Circulating microRNAs -192 and -194 are associated with the presence and incidence of diabetes mellitus.

We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR-194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes.

Hypercholesterolaemia - practical information for non-specialists.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

A comparison of the effects of low- and high-dose atorvastatin on lipoprotein metabolism and inflammatory cytokines in type 2 diabetes: Results from the Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA) randomized trial.

BACKGROUND: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. OBJECTIVES: Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. METHODS: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol <7 mmol/L, proteinuria <2 g/d, creatinine <200 µmol/L) were randomized to receive atorvastatin 10 mg (n = 59) or 80 mg (n = 60) daily. Baseline and 1-year follow-up data are reported. RESULTS: Patients were at high cardiovascular disease risk (observed combined mortality and nonfatal cardiovascular disease annual event rate 4.8%). The non-high-density lipoprotein cholesterol (HDL-C) goal of <2.6 mmol/L was achieved in 72% of participants receiving high-dose atorvastatin, but only in 40% on low-dose atorvastatin (P < .005). The proportion achieving apolipoprotein B (apoB) <0.8 g/L on high-dose and low-dose atorvastatin was 82% and 70%, respectively (NS). Total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, non-HDL-C, oxidized LDL, apoB, glyc-apoB, apolipoprotein E, and lipoprotein-associated phospholipase A2 decreased significantly, more so in participants on high-dose atorvastatin. Adiponectin increased and serum amyloid A decreased without dose dependency. Neither dose produced significant changes in HDL-C, cholesterol efflux, high-sensitivity C-reactive protein, glycated hemoglobin, serum paraoxonase-1, lecithin:cholesterol acyltransferase, or cholesteryl ester transfer protein. CONCLUSIONS: High-dose atorvastatin is more effective in achieving non-HDL-C therapeutic goals and in modifying LDL-related parameters. Recommended apoB treatment targets may require revision. Despite the increase in adiponectin and the decrease in serum amyloid A, HDL showed no change in functionality.

Diabetic dyslipidaemia.

PURPOSE OF REVIEW: The purpose is to discuss recent developments in the understanding of lipoprotein metabolism in diabetes, the cardiovascular risk associated with both type 1 and type 2 diabetes, recently published guidelines on the management of this risk, concerns over the use of statin treatment in diabetes, and other therapeutic options. RECENT FINDINGS: Diabetic dyslipidaemia can be gross with massive hypertriglyceridemia, or subtle with a lipid profile which would be regarded as normal in a nondiabetic patient, but which hides underlying increases in atherogenic subfractions of LDL (e.g., small dense LDL, glycated LDL) and remnant lipoproteins. Statins can decrease these without the clinician being aware from routine biochemistry. In type 2 diabetes, HDL cholesterol levels are often reduced, whereas in type 1, insulin can raise HDL, but its antiatherogenic properties are compromised. Dyslipidaemia and hypertension predate the onset of glycaemia of diabetic proportions (metabolic syndrome). Obese people can thus die of diabetes before they develop it. Obesity should be prevented and treated. Statins decrease the risk of cardiovascular disease in diabetes or metabolic syndrome regardless of whether glycaemia worsens. SUMMARY: One unassailable truth is that statin therapy is beneficial and should rarely, if ever, be withheld.

Diabetes Dyslipidemia.

Diabetes mellitus is associated with a considerably increased risk of premature atherosclerotic cardiovascular disease. Intensive glycemic control has essentially failed to significantly improve cardiovascular outcomes in clinical trials. Dyslipidemia is common in diabetes and there is strong evidence that cholesterol lowering improves cardiovascular outcomes, even in patients with apparently unremarkable lipid profiles. Here, the authors review the pathophysiology and implications of the alterations in lipoproteins observed in both type 1 and type 2 diabetes, the effect of medications commonly used in the management of diabetes on the lipid profile, the evidence for lifestyle and pharmaceutical interventions, and national and international recommendations for the management of dyslipidemia in patients with diabetes.

Antioxidant properties of HDL.

High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL.

Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment.

AIMS: Guidelines for primary prevention of cardiovascular disease (CVD) with statins, including the most recent, fail to make the best use of the evidence from clinical trials by concentrating on absolute CVD risk as a statin indication and not also considering that a major determinant of therapeutic benefit is the magnitude of the low-density lipoprotein (LDL) (or non-HDL) cholesterol reduction achieved. This decrease is proportional to the pretreatment concentration. We set out to apply this knowledge to the calculation of the number needed to treat to prevent one event (NNT) and to assess critically how current guidelines performed at different degrees of CVD risk across a range of LDL (or non-HDL) cholesterol concentrations. METHODS AND RESULTS: Number needed to treat to prevent one event revealed exclusion from the treatment of some people with higher cholesterol levels, who may benefit more than others needlessly exposed to statins with no realistic prospect of benefit. Furthermore, abandonment of cholesterol therapeutic goals disadvantaged people with higher levels. CONCLUSION: These problems can be overcome by basing the decision to treat on the NNT calculated both from absolute CVD risk and also on the LDL (or non-HDL) cholesterol reduction achievable with statin treatment. This need not adds an additional layer of complexity for the clinician, because computer programmes already used to estimate CVD risk could be easily amended, thus permitting more effective deployment of statins in the population.

