Reviews

Dyslipidemia, Kidney Disease, and Cardiovascular Disease in Diabetic Patients

Szu-chi Chen¹, Chin-Hsiao Tseng^1,2,3

Abstract

This article reviews the relationship between dyslipidemia, chronic kidney disease, and cardiovascular diseases in patients with diabetes. Diabetes mellitus is associated with complications in the cardiovascular and renal system, and is increasing in prevalence worldwide. Modification of the multifactorial risk factors, in particular dyslipidemia, has been suggested to reduce the rates of diabetes-related complications. Dyslipidemia in diabetes is a condition that includes hypertriglyceridemia, low high-density lipoprotein levels, and increased small and dense low-density lipoprotein particles. This condition is associated with higher cardiovascular risk and mortality in diabetic patients. Current treatment guidelines focus on lowering the low-density lipoprotein cholesterol level; multiple trials have confirmed the cardiovascular benefits of treatment with statins. Chronic kidney disease also contributes to dyslipidemia, and dyslipidemia in turn is related to the occurrence and progression of diabetic nephropathy. Different patterns of dyslipidemia are associated with different stages of diabetic nephropathy. Some trials have shown that treatment with statins not only decreased the risk of cardiovascular events, but also delayed the progression of diabetic nephropathy. However, studies using statins as the sole treatment of hyperlipidemia in patients on dialysis have not shown benefits with respect to cardiovascular risk. Diabetic patients with nephropathy have a higher risk of cardiovascular events than those without nephropathy. The degree of albuminuria and the reduction in estimated glomerular filtration rate are also correlated with the risk of cardiovascular events. Treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to reduce albuminuria in diabetic patients has been shown to decrease the risk of cardiovascular morbidity and mortality.

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The Role of Triglyceride in Cardiovascular Disease in Asian Patients with Type 2 Diabetes - A Systematic Review

Ai-Hua Chen^1,2, Chin-Hsiao Tseng^2,3,4

Abstract

In Asian populations, diabetes mellitus is increasing and has become an important health problem in recent decades. Cardiovascular disease (CVD) is one of the most important complications and the most common cause of death in diabetic patients. Among the risk factors of CVD, elevated low-density lipoprotein cholesterol has been a major concern. Studies suggested that serum triglyceride may also play a role in predicting CVD in patients with type 2 diabetes mellitus, but the association is still debated. In this review, we summarized published studies focusing on the relationship between serum triglyceride and CVD disease in Asian diabetic patients. Ten studies conducted in six different Asian countries (three from Hong Kong, two from Taiwan, tow from Japan, one from Indonesia, one from South India, and one from South Korea) were summarized and discussed. CVD was subdivided into coronary heart disease, stroke, and peripheral arterial disease. Of the ten studies analyzed, one focused on CVD, five on coronary heart disease, three on stroke, three on peripheral arterial disease, and one on mortality from CVD. Studies from Hong Kong, Taiwan, and Japan suggested that triglyceride is a significant and independent risk factor for coronary heart disease, but not a significant risk factor for stroke (studies conducted in Japan and South Korea) or peripheral arterial disease (studies conducted in Taiwan, Indonesia, and South India). Although serum triglyceride may be a significant risk factor for coronary heart disease in Asian diabetic patients, clinical trials evaluating whether lowering triglycerides using fibrates can reduce the risk of coronary heart disease in these patients need to be initiated.

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Dyslipoproteinemia and Impairment of Renal Function in Diabetic Kidney Disease: An Analysis of Animal Studies, Observational Studies, and Clinical Trials

Chi-Chih Hung^1,2, Jer-Chia Tsai^1,2,3, Hung-Tien Kuo^1,3, Jer-Ming Chang^1,3,4, Shang-Jyh Hwang^1,3, Hung-Chun Chen^1,3

