Use Of Cholesterol-lowering Agents Research Articles

Current pharmacotherapy and putative disease-modifying therapy for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease of the central nervous system correlated with the progressive loss of cognition and memory. β-Amyloid plaques, neurofibrillary tangles and the deficiency in cholinergic neurotransmission constitute the major hallmarks of the AD. Two major hypotheses have been implicated in the pathogenesis of AD namely the cholinergic hypothesis which ascribed the clinical features of dementia to the deficit cholinergic neurotransmission and the amyloid cascade hypothesis which emphasized on the deposition of insoluble peptides formed due to the faulty cleavage of the amyloid precursor protein. Current pharmacotherapy includes mainly the acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonist which offer symptomatic therapy and does not address the underlying cause of the disease. The disease-modifying therapy has garnered a lot of research interest for the development of effective pharmacotherapy for AD. β and γ-Secretase constitute attractive targets that are focussed in the disease-modifying approach. Potentiation of α-secretase also seems to be a promising approach towards the development of an effective anti-Alzheimer therapy. Additionally, the ameliorative agents that prevent aggregation of amyloid peptide and also the ones that modulate inflammation and oxidative damage associated with the disease are focussed upon. Development in the area of the vaccines is in progress to combat the characteristic hallmarks of the disease. Use of cholesterol-lowering agents also is a fruitful strategy for the alleviation of the disease as a close association between the cholesterol and AD has been cited. The present review underlines the major therapeutic strategies for AD with focus on the new developments that are on their way to amend the current therapeutic scenario of the disease.

Consecución del objetivo terapéutico del colesterol de las lipoproteínas de baja densidad en las unidades de lípidos y riesgo vascular de la Sociedad Española de Arteriosclerosis

ObjectiveTo evaluate low-density lipoprotein-cholesterol (LDLc) goal achievement among dyslipidemic patients treated in lipid and vascular risk units of the Spanish Society of Arteriosclerosis (SEA). The LDLc goal was based on the 2007 European guidelines for cardiovascular prevention. DesignObservational, longitudinal, retrospective, multicenter national study that included consecutive patients of both sexes over 18years of age referred for dyslipidemia and cardiovascular risk. Information was collected from medical records corresponding to two visits in the lipid unit. ResultsWe included 1,828patients from 43lipid units. In the initial visit, 846 (46.3%) patients were on lipid lowering drug treatment. On the follow-up there was a significant increase in the use of cholesterol-lowering agents, except for a decrease in the use of nicotinic acid. 65.3% of patients with vascular disease and 50.4% with diabetes achieved an LDLc level <100mg/dL. Overall, 44.7% of patients achieved the LDLc goal and the predictors in the multivariate analysis were age, waist circumference, diabetes and the presence of vascular disease. ConclusionDyslipidemic patients referred to SEA lipid units have improved LDLc goal achievement after follow-up compared with data reported from previous studies in other health care settings. This improvement was associated with a substantial increase in the prescription of statins, both in monotherapy and combined with ezetimibe. There is still a wide room for improvement in the effectiveness of hypercholesterolemia treatment.

HMG-CoA Reductase Inhibitors in Chronic Kidney Disease

The incidence of chronic kidney disease (CKD) is on the rise in the USA. Cardiovascular events are the leading cause of death in this patient population, therefore reducing the risk of these events has become a major focus. The aim of this review is to assess current literature on the use of statins in CKD and end-stage renal disease. Cholesterol reduction is important in preventing the development and progression of coronary heart disease and its negative effects. Statins have been widely studied and proven to reduce cardiovascular risk in the general population. The information gained from trials has been extrapolated to special populations, including CKD, despite these patients often being excluded. However, recent studies have begun to focus on CKD, hemodialysis, and transplant patients and the use of cholesterol-lowering agents and the potential association with decreased cardiovascular events. In addition, due to the unique pharmacokinetic and pharmacodynamic changes that occur in these patients, choosing the appropriate cholesterol-lowering agent becomes important for both safety and efficacy. The complexity of CKD patients is an important consideration when choosing cholesterol-lowering medication. Patients with CKD are often on medications that may interact with many of the cholesterol-lowering agents. Ensuring drug interactions are minimized is essential to the prevention of adverse events from the medications.

