Pathophysiology, diagnosis, and management of dyslipidemia

Atherosclerosis is a systemic diffuse disease that may manifest as an anglographically localized coronary, cerebral, mesenteric, renal, and/or peripheral arterial stenosis or as diffuse atherosclerosis. While relief of organ ischemia is frequently possible with percutaneous or surgical revascularization, this in itself does not alleviate the long-term risks of disease recurrence or modify the metabolic derangements that promote atherosclerosis. It is critically important to recognize the need for treatment of dyslipidemia and to institute necessary therapies. The complex role of lipoprotein abnormalities is well understood and the use of lipid-lowering agents (90% statins) is reviewed in both primary and secondary prevention. The clinical interaction with novel risk factors and the practical problems in patient management are discussed.     

Challenges in dyslipidemia

Dyslipidemia is recognized as a significant risk factor for atherosclerotic disease. There has been a great deal of progress in the detection and management of dyslipidemia, but challenges remain, including whether to treat children, adolescents, and the elderly. Challenges include convincing physicians who tend to manage an outpatient disease with a single therapy that the management of cardiovascular risk and disease often requires multiple therapies, describing how we can combine therapies to provide an additive benefit without adding side effects or increasing morbidity, and determining whether a patient with one or more cardiovascular risk factors but a normal lipid should receive lipid-lowering therapy. Finally, there is the challenge of the Human Genome Project and predictive medicine. How will genetic information be integrated into the practice of medicine for disease prevention and management?     

Chronic kidney disease, dyslipidemia, and atherosclerosis

Patients with chronic kidney disease (CKD) are at an increased risk not only for end-stage kidney disease (ESKD) but also for cardiovascular disease (CVD). In this review article, we summarize the current evidence of CKD as a high-risk condition for CVD based on reports from Japan and other countries to draw attention to the close clinical association between CKD and CVD. Several epidemiologic studies have shown that the presence of CKD and reduced renal function are independent predictors of CVD also in Japan. According to a post-hoc analysis of CASE-J, the power of CKD as a predictor of CVD is as strong as diabetes mellitus and a previous history of ischemic heart disease. CKD worsens classical risk factors including hypertension and dyslipidemia, and dyslipidemia is associated with increased thickness and stiffness of large arteries independent of major confounders. A post-hoc analysis of MEGA indicates that lipid-lowering therapy with statins reduces the risk of CVD, and that it appears to be more efficacious in patients with than without CKD. These reports from Japan and other countries suggest that CKD should be regarded as a high-risk condition comparable to diabetes mellitus, and that strict control of dyslipidemia would be beneficial in preventing CVD, at least early stages of CKD.     

Fatty liver,insulin resistance,and dyslipidemia

After recently being recognized as a feature of the metabolic syndrome, fatty liver has evolved as a key player in the pathogenesis of dyslipidemia. Development of nonalcoholic fatty liver disease comes from an imbalance between the influx and production of fatty acids and the use of fatty acids for oxidation or secretion as very low density lipoprotein (VLDL) triglycerides. Previously, we have shown a strong relationship between increased liver fat and overproduction of large VLDL particles. We observed recently that in patients with high liver fat, insulin was unable to regulate VLDL production. The result is increased concentrations of VLDL particles in the circulation. Consequently, changes are seen in the metabolism of other lipoproteins that interact with VLDL particles, the net result being decreased high-density lipoprotein cholesterol and increased formation of small, dense low-density lipoprotein. In this article, we review recent findings on the development of fatty liver and its role in the diabetic dyslipidemia pathogenesis.     

Thyroid diseases, dyslipidemia and cardiovascular risk

By affecting the metabolism of lipids, hypothyroidism accelerates the process of atherogenesis and increases cardiovascular risk. In manifest hypothyroidism the number of LDL receptors in the liver decreases and there is an increase in levels of overall cholesterol, LDL-cholesterol and apolipoprotein B in the blood. Levels of HDL particles remain normal or even rise slightly as a result of reduced activity of the Cholesterol ester transfer protein (CETP) and hepatic lipase. This leads to a reduction in the transport of cholesterol esters from HDL-(2) to VLDL and IDL. Subclinical hypothyroidism also has a negative effect on the lipid profile, but is more likely to lead to pro-atherogenic changes in the proportion of lipid particles than to a reduction in overall cholesterol. Subclinical hypothyroidism leads to the manifestation of certain risk factors of atherosclerosis. Although studies of overall mortality and cardiovascular morbidity have not been completely unanimous in their conclusions, increased cardiovascular risk can be considered likely in subclinical hypothyroidism. It remains an open question whether the treatment of subclinical hypothyroidism with levothyroxine. At present we have only indirect proof from studies that assessed the effect of levothyroxine treatment on risk factors of atherosclerosis. Starting treatment with lipid lowering agents (especially statins) for (sub)clinical hypothyroidism is extremely risky though due to the risk of the development or worsening of myopathy, which is a further cogent argument for the active screening and treatment of(sub)clinical hypothyroidism for all patients with dyslipidemia.     

