Meal-induced increases in C-reactive protein, interleukin-6 and tumour necrosis factor α are attenuated by prandial + basal insulin in patients with Type 2 diabetes.

AIM: To determine if a regimen with prandial + basal insulin compared with basal insulin attenuates post-meal inflammatory and glycative biomarkers in patients with Type 2 diabetes. METHODS: This test-meal sub-study in the USA is from a previously reported clinical trial comparing the effect on glycaemic control of 24 weeks of thrice-daily pre-meal insulin lispro mix 50 (50% insulin lispro, 50% insulin lispro protamine suspension) or bedtime insulin glargine, both plus metformin. In the sub-study, glucose, insulin, triglycerides, high-sensitivity C-reactive protein, tumour necrosis factor α, interleukin-6, methylglyoxal and 3-deoxyglucosone were measured during the post-meal period of a mixed-meal breakfast at the final visit. Prandial + basal (n = 25) and basal (n = 21) insulin were administered at the same times as during the previous 24 weeks. RESULTS: Post-meal, the prandial + basal insulin group had significantly higher insulin, lower glucose and triglycerides, as well as lower high-sensitivity C-reactive protein, tumour necrosis factor α and interleukin-6, than the basal insulin group. Glucose incremental area under the concentration curve significantly correlated with high-sensitivity C-reactive protein, tumour necrosis factor α, interleukin-6, methylglyoxal and 3-deoxyglucosone incremental area under the concentration curve. Insulin incremental area under the concentration curve correlated inversely with high-sensitivity C-reactive protein and tumour necrosis factor α incremental area under the concentration curve. However, after adjusting for glucose incremental area under the concentration curve, these inverse correlations were no longer significant. Triglyceride incremental area under the concentration curve was not correlated with any biomarker incremental area under the concentration curve. CONCLUSIONS: Controlling post-meal hyperglycaemia with prandial + basal insulin in patients with Type 2 diabetes attenuates meal-induced increases in high-sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor α compared with basal insulin. The rise in post-meal glucose, but not triglycerides, significantly correlated with the rise in post-meal inflammatory and glycative biomarkers.

Antiretroviral therapy in HIV-positive men is associated with increased apolipoprotein CIII in triglyceride-rich lipoproteins.

OBJECTIVES: Dyslipidaemia has become a common problem in HIV disease, especially in patients on current antiretroviral therapy. However, the pathogenic mechanisms involved are not well understood or documented using conventional lipid measurements. METHODS: Using a cross-sectional design, the prevalence of abnormal standard lipid measurements and novel biomarkers for abnormal lipid metabolism was determined in 271 HIV-positive men from two HIV clinics in Atlanta, GA, USA. RESULTS: A total of 147 men were treated with protease inhibitors (PIs) for >3 months (54%), 84 were treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) for >3 months (31%) and 40 had not received antiretroviral therapy in the past 3 months (15%). Patients being treated with a PI had higher total cholesterol and triglyceride (TG) levels than patients on no therapy (P<0.05 for each). Patients in the NNRTI group had higher TG, lower high-density lipoprotein (HDL) levels, and higher low-density lipoprotein (LDL) levels than patients on no therapy (P<0.05 for each). Patients treated with either PIs or NNRTIs were more likely to have higher apolipoprotein CIII (apoCIII) levels (P<0.05 for each) than patients on no therapy. Elevated TG was associated with disproportionably elevated apoCIII levels in both treatment groups. CONCLUSIONS: In this cross-sectional study of HIV-infected men, either PI or NNRTI therapy elevated levels of TG and apoCIII. Higher concentrations of apoCIII in apoB-containing lipoproteins [very low-density lipoproteins (VLDLs), intermediate density lipoprotein (IDL) and LDLs] have been predictive of an increased incidence of coronary events in clinical trials and more rapid progression of coronary lesions measured by angiography. These findings, on a background of an older population with additional risk factors of smoking and diabetes, portend future atherosclerotic events in these patients.

Preventive strategies for reducing coronary heart disease-related morbidity and mortality in patients with multiple risk factors.