Statin use and lower extremity amputation risk in nonelderly diabetic patients

To examine the association between use of statin and nonstatin cholesterol-lowering medications and risk of nontraumatic major lower extremity amputations (LEAs) and treatment failure (LEA or death). A retrospective cohort of patients with Type I and Type 2 diabetes mellitus (diabetes) was followed for 5 years between 2004 and 2008. The follow-up exposure duration was divided into 90-day periods. Use of cholesterol-lowering agents, diabetic medications, hemoglobin A1c, body mass index, and systolic and diastolic blood pressures were observed in each period. Demographic factors were observed at baseline. Major risk factors of LEA including peripheral neuropathy, peripheral artery disease, and foot ulcers were observed at baseline and were updated for each period. LEA and deaths were assessed in each period and their hazard ratios (HRs) were estimated. The study took place in the U.S. Department of Veterans Affairs Healthcare system, and the subjects consisted of cholesterol drug-naïve patients with Type I or II diabetes who were treated in the U.S. Department of Veterans Affairs Healthcare system in 2003 and were<65 years old at the end of follow-up. Of 83,953 patients in the study cohort, 217 (0.3%) patients experienced a major LEA and 11,716 (14.0%) patients experienced an LEA or death (treatment failure) after a mean follow-up of 4.6 years. Compared with patients who did not use cholesterol-lowering agents, statin users were 35% to 43% less likely to experience an LEA (HR, 0.65; 95% confidence interval [CI], 0.42-0.99) and a treatment failure (HR, 0.57; 95% CI, 0.54-0.60). Users of other cholesterol-lowering medications were not significantly different in LEA risk (HR, 0.95; 95% CI, 0.35-2.60) but had a 41% lower risk of treatment failure (HR, 0.59; 95% CI, 0.51-0.68). This is the first study to report a significant association between statin use and diminished amputation risk among patients with diabetes. In this nonrandomized cohort, beneficial effects of statin therapy were similar to that seen in large-scale clinical trial experience. For LEA risk, those given nonstatins did not have a statistically significant benefit and its effect on LEA risk was much smaller compared with statins. Unanswered questions to be explored in future studies include a comparison of statins of moderate vs high potency in those with high risk of coronary heart disease and an exploration of whether the effects seen in this study are simply effects of cholesterol-lowering or possibly pleiotropic effects.

Statins to treat Alzheimer’s disease: an incomplete story

Evaluation of: Sano M, Bell KL, Galasko D et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77(6), 556–563 (2011).The link between cholesterol and Alzheimer’s disease (AD) has been explored for almost two decades. The link stems from the observation that atherosclerotic heart disease increases the risk for AD and that people expiring from coronary artery disease had AD changes in their brains. Cholesterol is a cofactor of amyloid deposition, with substantial evidence showing that high cholesterol diets in animal models can accelerate amyloidogenesis. This link led investigators to posit the use of cholesterol-lowering agents as treatments for AD and cognitive decline. Indeed, the epidemiological data suggest that cholesterol-lowering agents may reduce the risk of developing AD. Early pilot studies suggested that statins may be useful as treatments for AD because of a reduction in the rates of decline. Recent reports of simvastatin and atorvastatin assessed in large randomized, double-blind, placebo-controlled multicenter trials have not confirmed a clinically demonstrable cognitive benefit for statins in the treatment of AD. This article will discuss the results of one of these trials and explore the reasons behind why the multicenter trials may not have been positive and the growing disparity between preclinical/epidemiological benefit and a lack of clinical efficacy.

Serum cholesterol and the progression of Parkinson's disease: results from DATATOP.

BackgroundRecent studies have suggested that higher serum cholesterol may be associated with lower occurrence of Parkinson's disease (PD). This study is to test the hypothesis that higher serum cholesterol correlates with slower PD progression.MethodsBaseline non-fasting serum total cholesterol was measured in 774 of the 800 subjects with early PD enrolled between 1987 and 1988 in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. Participants were followed for up to two years, with clinical disability requiring levodopa therapy as the primary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CI) were determined for increasing serum cholesterol concentration (in quintiles) for clinical disability requiring levodopa therapy, after adjusting for confounders. At baseline, only nine subjects reported use of cholesterol-lowering agents (two with statins).ResultsThe overall mean cholesterol level was 216 mg/dL (range 100–355). The HR of progressing to the primary endpoint decreased with increasing serum cholesterol concentrations. Compared to the lowest quintile, the HRs (95%CI), for each higher quintile (in ascending order) are 0.83 (0.59–1.16); 0.86 (0.61–1.20); 0.84 (0.60–1.18); and 0.75 (0.52–1.09). The HR for one standard deviation (SD) increase = 0.90 [(0.80–1.01), p for trend = 0.09]. This trend was found in males (HR per SD = 0.88 [(0.77–1.00), p for trend = 0.05], but not in females [HR = 1.03 (0.81–1.32)].ConclusionsThis secondary analysis of the DATATOP trial provides preliminary evidence that higher total serum cholesterol concentrations may be associated with a modest slower clinical progression of PD, and this preliminary finding needs confirmation from larger prospective studies.

