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Purpose of Review: Although the clinical benefit of reducing low-density lipoprotein cholesterol (LDLc) in patients with coronary artery disease (CAD) is well-established, the impact on plaque composition and stability is less clear. Our narrative review aimed to assess the clinical effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on coronary plaque characteristics specifically focusing from atheroma progression to regression and stabilization., Recent Findings: The combination of statin therapy and PCSK9 inhibitors (evolocumab and alirocumab) promotes plaque stability in patients following an acute coronary syndrome. The GLAGOV study highlighted the relationship between achieved LDLc levels and changes in percentage atheroma volume. Similarly, the PACMAN-AMI study concluded that the qualitative and quantitative changes in coronary plaque were associated with the levels of LDLc. Assessing the severity of coronary artery stenosis and the extent of atherosclerotic burden by means of imaging techniques (e.g., IVUS, OCT and near-infrared spectroscopic) have significantly advanced our understanding of the benefits from promoting plaque regression and achieving to features of plaque stabilization through increasingly intensive lipid-lowering strategies., (© 2024. The Author(s).)

Purpose of Review: Current guidelines for primary and secondary prevention of cardiovascular events in adults up to age 75 years are well-established. However, recommendations for lipid-lowering therapies (LLT), particularly for primary prevention, are inconclusive after age 75. In this review, we focus on adults ≥ 75 years to assess low-density lipoprotein-cholesterol (LDL-C) as a marker for predicting atherosclerotic cardiovascular disease (ASCVD) risk, review risk assessment tools, highlight guidelines for LLT, and discuss benefits, risks, and deprescribing strategies., Recent Findings: The relationship between LDL-C and all-cause mortality and cardiovascular outcomes in older adults is complex and confounded. Current ASCVD risk estimators heavily depend on age and lack geriatric-specific variables. Emerging tools may reclassify individuals based on biologic rather than chronologic age, with coronary artery calcium scores gaining popularity. After initiating LLT for primary or secondary prevention, target LDL-C levels for older adults are lacking, and non-statin therapy thresholds remain unknown, relying on evidence from younger populations. Shared decision-making is crucial, considering therapy's time to benefit, life expectancy, adverse events, and geriatric syndromes. Deprescribing is recommended in end-of-life care but remains unclear in fit or frail older adults. After an ASCVD event, LLT is appropriate for most older adults, and deprescribing can be considered for those approaching the last months of life. Ongoing trials will guide statin prescription and deprescribing among older adults free of ASCVD. In the interim, for adults ≥ 75 years without a limited life expectancy who are free of ASCVD, an LLT approach that includes both lifestyle and medications, specifically statins, may be considered after shared decision-making., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose of Review: In this review, we will discuss the data from early clinical studies of MK-0616 and summarize clinical trials of other oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors., Recent Findings: The success of PCSK9 inhibition with monoclonal antibody injections has fueled the development of additional therapies targeting PCSK9, including oral formulations, the most advanced of which is MK-0616. MK-0616 is a novel, orally administered macrocyclic peptide that binds to PCSK9 and inhibits binding of PCSK9 to the LDL receptor, thereby decreasing plasma levels of LDL-C. Clinical trial data on the safety and efficacy of MK-0616 are promising and report LDL-C-lowering efficacy comparable to that provided by injectable PCSK9 inhibitors. Ongoing and future studies of oral PCSK9 inhibitors in development will evaluate the safety, efficacy, and effectiveness of these agents and their potential role in preventing cardiovascular disease events., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients., Competing Interests: Ozlem Bilen declares no conflict of interest. Christie M. Ballantyne declares consultant fees, grants, and research support from Esperion, paid to her institution, during the conduct of the study; she also declares grants, research support, and/or consultant fees from Amarin, Amgen, Eli Lilly, Otsuka, Novartis, Pfizer, Regeneron, Sanofi-Synthelabo, Takeda, National Institutes of Health, American Heart Association, and American Diabetes Association; she also declares consultant fees from AstraZeneca, Ionis, Genzyme, Matinas BioPharma, and Merck. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Purpose: There is much controversy regarding the use of oral contraceptive pills (OCPs) on cardiometabolic parameters, which is why this longitudinal population-based study was conducted to assess the impact of OCP use and its duration on cardiometabolic factors., Methods: Of 5532 reproductive-aged participants of the Tehran lipid and glucose study, 3160 women who met our inclusion criteria were subdivided according to the duration of OCPs consumption into four sub-groups: (1) Non-users; (2) <11 month users; (3) 12-35 month users, and (4) ≥36 month users, and their cardiometabolic parameters were compared., Results: No statistical significant differences were observed between the cardiometabolic parameters of these sub-groups, after further adjustment for confounding factors including age, parity, and education, except for mean low-density lipoprotein-cholesterol which was significantly higher in women who used OCPs for >36 months in comparison to non-OCP users. The odds ratio of hypercholesterolemia was significantly higher in women who used OCPs for >36 months in comparison to non-OCP users; being 1.5 times higher than non-users (95 % CI 1.01-2.2)., Conclusion: Results showed that if used for less than 3 years, OCPs have no cardiometabolic effects.

