Thesis (M.S.)--University of Michigan, 1997. / Includes bibliographical references.

Hypercholesterolemia is one of the most prevalent, yet underdiagnosed diseases faced by the medical community today. Its prevalence can largely be attributed to diet, lack of exercise, and lifestyle choices such as smoking or drinking, but there is also a genetic component. Familial Hypercholesterolemia is the genetic disorder in which a person is unable to properly eliminate levels of low-density lipoprotein, mostly due to an ineffective receptor in the liver. Hypercholesterolemia has been positively correlated with the prevalence of cardiovascular disease, and patients with the severe homozygous familial hypercholesterolemia typically have abbreviated lifespans. In these situations, and also those less acutely dire, it’s necessary to rely on medication to help maintain one’s cholesterol levels to within low risk ranges. High does statin therapy has been shown to be the most effective therapy for maintaining LDL cholesterol. It has become the standard regardless of the cause of hypercholesterolemia because of its few side effects, its high tolerability, its ease of administration, its safety, and most of all because of its immense efficacy. This has not, however, prevented the exploration into other types of cholesterol therapies that may work in concurrence with statins. Drug classes such as PCSK9 inhibitors, ApoB inhibitors, MTP inhibitors, and thyromimetics have all been explored with varying success. Each of these potential therapies has a separate mechanism of action, allowing for modulation in conjunction with statins. PCSK9 inhibitors and ApoB inhibitors appear to provide the most upside by virtue of LDL lowering capabilities, followed by a drug known as ezetimibe that reduces dietary cholesterol uptake in the gut. MTP inhibitors have been shown to be effective therapies for homozygous familial hypercholesterolemia specifically due to their function of lowering LDL particle creation rather than LDL receptor number or function as statins and PCSK9 inhibitors do. Thyromimetics have yet to yield an effective therapy for cholesterol treatment, but the hope remains alive that this could come to fruition in the future.

No description available.

Class of 2017 Abstract / Objectives: To determine the cost-effectiveness of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors with high-intensity statins compared to high-intensity statins alone for the treatment of heterozygous familial hypercholesterolemia (HeFH). Methods: A Markov model was built through TreeAge Pro to model two groups: patients taking PCSK9 inhibitors with high-intensity statins or high-intensity statins alone. For each group, there were five health states that patients could be in: well, unstable angina, myocardial infarction, ischemic stroke, or death. The data used in the model were extracted from published clinical trials evaluating PCSK9 inhibitors and statins. Results: For the primary analysis, the overall cost and effectiveness was $31,390.93 and 23.01 for the statin alone group and $362,798.50 and 24.32 for the PCSK9 with statin group, respectively. The incremental cost, incremental QALY, and incremental cost-effectiveness ratio (ICER) was $331,407.60, 1.31 QALYs, and $252,833.60/QALY, respectively. Conclusions: Since the calculated ICER was higher than the pre-established threshold of $150,000, the results from our primary analysis suggest that treatment of patients with HeFH with a PCSK9 inhibitor and a high-intensity statin is not cost effective, compared to treatment with a high-intensity statin alone. However, when certain parameters (cost of PSCK9 and mortality rate) were adjusted in the secondary analyses, these agents appear to be cost-effective.

Statins are often the first-line therapy in the treatment of patients with hypercholesterolemia. Though often regarded as relatively low risk and widely effective in treating hypercholesterolemia, statin therapy has a variety of limitations, including statin resistance and statin intolerance. These limitations have led researchers to actively investigate other types of cholesterol-lowering remedies that utilize mechanisms unlike those targeted by statins. Bempedoic acid, an oral prodrug that upon activation reduces LDL-C by inhibition of ATP citrate lyase, has been thoroughly evaluated as one such therapy for treating hypercholesterolemia. Through a variety of clinical trials, bempedoic acid, formerly referred to as ETC-1002, has displayed efficiency as both a low-risk monotherapy and a secondary therapy. In this latter role, bempedoic acid has been used in conjunction with statin or ezetimibe treatment by hypercholesteremic patients with a history of atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) or both. Based on promising results from phase III clinical trials, the Food and Drug Administration (FDA) approved bempedoic acid, under the brand name Nexletol, for treatment of hypercholesterolemia in conjunction with other cholesterol-lowering medications.