Abstract

Dyslipoproteinemia is highly prevalent in diabetes, chronic kidney disease, and diabetic kidney disease (DKD). Both diabetes and chronic kidney disease (CKD) are associated with hypertriglyceridemia, lower high-density lipoprotein, and higher small, dense low-density lipoprotein. A number of observational studies have reported that dyslipidemia may be associated with albuminuria, renal function impairment, and end-stage renal disease (ESRD) in the general population, and especially in CKD and DKD patients. Diabetic glomerulopathy and the related albuminuria are the main manifestations of DKD. Numerous animal studies support the finding that glomerular atherosclerosis is the main mechanism of glomerulosclerosis in CKD and DKD. Some randomized, controlled trials suggest the use of statins for the prevention of albuminuria and renal function impairment in CKD and DKD patients. However, a large clinical study, the Study of Heart and Renal Protection (SHARP), does not support that statins could reduce ESRD in CKD. In this article, we analyze the complex association of dyslipoproteinemia with DKD and deduce its relevance from animal studies, observational studies, and clinical trials. We show that special subgroups could benefit from the statin treatment.

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Dyslipidemia and Diabetic Retinopathy

Yo-Chen Chang¹, Wen-Chuan Wu²

Abstract

Diabetic retinopathy (DR) is one of the major microvascular complications of diabetes. In developed countries, it is the most common cause of preventable blindness in diabetic adults. Dyslipidemia, a major systemic disorder, is one of the most important risk factors for cardiovascular disease. Patients with diabetes have an increased risk of suffering from dyslipidemia concurrently. The aim of this article is to review the association between diabetic retinopathy (DR) and traditional/nontraditional lipid markers, possible mechanisms involving lipid metabolism and diabetic retinopathy, and the effect of lipid-lowering therapies on diabetic retinopathy. For traditional lipid markers, evidence is available that total cholesterol and low-density lipoprotein cholesterol are associated with the presence of hard exudates in patients with DR. The study of nontraditional lipid markers is advancing only in recently years. The severity of DR is inversely associated with apolipoprotein A1 (ApoA1), whereas ApoB and the ApoB-to-ApoA1 ratio are positively associated with DR. The role of lipid-lowering medication is to work as adjunctive therapy for better control of diabetes-related complications including DR.

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Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Sandra J. Hamilton¹, Gerald F. Watts²

Abstract

Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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Reassessing the Benefits of Statins in the Prevention of Cardiovascular Disease in Diabetic Patients - A Systematic Review and Meta-Analysis

Yu-Hung Chang^1,2, Ming-Chia Hsieh^2,3, Cheng-Yuan Wang⁴, Kun-Cheng Lin¹, Yau-Jiunn Lee¹

Abstract

OBJECTIVES: Despite the fact that statins have been prescribed widely, cardiovascular disease (CVD) remains the leading cause of death in diabetic patients. The aim of this study was to reassess the benefits of statins for CVD prevention in patients with diabetes mellitus. METHODS: Two independent investigators searched for prospective, randomized statin trials that investigated the power of reducing CVD in statin-treated patients. The search was performed using Pubmed, Web of Science, and CENTRAL databases. Data was extracted from eligible studies. RESULTS: A total of 7061 articles were surveyed and 22 articles were identified as eligible articles. The meta-analyses of the 22 trials showed that statin treatment was positively associated with a lowered risk of CVD in the following groups: (i) total population with pooled odds ratios (OR) of 0.791 (95 % CI: 0.74-0.846, p < 0.001), (ii) diabetic population with OR 0.792 (95% CI: 0.721-0.872, p < 0.001), and (iii) non-diabetic population with OR 0.791 (95% CI: 0.730-0.857, p < 0.001). In diabetic patients, statins were also helpful in the primary and secondary prevention of CVD, with pooled ORs of 0.757 (95% CI: 0.676 to 0.847, p < 0.001) and 0.800 (95% CI: 0.712 to 0.898, p < 0.001), respectively. However, when trials that investigated only diabetic patients (i.e., CARDS, 4D, and ASPEN) were included in the analysis, statin treatment was not found to reduce CVD significantly (OR: 0.817, 95% CI: 0.649 to 1.029, p = 0.086). Furthermore, after performing subgroup analysis, no benefit of statin treatment was found in primary prevention (OR: 0.774, 95% CI: 0.506 to 1.186, p = 0.240) or secondary prevention (OR: 0.893, 95% CI: 0.734 to 1.088, p = 0.262) of CVD in diabetic patients. CONCLUSIONS: Although our study may be limited by unmeasured confounders and heterogeneity among the studies included, the results suggest that the effects of statins in the prevention of CVD in diabetic patients are not only beneficial. More informative data are needed to verify the benefits of statins in the protection against CVD in diabetic patients.