Statins fail to adequately reduce low-density lipoprotein-cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, requiring these patients to undergo weekly or bi-weekly sessions of LDL apheresis. Although efficacious, LDL apheresis is an invasive procedure with high cost and low availability, and additional options, such as inhibitors of microsomal transfer protein (MTP), may have benefit. Inhibition of MTP reduces levels of circulating cholesterol and triglycerides by preventing the formation of very-low-density lipoprotein and chylomicrons. LDL-C levels decrease by as much as 50%. Unfortunately, adverse effects-the most common of which are gastrointestinal-related and hepatic lipid accumulation-limit broader use of the drug. Furthermore, the cardiovascular benefit of MTP inhibition remains unclear. However, MTP inhibition offers a viable additional lipid-lowering option for patients with homozygous familial hypercholesterolemia.

Antisense oligonucleotide therapy is a promising approach for the treatment of a broad variety of medical conditions. It functions at the cellular level by interfering with RNA function, often leading to degradation of specifically targeted abnormal gene products implicated in the disease process. Mipomersen is a novel antisense oligonucleotide directed at apolipoprotein (apoB)-100, the primary apolipoprotein associated with low-density lipoprotein cholesterol (LDL-C), which has recently been approved for the treatment of familial hypercholesterolemia. A number of clinical studies have demonstrated its efficacy in lowering LDL-C and apoB levels in patients with elevated LDL-C despite maximal medical therapy using conventional lipid-lowering agents. This review outlines the risks and benefits of therapy and provides recommendations on the use of mipomersen.

Purpose: This study investigated the effect of leptin (LEP) 2548A/G and leptin receptor (LEPR) Q223R polymorphisms on the levels of HDL, LDL, TG, and total cholesterol (t-chol). In addition, the interactions between examined polymorphisms, statin therapy and environmental factors on lipid profile were examined., Methods: Adult diabetic patients (n-418) were recruited from diabetes/endocrine clinics in north of Jordan. Lipid profile was measured using standard protocols. Genotyping of LEP 2548A/G and LEPR Q223R polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphisms., Results: No significant association between LEP 2548A/G and LEPR genotypes and levels of HDL (P = 0.83), LDL (P = 0.40), TG (P = 0.23) and t-chol (P = 0.91). However, in patient on atorvastatin, those with GG or GA genotypes of LEP 2548 experienced significantly higher levels of LDL compared with AA genotype of LEP 2548 (P < 0.002). Patients with dyslipidemia had higher TG in comparison with those without (P < 0.03). Smokers had lower HDL and higher TG levels compared with none smokers or previous smokers (P < 0.002 and P < 0.02, respectively). Female patients tend to have a higher HDL in comparison with male patients (P < 0.05). Patients with HbA1c value greater than or equal to 7 had higher LDL and t-chol compared with patients who had an HbA1c levels of <7 (P < 0.02 and < 0.005, respectively). Patients with disease duration of 5 or more years had a lower HDL compared with those patients with duration of <5 years (P < 0.03)., Conclusion: In conclusion, and although lipid profile regulation is a multifactorial process, -2548G/A LEP polymorphism seems to affect statins treatment response among diabetic patients. More studies are required to specifically define factors that influence lipid profiles interaction with statin treatment response especially among patients with diabetes.

Among the range of lipid modifying medications currently available, statins clearly stand as the primary agent capable of reducing cardiovascular risk. While non-statin lipid-lowering drugs improve lipid parameters, their impact on clinical outcomes is less clear, thus necessitating an even closer look at ancillary effects. Recent studies have reported the potential cardiometabolic effects of statins, yet considerably less information has been published about cardiometabolic changes associated with non-statin lipid-lowering agents. This review describes the cardiometabolic profile of non-statin lipid-lowering agents--fibrates, niacin, omega-3 polyunsaturated fatty acids, ezetimibe, and bile acid sequestrants--and therefore aims to facilitate informed decision-making in the pharmacologic management of lipid abnormalities.

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease.

