Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins

Abstract

Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B) -emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP -Bezafibrate Infarction Prevention study, HHS -Helsinki Heart Study, VAHIT -Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD -Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy -selected on the basis of their safety and effectiveness -may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.

Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women

“…Dyslipidaemia, which is associated with increased CVD mortality in diabetic individuals [36], is among the most important modifiable risk factors. There is now a wide variety of antidyslipidemic drugs [37,38]; however, with the increasing combination of risk factors commonly found in several CV diseases, including in T2DM, the control of dyslipidaemia is not enough, requiring a more effective modulation of HDL-c, which remains only slightly modifiable with the current pharmacological arsenal [39,40]. Our study in diabetic patients under antidyslipidemic therapy reinforces the need of better intervention on HDL-c.…”

Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study

“…Metabolic syndrome is a cluster of interrelated risk factors that leads to metabolic dysregulation and atherosclerotic cardiovascular diseases 1. The increased risk of cardiovascular disease in people with metabolic syndrome has been well established by observational studies and meta-analyses,234 and considered to be partly attributable to the accompanying atherogenic dyslipidaemia, which is characterised by increased triglyceride levels, small dense low density lipoprotein particles with low levels of high density lipoprotein (HDL) cholesterol 56. Abundant evidence shows that lowering low density lipoprotein (LDL) cholesterol concentrations with statins is the primary treatment option for minimising cardiovascular disease in people at risk, including those with atherogenic dyslipidaemia 789.…”

The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

“…Effects of KB2115 on the hypothalamic-pituitary axis were determined by measuring TSH, free and total T 3, and free and total T4. This measurement was done in the single-dose study before and at 1,6,12,18,24,30,36,48,72,96, and 120 h after administration of KB211 and in the multiple-dose study at 1, 6, 12, 18, and 24 h after the first and last dose of KB2115. An indirect RIA assay was used to estimate levels of total and free T 4 and total and free T3.…”

“…C onsequences of atherosclerotic cardiovascular disease such as heart attack and stroke are major medical problems (1), and there is a need to develop improved means to treat these disorders and the risk factors that cause them, including hyperlipidemia and obesity (2). Thyroid hormones promote favorable effects on plasma cholesterol levels and weight loss (3)(4)(5)(6), but also when administered in high doses can have deleterious effects on the heart (tachycardia, arrhythmia, and heart failure), bone, and muscle (7)(8)(9).…”