Based on epidemiologic and clinical evidence, the National Cholesterol Education Program Adult Treatment Panel has identified low-density lipoprotein cholesterol as the primary target for lipid intervention to promote the reduction of high cholesterol through increased awareness and aggressive management of cardiovascular risk factors. These guidelines provide the basis for management of multiple risk factors and applied intervention using diet, exercise, and drug therapy to lower cholesterol levels. Data from primary- and secondary-prevention trials strongly support the rationale for aggressive therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to significantly reduce morbidity and mortality from coronary heart disease.

Therapies on the horizon for cholesterol reduction.

Statins are powerful agents for the reduction of low-density lipoprotein cholesterol (LDL-C) and reduction of cardiovascular risk. Newly developed statins with increased potency, such as rosuvastatin (Crestor) and NK-104 (in earlier clinical development), are capable of achieving marked LDL-C reductions. Cholesterol-lowering agents with mechanisms of action distinct from those of the statins are in active development. These include bile transport inhibitors, such as improved bile acid-absorbing resins and specific inhibitors of the ileal Na+/bile acid cotransporter. There are also specific inhibitors of cholesterol absorption, such as ezetimibe, which may provide cholesterol lowering that is additive to that achieved with statin treatment. Another approach is to reduce cardiovascular risk by modifying atherosclerotic processes within the arterial wall, as represented by the acyl CoA:cholesterol acyltransferase (ACAT) inhibitor avasimibe; ACAT inhibitors may reduce atherosclerotic lesions by inhibiting macrophage cholesterol storage.

What are the priorities for managing cholesterol effectively?

Many studies have confirmed the risk of coronary artery disease associated with elevated levels of low-density lipoprotein cholesterol (LDL-C). The precise role of other lipids, however, is still under investigation. The relation between elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C) is complex, and the results of clinical trials evaluating interventions to lower triglycerides or increase levels of HDL-C have been equivocal. Based on the data currently available, LDL-C remains the primary target for treatment. Ongoing clinical trials will help to answer the question of how low we should set our goals for lowering cholesterol in patients at risk.

New therapies on the horizon.

Statins have proved to be potent drugs for reducing low-density lipoprotein cholesterol (LDL-C) levels. However, because the response to current statin therapy regimens is not always sufficient to reach defined goal levels, additional drugs to lower LDL-C are needed. New drugs may soon be available to lower LDL-C levels by mechanisms that differ from those of the statins. Among these new agents are a bile acid binding resin, inhibitors of bile acid transport, inhibitors of cholesterol transport, inhibitors of cholesterol esterification, and triglyceride-lowering agents.

Novel approaches to lipid lowering: what is on the horizon?

New approaches to lipid lowering include new uses of proven treatments and development of novel agents. Several large-scale clinical trials are assessing whether additional reduction of low-density lipoprotein cholesterol (LDL-C) levels with statin therapy results in additional benefit in coronary artery disease prevention. Statins with increased LDL-C-lowering potency, such as the new statin rosuvastatin (formerly known as ZD4522), have been developed and are in advanced-phase clinical trials. New cholesterol transport inhibitors, such as ezetimibe, have been found to produce significant reductions in intestinal cholesterol absorption, and new bile acid transport inhibitors are in development. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and thereby in arterial lesions, have also been developed, with the agent avasimibe currently being evaluated in phase 2/3 trials. Combination approaches hold considerable promise, including combined use of statins with fibrates, niacin, and the new sterol absorption inhibitors.

The cuticular hydrocarbons of the giant soil-burrowing cockroach Macropanesthia rhinoceros saussure (Blattodea: Blaberidae: Geoscapheinae): analysis with respect to age, sex and location.