Background: Women with diabetes have higher low-density lipoprotein (LDL) levels than men, resulting in apparent disparities between genders on quality indicators tied to LDL thresholds., Objective: To investigate whether gender disparities persist when accounting for clinical action with statins or cardiovascular risk., Design: Retrospective cohort study., Participants: Veterans Health Administration patients (21,780 women and 646,429 men) aged 50-75 with diabetes., Main Measures: Threshold measure: LDL < 100 mg/dL; clinical action measure: LDL < 100 mg/dL; or LDL ≥ 100 mg/dL and the patient was prescribed a moderate or high-dose statin at the time of the test; or LDL ≥ 100 mg/dL and the patient received other appropriate clinical action within 90 days; adherence: continuous multiple interval measure of gaps in dispensed medication (CMG)., Key Results: Women were much less likely to have LDL < 100 mg/dL than were men (55 % vs. 68 %). This disparity narrowed from 13 % to 6 % for passing the clinical action measure (79 % vs. 85 %). These gender differences persisted among those with ischemic heart disease (IHD). Women had a lower odds of passing the clinical action measure (odds ratio 0.68, 95 % confidence interval 0.66-0.71). Among those with IHD, the gender gap increased with age. Differences in pass rates were explained by women's higher LDL levels, but not by their slightly worse adherence (3 % higher CMG)., Conclusions: Women and men veterans receive more similar quality of care for lipids in diabetes than previously indicated. Less reassuringly, the remaining gender differences appear to be as common in women at high cardiovascular risk as in those at low risk. Rather than focus on simply improving LDL levels in all women with diabetes, future efforts should ensure that patients with high cardiovascular risk are appropriately treated with statins when clinically indicated, feasible, and concordant with patient preferences.

The link between proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesterol metabolism was established only in 2003 when genetic mapping and positional cloning in patients with autosomal dominant hypercholesterolemia in which linkage to the loci coding for the LDL receptor and apolipoprotein B had been excluded identified the genetic defect missense as mutations in PCSK9, a protein/enzyme previously unknown to be related to lipid metabolism. Laboratory-based investigations confirmed that these were gain-of-function mutations. Further studies in cohorts with low LDL cholesterol (LDLc) levels from large epidemiological cardiovascular studies reported that loss-of-function mutations in PCSK9 were associated with protection from cardiovascular disease. An additional critical observation provided evidence that the interaction of PCSK9 and the LDL receptor was through circulating, not intracellular, PCSK9, which bound to the receptor, and then mediated the recycling of the LDL receptor. These findings established PSCK9 as a potential therapeutic target and resulted in biopharmaceutical companies developing interventions designed to lower LDLc levels. Clinical development programs for monoclonal antibodies against PCSK9 have advanced rapidly with completion of comprehensive phase 1 and 2 trials with both REGN727/SAR236553 (REGN727) and AMG 145, clearly demonstrating substantial reductions in LDLc levels in patients receiving diet alone, low, moderate, and high doses of statins, or statin combined with ezetimibe, and both heterozygous familial hypercholesterolemia and nonfamilial hypercholesterolemia subjects. Concomitant and parallel reductions in the levels of apolipoprotein B and its related lipoproteins, and small but significant increases in HDL cholesterol levels were seen as anticipated. An unanticipated and robust decrease in lipoprotein(a) levels was also noted. Although these trials have been relatively short term, no significant safety issues or target organs of interest have emerged. Larger and much longer phase 3 trials are now in progress to assess the long-term tolerability, safety, and impact on cardiovascular disease events of these very effective LDLc lowering compounds.

Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.

Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the "in-trial" periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.

The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 % the risk of heart attack and stroke among men and women with low levels of low-density lipoprotein (LDL)-cholesterol who are at increased vascular risk due to elevated levels of C-reactive protein (CRP), a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy were related to the level of CRP, whereas no such relationship was observed for LDL-C. Further, on-treatment levels of CRP and LDL-C were independently associated with residual risk, and the genetic determinants of statin-induced CRP reduction differed from the genetic determinants of statin-induced LDL reduction. Despite these data, it is impossible in any statin trial to establish whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes. To address the hypothesis that lowering inflammation will lower vascular event rates, two large-scale placebo controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction have been initiated. The first trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), is evaluating whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (≥ 2 mg/L), despite contemporary secondary prevention strategies. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and will evaluate whether low dose methotrexate (target dose 20 mg/week) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro-inflammatory response. Together, CANTOS and CIRT represent a core test of the inflammation hypothesis of atherothrombosis and the exploration of a potential new phase for cardiovascular therapeutics.