Diabetes in the UK: time for a reality check?

Diabetes in the UK: time for a reality check?

Holoprosencephaly in an 8.5-week triploidy gestation

Holoprosencephaly (HPE), the most common malformation of the human forebrain, is because of failed midline cleavage of the developing forebrain between the 18th and 28th days of gestation. HPE occurs in up to one in 250 gestations, though less than 3% of these survive to birth (Matsunaga and Shiota, 1977; Leoncini et al., 2008). Severity is defined by the extent of brain malformations; categories include alobar (the most severe type), semilobar, and lobar HPE (Plawner et al., 2002). The spectrum of facial dysmorphisms is wide, but at the severe end of the spectrum, individuals may show cyclopia or synophthalmia (fusion of the optic vesicles with incomplete eye development), a proboscis (a tubular nasal appendage above the fused eyes), and severe microcephaly. HPE may occur as one feature in a syndrome (as in Smith-Lemli-Opitz syndrome) (Kelley et al., 1996), result from teratogenic influences (such as the use of cholesterol lowering agents in early gestation) (Edison and Muenke, 2004), or be because of mutations in genes involved in forebrain development (such as SHH) (Muenke and Beachy, 2000). Most often, HPE occurs in the context of cytogenetic anomalies. Up to 50% of patients born with HPE have cytogenetic anomalies; an even greater proportion of fetuses with HPE have cytogenetic anomalies (Muenke and Beachy, 2000).

Prostate Weight and Early Potency in Robot-Assisted Radical Prostatectomy

Using an athermal technique for nerve preservation we noted that approximately 40% are potent compared with approximately 60% who are not at 3 months after robot-assisted laparoscopic prostatectomy (RLP). In an attempt to understand this difference, we examine factors potentially influencing potency at 3 months. Of 300 consecutive RLPs, we identified 139 men who met preoperative inclusion criteria: age <or= 65 years with International Index of Erectile Function (IIEF-5) scores of 22-25. All men were instructed to take 5'-phosphodiesterase inhibitors postoperatively. All data were collected and entered prospectively into an electronic database. Sexual outcomes were obtained via self-administered validated questionnaires. We defined potency by affirmative answers to the following questions: Were erections adequate for penetration, and were they satisfactory? At 3 months, 53 subjects (38%) were potent. Univariate and multivariate analysis demonstrated no effect for IIEF-5 score, body mass index, nerves spared, estimated blood loss, hypertension, diabetes, use of cholesterol-lowering agents, and lifestyle issues. Prostate weight (43.3 vs 51.4 g, P = .038) and age (55 vs 57, P = .03) were significant in univariate analysis. In multivariate analysis only prostate weight was predictive of potency (P = .04). To ascertain a possible relation between traction nerve injury and prostate weight, analysis between prostate weight groups and potency demonstrated an inverse relationship. Low prostate weight was the only factor found to correlate with early return of potency. Our data also suggest that increasing prostate weight increases the risk of delay in potency recovery.

Rationale, design, and baseline characteristics of a randomized trial to assess the effect of cholesterol lowering on the progression of aortic stenosis: The Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial

Aortic stenosis (AS) is a common health problem in the western world. Recent studies have suggested that cholesterol lowering may have a salutary effect on the progression of AS. The primary objective of the ASTRONOMER study is to determine whether patients with AS randomized to rosuvastatin will experience less progression in AS severity as measured by aortic transvalvular gradients and valve areas. The secondary objectives are to determine the effect of rosuvastatin on the rate of cardiac death and aortic valve replacement and to assess the time to outcome during a follow-up of 3 to 5 years. This is a double-blind placebo-controlled study. Patients with mild to moderate AS are randomized to receive 40 mg/d of rosuvastatin or placebo. Patients with any clinical indication for the use of cholesterol-lowering agents according to the 2000 Canadian guidelines are excluded. Recruitment of 272 patients from 23 Canadian sites was completed in December 2005. Compared with patients with AS in published trials, the patients in the ASTRONOMER study are younger (58.1 +/- 13.6 years), have less severe AS (AS jet velocity 3.2 +/- 0.4 m/s), and are composed of a great proportion (48.9%) of patients with bicuspid aortic valve. Prevention of the development of severe AS needs to be tested in large randomized studies. Recruitment for the ASTRONOMER trial has been completed and results will be available at the end of 2008.

