{"product_id":"redefining-normal-cholesterol-could-lower-ldl-targets-end-heart-disease-as-the-nations-1-killer","title":"Redefining \"Normal\" Cholesterol: Could Lower LDL Targets End Heart Disease as the Nation's #1 Killer?","description":"\u003cp\u003eIn 2010, a landmark paper published in the \u003cem\u003eJournal of the American College of Cardiology\u003c\/em\u003e proposed a radical shift in how doctors think about \"normal\" cholesterol levels and when to start treatment. Dr. James S. Forrester argued that the true normal range for LDL cholesterol (the \"bad\" cholesterol) may be 35 to 70 mg\/dl — far lower than the current targets used in medical practice — and that treatment should begin much earlier, even in young adulthood. Drawing on evidence from animal studies, traditional human societies, genetic research, and major clinical trials, the paper suggested that adopting these principles could displace heart disease as the nation's number one killer. This review examines the scientific rationale, the proposed changes, and the pros and cons of each recommendation.\u003c\/p\u003e\n\n\u003ch1\u003eRedefining \"Normal\" Cholesterol: Could Lower LDL Targets End Heart Disease as the Nation's #1 Killer?\u003c\/h1\u003e\n\n\u003ch2 id=\"table-of-contents\"\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#what-is-normal\"\u003eWhat Does \"Normal\" LDL Cholesterol Really Mean?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#nature-evidence\"\u003eThe Evidence from Nature and Traditional Societies\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#disease-begins-youth\"\u003eHeart Disease Begins in Youth\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-trials\"\u003eKey Clinical Trials: Testing the Putative Normal Range\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#genetic-insights\"\u003eGenetic Insights: PCSK-9 and KIF-6\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#proposed-changes\"\u003eProposed Changes to the Treatment Guidelines\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#arguments\"\u003eArguments For and Against the New Approach\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What This Study Couldn't Prove\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients and Doctors\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eProposed normal LDL range is 35-70 mg\/dl, based on mammals, newborns, and hunter-gatherers.\u003c\/li\u003e\n\u003cli\u003eAtherosclerosis begins in youth; risk factors in childhood increase plaque area in adulthood.\u003c\/li\u003e\n\u003cli\u003eJUPITER trial: lowering LDL to 55 mg\/dl cut cardiac events by 44% in asymptomatic people.\u003c\/li\u003e\n\u003cli\u003ePCSK-9 gene variants lower LDL and reduce heart risk; KIF-6 may guide statin intensity.\u003c\/li\u003e\n\u003cli\u003eLong-term safety of very low LDL is unknown; lifestyle changes remain essential.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\u003cp\u003eIn 2011, a group of lipid experts was scheduled to finalize a new set of recommendations that would shape the preventive management of coronary heart disease for the next decade. These guidelines — known as the Adult Treatment Panel (ATP) guidelines — are among the most important in all of medicine for two critical reasons. First, they address the leading cause of illness and death in the Western world. Second, they are endorsed by the U.S. Food and Drug Administration (FDA) and implemented by millions of health care practitioners worldwide.\u003c\/p\u003e\n\u003cp\u003eIronically, any proposed change to these guidelines cannot be free of controversy. Unlike many guidelines in cardiology, the LDL cholesterol guidelines cannot be based on rigorous medical science alone. Instead, they must find a practical middle ground between scientific proof and logical inference.\u003c\/p\u003e\n\u003cp\u003eThis paper proposes a logical rationale for \u003cstrong\u003ethree major changes\u003c\/strong\u003e to the existing management guidelines for low-density lipoprotein cholesterol (LDL-C), the \"bad\" cholesterol. If combined with effective implementation, these changes could lead to the displacement of atherosclerotic disease (hardening and narrowing of the arteries) as the nation's number one killer.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is-normal\"\u003eWhat Does \"Normal\" LDL Cholesterol Really Mean?\u003c\/h2\u003e\n\u003cp\u003eThe earliest approach to defining a normal level of LDL-C was traditional: determine its distribution in a clinically asymptomatic (symptom-free) population. At that time, the calculated \u003cstrong\u003emedian LDL-C level was approximately 130 mg\/dl\u003c\/strong\u003e. In the existing ATP III guidelines, this value appears as both the level for initiating therapy in patients with disease and as a therapeutic target for those without known disease.