Hypercholesterolemia is one of the main risk factors for the development of atherosclerotic diseases. Multiple clinical trials of lipid-lowering agents have demonstrated that lowering cholesterol effectively reduces the risk of cardiovascular events and death. Currently, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") is the most commonly used approach, given their superior efficacy relative to other cholesterol lowering agents. However, not all patients on statin monotherapy achieve target cholesterol levels, and even when cholesterol lowering is successful, significant residual cardiovascular risk remains. There is increasing interest in developing combination cholesterol-modifying therapies that may augment the treatment effect and minimize the side effects of statins. Although there is currently no evidence that any of the potential therapy combinations can improve clinical outcome compared to statin monotherapy alone, results of several large ongoing trials will help to clarify this important field.

Statins are highly effective drugs prescribed to millions of people to lower LDL-cholesterol and decrease cardiovascular risk. The benefits of statin therapy seen in randomized clinical trials will only be replicated in real-life if patients adhere to the prescribed treatment regimen. But, about half of patients discontinue statin therapy within the first year, and adherence decreases with time. Patient, physician and healthcare system-related factors play a role in this problem. Recent studies have focused more on the patients' perspectives on non-adherence. Adverse events are cited as the most common cause of statin discontinuation; thus, the healthcare provider must be willing to ally and dialogue with patients to address concerns and assess the risks and benefits of continued statin therapy.

Although evidence from epidemiological studies examining a relationship between cholesterol level and stroke is less than definitive, there is a compelling evidence from the clinical therapy trials primarily designed to examine the coronary benefits of statins that statin therapy also causes a reduction in the risk of stroke. Even though a stroke does not have the same exact pathophysiology as a heart attack, specific trials in stroke patients confirm advantages and risks of statin therapy in this kind of population. In primary prevention, statins are effective both when low-density lipoprotein (LDL) is raised and when hs-CRP is elevated. In secondary prevention, an absolute reduction of recurrent stroke can be obtained with statins, with a number needed to treat at 5 years of 45.

Despite aggressive lipid-lowering therapy, patients continue to be at significant risk of coronary heart disease (CHD). Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, non-HDL-C was introduced as a secondary target of therapy in persons with triglycerides ≥200 mg/dL. A recent meta-analysis of the relationship between non-HDL-C reduction and CHD risk showed non-HDL-C as an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have a 1:1 relationship between percent non-HDL-C lowering and percent CHD reduction. In the EPIC-Norfolk prospective population study, 21,448 participants without diabetes or CHD between 45 and 79 years of age were followed for 11.0 years. Participants with high non-HDL-C levels were at increased CHD risk independently of their LDL-C levels. Also, compared to apolipoprotein B, non-HDL-C appears to be a better choice given the fact that no additional tests or costs are needed and established cut points are already available. Future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies with an increased need to have non-HDL-C reported on routine lipid panels.

This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome.

Purpose: Cisplatin-based chemotherapy is widely used in the treatment for germ cell testicular tumors. However, long-term complications of this treatment have gained importance, and hypercholesterolemia is one of these. In some studies, hypercholesterolemia is reported following the cisplatin-based chemotherapy. In this study, we evaluated the relationship of cisplatin-based chemotherapy and blood lipid levels in long-term survivors of patients with germ cell testicular tumors., Patients and Methods: A total of 89 testicular cancer patients were evaluated between December 1989 and December 2001. Of these, while 39 received cisplatin-based chemotherapy (Group 1), the remaining control group of 50 testicular cancer patients (Group 2) had no adjuvant treatment. The patients in both groups had at least 5-year follow-up and had no known cardiovascular disease. Fasting lipid profiles were obtained including total cholesterol, triglyceride, low- and high-density lipoprotein and very low-density lipoprotein. These values were compared with the normal range, and the statistical difference between the two groups was evaluated. Student's t test was used for continuous variables, and P < 0.05 was accepted as significant., Results: Groups 1 and 2 had 39 and 50 cases, respectively. Mean follow-up period for Group 1 was 110 months (60-187) and 107 months (60-282) for Group 2. Mean total cholesterol in Groups 1 and 2 was 199.5 ± 44.1 mg/dl and 210.3 ± 41 mg/dl (P = 0.398), mean triglyceride 189.9 ± 131.0 mg/dl and 156.6 ± 105.5 mg/dl (P = 0.334), mean high-density lipoprotein cholesterol 38.3 ± 7.3 and 41.6 ± 10.9 mg/dl (P = 0.242), respectively, while very low density lipoprotein cholesterol was 38.2 ± 22.1 and 34.6 ± 26.7 mg/dl (P = 0.621). The only difference between the two groups was the low-density lipoprotein levels. The mean low-density lipoprotein cholesterol was 116.6 ± 51.7 and 141.9 ± 28.1 mg/dl (P = 0.036), respectively., Conclusion: Cisplatin-based chemotherapy in germ cell testicular tumors did not have long-term negative effect on blood lipid levels.