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Does Combination Therapy with Statins and Fibrates Prevent Cardiovascular Disease in Diabetic Patients with Atherogenic Mixed Dyslipidemia?

Aris P. Agouridis, Christos V. Rizos, Moses S. Elisaf, Theodosios D. Filippatos

Abstract

Type 2 diabetes mellitus (T2DM) is associated with the development and progression of cardiovascular disease (CVD). Statins have an established efficacy in the management of dyslipidemia primarily by decreasing the levels of low-density lipoprotein cholesterol and thus decreasing CVD risk. They also have a favorable safety profile. Despite the statin-mediated benefit of CVD risk reduction a residual CVD risk remains, especially in T2DM patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) values. Fibrates decrease TG levels, increase HDL-C concentrations, and improve many other atherosclerosis-related variables. Fibrate/statin co-administration improves the overall lipoprotein profile in patients with mixed dyslipidemia and may reduce the residual CVD risk during statin therapy. However, limited data exists regarding the effects of statin/fibrate combination on CVD outcomes in patients with T2DM. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study the statin/fibrate combination did not significantly reduce the rate of CVD events compared with simvastatin/placebo in patients with T2DM. However, it did show a possible benefit in a pre-specified analysis in the subgroup of patients with high TG and low HDL-C levels. Furthermore, in the ACCORD study the simvastatin/fenofibrate combination significantly reduced the rate of progression of retinopathy compared with statin/placebo administration in patients with T2DM. The present review presents the available data regarding the effects of statin/fibrate combination in patients with T2DM and atherogenic mixed dyslipidemia.

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Atherogenic Dyslipidemia and Combination Pharmacotherapy in Diabetes: Recent Clinical Trials

Sandra J. Hamilton¹, Gerald F. Watts²

Abstract

Patients with type 2 diabetes (T2D) are at a markedly increased risk of cardiovascular disease (CVD). Dyslipidemia is a common risk factor and a strong predictor of CVD in T2D patients. Although statins decrease the incidence of CVD in T2D, residual cardiovascular risk remains high despite the achievement of optimal or near-optimal plasma low-density lipoprotein (LDL) cholesterol concentrations. This may, in part, be due to uncorrected atherogenic dyslipidemia. Hypertriglyceridemia, the driving force behind diabetic dyslipidemia, results from hepatic overproduction and/or delayed clearance of triglyceride-rich lipoproteins. In patients treated with a statin to LDL-cholesterol goals, the addition of ezetimibe, fenofibrate, niacin, or n-3 fatty acid ethyl esters may be required to correct the persistent atherogenic dyslipidemia. Clinical trial evidence describing best practice is limited, but recent data supports the strategy of adding fenofibrate to a statin, and suggests specific benefits in dyslipidemic patients and in the improvement of diabetic retinopathy. However, based on results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled LDL-cholesterol. Further evidence is required to support the role of ezetimibe and n-3 fatty acids in treating residual CVD risk in statin-treated T2D patients.

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New Frontiers in the Treatment of Diabetic Dyslipidemia

Shu-Yi Wang¹, Ming-Chia Hsieh^1,2, Shih-Te Tu¹, Chieh-Sen Chuang^3,4

Abstract

Dyslipidemia is a major risk factor for cardiovascular complications in people with diabetes. Lowering low-density lipoprotein cholesterol (LDL-C) levels is effective in the primary and secondary prevention of diabetic vascular complications. However, LDL-C levels do not reflect all aspects of diabetic dyslipidemia, which is characterized by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). Statins, nicotinic acid, and fibrates play a role in treating diabetic dyslipidemia. Atherosclerosis is a major disorder of the blood vessel wall in patients with diabetes. A number of antihyperlipidemic agents may be beneficial and exhibit effects at the actual site of vascular disease and not only on plasma lipoprotein concentrations. Several novel therapeutic compounds are currently being developed. These include additional therapeutics for LDL-C, triglycerides, HDL-C, and modulators of inflammation that can be used as possible synergic agents for the treatment of atherosclerosis and irregularities in plasma lipoprotein concentrations.

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