\u003c\/p\u003e\n\u003cp\u003eHowever, this approach has a critical flaw. \u003cstrong\u003e35% of patients who have a myocardial infarction (heart attack) are asymptomatic before the event\u003c\/strong\u003e, meaning they had no warning signs. A \"normal\" population cannot be defined simply by the absence of symptoms.\u003c\/p\u003e\n\u003cp\u003eFurther evidence against the 130 mg\/dl threshold comes from statin trials: \u003cstrong\u003eonly 25% to 35% of cardiac events are prevented when LDL-C is reduced to 100 to 130 mg\/dl\u003c\/strong\u003e, regardless of whether patients had symptoms or not. This suggests that clinical presentation cannot be used to establish a truly \"normal\" LDL-C level, and the 130 mg\/dl cut point has little support in recent published literature.\u003c\/p\u003e\n\n\u003ch2 id=\"nature-evidence\"\u003eThe Evidence from Nature and Traditional Societies\u003c\/h2\u003e\n\u003cp\u003eAn alternative approach was suggested in 2005 by O'Keefe and colleagues. Beginning with the observation that the total cholesterol level in nonatherosclerotic (plaque-free) wild mammalian species is \u003cstrong\u003e80 to 110 mg\/dl\u003c\/strong\u003e, they calculated the LDL-C level to be approximately \u003cstrong\u003e35 to 70 mg\/dl\u003c\/strong\u003e across species including baboons, monkeys, horses, bears, rhinoceroses, elephants, and wild pigs.\u003c\/p\u003e\n\u003cp\u003eHumans are born with LDL-C levels in this same range, but the level gradually increases with age. Yet at least two adult human populations do not exhibit this progressive increase:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHunter-gatherer societies\u003c\/strong\u003e — diverse in geographic location and ethnic origin, but arguably living the way humans did 10,000 years ago — maintain LDL-C levels in the 35 to 70 mg\/dl range.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRural Chinese populations\u003c\/strong\u003e often have blood levels that fall within this range as well.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eIn newborn humans and in these two adult groups, atherosclerotic coronary disease is rare. The consistency of these diverse human data sources, taken together with the mammalian species data, supports the speculation that the \u003cstrong\u003eputative normal range of LDL-C in adult humans may be approximately 35 to 70 mg\/dl\u003c\/strong\u003e.\u003c\/p\u003e\n\u003cp\u003eIt's worth noting that humans are the only animal species with LDL-C levels roughly twice the putative normal range — a reasonable question is whether the normal LDL-C for all mammals is in fact the 35 to 70 mg\/dl range.\u003c\/p\u003e\n\n\u003ch2 id=\"disease-begins-youth\"\u003eHeart Disease Begins in Youth\u003c\/h2\u003e\n\u003cp\u003eAs LDL-C levels rise above the putative normal range, atherosclerosis begins to appear surprisingly early in life. At \u003cstrong\u003eages 12 to 17 years\u003c\/strong\u003e, LDL-C reaches an average of \u003cstrong\u003e87 mg\/dl\u003c\/strong\u003e, with approximately \u003cstrong\u003e5% to 7%\u003c\/strong\u003e of this age group already at or above 130 mg\/dl.\u003c\/p\u003e\n\u003cp\u003eThe monotonically progressive (steadily worsening) nature of coronary atherosclerosis with decades of age has been documented by intracoronary ultrasound imaging of donor hearts at the time of heart transplantation. In a study of \u003cstrong\u003e262 heart transplant recipients\u003c\/strong\u003e, examining \u003cstrong\u003e2,014 sites within 1,477 segments in 574 coronary arteries\u003c\/strong\u003e:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e52%\u003c\/strong\u003e of the population had atherosclerotic lesions (defined as intimal thickness of at least 0.5 mm)\u003c\/li\u003e\n  \u003cli\u003eLesions were found in \u003cstrong\u003e17% of individuals younger than 20 years\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eThis increased to \u003cstrong\u003e60% in 30 to 39 year olds\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eAnd reached \u003cstrong\u003e85% in those older than 50 years\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eIn those with lesions, intimal thickness averaged \u003cstrong\u003e1.1 mm\u003c\/strong\u003e and area stenosis (narrowing) was \u003cstrong\u003e33%\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThe presence of these ultrasound-identified plaques predicts long-term illness and death at follow-up.\u003c\/p\u003e\n\u003cp\u003eOf critical importance to the new guidelines: \u003cstrong\u003ethose at risk of developing atherosclerosis can be identified in youth\u003c\/strong\u003e. In the Bogalusa Heart Study, autopsy of young adults who had a previous risk factor analysis showed that those with \u003cstrong\u003e3 or more childhood risk factors had a 9-fold increase in atherosclerotic plaque area\u003c\/strong\u003e compared with those with no risk factors.