Background: Mail order pharmacies are commonly used to deliver CVD risk factor medications. Previous studies have shown that mail order pharmacy use is associated with greater medication adherence; however, no studies have examined whether mail order pharmacy use is related to improved CVD risk factor outcomes., Objective: To examine the comparative effectiveness of mail order pharmacy vs. local pharmacy use on LDL-C control in new statin users., Design: Observational cohort study., Patients: 100,298 adult Kaiser Permanente Northern California (KPNC) members who were new users of statins between January 1, 2005 and December 31, 2007., Measurements: The main outcome measure was LDL-C control in the 3-15 month period after statin therapy was initiated., Results: After adjustment for patient, clinical, and census-block characteristics, and for potential unmeasured differences between mail order and local KPNC pharmacy users with instrumental variables analysis, 85.0% of patients who used the mail order pharmacy to deliver their statin at any time achieved target LDL-C levels compared with 74.2% of patients who only used the local KPNC pharmacy to dispense the statin (p < 0.001). Greater adjusted rates of LDL-C control in mail order pharmacy users were seen across all gender and race/ethnicity subgroups., Conclusions: Mail order pharmacy use was positively associated with LDL-C control in new statin users. Future research should continue to explore the relationship between mail order pharmacy use and outcomes, and address how to appropriately target mail order services to patients most likely to benefit without compromising patient choice, care, and safety.

Despite substantial progress in the characterization and pharmacological treatment of risk factors associated with cardiovascular disease (CVD), residual cardiovascular risk represents a challenge to an effective CVD primary and secondary prevention. A multifactorial approach aimed at controlling all risk factors present in each individual patient is of paramount importance to effectively reduce the risk of CV events. While aggressive as compared to conventional LDL-cholesterol lowering provides further CV events reduction in secondary prevention patients, significant residual cardiovascular risk remains even after intensive statin therapy and an LDL-C levels of <70 mg/dL. Combination lipid-lowering strategies with a statin and fenofibrate or a statin and nicotinic acid may provide significant residual CV risk reduction in selected subgroups of patients (i.e. patients with diabetes on statin therapy and persistently low HDL-C and/or high triglycerides). Intensive risk factor management approaches aimed at controlling plasma LDL-C, glucose metabolism and blood pressure may significantly reduce residual CV risk; they should however be implemented based on individual cardiovascular risk profiles and clinical phenotypes, following the footsteps of personalized medicine.

In this open-label, balanced, randomized, placebo-controlled, parallel study, healthy male volunteers were randomly divided into two groups. Each group received either a single oral dose of rosuvastatin 20 mg or placebo. Estimations were done at predose on day 1 of dosing (baseline) and 24 h postdose after days 7 and 14. Serum cortisol and serum lipid levels were estimated using enzyme-linked immunosorbent assay kits and serum mevalonic acid (MVA) levels were measured using validated liquid chromatography-tandem mass spectrometry method. Rosuvastatin produced a statistically significant (P < 0.05) decrease in total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides. However, the increase in high-density lipoprotein cholesterol and decrease in cortisol and MVA were not statistically significant when compared to the placebo-treated group. The study showed that rosuvastatin at a dose of 20 mg/day for a period of 14 days was very potent as cholesterol-lowering agent, without any significant change in serum cortisol level in the healthy Indian male population.

Cardiovascular disease remains the leading cause of morbidity and mortality in developed nations. Inflammation plays an increasingly important role in the cardiovascular disease process. Recent statin trials have demonstrated a correlation between the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) and cardiovascular risk. This review describes the results of changes in hsCRP in the major statin outcome trials and the concept of a "dual target" for both low-density lipoprotein cholesterol and hsCRP. The effect on hsCRP of combination statin therapy with ezetimibe, fenofibric acid, niacin, and colesevelam is reviewed. Although some statin combination therapies have additional effects on CRP and other atherogenic lipids, evidence for their effect on cardiovascular risk beyond statin monotherapy is lacking. Ongoing placebo-controlled trials investigating statin combination therapy versus statin monotherapy may provide additional clues to the role of additional changes in lipids versus markers of inflammation on cardiovascular risk reduction. Until these trials are completed, current evidence suggests focusing on low-density lipoprotein cholesterol targets.