Background. The published reports of the effectiveness of simvastatin in treatment of hypercholesterolemia were mostly conducted in western populations, and only few studies in Asian or domestic populations have ever been reported. By regulations from Bureau of National Health Insurance, the effective dosage of lipid lowering agents should be started from lower dose, such as 20 mg of simvastatin per day. Whether this dosage of simvastatin is effective for treatment of patients with hypercholesterolemia and the efficacy and safety of such dosage are the objects of this study. Materials and Methods. After the approval of IRB in a medical center located at north Taiwan, a randomized 12-week study was conducted to evaluate the efficacy and safety of 20mg/day simvastatin treatment on hypercholesterolemia. By randomization 65 patients, followed up at cardiovascular outpatient department under the diagnosis of primary hypercholesterolemia, were enrolled into a 4-week washout period, and finally 49 intent-to-treat patients entered a 12-week treatment with 20mg simvastatin per day, given through oral routine in the evening. Demographic and laboratory data were obtained before and after treatment. The primary efficacy measure was the changes from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the most commonly reported adverse experiences. Results. The per-protocol analyses included 39 hypercholesterolemic patients whom completed 12 weeks of therapy. Total cholesterol and LDL cholesterol at the end of the study period showed significant reductions by 22.5¢H (p<0.001) and 29.8¢H(p<0.001), respectively. Triglyceride also showed a significant reduction by 31.8% (p=0.006), whereas total alkaline phosphatase and calcium showed a weak and insignificant change over the study period. The female group had significantly greater reduction in triglyceride than that in the male group, and the non-smoking group also had significantly greater reduction in triglyceride than that in smoking group after 12-week treatment. There were 17 studied cases (34.7%) had minor transient but clinical insignificant increases in serum aspartate aminotransferase and alanine aminotransferase, and 7 cases (14.3%) experienced symptom of painful muscle, of whom 3 cases (6.1%) dropped out this study. Conclusion. Our results, although obtained from a small scale of hypercholesterolemic patients, suggest a probable positive efficacy and good tolerability with only few minor side effects of simvastatin on blood lipids.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 149-160).

Orientador: Osvaldo Magro Filho / Coorientador: Leonardo Perez Faverani / Banca: Roberta Okamoto / Banca: André Luís da Silva Fabris / Resumo: Esse estudo objetivou-se em avaliar o papel da membrana de fibrina rica em plaquetas na reparação óssea em defeito crítico de calota de ratos induzidos à hipercolesterolemia, bem como a atuação do tratamento de atorvastatina nesse processo. Quarenta defeitos críticos de 6 mm de diâmetro foram criados em calotas cranianas de ratos. Cada defeito foi aleatoriamente dividido em 8 grupos experimentais (GC, GCPRF, GCA, GCH, GHA, GPRFA, GPRFH, GPRFHA), avaliados aos 28 dias pós-operatórios com análises histológica e microtomográfica. Os resultados mostraram que houve formação óssea em todos os grupos analisados. O grupo GPRFH apresentou formação óssea mais acentuada com relação aos demais grupos. Dos grupos em que foi administrado atorvastatina, o GPRFHA apresentou maior taxa de formação óssea (p < 0,05). Com a metodologia utilizada, a fibrina rica em plaquetas, quando associada à condição de hipercolesterolemia, induziu ao aumento da formação óssea / Abstract: Objectives: The aim of this study was to evaluate the efficacy of Platelet Rich Fibrin (PRF) in the healing process of surgically created critical-size defects in rat calvarial induced to hypercholesterolemia treated or not with atorvastatin. Materials and method: 40 critical defects were created with 6 mm diameter calvaria of rats. Each defect was randomly divided into eight experimental groups (GC, GCPRF, GCA, GCH, GHA, GPRFA, GPRFH, GPRFHA), evaluated at 28 postoperative days for histomorphometry and microtomography. Results: The results showed new bone formation in all groups. The GPRFH group just did differ from all groups in the new bone formation (p < 0.05). Among the groups treated with atorvastatin, the GPRFHA group showed the highest bone formation rate. Conclusion: With the methodology used, the platelet-rich fibrin associated with the hypercholesterolemia induced to new bone formation. Clinical relevance: Based on these results, it is necessary to unveil the mechanisms of the association of platelet-rich fibrin with hypercholesterolemia and how it interferes in PRF microstructure and bone regeneration, to confer clinical predictability in patients in this condition who will undergo bone reconstruction and implant rehabilitation / Mestre