\u003c\/p\u003e\n\u003cp\u003eLipid abnormalities in childhood also predict early onset of clinical disease. In adults with onset of cardiovascular disease between \u003cstrong\u003eages 39 and 45 years\u003c\/strong\u003e, their childhood mean triglyceride level was \u003cstrong\u003e127 mg\/dl\u003c\/strong\u003e and body mass index (BMI) was \u003cstrong\u003e24 kg\/m²\u003c\/strong\u003e — contrasted to those without clinical disease who had a triglyceride level of \u003cstrong\u003e72 mg\/dl\u003c\/strong\u003e and a BMI of \u003cstrong\u003e20 kg\/m²\u003c\/strong\u003e.\u003c\/p\u003e\n\u003cp\u003eFinally, LDL-C lowering during early atheroma development induces regression (shrinking of plaques). In children with familial hypercholesterolemia (a genetic condition causing very high cholesterol), \u003cstrong\u003epravastatin 20 to 40 mg\/day for 2 years\u003c\/strong\u003e induced a \u003cstrong\u003e24% reduction in LDL-C\u003c\/strong\u003e, accompanied by a significant reduction in carotid intima-media thickness (a measurement of artery wall thickness) compared with both baseline and placebo controls — with \u003cstrong\u003eno difference in growth, muscle, liver enzymes, or endocrine function\u003c\/strong\u003e.\u003c\/p\u003e\n\u003cp\u003eThe conclusion is clear: atherosclerotic disease begins in youth, the risk of developing clinical disease can be identified decades before it appears, and the disease can be arrested or reversed during this period.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-trials\"\u003eKey Clinical Trials: Testing the Putative Normal Range\u003c\/h2\u003e\n\u003cp\u003eTwo recent randomized clinical trials allowed researchers to take the next logical step: examining the effect of actually lowering LDL-C into the putative normal range of 35 to 70 mg\/dl.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eASTEROID trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eReduction of LDL-C from \u003cstrong\u003e130 mg\/dl to 61 mg\/dl\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003e12% of patients achieved LDL-C below 40 mg\/dl, and 41% achieved levels between 40 and 60 mg\/dl\u003c\/li\u003e\n  \u003cli\u003eResult: \u003cstrong\u003eregression of carotid atherosclerosis\u003c\/strong\u003e (plaque shrinkage)\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003e\u003cstrong\u003eJUPITER trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eReduction of LDL-C from \u003cstrong\u003e108 mg\/dl to 55 mg\/dl\u003c\/strong\u003e in an asymptomatic intermediate-risk population\u003c\/li\u003e\n  \u003cli\u003eResult: a \u003cstrong\u003e44% reduction in adverse cardiac events\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eIn patients achieving on-treatment LDL-C below 70 mg\/dl, the event rate was only \u003cstrong\u003e1.4%\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eNotably, neither trial identified increased statin-induced toxicity at lower on-treatment LDL-C levels\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThese new data are supported by linear extrapolation of on-treatment LDL-C levels in both secondary angiographic and primary prevention trials:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eIn secondary prevention trials (patients with known disease): \u003cstrong\u003elesion progression reaches zero at an LDL-C of 67 mg\/dl\u003c\/strong\u003e, and \u003cstrong\u003ecoronary events reach zero at approximately 30 mg\/dl\u003c\/strong\u003e\n\u003c\/li\u003e\n  \u003cli\u003eIn primary prevention trials (patients without known disease): \u003cstrong\u003emajor adverse cardiac events reach zero at an on-treatment LDL-C level of 57 mg\/dl\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThus, to the lipid profiles in mammals, neonatal humans, and isolated human societies, we may add clinical trials that point to the same conclusion: the putative normal LDL-C level may be approximately \u003cstrong\u003e35 to 70 mg\/dl\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003ch2 id=\"genetic-insights\"\u003eGenetic Insights: PCSK-9 and KIF-6\u003c\/h2\u003e\n\u003cp\u003eAn experiment of nature provides powerful evidence about the benefits of a lifetime of lower LDL-C. In the \u003cstrong\u003eARIC (Atherosclerosis Risk in Communities) study\u003c\/strong\u003e of a free-living population of \u003cstrong\u003e12,787 subjects\u003c\/strong\u003e, approximately \u003cstrong\u003e3% had sequence variants in the gene colloquially called PCSK-9\u003c\/strong\u003e (pro-protein convertase subtilisin\/kexin type 9 serine protease).