Current guidelines recommend statins as first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C) and preventing cardiovascular events. Patients taking statins frequently experience adverse effects during therapy. The first step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Strategies for managing statin intolerance include changing statins, intermittent dosing, intensification of lifestyle modifications, and using other LDL-C-lowering agents such as ezetimibe, bile acid sequestrants, and LDL apheresis in suitable patients. More controversial approaches include red yeast rice, coenzyme Q10, and vitamin D supplementation. New therapies for LDL-C lowering are in development.

Hyperlipidemia is a risk factor for the development of coronary heart disease. Many patients decline prescription lipid-lowering agents and opt instead for supplements. Before any supplement can be routinely recommended it is crucial to examine the types of clinical trials that have been performed, the mechanism by which a supplement is felt to alter lipids, the population studied, potential adverse effects, and the possibility that investigators might be biased. Clinical trial evidence strongly supports the notion that both red yeast rice and plant stanols and sterols effectively lower low-density lipoprotein (LDL) cholesterol. Preliminary evidence supports the possibility that green tea catechins and black tea theaflavins may lower LDL. Data do not support an LDL-lowering claim for guggulipid, policosanol, or cinnamon. Finally, there is strong clinical trial evidence suggesting that marine omega-3 fatty acids lower triglycerides.

Acute coronary syndromes (ACS) represent an enormous disease burden, especially in the Western world, where they are one of the largest causes of mortality and morbidity. Patients suffering an acute coronary event are at very high risk of further coronary events, and although improvements in medical therapy over the past two decades have significantly reduced the risk, it remains high. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are now fully established in the primary and secondary prevention of stable coronary heart disease, and recently a substantial body of evidence has proven their efficacy in ACS. This paper examines the evidence for statin use in ACS.

Given the increased prevalence of obesity in the United States (and its associated cardiovascular risk) despite reduced fat intake, there has been increasing interest in the effect of low-carbohydrate diets on obesity. Recent prospective trials have demonstrated equivalent weight loss on low-carbohydrate versus low-fat diets, but with significantly different effects on metabolic risk factors for cardiovascular disease. Low-carbohydrate diets have more favorable effects on metabolic abnormalities found in insulin resistance syndromes, including serum triglyceride levels, high-density lipoprotein cholesterol levels, and small, dense low-density lipoprotein particles. The translation of these different metabolic effects on cardiovascular disease and events requires future studies. These studies should take into consideration that patients with insulin resistance syndromes would be the most likely group to benefit from carbohydrate restriction.

Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.

There is considerable disparity between the major clinical guidelines on lipid targets in diabetes and metabolic syndrome. Over the past few years, several trials have reported results that contribute to the evidence base for such lipid targets. The Treat to New Targets study data provide support for the efficacy and safety of using high-dose statin therapy for reducing low-density lipoprotein cholesterol (LDL-C) to at least 2 mmol/L in patients with diabetes and established cardiovascular disease (CVD). The Collaborative Atorvastatin Diabetes Study and the Heart Protection Study provide support for the efficacy and safety of lowering LDL-C to at least 2 mmol/L with lower doses of statins. Once these LDL-C targets have been reached, it is unknown whether targeting high-density lipoprotein cholesterol (HDL-C) and triglycerides is more efficacious than further lowering of LDL-C. The optimal treatment strategy, therefore, is unclear. Trials are underway to resolve this question. Patients with metabolic syndrome derive similar relative reduction in CVD from statin therapy as those without, and the appropriate treatment and targets depend on the estimated CVD risk. Prediction of CVD risk with currently available risk scores is imperfect but there is little evidence that including metabolic syndrome improves risk prediction beyond Framingham Risk Score mainly because the latter already includes blood pressure and HDL-C.

Unlike coronary heart disease, epidemiologic studies find a weak and inconsistent relationship between cholesterol levels and overall stroke risk. There does, however, appear to be a positive relationship between total and low-density lipoprotein cholesterol levels and the risk of ischemic stroke, with an inverse relationship between cholesterol levels and hemorrhagic stroke. Treatment with statins is associated with the reduction in the risk of a first stroke in various populations of patients at increased risk of cardiovascular events. Treatment of patients with prior cerebrovascular disease is associated with a reduction in major cardiovascular events and, in a single study, with a reduction in fatal and nonfatal stroke in patients with prior stroke or transient ischemic attack and no known coronary heart disease. Whether the benefit of statins in reducing the risk of stroke is due to their potent lipid-lowering effects, pleiotropic effects, or a combination of the two cannot be determined based on data available from clinical trials.