糖尿病患者血脂异常的治疗

有93%的糖尿病患者伴有心血管病,约80%伴有动脉粥样硬化,其中75%死于冠心病。血脂异常是动脉粥样硬化和冠心病的一个重要危险因素,因此糖尿病患者血脂异常的治疗是一个应十分重视的问题。本文简要介绍了糖尿病患者血脂异常的特点,糖尿病患者血脂异常的治疗对临床预后的影响及糖尿病患者血脂异常的药物治疗。     

Management of dyslipidemia in diabetes

Diabetes is associated with a high risk of cardiovascular disease. The management of dyslipidemia, a well-recognized and modifiable risk factor among patients with type 2 diabetes, is an important element in the multifactorial approach to prevent coronary heart disease. Diabetic dyslipidemia typically consists of elevated triglyceride, low high-density lipoprotein cholesterol (HDL-C), and the predominance of small dense low-density lipoprotein (LDL) particles. LDL cholesterol (LDL-C) levels in patients with diabetes are similar to those found in the rest of the population. During the past few years, clinical trials have provided evidence that lipid-lowering therapy has a similar beneficial effect on cardiovascular outcomes in diabetic and nondiabetic individuals. According to current guidelines, the primary lipid target is an LDL-C <100 mg/dL (<70 mg/dL in very high-risk patients) and, to this end, statins are the agents of choice. The appropriate management of dyslipidemia in patients with diabetes, particularly in individuals with low LDL-C, remains controversial. To achieve lipid targets, attention should be directed first toward nonpharmacologic therapeutic interventions to control dyslipidemia, such as diet, exercise, smoking cessation, weight loss, and glycemic control. Statin therapy is recommended for most subjects but, frequently, a combination of lipid-lowering agents is required. A number of combinations are possible, and several factors should be considered to improve the safety of this strategy.     

Diabetic dyslipidemia

Diabetic dyslipidemia is characterized by elevated fasting and postprandial triglycerides, low HDL-cholesterol, elevated LDL-cholesterol and the predominance of small dense LDL particles. These lipid changes represent the major link between diabetes and the increased cardiovascular risk of diabetic patients. The underlying pathophysiology is only partially understood. Alterations of insulin sensitive pathways, increased concentrations of free fatty acids and low grade inflammation all play a role and result in an overproduction and decreased catabolism of triglyceride rich lipoproteins of intestinal and hepatic origin. The observed changes in HDL and LDL are mostly sequence to this. Lifestyle modification and glucose control may improve the lipid profile but statin therapy mediates the biggest benefit with respect to cardiovascular risk reduction. Therefore most diabetic patients should receive statin therapy. The role of other lipid lowering drugs, such as ezetimibe, fibrates, omega-3 fatty acids, niacin and bile acid sequestrants is less well defined as they are characterized by largely negative outcome trials. This review examines the pathophysiology of diabetic dyslipidemia and its relationship to cardiovascular diseases. Management approaches will also be discussed.     

Risk stratification of dyslipidemia: insights from the Framingham Study

Dyslipidemia, fundamental to the atherosclerotic process, is now a readily correctable risk factor with established efficacy of treatment for reducing risk of CHD and strokes. The current focus on LDL-cholesterol for risk assessment needs to be broadened to accommodate the two-way traffic of cholesterol entering and leaving the arterial intima reflected by the LDL/HDL ratio or the Total/HDL ratio. The choice of lipid therapy should be individualized to take into account the presence of the metabolic syndrome and the lipid profile of the patient. The intensity of therapy and goals should be linked to multivariable risk, particularly in those with modest lipid values. Cardiovascular risk factor clustering is pronounced for each lipid, is promoted by adiposity and greatly influences its CHD hazard. Global risk assessment taking clustering into account is essential for efficient preventive management of lipids. More attention needs to be afforded the absolute risk reduction attainable and must recognize that the number needed to treat to prevent one event increases the lower the lipid value, the lower global risk and the healthier the subject.     