\u003c\/p\u003e\n\u003cp\u003eThese genetic variants lower LDL-C by a mean of approximately \u003cstrong\u003e19%\u003c\/strong\u003e compared with the general population. The findings were striking:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eAmong \u003cstrong\u003e3,363 black subjects\u003c\/strong\u003e, the mutations were associated with a \u003cstrong\u003e28% reduction in mean LDL cholesterol\u003c\/strong\u003e and an \u003cstrong\u003e88% reduction in the risk of coronary heart disease\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eAmong \u003cstrong\u003e9,524 white subjects\u003c\/strong\u003e, a sequence variation in PCSK-9 was associated with a \u003cstrong\u003e15% reduction in LDL cholesterol\u003c\/strong\u003e and a \u003cstrong\u003e47% reduction in risk\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eOverall, individuals with the PCSK mutation had a \u003cstrong\u003e62% lower rate of cardiac events over the first 15 years of observation\u003c\/strong\u003e.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThese data suggest that a lifetime of lower LDL-C levels is powerfully protective — and raise the inference that if therapeutic lowering of LDL-C had a similar long-term impact in higher-risk asymptomatic younger individuals, well-constructed guidelines could result in a major reduction in cardiac events.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePharmacogenetics (using genetics to guide drug choice)\u003c\/strong\u003e may also help target treatment. In the \u003cstrong\u003ePROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial\u003c\/strong\u003e, a common polymorphism called \u003cstrong\u003eKIF-6\u003c\/strong\u003e (the kinesin-like protein 6 Trg 719 Arg polymorphism) was shown to influence both intracellular transport and endothelial function:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eIn \u003cstrong\u003ecarriers of KIF-6\u003c\/strong\u003e, intensive statin therapy (atorvastatin 80 mg) was associated with a \u003cstrong\u003e6.8-fold greater reduction in cardiac events\u003c\/strong\u003e than in non-carriers, despite achieving the same level of on-treatment LDL-C and C-reactive protein (CRP).\u003c\/li\u003e\n  \u003cli\u003eThe \u003cstrong\u003enumber needed to treat\u003c\/strong\u003e (the number of patients who must be treated to prevent one event) with atorvastatin versus pravastatin was \u003cstrong\u003e10 in KIF-6 carriers\u003c\/strong\u003e — but \u003cstrong\u003e125 in non-carriers\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNon-carriers of the KIF-6 variant — approximately 40% of the U.S. population\u003c\/strong\u003e — experienced virtually no difference in adverse outcomes despite the major differences in on-treatment LDL-C levels between the two treatment groups.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThis finding suggests that the dose and\/or use of statins could be tempered by better selection of therapeutic candidates if pharmacogenetic testing can identify those most likely to benefit.\u003c\/p\u003e\n\n\u003ch2 id=\"proposed-changes\"\u003eProposed Changes to the Treatment Guidelines\u003c\/h2\u003e\n\u003cp\u003eBased on the evidence, the author proposed reconsidering all three principal features of the ATP III guidelines for LDL-C management. Below is a comparison of the existing and proposed approaches:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eInitiation of treatment:\u003c\/strong\u003e Based on events (absolute 10-year risk) → Proposed: based on pathogenesis (relative risk within the individual's age group)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUse of statins:\u003c\/strong\u003e Those who meet risk criteria → Proposed: further stratified by genetic capability of response\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eChoice of statin:\u003c\/strong\u003e No recommendation → Proposed: use a generic drug first in asymptomatic individuals\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTarget of treatment:\u003c\/strong\u003e Stratified by risk → Proposed: putative normal LDL-C range (35–70 mg\/dl) in all treated individuals, in the absence of toxicity\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch3\u003eRethinking Initiation Criteria\u003c\/h3\u003e\n\u003cp\u003eThe ATP III initiation levels now seem far too high. Examples include \u003cstrong\u003e190 mg\/dl for Framingham low-risk individuals\u003c\/strong\u003e and \u003cstrong\u003e130 to 160 mg\/dl for asymptomatic individuals with risk factors\u003c\/strong\u003e. In the asymptomatic JUPITER population, with a mean LDL-C level of 108 mg\/dl, \u003cstrong\u003eapproximately one-half of the patients had a calculated 10-year Framingham risk level below 10%\u003c\/strong\u003e — yet there was still a 44% reduction in events when LDL-C was reduced to the middle of the putative normal range.