The cuticular hydrocarbons of a widespread species of soil-burrowing cockroach, Macropanesthia rhinoceros, have been sampled from most of its known geographical locations. Analysis of extracts from individual insects has enabled a study of differences within a population as well as among geographical locations. In the case of M. rhinoceros, except for newly hatched first-instar nymphs, variations in hydrocarbon composition among individuals of different cohorts of M. rhinoceros, based on age and sex, are no greater than those among individuals of a single cohort. Geographical populations of this species are variable in hydrocarbon composition unless they occur within a few kilometres of each other. A few populations showed very different hydrocarbon patterns but, in the absence of any correlating biological differences, it is uncertain whether this signifies the presence of otherwise unrecognizable sibling species or just extreme examples of the geographical variation characteristic of this group of insects.

Evidence for the in vivo generation of oxidatively modified epitopes in patients with atherosclerotic endothelium.

There is increasing evidence that autoantibodies (AAbs) against oxidatively modified low-density lipoprotein (LDL) are present in humans and may be detected in fasting plasma. Using a standardized immunoassay for the detection of circulating levels of AAbs against malondialdehyde (MDA)-modified LDL, we examined the acute changes in AAb levels during postprandial lipemia in a group of men and women without (n = 28) and with (n = 17) normal endothelium. The presence of atherosclerotic vessel is documented by clinical evidence of coronary artery disease (CAD). In response to the oxidative stress associated with postprandial lipemia, statistically significant reductions in AAb levels were demonstrated at 2 and 4 hours postprandially by paired t test. In patients with atherosclerotic arterial wall, the mean AAb level was reduced to 90.8% of fasting levels (P < .001) after 2 hours and to 90% after 4 hours (P < .01). This acute reduction in AAbs against MDA-LDL appears to be unique to atherosclerotic patients and could not be demonstrated in young controls with healthy blood vessels. In nonatherosclerotic controls, the mean normalized levels during postprandial lipemia were not statistically different from baseline (104.5% at 2 hours and 104.6% at 4 hours). The transient reduction in AAb levels with postprandial lipemia in atherosclerotic patients could be reproduced in a subset of the CAD patients after significant improvement in the lipid profile with weight loss. In patients with atherosclerotic disease, the transient reduction in the level of circulating AAbs reflects either an increased propensity to generate oxidatively modified epitopes or a reduced capacity to remove excess modified epitopes. These data are the first in vivo demonstration of an acute change in the oxidative process during postprandial lipemia.

Cholesterol lowering in atherosclerosis.

Lipid-lowering with statins reduces disease progression, prevents myocardial infarction and other hard end points, and prolongs survival. Data from large-scale trials with these agents further show that lowering low-density lipoprotein (LDL) cholesterol in patients with coronary artery disease reduces the incidence of cardiovascular events and that the lower the LDL cholesterol achieved, the lower the event rate. Currently available evidence supports the National Cholesterol Education Program (NCEP) recommendations for reduction of LDL-cholesterol levels to at least 100 mg/dL in patients with coronary artery disease. The Treating to New Targets study, which will evaluate the effects of LDL-cholesterol lowering to < or = 75 mg/dL with atorvastatin, may help clarify if additional benefit accrues with further reductions. However, up to 82% of patients with proven coronary disease are not even at the current NCEP lipid goal. Up to 55% need a > 30-mg/dL reduction in LDL cholesterol to reach that goal. These data suggest that many patients are not receiving a statin or are receiving an inadequate dose. Aggressive lipid lowering, although a desirable goal, does not yet appear to be standard practice.

Long-term cholesterol-lowering effects of psyllium as an adjunct to diet therapy in the treatment of hypercholesterolemia.

BACKGROUND: Hypercholesterolemia is a major risk factor for coronary heart disease and nutrition management is the initial therapeutic approach. OBJECTIVE: This multicenter study evaluated the long-term effectiveness of psyllium husk fiber as an adjunct to diet in the treatment of persons with primary hypercholesterolemia. DESIGN: Men and women with hypercholesterolemia were recruited. After following an American Heart Association Step I diet for 8 wk (dietary adaptation phase), eligible subjects with serum LDL-cholesterol concentrations between 3.36 and 4.91 mmol/L were randomly assigned to receive either 5.1 g psyllium or a cellulose placebo twice daily for 26 wk while continuing diet therapy. RESULTS: Serum total and LDL-cholesterol concentrations were 4.7% and 6.7% lower in the psyllium group than in the placebo group after 24-26 wk (P < 0.001). Other outcome measures did not differ significantly between groups. CONCLUSIONS: Treatment with 5.1 g psyllium twice daily produces significant net reductions in serum total and LDL-cholesterol concentrations in men and women with primary hypercholesterolemia. Psyllium therapy is an effective adjunct to diet therapy and may provide an alternative to drug therapy for some patients.