Objective: Arterial stiffness and highly sensitive C-reactive protein (hsCRP) serum level predict the risk for cardiovascular events. The most commonly used drugs for lowering cholesterol levels, the statins, also have anti-inflammatory effects and can decrease arterial stiffness. Ezetimibe is the first drug of a new class of cholesterol absorption inhibitors in common use and, to date, its effect on arterial stiffness has not yet been studied. The aim of this study was to compare the effect of simvastatin and ezetimibe, both singly and in combination, on arterial stiffness and hsCRP serum concentration in hypercholesterolemic patients., Methods: Forty hypercholesterolemic patients were studied. Group1 comprised previously untreated patients, who received simvastatin at doses of 40 mg/day during the study; group 2 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 80 mg/day during the study; group 3 consisted of patients previously untreated, who received ezetimibe at doses of 10 mg/day during the study; group 4 comprised patients previously treated with simvastatin at 40 mg/day, who received simvastatin at 40 mg/day and ezetimibe at 10 mg/day during the study. Arterial stiffness expressed as the Augmentation Index (AIx) (assessed by pulse wave analysis), the lipid profile and the hsCRP level were measured at baseline and after 3 months of treatment., Results: The reduction in low-density lipoprotein (LDL) after treatment was significantly greater in groups 1 and 4 (39.9 and 35.7%) than in groups 2 and 3 (17.7 and 16.9%; p = 0.005). The AIx decreased significantly only in group 1 patients, from 30.2 +/- 8.3% before treatment to 21.6 +/- 6.5% after treatment (p < 0.001). Changes in hsCRP paralleled the changes in AIx, with a significant decrease in patients in group 1 only, from 2.8 +/- 2.5 mg/L before treatment to 1.6 +/- 1.5 mg/L after treatment (p = 0.016)., Conclusion: Ezetimibe as a monotherapy had no effect on arterial stiffness or hsCRP, while the administration of simvastatin at 40 mg per day improved arterial stiffness and CRP. However, increasing the dose of simvastatin or administering ezetimibe in combination with simvastatin had no beneficial effects on arterial stiffness.

Cardiovascular disease remains the leading cause of death in both men and women in the United States. Treating elevated low-density lipoprotein (LDL) cholesterol has been shown to be very effective in reducing the rate of coronary heart disease (CHD) in primary prevention trials; however, the data are not as robust for treating individuals categorized at either lower risk for CHD or with below-average LDL cholesterol levels. The next frontier for investigation will include strategies to determine who in these lower risk categories should be treated with statins. The growing epidemics of obesity, diabetes, and metabolic syndrome also loom as major problems that need to be incorporated into any strategy that focuses on the prevention of cardiovascular disease. In individuals with multiple cardiovascular risk factors, combination therapies tailored to address each individual's risk profile need to be considered to best decrease the likelihood of their first coronary event.

In the 1960s, epidemiologic studies established a link between elevated serum cholesterol and increased risk of cardiovascular events. Extensive clinical trial data subsequently highlighted 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) as the most effective pharmacotherapy for lowering low-density lipoprotein (LDL) cholesterol, and showed that statin-mediated LDL cholesterol reductions were associated with significant improvements in cardiovascular outcomes. Such findings are reflected in current cardiovascular disease management guidelines, which focus on LDL cholesterol as the primary therapeutic target. These guidelines recommend target LDL cholesterol levels. However, a number of clinical trials have failed to identify an LDL cholesterol threshold level below which no further cardiovascular risk reduction occurs. Such findings suggest that optimal risk reduction may require greater reductions in LDL cholesterol than are currently being achieved. This review examines recent data highlighting the benefits of more pronounced LDL cholesterol reductions and considers how this could be achieved in clinical practice when many patients are not even reaching current targets.

Until recently, the role of statin therapy in diabetic patients without clinical signs or symptoms of coronary heart disease had been inadequately defined. The Collaborative Atorvastatin Diabetes Study (CARDS) is a prospective, randomized, placebo-controlled trial designed to compare the effects of atorvastatin with placebo in preventing primary coronary events in diabetic patients. After a median of only 3.9 years (the study was terminated approximately 2 years early due to the magnitude of benefit attributable to atorvastatin therapy), risk for major cardiovascular events was decreased by 37%, acute coronary heart disease-related events were also reduced by 36%, coronary revascularizations by 31%, and stroke by 48%. Benefit emerged within 1 year of initiating therapy.