The control of dyslipidemia in outpatient clinics in Greece (OLYMPIC) Study

The objective of this study was to determine the proportion of Greek patients referred to outpatient clinics for dyslipidemia who achieved the low-density lipoprotein cholesterol (LDL-C) goal defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines, using lifestyle changes, lipid-lowering drug treatment (LLDT), or both. Adult patients with dyslipidemia, who had been receiving a hypolipidemic diet and/or LLDT for at least 3 months were assessed in a multicenter study performed at 66 sites across Greece. Patients were followed up for an additional 3-month treatment period. Lipid levels were recorded at baseline and at the end of the study. The primary endpoint was the proportion of patients achieving their individual LDL-C target at the end of the study, according to their coronary heart disease (CHD) risk status or its equivalents, as defined by the NCEP-ATP III guidelines. Multivariate logistic models were used to identify determinants of undertreatment. The study included 2,660 adults (20-75 years) from 7 regions of Greece. Of the evaluable sample (n = 2,211; men 51%; mean age 62 +/-9 years) 81% were receiving LLDT (96% with statins and 3% with fibrates), 44% had a history of CHD, 61% arterial hypertension, 36% diabetes, and 26% a family history of premature CHD. Overall, 6% were at low CHD risk, 30% at medium CHD risk, and 63% at high CHD risk. At the end of the study, 26% of all patients and 30% of those receiving LLDT achieved the NCEP-specified LDL-C target levels. The percentage of patients at LDL-C goal according to CHD risk status was: low risk 67% (95% CI = 59-75), medium risk 29% (95% CI = 26-33), and high risk 20% (95% CI = 18-22). Statins proved to be more effective than fibrates (p <0.0001). Atorvastatin-treated subjects (n = 1,222, mean dose 19 mg/day) attained the LDL-C target (31% of the cases) at a higher rate than those receiving other LLDT (n = 574, 26% at target, p <0.01) or not receiving drug treatment (n = 415, 8%, p <0.001). This outcome was more evident in the high-CHD risk group (n = 1,402, 26% with atorvastatin vs 16% with other LLDT and 3% not receiving LLDT attained the LDL-C goal, ANOVA, p <0.001). The majority of dyslipidemic patients receiving LLDT, mainly those with high-CHD risk, are not achieving the NCEP LDL-C target. This is mainly explained by inadequate dose titration to ensure target goals are met. Promoting healthy lifestyle and appropriate LLDT (potent statins with sufficient dose titration) must be implemented to ensure that patients attain LDL-C treatment goals and thus benefit from the reduction in individual CHD risk.     

Diabetic dyslipidemia

By the year 2025, there will be more than 300 million type 2 diabetes sufferers worldwide. This epidemic will be followed by a wave of cardiovascular disease. Diabetes is in fact a serious vascular disease with poor prognosis, and not only a disease characterized by elevated blood glucose. If adequate attention were paid to this, it would be much easier to relieve the burden of cardiovascular disease in type 2 diabetes patients. One important cardiovascular risk factor in type 2 diabetic people is dyslipidemia. This is characterized by low HDL-cholesterol, high serum VLDL-triglycerides, and a preponderance of small, dense LDL. Even slight elevations of LDL-cholesterol in type 2 diabetic patients are associated with a substantial increase in cardiovascular risk. The composition of lipid particles in diabetic dyslipidemia is more atherogenic than in dyslipidemia in general. This means in turn that normal lipid concentrations are more atherogenic in diabetic than in non-diabetic patients. Retrospective analyses show that, in terms of protection from cardiovascular endpoints, the benefit of lipid lowering in type 2 diabetic patients is at least as great as in the non-diabetic population. Lowering of LDL-cholesterol is a very attractive target for the reduction of coronary heart disease in type 2 diabetic people.     

Atherogenic dyslipidemia, metabolic syndrome and cardiovascular risk

The combination of high serum triglyceride levels and small low density lipoprotein particles, with a reduction in high density lipoprotein cholesterol levels has been named atherogenic lipoprotein phenotype or, simply, lipid triad. These lipid factors are commonly associated with peripheral resistance to the action of insulin, hyperinsulinism, central and visceral obesity, hypertension, hyperuricemia, hypercoagulability. The clustering of these nonlipid factors along with the lipid factors has been called metabolic syndrome. Insulin resistance plays a central role in the development of the lipid triad increasing the production of triglyceride-rich lipoproteins and decreasing their catabolism. There is currently great interest about the origins of the metabolic syndrome. One question under considerable research is whether genetic or acquired factors predominate in causing this syndrome. There seems to be little doubt that the metabolic syndrome taken as a whole constitutes a major risk factor for coronary heart disease. What is less certain is that each component of the syndrome is an independent risk factor. People with lipid triad are at very high risk of developing coronary heart disease, and careful management is warranted. Nonetheless, appropriate therapeutic strategies that will modify the metabolic syndrome as a whole are needed. More investigations about key metabolic steps that simultaneously affect multiple pathways will be required to yield a satisfactory therapy for high risk patients exhibiting the metabolic syndrome.     