Lower low‐density lipoprotein cholesterol levels are associated with Parkinson's disease

The apolipoprotein E (APOE) epsilon2 allele has been associated with both Parkinson's disease (PD) and lower low-density lipoprotein cholesterol (LDL-C). We tested the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 112 controls. The PD cases were recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and the controls were recruited from the spouse populations of the same clinic. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterol-lowering agents. Lower LDL-C concentrations were associated with a higher occurrence of PD. Compared with participants with the highest LDL-C (> or =138 mg/dL), the OR was 2.2 (95% CI = 0.9-5.1) for participants with LDL-C of 115 to 137, 3.5 (95% CI = 1.6-8.1) for LDL-C of 93 to 114, and 2.6 (95% CI = 1.1-5.9) for LDL-C of < or = 92. Interestingly, use of either cholesterol-lowering drugs, or statins alone, was related to lower PD occurrence. Thus, our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence, either of which finding warrants further investigation.

Prevention of Alzheimer's Disease and Other Dementias

Alzheimer's disease (AD) affects 150 000 Australians and prevention is a high priority. Approaches to reduce the risk of AD and other dementias can be based on the risk factors that have been suggested from case‐control and longitudinal studies. There is some evidence of benefit from vitamin E supplements (and possibly also vitamin C), a well'balanced diet including adequate folate and vitamin B12, keeping physically and mentally alert, avoiding head injury, continuing moderate alcohol intake, avoiding excess aluminium exposure, avoiding smoking, and keeping elevated blood pressure, diabetes and other vascular risk factors under control. There are currently insufficient data to support the use of cholesterol'lowering agents, anti'inflammatory agents, oestrogen, caffeine, or ginkgo biloba to prevent dementia, but large prospective randomised placebo'controlled prevention trials are in progress for some of these agents and may alter these recommendations. Approaches in the future which look very promising are anti'amyloid vaccination and gene therapy. Targeting high risk groups, such as those with mild cognitive impairment, may increase the benefit of preventative approaches.

Chemoprevention for pancreatic cancer.

For a number of solid tumors, including pancreatic cancer, efforts aimed at disease prevention may be more successful than currently available anticancer treatments. While specific interventions are emerging to prevent breast, prostate, lung, and colorectal cancer, no trials of chemoprevention are being conducted in pancreatic cancer. Importantly, there are significant obstacles to the conduct of such research. However, preclinical and epidemiologic studies suggest that several drugs may have chemopreventive potential in pancreatic cancer. These include aspirin and other non-steroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase inhibitors, somatostatin analogs, selective estrogen receptor modulators (SERMs), and anti-androgenic agents. As the oncology community evaluates some of these agents in large chemoprevention trials for breast, colon, and prostate cancer, it may be found that pancreatic cancer prevention occurs as an unintended, but desirable consequence. Moreover, other general societal trends, such as smoking cessation and the widespread use of cholesterol-lowering agents and aspirin, could have a role in reducing the risk of pancreatic cancer, and in the future, may lead to a decrease in its incidence.

South Asians with diabetes mellitus do not receive lipid-lowering treatment despite an identical calculated risk of coronary heart disease compared with Caucasians