\u003c\/p\u003e\n\u003cp\u003eAn even more serious problem involves calculating risk based on the \u003cstrong\u003e10-year probability of a cardiac event\u003c\/strong\u003e. This risk calculation is very heavily weighted by age — the calculated mean 10-year risk for 25-year-old men \u003cstrong\u003eincreases 7-fold over 30 years\u003c\/strong\u003e. Younger individuals with a high risk factor burden clearly have a high probability of atherosclerotic disease, but they have a low calculated 10-year risk. As a result, they do not become candidates for treatment until the disease is very well established.\u003c\/p\u003e\n\u003cp\u003eThe magnitude of this limitation is substantial: \u003cstrong\u003eapproximately one-half of those in whom coronary artery disease develops first present with either sudden death or acute infarction\u003c\/strong\u003e.\u003c\/p\u003e\n\u003cp\u003eReorienting the initiation criteria toward the pathogenesis of atherosclerosis (the disease process itself) rather than its first clinical manifestation is feasible. \u003cstrong\u003eThree methods\u003c\/strong\u003e are currently available:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003eExpress the individual's risk \u003cstrong\u003erelative to the average risk for that person's age group\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eExpress the individual's calculated risk \u003cstrong\u003erelative to optimal values\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eCalculate the \u003cstrong\u003eFramingham risk over 30 years\u003c\/strong\u003e rather than the current 10-year period.\u003c\/li\u003e\n\u003c\/ol\u003e\n\u003cp\u003eAs an example: a young individual with risk in the upper \u003cstrong\u003e10% of that age group\u003c\/strong\u003e, or a calculated \u003cstrong\u003e2- to 3-fold greater risk\u003c\/strong\u003e than optimum, or a \u003cstrong\u003e40% 30-year risk\u003c\/strong\u003e, might be identified as a candidate for pharmacologic therapy. To dislodge atherosclerotic disease from its number one position, it seems essential that new guidelines incorporate the concept that \u003cstrong\u003ea long-term disease requires a long-term solution\u003c\/strong\u003e — meaning management should begin earlier in the course of the disease.\u003c\/p\u003e\n\n\u003ch3\u003eRethinking the LDL-C Target\u003c\/h3\u003e\n\u003cp\u003eA logical LDL-C target for individuals selected for therapy is the \u003cstrong\u003eputative normal range of 35 to 70 mg\/dl\u003c\/strong\u003e, with the proviso that it can be achieved at acceptable cost, without toxicity, and that neither patient nor health care provider uses drug therapy as a substitute for lifestyle modification.\u003c\/p\u003e\n\u003cp\u003ePathologic, epidemiologic, and clinical trial data suggest that a \u003cstrong\u003esingle putative normal LDL-C target might reasonably replace existing arbitrary multiple targets\u003c\/strong\u003e stratified by risk. The 70 mg\/dl target for individuals with coronary artery disease and diabetes is already widely accepted as highly beneficial. Simply offering this benefit to all individuals selected for treatment seems reasonable — both because asymptomatic individuals may have life-threatening disease and because the pathogenesis of the disease is identical.\u003c\/p\u003e\n\n\u003ch3\u003eControlling the Potential Major Expansion in Statin Use\u003c\/h3\u003e\n\u003cp\u003eAn inevitable outcome of changing the LDL-C initiation and target would be a significant increase in the use of statin drugs. The emergence of \u003cstrong\u003epharmacogenetic testing\u003c\/strong\u003e (using a person's genetic profile to predict drug response) offers a possible solution to overuse. One reason potent lipid-lowering therapy fails to markedly reduce cardiac events is the \"too little\/too late\" hypothesis. A second, seldom-considered reason is that the drugs may simply be ineffective in as-yet-unrecognized subsets of patients — and pharmacogenetics suggests this is highly likely.\u003c\/p\u003e\n\n\u003ch2 id=\"arguments\"\u003eArguments For and Against the New Approach\u003c\/h2\u003e\n\u003cp\u003eThere are strong arguments for avoiding these significant changes to the current guidelines:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eThe stepwise approach to LDL-C initiation levels and targets is a \u003cstrong\u003ewell-established structure\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eGuidelines typically are based on randomized clinical trials, whereas the putative normal range of LDL-C is based on \u003cstrong\u003einference\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eThe principal concern for most will be \u003cstrong\u003euncertainties surrounding toxicity and cost\u003c\/strong\u003e in implementation.