Heart disease is the leading cause of death in the United States. Hyperlipidemia is a predominant risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). The statin drug class is the first line therapeutic for lowering atherogenic low-density lipoprotein (LDL) levels by competitively inhibiting 3-hydroxyl-3methyl-glutaryl-coenzyme A (HMGCR) reductase, the rate-limiting enzyme in cholesterol biosynthesis. However, there are patients who are unable to achieve desirable LDL levels despite statin therapy, such as those with familial hypercholesterolemia or those who are statin intolerant. A new therapy was discovered in 2015 to benefit patients with uncontrolled LDL levels by inhibiting Proprotein convertase subtilisin-kexin type 9 (PCSK9), a key protein in LDL receptor metabolism. Evolocumab (Repatha, AMGEN) is a human monoclonal antibody against human PSCK9. Evolocumab is approved to lower LDL-cholesterol in adult patients who have, despite dietary and lifestyle changes and maximally tolerated statin dose continued suboptimal lipid levels with either ASCVD or Heterozygous Familial Hypercholesterolemia (HeFH). Evolocumab has been shown to significantly reduce atherogenic lipid levels and the recent FOURNIER clinical trial showed that evolocumab reduces cardiovascular events. However, the high annual cost of evolocumab has raised questions as to its cost-effectiveness and role in the prevention and treatment of ASCVD. At the present price levels, this therapy does not appear to be cost-effective with multiple analyses suggesting significant price reduction will be necessary before this drug can be used in standard treatment for secondary prevention of cardiovascular disease in the United States.

abstract: Background: Evidence about the purported hypoglycemic and hypolipidemic effects of nopales (prickly pear cactus pads) is limited. Objective: To evaluate the efficacy of nopales for improving cardiometabolic risk factors and oxidative stress, compared to control, in adults with hypercholesterolemia. Design: In a randomized crossover trial, participants were assigned to a 2-wk intervention with 2 cups/day of nopales or cucumbers (control), with a 2 to 3-wk washout period. The study included 16 adults (5 male; 46±14 y; BMI = 31.4±5.7 kg/m2) with moderate hypercholesterolemia (low density lipoprotein cholesterol [LDL-c] = 137±21 mg/dL), but otherwise healthy. Main outcomes measured included: dietary intake (energy, macronutrients and micronutrients), cardiometabolic risk markers (total cholesterol, LDL-c, high density lipoprotein cholesterol [HDL-c], triglycerides, cholesterol distribution in LDL and HDL subfractions, glucose, insulin, homeostasis model assessment, and C-reactive protein), and oxidative stress markers (vitamin C, total antioxidant capacity, oxidized LDL, and LDL susceptibility to oxidation). Effects of treatment, time, or interactions were assessed using repeated measures ANOVA. Results: There was no significant treatment-by-time effect for any dietary composition data, lipid profile, cardiometabolic outcomes, or oxidative stress markers. A significant time effect was observed for energy, which was decreased in both treatments (cucumber, -8.3%; nopales, -10.1%; pTime=0.026) mostly due to lower mono and polyunsaturated fatty acids intake (pTime=0.023 and pTime=0.003, respectively). Both treatments significantly increased triglyceride concentrations (cucumber, 14.8%; nopales, 15.2%; pTime=0.020). Despite the lack of significant treatment-by-time effects, great individual response variability was observed for all outcomes. After the cucumber and nopales phases, a decrease in LDL-c was observed in 44% and 63% of the participants respectively. On average LDL-c was decreased by 2.0 mg/dL (-1.4%) after the cucumber phase and 3.9 mg/dL (-2.9%) after the nopales phase (pTime=0.176). Pro-atherogenic changes in HDL subfractions were observed in both interventions over time, by decreasing the proportion of HDL-c in large HDL (cucumber, -5.1%; nopales, -5.9%; pTime=0.021) and increasing the proportion in small HDL (cucumber, 4.1%; nopales, 7.9%; pTime=0.002). Conclusions: These data do not support the purported benefits of nopales at doses of 2 cups/day for 2-wk on markers of lipoprotein profile, cardiometabolic risk, and oxidative stress in hypercholesterolemic adults. / Dissertation/Thesis / Ph.D. Nutrition 2013