Lipid and apolipoprotein levels and distribution in patients with hypertriglyceridemia: effect of triglyceride reductions with atorvastatin.

Atorvastatin is a new hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor that has been demonstrated to be efficacious in reducing both triglyceride (TG) and cholesterol (CHOL) levels in humans. Twenty-seven (N = 27) patients with primary hypertriglyceridemia (TG > 350 mg/dL) were studied before and after 4 weeks on atorvastatin treatment at a dosage of either 20 (n = 16) or 80 (n = 11) mg/d. The present report examines changes in the plasma levels of several apolipoproteins, including apolipoprotein C-II (apoC-II), apoC-III, and apoE, after atorvastatin. Dose-dependent reductions in both CHOL (20.3% v 43.1%) and TG (26.5% v 45.8%) for the low and high dose, respectively, have been reported in these individuals. In addition to the reductions in apoB commonly associated with the use of HMG-CoA reductase inhibitors, significant reductions in apoE (37% and 49%), apoC-II (28% and 42%), and apoC-III (18% and 30%) were observed with this agent at the 20- and 80-mg/d dosage, respectively. Using fast protein liquid chromatography (FPLC) to fractionate whole plasma according to particle size, the effect of atorvastatin on lipid and apolipoprotein distribution in 20 lipoprotein fractions was also determined. Our results indicate that after 4 weeks on atorvastatin, (1) there was a 2-fold increase in the CHOL content as assessed by the CHOL/apoB ratio for 13 subfractions from very-low-density lipoprotein (VLDL) to small low-density lipoprotein (LDL); (2) there was a statistically significant reduction in the percentage of plasma apoB associated with VLDL-sized particles (30.5% v 26.8%); (3) there was a preferential reduction in plasma apoE from non-apoB-containing lipoproteins with treatment; (4) the losses of apoC-II and apoC-III, on the other hand, were comparable for all lipoprotein fractions; and (5) the fraction of plasma TG associated with HDL was increased after treatment. These changes in lipids and apolipoproteins did not depend on the dose of atorvastatin. There was, on the other hand, a dose-dependent reduction in cholesteryl ester transfer protein (CETP) activity, defined as the percentage of 3H-cholesteryl oleate transferred from high-density lipoprotein (HDL) to LDL. CETP activity was reduced by 10.3% and 26.4% with the low and high dose of atorvastatin. Together, these composition data would be consistent with a net reduction in the number of TG-rich lipoproteins that may be explained by (1) a reduction in VLDL synthesis, (2) a preferential removal of VLDL without conversion to LDL, and (3) a preferential accelerated removal of a subpopulation of LDL.

Risk factors for vascular disease in patients with diabetes.

The risks of cardiovascular and cerebrovascular disease in patients with diabetes are greater than those in persons without diabetes. This is due, in part, to the metabolic effects of insulin resistance. Other contributing factors include hyperglycaemia, dyslipidaemia, hypertension, hypercoagulability, homocysteinaemia, smoking, and obesity. Risk factor modification, where possible, can reduce the risk of complications of diabetes and macrovascular disease.

The benefit of aggressive lipid lowering.