Vitamin d, metabolic dyslipidemia, and metabolic syndrome in rheumatoid arthritis

PurposeVitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated the associations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoid arthritis, a group at high risk for cardiovascular disease.MethodsSerum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of 499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORE Trial). Participants had rheumatoid arthritis with active disease, and were naïve to methotrexate and biologic therapies. Multivariable linear regression was performed to assess associations between vitamin D levels and lipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemia and the metabolic syndrome in participants with vitamin D deficiency (<20 ng/mL).ResultsIn multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inversely with low-density lipoprotein (β: ?0.029 [?0.049, ?0.0091], P = .004) and triglyceride (β: ?0.094 [?0.15, ?0.039] P = .001) levels, adjusted for demographic, cardiovascular, and disease-specific variables. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariate analyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemia (odds ratio 1.72; 95% confidence interval, 1.10-2.45; P = .014) and metabolic syndrome (odds ratio 3.45; 95% confidence interval, 1.75-6.80; P <.001) in adjusted models.ConclusionsIn conclusion, vitamin D deficiency was associated with the metabolic syndrome and dyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale, prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels and reduces cardiovascular risk in rheumatoid arthritis.     

Management of dyslipidemia in primary care

BACKGROUND: Cardiovascular disease remains the leading cause of mortality in Canada. The link between hyperlipidemia and coronary heart disease has been clearly established. There is overwhelming evidence for reductions in coronary events and cardiovascular mortality with lowering of low-density lipoprotein cholesterol (LDL-C). Despite the evidence, hyperlipidemia treatment remains suboptimal. OBJECTIVE: To evaluate compliance with published dyslipidemia guidelines in a primary care setting. The primary outcome measure was target LDL-C level. METHODS: Retrospective chart review of a random selection of 300 patients diagnosed with hyperlipidemia in a large academic family medicine clinic. The primary outcome measure was a target LDL-C level of less than 2.5 mmol/L for patients with diabetes or coronary heart disease. For patients without diabetes or coronary heart disease, Framingham risk assessment tables were used to determine ideal target LDL-C levels. RESULTS: Overall, 53% of patients achieved target LDL-C. Target LDL-C levels were achieved in 48% of patients with diabetes or coronary heart disease. Males were twice as likely to be prescribed lipid lowering therapy than females. Males on lipid lowering therapy were twice as likely as females on lipid lowering therapy to achieve target LDL-C levels. Males with diabetes or coronary heart disease were twice as likely as females with diabetes or coronary heart disease to achieve target LDL-C levels. Only 44% of patients with diabetes or coronary heart disease were prescribed lipid lowering therapy. CONCLUSION: Results from an academic family medicine clinic indicate suboptimal compliance with current dyslipidemia management guidelines. Primary care physicians need to continue to take an aggressive stance on lipid lowering strategies, especially in high-risk patients and females.     

Treatment of dyslipidemia in diabetes.

Atherosclerosis kills more patients with diabetes than all other causes combined. Treatment must be focused on several targets: glycemic control, bulk reductions of LDL cholesterol, and shifting LDL particle size. Aggressive treatment and reversal of dyslipidemias is a proven prevention for coronary events in patients with type 2 diabetes. Glycemic control with diet, oral hypoglycemic agents, and insulin, when necessary, is often only partially effective in normalizing lipid values in type 2 diabetes. Intensive treatment with lipid-regulating agents, particularly statins, is often necessary to normalize diabetes-associated dyslipidemias. Statins are also the only agents thus far shown in prospective, controlled trials to reduce the risk of coronary events in diabetic patients definitively.     

Lifetime risk for developing dyslipidemia: the Framingham Offspring Study

Background

High serum low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol are major vascular risk factors. National surveys indicate that 40% of individuals in the United States have borderline-high LDL cholesterol, and 13-34% have low HDL. The lifetime risk of developing dyslipidemia is unknown, however.

Methods

We estimated the 10- to 30-year long-term risks of developing “borderline-high” LDL cholesterol (≥130 mg/dL [3.4 mmol/L]), “high” LDL cholesterol (≥160 mg/dL [4.1 mmol/L]) and “low” HDL cholesterol (<40 mg/dL [1.0 mmol/L]) in 4701 Framingham Offspring Study participants (53% women) who attended at least 2 examinations between 1971 and 2000. We performed sex-specific analyses (for age groups 30-34, 40-44, 50-54 years), and estimated risks conditional on surviving without the lipid abnormality up to the baseline age. We also estimated risks accounting for baseline prevalence of dyslipidemia (elevated LDL, low HDL).

Results

Over a 30-year period, approximately 6 of 10 participants developed borderline-high LDL, 4 of 10 people developed high LDL, and 2 (women) to 4 (men) of 10 individuals developed low HDL levels; estimates were generally similar for different age groups. Adjustment for baseline prevalence of dyslipidemia increased these estimates: 30-year risks exceeded 80% for borderline-high LDL, 50% for high LDL, and 25% (women) to 65% (men) for low HDL; 20-50% had or developed a low HDL along with a high LDL level. The 30-year estimates approximate the lifetime risk in 50-year-olds.

Conclusions

The long term risks of developing dyslipidemia are substantial in both sexes, and considerably exceed prevalence estimates from cross-sectional surveys.