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Treatment guidelines have proliferated in cardiology, although most guideline recommendations are not supported by clinical trial evidence. What is considered to be a normal cholesterol level has progressively declined over the past 50 years, with the increasing realization that "normal" is far from optimal and that lower is better. The first important United States and Canadian cholesterol guidelines were published in 1988, and recommended diet for 6 months to be followed by consideration of bile acid sequestrants or nicotinic acid. Over the ensuing 25 years guidelines have changed rapidly and dramatically in response to a large number of definitive clinical trials, usually with statins. Low-density lipoprotein cholesterol targets have moved progressively lower, and in some guidelines, have been abandoned entirely. The concept of selecting patients for treatment according to the absolute risk reduction expected from treatment on the basis of clinical trial data seems to be a rational approach. For secondary prevention, some patients are still untreated or undertreated, presenting an opportunity for improving outcomes.

Lipid abnormalities are prevalent among persons living with HIV infection and contribute to increasing the risk of cardiovascular events. Antiretroviral therapy (ART) is associated with lipid abnormalities, most commonly hypertriglyceridemia, but also increases in low-density lipoprotein cholesterol and total cholesterol. Different classes of ART, and different drugs within classes, have differing effects on lipid levels, but in general newer drugs have more favourable effects compared with older ones. Low-level inflammation and chronic immune activation act on lipids through a variety of mechanisms to make them more atherogenic. As a consequence, risk is higher than would be expected for any given cholesterol level. Clinical outcome trials of cholesterol-lowering therapies have not yet been completed in people living with HIV, so that treatment decisions depend on extrapolation from studies in uninfected populations. Traditional risk assessment tools underestimate cardiovascular risk in individuals with HIV. Statins are the mainstay of lipid-lowering drug treatment; however, drug-drug interactions with ART must be considered. Simvastatin and lovastatin are contraindicated in patients taking protease inhibitors, and the dose of atorvastatin and rosuvastatin should be limited to 40 mg and 10 mg/d with some ART combinations. Switching from older forms of ART to lipid-friendly newer ones is a useful strategy as long as virologic suppression is maintained, but adding a statin lowers low-density lipoprotein cholesterol more effectively. Studies indicate that lipid abnormalities are not treated as aggressively in individuals living with HIV as they are in uninfected people, making this an opportunity to improve care.

Treatment guidelines have proliferated in cardiology, although most guideline recommendations are not supported by clinical trial evidence. What is considered to be a normal cholesterol level has progressively declined over the past 50 years, with the increasing realization that "normal" is far from optimal and that lower is better. The first important United States and Canadian cholesterol guidelines were published in 1988, and recommended diet for 6 months to be followed by consideration of bile acid sequestrants or nicotinic acid. Over the ensuing 25 years guidelines have changed rapidly and dramatically in response to a large number of definitive clinical trials, usually with statins. Low-density lipoprotein cholesterol targets have moved progressively lower, and in some guidelines, have been abandoned entirely. The concept of selecting patients for treatment according to the absolute risk reduction expected from treatment on the basis of clinical trial data seems to be a rational approach. For secondary prevention, some patients are still untreated or undertreated, presenting an opportunity for improving outcomes.

Lipid abnormalities are prevalent among persons living with HIV infection and contribute to increasing the risk of cardiovascular events. Antiretroviral therapy (ART) is associated with lipid abnormalities, most commonly hypertriglyceridemia, but also increases in low-density lipoprotein cholesterol and total cholesterol. Different classes of ART, and different drugs within classes, have differing effects on lipid levels, but in general newer drugs have more favourable effects compared with older ones. Low-level inflammation and chronic immune activation act on lipids through a variety of mechanisms to make them more atherogenic. As a consequence, risk is higher than would be expected for any given cholesterol level. Clinical outcome trials of cholesterol-lowering therapies have not yet been completed in people living with HIV, so that treatment decisions depend on extrapolation from studies in uninfected populations. Traditional risk assessment tools underestimate cardiovascular risk in individuals with HIV. Statins are the mainstay of lipid-lowering drug treatment; however, drug-drug interactions with ART must be considered. Simvastatin and lovastatin are contraindicated in patients taking protease inhibitors, and the dose of atorvastatin and rosuvastatin should be limited to 40 mg and 10 mg/d with some ART combinations. Switching from older forms of ART to lipid-friendly newer ones is a useful strategy as long as virologic suppression is maintained, but adding a statin lowers low-density lipoprotein cholesterol more effectively. Studies indicate that lipid abnormalities are not treated as aggressively in individuals living with HIV as they are in uninfected people, making this an opportunity to improve care.