Outcomes from recent lipid-lowering trials have led to an update of the third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel's guidelines for treatment of hypercholesterolemia in adults. The updated NCEP guidelines now offer an optional goal of low-density lipoprotein (LDL) cholesterol of less than 70 mg/dL for high-risk individuals. Epidemiologic and clinical trial data suggest that for every 30-mg/dL change in LDL, the relative risk for coronary heart disease changes by about 30%. Statin therapy effectively lowers LDL and has an overall excellent safety profile in clinical trials. However, the use of high-dose statin therapy also entails greater risk of adverse events, such as myopathy and liver function test abnormalities, and this must be carefully weighed against the potential benefit for each patient. Alternative approaches targeting high-density lipoproteins and triglycerides may offer yet another option for coronary heart disease prevention in high-risk patients.

Cholesterol absorption and synthesis are inter-regulated, so if one changes then the other changes in the opposite direction. The regulation and detailed mechanism of cholesterol absorption have been intensely investigated. Inhibition of cholesterol absorption has become an additional factor for cholesterol lowering. Agents inhibiting cholesterol absorption, mainly plant stanols and sterols or ezetimibe, usually lower low-density lipoprotein cholesterol in monotherapy by less than 20%, indicating that these inhibitors can normalize cholesterol levels only in patients with a modest baseline hypercholesterolemia. Body weight, especially obesity with and without diabetes, and dietary plant sterols alter cholesterol absorption differently. This article briefly reviews some special questions of cholesterol absorption under these conditions.

The elderly (men aged 65 years and older and women aged 75 years and older) constitute a population at high absolute risk for the morbidity and mortality of atherosclerotic cardiovascular disease. Statins have been shown in multiple large trials to reduce the burden of atherosclerotic disease in both middle-aged and elderly patients at elevated risk for coronary events, stroke, and death. We reviewed the major statin trials with particular emphasis on the significant number of elderly subjects. The impact of statins on the elderly, both positive and negative, is tabulated. In addition, we briefly discuss risk assessment in the elderly because selection of elderly patients for intensive low-density lipoprotein cholesterol reduction with statins requires clinical judgment that must weigh the need for subclinical measures of atherosclerosis. We also consider negative aspects, risks, and costs of such therapy.

Coronary heart disease (CHD) is the leading cause of death and disability in the industrialized world. Included among the risk factors for CHD are an elevated level of low-density lipoprotein (LDL) cholesterol and a low level of high-density lipoprotein (HDL) cholesterol. The discovery of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins), the rate-limiting enzyme in cholesterol biosynthesis, constituted a major advance in the treatment of patients with elevated plasma concentrations of LDL cholesterol. However, although the statins are potent LDL-lowering agents, they may not be the therapy of choice for all dyslipidemic patients. This is particularly true for subjects whose primary lipid abnormality is a low level of HDL cholesterol with or without hypertriglyceridemia, a group that includes about one half of patients with CHD. In this report, we review emerging options for the treatment of patients with lipid disorders, including inhibitors of cholesterol absorption, acyl coenzyme A-cholesterol acyltransferase, microsomal triglyceride transfer protein, and cholesteryl ester transfer protein, as well as liver X receptor agonists that up-regulate the expression of ATP-binding cassette transporter A1.

The soybean diet is the most potent dietary tool for hypercholesterolemia. The United States Food and Drug Administration recently approved the health claim for its role in reducing the risk of coronary disease. The hypocholesterolemic effect is directly correlated to the patient's cholesterolemia, with minimal or no reductions occurring at cholesterol of 6 mmol/L or less, and the most benefit occurring in patients with cholesterol of greater than 7 mmol/L. Hypotheses on the mechanism of action include soy fiber, isoflavones (phytoestrogens), and the protein itself. Although there is no evidence for the effect of fiber, studies with ethanol-extracted soy (devoid of isoflavones) indicated a loss of effect, but the extract itself (isoflavone rich) has no hypocholesterolemic activity. In humans, soy protein activates the low-density lipoprotein (LDL) receptor pathway. Recent data suggest that soy protein subunits, particularly 7S, directly activiate LDL receptors in the human liver, thus providing a novel mechanism of plasma cholesterol reduction different from currently available diets and hypolipidemic drugs.

Clinical trials have shown that 3-hydoxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known as statins, significantly reduce the risk of both primary and secondary coronary heart disease events. Although these trials have included few women, the evidence suggests that statins are as effective in women as in men. The addition of hormone replacement therapy to statin therapy augments lowering of low- density lipoprotein cholesterol, but may not increase the favorable effects on clinical events achieved with statins alone. Finally, new data suggest that statins may also reduce the risk of osteoporotic fractures, a provocative finding still in need of verification by clinical trials.