We have evaluated the effect of a computerised CHD risk calculation program, based on the Framingham algorithm, on the use of cholesterol-lowering agents in a hospital diabetes clinic. For a period of six months we audited the appropriateness of the original request for CHD risk calculation, the clinical action taken and the outcome for all patients with a calculated 10 year CHD risk ≥30%. CHD risk calculations were performed on 1264 patients, of whom 180 (14.2%) had calculated 10 year CHD risks ≥30%. The case notes were available on 128 (71.1%) of these patients of whom 38 (30%) were of South Asian ethnicity. 47 patients (37%) had CHD risk calculations performed inappropriately, primarily due to pre-existing cardiovascular disease. There were no significant racial differences in calculated CHD risk, systolic blood pressure, cholesterol/HDL ratio, prevalence of current cigarette smoking or left ventricular hypertrophy in the remaining 81 patients. The South Asian group had significantly lower total and HDL cholesterol levels (p=0.001 and 0.004 versus Caucasians). Statins were prescribed in 49 patients (60.5%) (15/31 Asians versus 34/50 Caucasians; p=0.064). Those patients without pre-existing cardiovascular disease but who have calculated 10 year CHD risks ≥30% should be candidates for cholesterol-lowering drugs. South Asians appear less likely to receive such treatment, possibly because they have on average lower total serum cholesterol concentrations than do Caucasian patients at identical levels of calculated CHD risk. During the audit, 3/31 South Asians and 2/50 Caucasians had a first non-fatal myocardial infarct (p=0.28, Fisher exact probability). Copyright © 2000 John Wiley & Sons, Ltd.

The Effects of Long Term Use of HMG-CoA Reductase Inhibitor on the Level of Lp (a)

Background:Lipoprotein (a) concentration is mainly determined by apo (a) genotype, but elevated in the atherosclerotic vascular disease more than in normal group with the same apo (a) phenotype. It has been known that Lp (a) has independent metabolism in contrast with other lipoproteins and that the use of cholesterol lowering agent such as HMG-CoA reductase inhibitor for 6 months does not change the level of Lp (a). The results of several studies suggests that Lp (a) may be related to inflammation of atherosclerotic plaque and therefore, long term use of cholesterol lowering agents make plaque stable by reduction of inflammation at plaque. We hypothesized that there is a relationship between long term use of HMG-CoA reductase inhibitor and change of Lp (a) level. We prospectively measured Lp (a), lipids and inflammatory markers before and after long term use of HMG-CoA reductase inhibitor to examine our hypothesis. Methods:Forty-nine subjects (M: F=28:21, age=59.1±12.0) with hyperlipidemia were administered HMG-CoA reductase inhibitor for 15 months (minimum 6 months, maximun 44 months), and Lp (a), lipids and inflammatory markers were measured before and after use of the HMG-CoA reductase inhibitor. In control group (ninty-nine subjects, M:F= 60:39, age=61.2±9.2), these parameters were measured more than 6 months. Results:In the hyperlipidemia group who were given HMG-CoA reductase inhibitor, baseline levels of total cholesterol, TG, LDL were significantly elevated more than those of the control group, but Lp (a) and inflammatory markers were not significantly different. After use of HMG-CoA reductase inhibitor, the level of Lp (a) was reduced significantly (before 28.9±29.3 mg/dl, after 20.0±19.0 mg/dl, p=0.009), but not significantly in the control group. There was a minimal relation between baseline Lp (a) levels and percent changes of Lp (a) levels. Total cholesterol and LDL levels reduced significantly after use of the drug, but inflammatory markers did not. Conclusion:These data showed that Lp (a) level in the hyperlipidemia group after the long term use of HMG-CoA reductase inhibitor decreased significantly. We suggest that these changes of Lp (a) level may be one of reliable markers 논문접수일:1999년 7월 19일 심사완료일:1999년 11월 18일 교신저자:서홍식, 152-703 서울 구로구 구로동 80 고려대학교 의과대학 순환기내과학교실 전화:(02) 816-6634·전송:(02) 864-3062 E-mail:mdhsseo@unitel.co.kr

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

Diet and coronary heart disease. Helping patients reduce serum cholesterol level.

Although coronary heart disease (CHD) remains the No. 1 cause of death in the United States, the CHD mortality rate has shown a recent decline. This has been attributed to lower fat consumption in the general population, with associated lower serum cholesterol levels. Thus, diet seems to be an important factor in controlling cholesterol level. Acting on this hypothesis, primary care physicians can help patients make appropriate dietary changes. We believe that persons at risk of hypercholesterolemia need to be identified in adolescence by measurement of total serum cholesterol level and that testing should be done every two years after age 25. The American Heart Association's prudent diet is recommended for all patients, especially those with a serum cholesterol level above 240 mg/dl. When dietary restriction does not bring the level within this limit, use of cholesterol-lowering agents is considered. To be lasting, dietary change must be gradual; realistic immediate and long-term goals should be established. In addition, the diet must be nutritionally sound and the patient must receive support from family members.