The beneficial effects of lipid-lowering therapy for the primary and secondary prevention of coronary heart disease (CHD) have been conclusively demonstrated in large-scale clinical trials. Does more aggressive lipid lowering provide even greater clinical benefit? The post coronary artery bypass graft (post-CABG) study was the first angiographic trial to show that aggressive lipid-lowering therapy was more effective at reducing disease progression than conventional approaches to cholesterol management. Recently, the results of the atorvastatin versus revascularization treatments (AVERT) trial have also shown significant benefit on clinical events with aggressive lipid lowering. A total of 341 patients with stable CHD were randomly assigned to receive medical therapy with atorvastatin 80 mg/day plus conventional treatment or angioplasty followed by usual care. Atorvastatin therapy resulted in a 46% reduction in the mean low-density lipoprotein cholesterol level compared with an 18% decrease for patients in the angioplasty/usual care group. Patients treated with atorvastatin had fewer ischemic events compared with those who had angioplasty (13 vs. 21%, P = 0.048) and a significantly greater time to first ischemic event (P = 0.027). AVERT is the first clinical study demonstrating that patients with stable CHD achieve significant cardiovascular benefit by aggressively lowering cholesterol levels with atorvastatin. It would therefore appear that an aggressive approach to lipid-lowering therapy is beneficial in patients with existing CHD.

Apolipoprotein C-III displacement of apolipoprotein E from VLDL: effect of particle size.

ApoC-III and apoE are important determinants of intravascular lipolysis and clearance of triglyceride-rich chylomicrons and VLDL from the blood plasma. Interactions of these two apolipoproteins were studied by adding purified human apoC-III to human plasma at levels observed in hypertriglyceridemic subjects and incubating under specific conditions (2 h, 37 degrees C). As plasma concentrations of apoC-III protein were increased, the contents in both VLDL and HDL were also increased. Addition of apoC-III at concentrations up to four times the intrinsic concentration resulted in the decreasing incremental binding of apoC-III to VLDL while HDL bound increasing amounts without evidence of saturation. No changes were found in lipid content or in particle size of any lipoprotein in these experiments. However, distribution of the intrinsic apoE in different lipoprotein particles changed markedly with displacement of apoE from VLDL to HDL. The fraction of VLDL apoE that was displaced from VLDL to HDL at these high apoC-III concentrations varied among individuals from 20% to 100% its intrinsic level. The proportion of VLDL apoE that was tightly bound (0% to 80%) was found to be reproducible and to correlate with several indices of VLDL particle size. In the group of subjects studied, strongly adherent apoE was essentially absent from VLDL particles having an average content of less than 50,000 molecules of triglyceride. Addition of apoC-III to plasma almost completely displaces apoE from small VLDL particles. Larger VLDL contain tightly bound apoE which are not displaced by increasing concentration of apoC-III.

Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators.

BACKGROUND: Percutaneous coronary revascularization is widely used in improving symptoms and exercise performance in patients with ischemic heart disease and stable angina pectoris. In this study, we compared percutaneous coronary revascularization with lipid-lowering treatment for reducing the incidence of ischemic events. METHODS: We studied 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of low-density lipoprotein (LDL) cholesterol of at least 115 mg per deciliter (3.0 mmol per liter) who were referred for percutaneous revascularization. We randomly assigned the patients either to receive medical treatment with atorvastatin, at 80 mg per day (164 patients), or to undergo the recommended percutaneous revascularization procedure (angioplasty) followed by usual care, which could include lipid-lowering treatment (177 patients). The follow-up period was 18 months. RESULTS: Twenty-two (13 percent) of the patients who received aggressive lipid-lowering treatment with atorvastatin (resulting in a 46 percent reduction in the mean serum LDL cholesterol level, to 77 mg per deciliter [2.0 mmol per liter]) had ischemic events, as compared with 37 (21 percent) of the patients who underwent angioplasty (who had an 18 percent reduction in the mean serum LDL cholesterol level, to 119 mg per deciliter [3.0 mmol per liter]). The incidence of ischemic events was thus 36 percent lower in the atorvastatin group over an 18-month period (P=0.048, which was not statistically significant after adjustment for interim analyses). This reduction in events was due to a smaller number of angioplasty procedures, coronary-artery bypass operations, and hospitalizations for worsening angina. As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (P=0.03). CONCLUSIONS: In low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy is at least as effective as angioplasty and usual care in reducing the incidence of ischemic events.