Unintended positive and negative effects of drugs on lipoproteins.

PURPOSE OF REVIEW: Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism. RECENT FINDING: Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects. SUMMARY: Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.

How HDL protects LDL against atherogenic modification: paraoxonase 1 and other dramatis personae.

PURPOSE OF REVIEW: To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL. RECENT FINDINGS: Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties. SUMMARY: The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.

A review of paradoxical HDL-C responses to fenofibrate, illustrated by a case report.

High-density lipoprotein cholesterol (HDL-C) concentration is an independent risk factor for cardiovascular disease. Fibrates are widely used in the management of atherogenic dyslipidemia, principally for their triglyceride-lowering and HDL-C-raising effects. Fibrates may cause paradoxical reductions in HDL-C. These reductions are usually modest, but significant reductions have been observed. The molecular mechanism for these paradoxical reductions remains unexplained despite advances in our understanding of lipid metabolism. This review considers possible mechanisms for this effect, illustrated by a patient with an observed reduction in HDL-C of 88% after introduction of fenofibrate.

The importance of considering LDL cholesterol response as well as cardiovascular risk in deciding who can benefit from statin therapy.

PURPOSE OF REVIEW: Guidelines seeking to deploy statin treatment rely heavily on the use of estimates of absolute cardiovascular disease (CVD) risk as an arbiter of who should receive statins. We question whether this is an effective strategy unless the LDL-cholesterol (LDL-C) response is also considered. RECENT FINDINGS: Recently, meta-analyses of randomized clinical trials of statins have revealed that CVD risk decreases linearly by 22% for each 1 mmol/l reduction in LDL-C. Calculation of the number needed to treat with statins to prevent one CVD event using both the pretreatment absolute CVD risk and the LDL-C response that can be achieved is thus possible. Application of this evidence reveals that many people (including younger ones) with high LDL-C levels can benefit more than people currently receiving statin treatment solely on the basis of their absolute CVD risk, whereas others at higher CVD risk, but with lower LDL-C, will derive little benefit. This does not seem to have been adequately considered in recent clinical guidelines. SUMMARY: A simple additional mathematical step in risk assessment to take account of the LDL-C response to statins and provide knowledge of number needed to treat would greatly improve individual management, cost-effectiveness and the population impact of statins.

Lipoprotein (a): gene genie.

PURPOSE OF REVIEW: Despite being both the longest known and the most prevalent genetic risk marker for atherosclerotic cardiovascular disease (CVD), little progress has been made in agreeing a role for lipoprotein (a) [Lp(a)] in clinical practice and developing therapies with specific Lp(a)-lowering activity. We review barriers to progress, and discuss areas of controversy which are important to future research. RECENT FINDINGS: Epidemiological and genetic studies have supported a causal role for Lp(a) in accelerated atherosclerosis, independent of other risk factors. Progress continues to be made in the understanding of Lp(a) metabolism, and Lp(a) levels, rather than apolipoprotein (a) isoform size, have been shown to be more closely related to CVD risk. Selective Lp(a) apheresis has offered some evidence that Lp(a)-lowering can improve cardiovascular end-points. SUMMARY: We have acquired a great deal of knowledge about Lp(a), but this has not yet led to reductions in CVD. This is at least partially due to disagreement over Lp(a) measurement methodologies, its physiological role and the importance of the elevations seen in renal diseases, diabetes mellitus and familial hypercholesterolaemia. Renewed focus is required to bring assays into clinical practice to accompany new classes of therapeutic agents with Lp(a)-lowering effects.

High-density lipoprotein cholesterol raising: does it matter?

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of morbidity and premature mortality in Europe and the United States, and is increasingly common in developing countries. High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for CVD and is superior to low-density lipoprotein cholesterol (LDL-C) as a predictor of cardiovascular events. The residual risk conferred by low HDL-C in patients with a satisfactory LDL-C was recently highlighted by the European Atherosclerosis Society. Despite the lack of randomized controlled trials, it has been suggested that raising the level of HDL-C should be considered as a therapeutic strategy in high-risk patients because of the strong epidemiological evidence, compelling biological plausibility, and both experimental and clinical research supporting its cardioprotective effects. RECENT FINDINGS: Three recent large randomized clinical trials investigating the effect of HDL-C raising with niacin and dalcetrapib in statin-treated patients failed to demonstrate an improvement in cardiovascular outcomes. SUMMARY: There is evidence to support the view that HDL functionality and the mechanism by which a therapeutic agent raises HDL-C are more important than plasma HDL-C levels. Future therapeutic agents will be required to improve this functionality rather than simply raising the cholesterol cargo.