\u003c\/li\u003e\n  \u003cli\u003eHigher drug doses imply an \u003cstrong\u003einevitable risk of increased drug toxicity\u003c\/strong\u003e; the risk of long-term aggressive therapy beyond the 5-year clinical trials is unknown.\u003c\/li\u003e\n  \u003cli\u003eLong-delayed adverse effects are exceptionally difficult to detect by their nature.\u003c\/li\u003e\n  \u003cli\u003eEven with potent agents, \u003cstrong\u003ea low LDL-C target will not be achievable in many individuals\u003c\/strong\u003e — the target will be unachievable in at least one-fourth of treated patients.\u003c\/li\u003e\n  \u003cli\u003eYounger people may be reluctant to take a daily drug, creating practical hurdles to implementation.\u003c\/li\u003e\n  \u003cli\u003eBecause lowering initiation levels and targets increases the number of people on therapy, \u003cstrong\u003ethe number of individuals not benefiting from therapy must also increase\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eThe impact on health care cost is unpredictable.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eThe author notes that acute toxicity results from trials are made grossly misleading by the \u003cstrong\u003e1-month run-in period\u003c\/strong\u003e before randomization (a period during which patients who experience side effects are excluded). Short-term absence of toxicity cannot be taken to predict long-term absence of toxicity.\u003c\/p\u003e\n\u003cp\u003eBecause of these concerns, the text of new guidelines must place strong emphasis on a \u003cstrong\u003eprudent, conservative approach to implementation\u003c\/strong\u003e, presenting the target as a desirable option rather than a mandate. Such guidelines should include both cautionary data and caveats concerning the tradeoffs among potency, cost, and toxicity of statins — recognizing that these issues will probably outweigh achievement of the target in at least one-fourth of treated patients.\u003c\/p\u003e\n\u003cp\u003eOn the other side, several arguments support making the change:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003ePotent \u003cstrong\u003egeneric statins\u003c\/strong\u003e allow the new strategy to be implemented at low individual patient cost.\u003c\/li\u003e\n  \u003cli\u003eA better distribution of individuals selected for statin therapy probably can be achieved through \u003cstrong\u003epharmacogenetics\u003c\/strong\u003e to predict the magnitude of response to therapy.\u003c\/li\u003e\n  \u003cli\u003eLong-term preventive therapy for coronary artery disease has a well-established precedent — one may ask whether a low-cost generic statin used in a well-defined at-risk population might provide both more benefit and less risk than \u003cstrong\u003easpirin\u003c\/strong\u003e.\u003c\/li\u003e\n  \u003cli\u003eGuideline classification systems make clear the strength of supporting information — no one need be misled about the strength of evidence.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eClinical Implications for Patients\u003c\/h2\u003e\n\u003cp\u003eIf these proposed changes were adopted, the implications for patients would be significant:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMore people would qualify for statin therapy\u003c\/strong\u003e, including younger adults who currently have \"low\" 10-year risk scores but high lifetime risk.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreatment targets would be lower\u003c\/strong\u003e — the goal for most treated patients would be an LDL-C level of 35 to 70 mg\/dl, similar to levels found in hunter-gatherer societies and newborn humans.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGenetic testing\u003c\/strong\u003e might be used to identify who benefits most from intensive statin therapy, potentially sparing non-carriers of genetic variants like KIF-6 from unnecessary aggressive treatment.\u003c\/li\u003e\n  \u003cli\u003eThe paper anticipates that \u003cstrong\u003eat least 25% of treated patients would not achieve the lower target\u003c\/strong\u003e, meaning doctors would need to balance ideal goals with practical realities, cost, and side effects.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLifestyle modification remains essential\u003c\/strong\u003e — a naturally or lifestyle-induced low LDL-C is not necessarily the same as medication-induced low LDL-C, and drug therapy should never be a substitute for healthy habits.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003cp\u003eFor patients, this means having an informed conversation with your doctor about your \u003cstrong\u003elifetime risk\u003c\/strong\u003e of heart disease — not just your 10-year risk — and understanding that \"normal\" cholesterol levels in modern society may not be optimal levels. The paper also emphasizes that \u003cstrong\u003ecoronary artery disease is a lifelong disease that begins in youth\u003c\/strong\u003e, so prevention may need to start decades earlier than current guidelines suggest.