An efficient chromatographic system for lipoprotein fractionation using whole plasma.

We have validated a semi-automatic procedure for the efficient isolation of plasma lipoproteins from 300 microl of whole plasma (actual injection volume 200 microl) by Fast Phase Liquid Chromatography (FPLC). Modified enzymatic assays were established to allow the determination of low concentrations (1-20 mg/dl) of triglycerides and cholesterol using the Beckman CX-5 Autoanalyzer. The sum of the cholesterol contents in the fractions corresponding to low density (LDL) and high density lipoprotein (HDL) can be demonstrated to be highly correlated to values obtained with dextran sulfate/MgCl2 precipitation for HDLc (slope = 0.98, r2 = 0.997) and ultracentrifugation (beta-quant) for LDLc (slope = 1.03, r2 = 0.988). Using pure lipoprotein fractions isolated by ultracentrifugation, linear ranges of detection for HDLc and HDL apoA-I were performed at 18-95 mg/dl and 59-262 mg/dl, respectively. The ranges for LDLc were 41-435 mg/dl and 21-280 mg/dl for LDL apoB. The mean (range) fractional standard deviations for quadruplicate runs for 15 individual plasma samples ranging widely in lipoprotein concentrations were 0.97 (0.29-2.86%) for LDLc (range: 101.5-258.5 mg/dl), 3.67 (0.62-14.11%) for HDLc (range: 27.1-85.1 mg/dl) and 2.19 (0.16-6.56%) for VLDL-TG (range: 6.1-515.0 mg/dl).

Impact of dyslipidaemia. Lessons from clinical trials.

Coronary heart disease (CHD) is a major cause of morbidity and mortality in Western countries, and is associated with significant healthcare costs. Epidemiological studies have shown that elevated cholesterol levels, particularly elevated low density lipoprotein (LDL) cholesterol, are a major established risk factor for the development of CHD. There is a large amount of clinical data available to indicate that lowering total or LDL-cholesterol levels reduces the risk of cardiovascular events and mortality. The most recent cholesterol treatment guidelines from the US and Europe recommend intensive treatment (usually pharmacological) for patients at highest risk for CHD. Results from a number of landmark primary and secondary prevention studies are in support of these guidelines and also suggest that the lower the level of LDL-cholesterol achieved with treatment, the better clinical benefit attained. Thus, these findings indicate that even more aggressive lipid lowering than that recommended by available treatment guidelines may be warranted. Finding and treating all individuals at risk for CHD would be expected to increase the overall treatment costs of hypercholesterolaemia because many patients may not otherwise be treated; however, targeting high risk patients, rather than treating all patients or treating inappropriately, would be expected to reduce other healthcare costs and the indirect costs of lost productivity due to cardiovascular morbidity and mortality. Studies with the HMG-CoA reductase inhibitors, which show that these drugs substantially lower LDL-cholesterol, are the most convincing since they have consistently shown reductions in cardiovascular morbidity and mortality. As a result, statins are now well-established agents for the treatment of dyslipidaemia.

Landmark trials in lipid reduction.

Since the first epidemiological evidence on the benefit of lipid reduction in coronary heart disease (CHD) was gathered, a number of questions have emerged in this field of research. Consistent findings across a number of landmark trials have shown that lipid-lowering therapies significantly reduced major subsequent cardiovascular events in coronary patients with high and moderate low density lipoprotein (LDL) blood cholesterol levels. Although there has been some confusion on the effect of lipid intervention on mortality, recently definite answers have come from several major trials that establish a clear decrease in coronary death for patients after reduction of plasma cholesterol levels. Primary prevention in individuals with high LDL cholesterol levels was shown to be beneficial in terms of cardiovascular event reduction; more data are needed to address this issue for subjects with moderate LDL cholesterol levels. Reduction of LDL cholesterol below normal levels appeared to be beneficial for coronary patients, but again, further research is needed to elucidate this point. To date, major trials have answered some of the many questions pertaining to lipid-lowering therapies; further research will continue to provide information and allow patients to benefit maximally from lipid interventions.