BACKGROUND:Higher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events. OBJECTIVE:The purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease. METHODS:We assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9 years. RESULTS:In the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11-1.21, P < .0001), for triglycerides (HR 1.09, 95% CI 1.04-1.15, P = .0005), and for LDL-cholesterol (HR 1.14, 95% CI 1.09-1.19, P < .0001). Similar results were found for the 3 other measures of variability, standard deviation, coefficient of variability, and variability independent of the mean. Similar results were seen for CV events, stroke, and nonfatal myocardial infarction. Higher variability in triglyceride and LDL-cholesterol, but not HDL-cholesterol, was predictive of incident diabetes. The correlation among the variability of the 3 lipid measurements was weak. CONCLUSION:Visit-to-visit variability in fasting measurements of HDL-cholesterol, triglycerides, and LDL-cholesterol are predictive of coronary events, CV events, and for triglyceride and low-density lipoprotein cholesterol variability, incident diabetes. The mechanisms accounting for these associations remain to be determined.

BACKGROUND:Higher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events. OBJECTIVE:The purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease. METHODS:We assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9 years. RESULTS:In the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11-1.21, P < .0001), for triglycerides (HR 1.09, 95% CI 1.04-1.15, P = .0005), and for LDL-cholesterol (HR 1.14, 95% CI 1.09-1.19, P < .0001). Similar results were found for the 3 other measures of variability, standard deviation, coefficient of variability, and variability independent of the mean. Similar results were seen for CV events, stroke, and nonfatal myocardial infarction. Higher variability in triglyceride and LDL-cholesterol, but not HDL-cholesterol, was predictive of incident diabetes. The correlation among the variability of the 3 lipid measurements was weak. CONCLUSION:Visit-to-visit variability in fasting measurements of HDL-cholesterol, triglycerides, and LDL-cholesterol are predictive of coronary events, CV events, and for triglyceride and low-density lipoprotein cholesterol variability, incident diabetes. The mechanisms accounting for these associations remain to be determined.

Since 2014, guidelines for the management of lipid disorders to reduce cardiovascular (CV) events have been updated in the United States, the United Kingdom, Europe, and Canada. Some of these guidelines are almost entirely evidence-based whereas others are a mix of evidence and expert opinion. Guidelines differ on such simple questions as to whether blood samples should be fasting or nonfasting, and whether low-density lipoprotein cholesterol (LDL-C) or another lipid parameter should be the primary focus of treatment. Different risk assessment tools are recommended by different guidelines. Lifetime risk is highlighted in some guidelines, with the suggestion that earlier treatment will reduce lifetime risk in younger people even when short-term risk is low. Some guidelines have numerical treatment targets that differ according to level of risk, while others eschew targets but recommend statins at high or moderate intensity to reduce LDL-C by ≥ 50% or 30%-50%, respectively. Statins are the backbone of therapy in all guidelines. Ezetimibe produced a 6.4% relative risk reduction in the only large clinical outcomes trial in which it was tested, and is recommended for high-risk patients with an inadequate response to statins, despite the high number needed to treat to prevent 1 CV event. Proprotein convertase subtilisin/kexin 9 inhibitors lack outcome data to support their use, but are approved for patients with familial hypercholesterolemia or clinical atherosclerotic CV disease who require additional LDL-C lowering beyond statins. All these new guidelines are aimed at improving the problem of undertreatment of high-risk groups, leading to better outcomes for these patients.

