Heart disease: The forgotten pandemic.

Over the past 10 years cholesterol levels have been falling while the number of Americans dying of heart disease has been steadily climbing. This apparent paradox compels us to question whether lowering cholesterol is the best way to prevent coronary heart disease. A number of recent studies suggest that cholesterol, specifically LDL-C, may not be a primary risk factor for coronary heart disease and other markers, such as insulin resistance or remnant cholesterol, may be much more important. Furthermore, therapies designed to prevent coronary heart disease by lowering cholesterol with drugs or diet have yielded inconsistent results. Despite the widespread utilization of cholesterol-lowering statins in Europe, observational studies indicate that there has been no accompanying decline in coronary heart disease deaths. This new evidence should give us pause as we try to understand why the campaign to prevent heart disease by lowering cholesterol has not achieved its goals.

Cholesterol paradox: a correlate does not a surrogate make.

The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.

Does IMPROVE-IT prove it?

The recently published IMPROVE-IT trial has been hailed as proof that lowering cholesterol reduces the risk of cardiovascular disease (Cannon et al., 2015). Although this study did demonstrate a modest clinical benefit with incremental low-density lipoprotein cholesterol lowering, many physicians tend to ignore the numerous clinical studies which have failed to demonstrate a benefit of cholesterol lowering. This article challenges the cholesterol hypothesis by reviewing these negative studies and our reluctance to acknowledge them. Paradoxically, cholesterol lowering remains the focus of cardiovascular disease prevention despite the inconsistent benefit demonstrated in dozens of clinical trials. The cholesterol-lowering, statin-centric approach to cardiovascular disease prevention may in fact distract us from other beneficial therapies. Dr. Alexander Leaf, former chief of medicine at Massachusetts General Hospital, commented on this paradox and the Lyon Diet Heart Study nearly 15years ago by writing, "At a time when health professionals, the pharmaceutical industries, and the research funding and regulatory agencies are almost totally focused on lowering plasma cholesterol levels by drugs, it is heartening to see a well-conducted study finding that relatively simple dietary changes achieved greater reductions in risk of all-cause and coronary heart disease mortality in a secondary prevention trial than any of the cholesterol-lowering studies to date" (Leaf, 1999).

A Prospective Trial of Ayurveda for Coronary Heart Disease: A Pilot Study.

CONTEXT: Coronary heart disease is the leading cause of death worldwide, and its incidence is rapidly accelerating in developing nations. Patients often search for therapies that are alternatives to traditional treatments, such as heart medicines, coronary bypass surgery, or coronary stenting. Ayurveda is an ancient, East Indian, holistic approach to health care, and its use has never been formally evaluated for patients with coronary heart disease. OBJECTIVES: The study intended to examine the feasibility and effectiveness of comprehensive ayurvedic therapy-incorporating diet, meditation, breathing exercises, yoga, and herbs-for patients with established coronary heart disease. DESIGN: The study was a prospective, single-group, pilot study. SETTING: The study took place at the University of New Mexico Cardiology Clinic and at the Ayurvedic Institute in Albuquerque, NM, USA. PARTICIPANTS: The participants were adults with a history of a prior heart attack, coronary bypass surgery, or a coronary intervention (ie, a coronary angioplasty and/or stent). INTERVENTION: All enrolled patients were evaluated by a single ayurvedic physician with >40 y of experience, and each received therapy consisting of a calorically unrestricted ayurvedic diet; instruction in yoga, meditation, and breathing; and use of ayurvedic herbs. OUTCOME MEASURES: The primary endpoint was arterial pulse wave velocity, a marker of arterial function and vascular health. Secondary endpoints included the following measurements: (1) body mass index (BMI); (2) blood pressure (BP) and amount of reduction in BP medications; and (3) levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. All parameters were measured at baseline and after 90 d of therapy. RESULTS: Twenty-two patients were enrolled in the study, and 19 patients completed it. The research team observed significant improvements in arterial pulse wave velocity (P = .015), and favorable reductions in BMI (P < .0001), total cholesterol (P = .028), LDL cholesterol (P = .024), and triglycerides (P = .046). HDL cholesterol did not change significantly (P = .90). A majority of hypertensive patients were able to reduce or eliminate their antihypertensive medications (P = .0058). CONCLUSIONS: The study's results suggest a favorable effect for ayurveda on arterial function and multiple risk factors in patients with established coronary heart disease.

Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis.

Importance: The association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of individual, rather than composite, outcomes, such as all-cause mortality, myocardial infarction, or stroke, is unclear. Objective: To assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy. Data Sources: PubMed and Embase were searched to identify eligible trials from January 1987 to June 2021. Study Selection: Large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes with a planned duration of 2 or more years and that reported absolute changes in LDL-C levels. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care. Participants were men and women older than 18 years. Data Extraction and Synthesis: Three independent reviewers extracted data and/or assessed the methodological quality and certainty of the evidence using the risk of bias 2 tool and Grading of Recommendations, Assessment, Development and Evaluation. Any differences in opinion were resolved by consensus. Meta-analyses and a meta-regression were undertaken. Main Outcomes and Measures: Primary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke. Findings: Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive. Conclusions and Relevance: The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Hit or miss: the new cholesterol targets.

Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.

Are diabetes guidelines truly evidence based?

The global epidemic of obesity and diabetes underscores the urgency to develop strategies to prevent cardiovascular (CV) disease in this vulnerable population. Clinical guidelines are intended to help the clinician manage these patients, but guidelines are often discordant among professional organizations and not always evidence based. Clinicians must rely upon the best available evidence, and therefore we critically reviewed the evidence behind the American Diabetes Association (ADA) 2016 guidelines on the prevention of CV disease in diabetes. We believe the most robust evidence comes from randomized controlled trials specifically designed for diabetes with hard clinical endpoints such as mortality and CV events. Our analysis supports the ADA recommendations regarding a Mediterranean diet, glycemic control, and BP control, but we believe the evidence to support aspirin and statin therapy in diabetes is inconclusive. This discordance may be multi-factorial including the exclusion of some relevant studies and an over-reliance upon subgroup and meta-analysis. Given the lack of mortality benefit and inconsistent clinical benefits of aspirin and statins, it is essential that clinicians individualize treatment decisions while carefully weighing the risks and harms of any intervention.

Cholesterol confusion and statin controversy.

The role of blood cholesterol levels in coronary heart disease (CHD) and the true effect of cholesterol-lowering statin drugs are debatable. In particular, whether statins actually decrease cardiac mortality and increase life expectancy is controversial. Concurrently, the Mediterranean diet model has been shown to prolong life and reduce the risk of diabetes, cancer, and CHD. We herein review current data related to both statins and the Mediterranean diet. We conclude that the expectation that CHD could be prevented or eliminated by simply reducing cholesterol appears unfounded. On the contrary, we should acknowledge the inconsistencies of the cholesterol theory and recognize the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD.