolerance and non-adherence to therapy. Moreover, dietary supplements are a 50 billion dollar US industry (250 billion worldwide) with very limited government regulation and claims of benefit that have not been demonstrated. Just recently, the FDA has issued warning letters to 7 companies for “illegally selling dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease or related conditions such as atherosclerosis, a stroke or heart failure.”
STATIN FOR HIGH CHOLESTEROL AND PRIMARY PREVENTION.
For adults 40-75 of age, clinicians should routinely assess traditional cardiovascular risk factors and calculate a 10-year risk of atherosclerotic cardiovascular disease (ASCVD) using the pooled equation. In adults with borderline risk (5-7.5% 10-yr risk) and intermediate risk (>7.5-<20%), it is reasonable to use additional risk-enhancing factors to guide decisions about instituting statin therapy. Among those is a family history of premature CVD, South Asian ancestry, chronic inflammatory disease (Rheumatoid or Lupus arthritis), early menopause, pre-eclampsia, erectile dysfunction, metabolic syndrome, or chronic kidney disease.
In patients with cholesterol between 70 and 189 mg/dL, it is recommended to start with a healthy lifestyle that includes exercise and eating a diet rich in fruits and vegetables as well as a Mediterranean-style diet. When elevated cholesterol persists, a medium-intensity statin is recommended.
The data on a statin for primary prevention is very compelling. The US Preventive Services Task Force (USPSTF) recently reviewed 22 trials of moderate-statin intensity in patients 40-75 years of age and no coronary artery disease (CAD) or symptoms of CAD and moderate risk (7.5-20 % 10-yr risk). In the pooled analysis, statin decreased all-cause mortality by 8% (85,516 pts), fatal or non-fatal stroke by 22% (76,000 pts), and fatal or non-fatal myocardial infarction by 33% (76,000 pts). In the landmark, WOSCOPS study of pravastatin 40 mg, cardiovascular mortality and nonfatal MI were reduced by 31% at 6 years. Twenty years later, a reduced total burden of disease is evident with reductions in cardiac admissions for cardiac events including PCI (18% lower in the pravastatin), myocardial infarctions (24%), and a 35% reduction in heart failure hospitalizations. For these reasons, the majority of countries, including those with socialized Medicine and conservative governments such as Canada and Great Britain, are much more likely to use a statin.
The magnitude of statin benefit is proportional to a person’s ASCVD risk: a patient with a 10-year risk of 5-7.5% will have a smaller benefit compared to a patient with a 10-year risk of >10%, but both groups benefit. Several mechanisms are involved in the improvement of clinical outcomes with statin and include: atherosclerotic plaque stabilization, decreased inflammation of the arteries and regression of atherosclerosis reducing new plaque formation and reduction of blockages in the arteries.
CAN STATIN CAUSE HARM?
The USPSTF reviewed 19 clinical trials (75,000 pts) and 3 observational studies (417,000 pts) and found no increased withdrawal of treatment due to adverse or serious events. In the observational studies, more patients had muscle pain or liver enzyme abnormalities. The increased risk of diabetes was most prevalent in pts with pre-diabetes or metabolic syndrome.
WHAT ABOUT STATIN INTOLERANCE?
True statin intolerance is difficult to evaluate because of the “nocebo effect”: muscle pain can occur due to the belief that statin will cause harm. In the STOMP study, muscle pain occurred in 9.4% of pts taking Lipitor 80 mg vs 4.6% taking a placebo. In the ODYSSEY alternative study in pts previously intolerant to a statin, 80% could tolerate Lipitor 20 mg. In the GAUSS-3 trial of cross-over Lipitor/placebo for 10 weeks, <50% reported symptoms. The most common muscle symptoms include soreness, aches, weakness, and cramps affecting symmetrical, large proximal muscle groups (quadriceps or hamstrings) without CPK enzyme elevation. Rarely, rhabdomyolysis (damage of muscle with CPK elevation) can occur (1/10,000) and has been seen with the use of simvastatin, primarily. Complete intolerance is rare (<5%). Partial intolerance can be managed by lowering the dose of statin or using another statin, alternate dose scheduling.
WHAT ABOUT THE DIETARY SUPPLEMENTS?
Dietary supplements are manufactured products intended to supplement a diet with nutrients extracted from food sources or that are synthesized. Supplements are regulated under the Dietary supplements Health and Education, the Federal Trade Commission, and not the FDA. The US combined sale of 50 billion dollars of supplements is marketed as natural alternatives for heart health and cholesterol management. It becomes a major public concern when patients are using supplements in place of statin for the treatment of hyperlipidemia in absence of good-quality data.
For these reasons, the comparative study of low-dose rosuvastatin, placebo, and dietary supplements on lipids is very timely. The study was performed at the Cleveland Clinic and headed by Dr. Laffin. They studied 190 adults, 40-75 yrs, without CAD or diabetes, with cholesterol between 70-189 mg/dL and a 10-yr ASCVD risk of 5-20%. Excluded were CKD, liver disease, or TG >200. Participants were randomized to 5 mg daily of rosuvastatin, placebo, fish oil, cinnamon, garlic, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL cholesterol from baseline from rosuvastatin compared to placebo and each supplement after 28 days. The percent LDL reduction with rosuvastatin was greater than all supplements and placebo. Compared to placebo, rosuvastatin reduced LDL cholesterol by 35%. None of the supplements reduced LDL cholesterol significantly compared to the placebo. Adverse events were low and similar across the groups.
Meta-analysis and prospective studies involving over 2 million participants using multivitamins and supplements found no benefit in cardiovascular mortality. In a recent review, the USPSTF concluded that the evidence is insufficient to determine the balance of benefits and harms of supplements for the prevention of cardiovascular disease or cancer. The evidence is lacking. Separately, red yeast rice has been associated with lowering LDL but different product formulations and manufacturing can result in different levels of efficacy. Plant sterols have been endorsed in Europe to lower cholesterol levels but some studies have indicated that they may be atherogenic. In 2021, a meta-analysis showed that garlic had no significant effect on LDL.
The use of supplements has increased in the last 20 yrs with 4,000 products available in 1994 and now over 90,000 products are available in the US. According to the National Health and Nutrition Examination Survey data, 52% of surveyed US adults are using at least 1 dietary supplement. Yet they can cause harm. An estimated 23,000 ER visits in the US can be attributed to adverse events caused by supplements mostly involving young adults and unsupervised children. Weight loss and energy products caused over 70% of supplement adverse events including palpitations, tachycardia, and chest pain. Among adults >65 yo, choking and pill-induced dysphagia caused over a third of ER visits. There have been cases of microbial contamination, heavy metal contamination, and inappropriate ingredients incorporated in supplements. Finally, some dietary supplements can interact with the cytochrome system of the liver and affect the metabolism of certain medications.
In the words of Dr. Steven Nissen, Chief Academic Officer of the Heart and Vascular Institute at the Cleveland Clinic and Professor of Medicine at the Lerner College of Medicine:
“Statins are cheap and are meant to do what they are supposed to do, Supplements are NOT!”