Since 2014, guidelines for the management of lipid disorders to reduce cardiovascular (CV) events have been updated in the United States, the United Kingdom, Europe, and Canada. Some of these guidelines are almost entirely evidence-based whereas others are a mix of evidence and expert opinion. Guidelines differ on such simple questions as to whether blood samples should be fasting or nonfasting, and whether low-density lipoprotein cholesterol (LDL-C) or another lipid parameter should be the primary focus of treatment. Different risk assessment tools are recommended by different guidelines. Lifetime risk is highlighted in some guidelines, with the suggestion that earlier treatment will reduce lifetime risk in younger people even when short-term risk is low. Some guidelines have numerical treatment targets that differ according to level of risk, while others eschew targets but recommend statins at high or moderate intensity to reduce LDL-C by ≥ 50% or 30%-50%, respectively. Statins are the backbone of therapy in all guidelines. Ezetimibe produced a 6.4% relative risk reduction in the only large clinical outcomes trial in which it was tested, and is recommended for high-risk patients with an inadequate response to statins, despite the high number needed to treat to prevent 1 CV event. Proprotein convertase subtilisin/kexin 9 inhibitors lack outcome data to support their use, but are approved for patients with familial hypercholesterolemia or clinical atherosclerotic CV disease who require additional LDL-C lowering beyond statins. All these new guidelines are aimed at improving the problem of undertreatment of high-risk groups, leading to better outcomes for these patients.

Purpose of reviewPatients with chronic kidney disease (CKD) are at high risk for cardiovascular events. Statins reduce cardiovascular risk in a broad spectrum of patients. This article summarizes the evidence that statins reduce risk in CKD patients, and that statins have a small but favorable effect on renal function. Current guidelines for lipid management in patients with CKD are also reviewed.Recent findingsTwo well conducted randomized trials showed no significant benefit for statins among patients receiving dialysis. One large trial demonstrated that simvastatin/ezetimibe reduced cardiovascular events in a broad spectrum of CKD patients. A recent meta-analysis concluded that CKD patients benefit from statins, and that the relative benefit decreases as the severity of CKD worsens. In large trials, statin-treated patients have slightly less worsening of renal function overtime, and there are data to suggest that statins actually do not only preserve, but also increase renal function. Recent guidelines recommend a statin for CKD patients aged 50 years or older, for younger patients with known vascular disease, diabetes, or a 10-year risk greater than 10%, and for adult renal transplant recipients.SummaryStatins should be prescribed to older patients with CKD, and to younger patients with CKD who are at high CVD risk.

New clinical trials with the proprotein convertase subtilisin- kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab show that these drugs not only lower lowdensity lipoprotein cholesterol (LDL-C) profoundly, but also seem to reduce cardiovascular events, although the number of events and duration of follow-up are limited. Larger trials are underway to confirm these findings and to document safety.

New clinical trials with the proprotein convertase subtilisin- kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab show that these drugs not only lower lowdensity lipoprotein cholesterol (LDL-C) profoundly, but also seem to reduce cardiovascular events, although the number of events and duration of follow-up are limited. Larger trials are underway to confirm these findings and to document safety.

Purpose of reviewPatients with chronic kidney disease (CKD) are at high risk for cardiovascular events. Statins reduce cardiovascular risk in a broad spectrum of patients. This article summarizes the evidence that statins reduce risk in CKD patients, and that statins have a small but favorable effect on renal function. Current guidelines for lipid management in patients with CKD are also reviewed.Recent findingsTwo well conducted randomized trials showed no significant benefit for statins among patients receiving dialysis. One large trial demonstrated that simvastatin/ezetimibe reduced cardiovascular events in a broad spectrum of CKD patients. A recent meta-analysis concluded that CKD patients benefit from statins, and that the relative benefit decreases as the severity of CKD worsens. In large trials, statin-treated patients have slightly less worsening of renal function overtime, and there are data to suggest that statins actually do not only preserve, but also increase renal function. Recent guidelines recommend a statin for CKD patients aged 50 years or older, for younger patients with known vascular disease, diabetes, or a 10-year risk greater than 10%, and for adult renal transplant recipients.SummaryStatins should be prescribed to older patients with CKD, and to younger patients with CKD who are at high CVD risk.

ObjectivesThe purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk.BackgroundStatins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension.MethodsWe compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest.ResultsAmong 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.ConclusionsCompared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.