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What This Study Couldn't Prove\u003c\/h2\u003e\n\u003cp\u003eIn guideline jargon, the level of evidence of the putative normal LDL-C level is clearly \u003cstrong\u003elevel C\u003c\/strong\u003e, supported only by inference from existing data — as are the current guidelines. A further daunting issue is that if atherosclerotic disease begins in youth, then the duration of disease vastly exceeds the duration of randomized trials of lipid-lowering therapy used to support guideline development.\u003c\/p\u003e\n\u003cp\u003eThe author states this limitation directly: \u003cstrong\u003ea 2-to-5-year trial cannot be assumed to predict either efficacy or toxicity over 40 to 60 years of therapy\u003c\/strong\u003e with scientific rigor. The remarkable implication is that, unlike other guidelines, those for LDL-C now and for the foreseeable future will be based on \u003cstrong\u003einference rather than scientific rigor\u003c\/strong\u003e.\u003c\/p\u003e\n\u003cp\u003eAdditional limitations include:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eHumans are the only free-living animal in which atherosclerosis develops, so animal research cannot fully define natural history.\u003c\/li\u003e\n  \u003cli\u003eThe traditional use of \"apparently normal\" individuals to establish a normal range cannot be used for LDL-C, because 35% of heart attack victims were asymptomatic before their event.\u003c\/li\u003e\n  \u003cli\u003eThe 1-month run-in period before randomization in clinical trials makes acute toxicity results misleading.\u003c\/li\u003e\n  \u003cli\u003eShort-term absence of toxicity in trials cannot be taken to predict long-term safety over decades of therapy.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients and Doctors\u003c\/h2\u003e\n\u003cp\u003eWhile this paper is a review and proposal rather than a clinical trial, it offers practical guidance that patients can discuss with their health care providers:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow your numbers early.\u003c\/strong\u003e Since atherosclerosis begins in youth, consider having your cholesterol checked in young adulthood — and don't wait until symptoms appear.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about lifetime risk, not just 10-year risk.\u003c\/strong\u003e A young person with multiple risk factors may have a low 10-year risk but a very high lifetime risk of heart disease.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eConsider the \"putative normal\" perspective.\u003c\/strong\u003e The evidence suggests that LDL-C levels of 35 to 70 mg\/dl may be truly normal for humans, and levels well above 100 mg\/dl carry risk even if they are \"average\" in modern society.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDon't skip lifestyle changes.\u003c\/strong\u003e A naturally low LDL-C achieved through diet, exercise, and healthy habits is not the same as a medication-induced low LDL-C — drug therapy should complement, not replace, lifestyle modification.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIf you're prescribed a statin, low-cost generic options may be appropriate.\u003c\/strong\u003e The paper suggests using a generic drug first in asymptomatic individuals.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRecognize that guideline changes take time.\u003c\/strong\u003e Even if these proposals were fully adopted, they would be implemented gradually, and targets should be viewed as desirable options rather than rigid mandates — especially when balancing cost, potency, and potential toxicity.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eStay informed about pharmacogenetic testing.\u003c\/strong\u003e While still requiring further validation, genetic testing may eventually help identify which patients benefit most from intensive statin therapy.\u003c\/li\u003e\n\u003c\/ol\u003e\n\u003cp\u003eLDL-C management recommendations are being developed in a new era in which longer-term risk stratification, more objective initiation criteria, a reasonable LDL-C target, and pharmacogenetic stratification are all clearly possible. Since the concepts of a putative normal LDL-C and initiation criteria based on pathogenesis both incorporate uncertainties, it may be worthwhile to recognize the fundamental principle: \u003cstrong\u003ea long-term disease requires a long-term solution\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat LDL cholesterol level is considered truly normal for humans?