statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of ldl levels. it has been estimated from the results of multiple human pharmacologic ldl lowering trials that ldl should be lowered to below 30 to reduce cardiovascular event rates to near zero. for reference, from longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthood, the usual ldl in childhood, before the development of fatty streaks, is about 35 mg/dl. however, all the above values refer to chemical measures of lipid/cholesterol concentration within ldl, not measured low-density lipoprotein concentrations, the accurate approach. a study was conducted measuring the effects of guideline changes on ldl cholesterol reporting and control for diabetes visits in the us from 1995 to 2004. it was found that although ldl cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ada guidelines nor the 2001 atp iii guidelines increased ldl cholesterol control for diabetes relative to coronary heart disease. direct measurement of ldl particle concentrations there are several competing methods for measurement of lipoprotein particle concentrations and size. the evidence is that the nmr methodology (developed, automated & greatly reduced in costs while improving accuracy as pioneered by jim otvos and associates) results in a 22-25% reduction in cardiovascular events within one year, contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents. since the later 1990s, because of the development of nmr measurements, it has been possible to clinically measure lipoprotein particles at lower cost and higher accuracy. there are two other assays for ldl particles, however, like ldl-c, most only estimate ldl particle concentrations. direct ldl particle measurement by nmr was mentioned by the ada and acc, in a 28 march 2008 joint consensus statement, as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive . debate continues that it is "...unclear whether ldl particle size measurements add value to measurement of ldl-particle concentration", though outcomes have always tracked ldl particle, not ldl-c, concentrations. using nmr, the total ldl particle concentrations, in nmol/l plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who are participating in the mesa trial. optimal ranges the ldl particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being tracked in the mesa trial, a medical research study sponsored by the united states national heart, lung, and blood institute. mesa percentile ldl particles nmol/l interpretation 0–20% <1,000 those with lowest rate of cardiovascular disease events & low (optimal) ldl particle concentration 20–50% 1,000–1,299 those with moderate rate of cardiovascular disease events & moderate ldl particle concentration 50–80% 1,300–1,599 those with borderline-high rate of cardiovascular disease events & higher ldl particle concentration 89–95% 1,600–2,000 those with high rate of cardiovascular disease events and even higher ldl particle concentration >95% >2,000 those with very high rate of cardiovascular disease events and highest ldl particle concentration the lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. multiple other measures, including particle sizes, small ldl particle concentrations, large total and hdl particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided. lowering ldl-cholesterol markers indicating a need for ldl-c reduction (per 2004 united states government minimum guidelines) if the patient's cardiac risk is... then the patient should consider ldl-c reduction if the count in mg/dl is over... and ldl-c reduction is indicated if the count in mg/dl is over... high, meaning a 20% or greater risk of heart attack within 10 years, or an extreme risk factor 70 100 moderately high, meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors 100 130 moderate, meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors 130 160 low, meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors 160 190 the mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. the enzyme 3-hydroxy-3-methylglutaryl coenzyme a reductase (hmg coa reductase) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. ldl-c is not a measurement of actual ldl particles. ldl-c is only an estimate (not measured from the individual's blood sample) of how much cholesterol is being transported by all ldl particles, which is either a smaller concentration of large particles or a high concentration of small particles. ldl particles carry many fat molecules (typically 3,000 to 6,000 fat molecules per ldl particle); this includes cholesterol, triglycerides, phospholipids and others. thus even if the hundreds to thousands of cholesterol molecules within an average ldl particle were measured, this does not reflect the other fat molecules or even the number of ldl particles. pharmaceutical pcsk9 inhibitors, in clinical trials, by several companies, are more effective for ldl reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe). statins reduce high levels of ldl particles by inhibiting the enzyme hmg-coa reductase in cells, the rate-limiting step of cholesterol synthesis. to compensate for the decreased cholesterol availability, synthesis of ldl receptors (including hepatic) is increased, resulting in an increased clearance of ldl particles from the extracellular water, including of the blood. ezetimibe reduces intestinal absorption of cholesterol, thus can reduce ldl particle concentrations when combined with statins. niacin (b3), lowers ldl by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and vldl secretion through a receptor hm74 and hm74a or gpr109a. several cetp inhibitors have been researched to improve hdl concentrations, but so far, despite dramatically increasing hdl-c, have not had a consistent track record in reducing atherosclerosis disease events. some have increased mortality rates compared with placebo. clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels. other, more recently developed and tested fibrates, e.g. fenofibric acid have had a better track record and are primarily promoted for lowering vldl particles (triglycerides), not ldl particles, yet can help some in combination with other strategies. some tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. in particular, gamma-tocotrienol appears to be another hmg-coa reductase inhibitor, and can reduce cholesterol production. as with statins, this decrease in intra-hepatic (liver) ldl levels may induce hepatic ldl receptor up-regulation, also decreasing plasma ldl levels. as always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s. phytosterols are widely recognized as having a proven ldl cholesterol lowering efficacy' a 2018 review found a dose-response relationship for phytosterols, with intakes of 1.5 to 3 g/day lowering ldl-c by 7.5% to 12%, but reviews as of 2017 had found no data indicating that the consumption of phytosterols may reduce the risk of cvd. current supplemental guidelines for reducing ldl recommend doses of phytosterols in the 1.6-3.0 grams per day range (health canada, efsa, atp iii, fda) with a 2009 meta-analysis demonstrating an 8.8% reduction in ldl-cholesterol at a mean dose of 2.15 gram per day. gene editing in 2021, scientists demonstrated that crispr gene editing can decrease blood levels of ldl cholesterol in vivo in macaca fascicularis monkeys for months by 60% via knockout of pcsk9 in the liver. lifestyle the most effective lifestyle approach to reduce ldl cholesterol has been minimizing total body fat, in particular fat stored inside the abdominal cavity (visceral body fat). visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating vldl particle concentrations, thus both increasing ldl particle concentrations and accelerating the development of diabetes mellitus.