\u003c\/h3\u003e\n\u003cp\u003eBased on evidence from wild mammals, newborn humans, hunter-gatherer societies, and some rural populations, the proposed normal LDL range is 35 to 70 mg\/dl. This is much lower than the average level of about 130 mg\/dl seen in modern asymptomatic populations, which may not represent true health.\u003c\/p\u003e\n\u003ch3\u003eWhy might heart disease start in youth even if I feel fine?\u003c\/h3\u003e\n\u003cp\u003eResearch shows atherosclerosis begins early. In one transplant study, 17% of people under 20 had arterial lesions, rising to 60% by ages 30-39. Childhood risk factors, like high triglycerides or BMI, are linked to more plaque in adulthood. This means prevention may need to start decades before symptoms appear.\u003c\/p\u003e\n\u003ch3\u003eCan lowering LDL cholesterol to 35-70 mg\/dl really prevent heart attacks?\u003c\/h3\u003e\n\u003cp\u003eIn the JUPITER trial, lowering LDL from 108 to 55 mg\/dl reduced cardiac events by 44%. In ASTEROID, reaching about 61 mg\/dl led to plaque regression. However, these were relatively short trials, and long-term benefits and risks over many decades are not yet proven.\u003c\/p\u003e\n\u003ch3\u003eWhat are PCSK-9 and KIF-6 gene variants, and do they affect treatment?\u003c\/h3\u003e\n\u003cp\u003ePCSK-9 variants naturally lower LDL and reduce heart risk—by 88% in black subjects and 47% in white subjects in one study. KIF-6 variants may predict greater benefit from intensive statins, with a much lower number needed to treat. Genetic testing is promising but not yet routine.\u003c\/p\u003e\n\u003ch3\u003eIs it safe to have very low LDL cholesterol from statin therapy?\u003c\/h3\u003e\n\u003cp\u003eIn the ASTEROID and JUPITER trials, achieving very low LDL levels (below 70 mg\/dl) was not linked to increased toxicity during the study period. However, these trials lasted only a few years. Long-term safety over decades of such low levels is unknown, and side effects are still possible.\u003c\/p\u003e\n\u003ch3\u003eShould I get my cholesterol checked when I am young?\u003c\/h3\u003e\n\u003cp\u003eThe article suggests that since atherosclerosis begins in youth, checking LDL early—even in young adulthood—could help identify risk before symptoms occur. However, decisions about testing and treatment should be made with a doctor, considering your full risk profile and not just your age or 10-year risk.\u003c\/p\u003e\n\u003ch3\u003eWhat should I ask my doctor about my heart disease risk?\u003c\/h3\u003e\n\u003cp\u003eAsk about your lifetime risk of heart disease, not just your 10-year risk. Discuss whether your LDL target should be lower than current guidelines, and remember that lifestyle changes are essential—medication should complement, not replace, healthy habits. Also ask about generic statins and potential genetic testing.\u003c\/p\u003e\n\u003ch3\u003eMy doctor says my LDL cholesterol is 'normal' and I don't need a statin. Should I get a second opinion about starting treatment?\u003c\/h3\u003e\n\u003cp\u003eA second opinion can help if you have been told your LDL cholesterol is 'normal' or that you do not need treatment yet. Evidence from clinical trials and genetic studies suggests a truly normal LDL may be 35 to 70 mg\/dl, lower than the usual 130 mg\/dl target. Lowering LDL to this range reduced cardiac events by 44% in one large trial and caused plaque shrinkage in another. However, long-term side effects beyond five years are unknown, and lifestyle changes remain essential. A second opinion can clarify your lifetime risk and whether pharmacogenetic testing, such as looking at the KIF-6 gene, might guide treatment. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal Article:\u003c\/strong\u003e \"Redefining Normal Low-Density Lipoprotein Cholesterol: A Strategy to Unseat Coronary Disease as the Nation's Leading Killer\"\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Journal of the American College of Cardiology, Vol. 56, No. 8, 2010, pages 630–636\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1016\/j.jacc.2009.11.090\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication Date:\u003c\/strong\u003e August 17, 2010\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures:\u003c\/strong\u003e Dr. Forrester has received Speakers' Bureau honoraria in the past 2 years from Merck, Pfizer, AstraZeneca, Bristol-Myers Squibb, Berkeley Heart Lab, Sanofi-Aventis, and St. Jude Medical.\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Patients should consult their health care providers about their individual cholesterol management.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47499365351580,"sku":null,"price":0.0,"currency_code":"RUB","in_stock":true}],"url":"https:\/\/diagnosticdetectives.ru\/products\/redefining-normal-cholesterol-could-lower-ldl-targets-end-heart-disease-as-the-nations-1-killer","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}