Treatment Of Lipid Disorders Research Articles

Editorial Lipid-lowering therapies and achievement of LDL-cholesterol targets

Editorial Lipid-lowering therapies and achievement of LDL-cholesterol targets

Treatment of lipid disorders in obesity

Obesity is the most common cause of secondary hyperlipidemia. Atherogenic dyslipidemia refers to elevated triglycerides, low HDL-cholesterol and small dense LDL associated with visceral obesity and metabolic syndrome. Obesity may also be associated with isolated low HDL-cholesterol or high triglycerides and postprandial hyperlipidemia. While some obese patients have high LDL cholesterol concentrations, obesity has a more pronounced effect on other atherogenic lipids and lipoproteins. Obesity may aggravate familial lipid disorders. Lipid disorders in obesity are responsive to weight loss, pharmacotherapy and weight loss surgery. Statins are the lipid-lowering drug of choice, together with lifestyle change. Hard clinical end point data to support combinations of statins with other drugs is lacking. After weight loss surgery, the absolute risk of cardiovascular disease should be reassessed, but tools to facilitate risk assessment need to be developed.

Fenofibric Acid: Safety and Efficacy in the Treatment of Dyslipidemia, Hypertriglyceridemia and Hyperlipidemia

Adequate control of lipids is a cornerstone in the management of coronary heart disease. Numerous studies have demonstrated the effectiveness of HMG-Co A reductase inhibitors (statins) in controlling LDL-C. Unfortunately, the effect of statins on other lipid parameters, such as HDL-C and triglycerides, is not as robust. Emerging evidence suggests that these other lipid parameters may contribute to residual cardiovascular risk. The recent release of fenofibric acid offers a potential therapy which can be used in conjunction with statins to achieve an optimal lipid profile. Clinical trials have demonstrated fenofibric acid to be safe for use as dual therapy with low and moderate dose statins. The following article will address the safety and efficacy of fenofibric acid in the treatment of lipid disorders, both alone and as combination therapy with statins. Additionally, the potential role of fenofibric acid in the management of the complex cardiovascular patient with abnormal lipid parameters will be evaluated.

TRIB1, chromosome 8 and the regulation of blood lipids

found 95 loci significantly associated with at least one plasma lipid trait [7]. Many of these associations are mapped in or near genes with described functions in lipid metabolism and, in some cases, genes responsible for relatively rare Mendelian lipid disorders. These findings provide strong evidence for the validity of the GWAS approach. More excitingly, some of the newly discovered variants lie in genomic regions containing genes for which there is no existing evidence for a role in lipid metabolism. These loci offer the chance to broaden our understanding of lipid metabolism by discovering new modulator genes and ultimately hold the potential to yield new drug targets for the treatment of lipid disorders. At present, there is active debate as to whether new GWAS loci can fulfill these promises. Critics have questioned the scientific value of the GWAS approach and its capability to identify biologically relevant disease genes, since the identified loci have modest predictive power and explain only a small fraction of the heritability [9,10]. However, publication of the first studies tying novel genes from GWAS loci to functions in lipid metabolism [11–13] gives confidence that one can expect significant advances in lipid biology based on GWAS discoveries. In the following sections, we will take on the example of TRIB1 to illustrate how GWAS have led to the discovery of a novel regulator of lipoprotein metabolism.

Abstract A72: A phase II randomized trial with nimesulide, simvastatin, and placebo in subjects at increased risk for breast cancer

Abstract Background: Breast cancer (BC) prevention has been successful for estrogen receptor positive cancer, whereas no significant results have been reached so far to prevent hormone non-responsive tumors. Epidemiological and in vitro studies have suggested the possible preventive role of several compounds, in particular NSAIDs (nonsteroidal anti-inflammatory drugs) and more recently statins. Several data suggest the ability of NSAIDs to reduce the risk of many tumors including BC. Nimesulide is a NSAID largely used in several European countries. It is defined as a preferential COX-2 inhibitor, because it maintains a modest inhibitory activity on COX-1. The incomplete COX-2 selectivity of nimesulide gives a favorable profile, avoiding most side effects of the nonspecific COX inhibitors and the super-selective COX-2 inhibitors. Statins are widely used for the treatment of lipid disorders in cardiovascular disease prevention. They have shown a possible role in cancer prevention through the modulation of cell cycle arrest and apoptosis. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for BC, focused particularly on hormone nonresponsive tumor risk. Study design: 150 women will be randomized to receive nimesulide versus simvastatin versus placebo for one year followed by a second year of follow-up. Eligible subjects are: patients with previous estrogen receptor negative ductal intraepithelial neoplasia (DIN) or lobular intraepithelial neoplasia (LIN) or atypical hyperplasia (AH), and unaffected subjects carrying a mutation of BRCA1/2 or with a probability of mutation >10% (according to BRCAPRO). At baseline, 6, 12 and 24 month clinical examination, blood tests and annual mammography are scheduled. Ductal lavage (DL) or fine needle aspirate (FNA) — if for any reason the DL is not possible or result inadequate — is performed annually to obtain a breast cell sample. For safety reasons the blood tests are performed also at 3 and 9 month time. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or FNA samples, after 12 months of treatment and 12 months after treatment suspension. Secondary endpoints are: treatment safety and the modulation of a large set of cell and circulating surrogate endpoint biomarkers (SEBs) of breast cancerogenesis. Recruitment and preliminary results: at August 2010 we have randomized 140 subjects of which 64 ER neg DIN, 48 LIN and AH and 28 subjects with mutation or mutation probability. So far 83 subjects completed the study. The treatment is very well tolerated and the safety blood tests did not show any significant liver toxicity, only few subjects had grade 1 liver enzyme alterations. CPK alteration was seen in 9 subjects (grade 1 toxicity). One case was included in the study with a baseline level of CPK grade 2, the patient was withdrawn from the study. Including this last case five subjects dropped out: two for gastrointestinal symptoms, one for muscle ache, and one refused to continue. To our knowledge this is the first randomazied placebo controlled trial to study SEBs and their modulation after intervention with DL. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A72.

New options in the treatment of lipid disorders in HIV-infected patients.

Since the introduction of HAART, there was a remarkably change in the natural history of HIV disease, leading to a notable extension of life expectancy, although prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of HIV-infected persons, and there is an increasing concern about the cardiovascular risk in this population. Current recommendations suggest that HIV-infected perons undergo evaluation and treatment on the basis of the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines for dyslipidemia, with particular attention to potential drug interactions with antiretroviral agents and maintenance of virologic control of HIV infection. While a hypolipidemic diet and physical activity may certainly improve dyslipidemia, pharmacological treatment becomes indispensable when serum lipid are excessively high for a long time or the patient has a high cardiovascular risk, since the suspension or change of an effective antiretroviral therapy is not recommended. Moreover, the choice of a hypolipidemic drug is often a reason of concern, since expected drug-drug interactions (especially with antiretroviral agents), toxicity, intolerance, effects on concurrent HIV-related disease and decrease patient adherence to multiple pharmacological regimens must be carefully evaluated. Often the lipid goals of patients in this group are not achieved by the therapy recommended in the current lipid guidelines and in this article we describe other possibilities to treat lipid disorders in HIV-infected persons, like rosuvastatin, ezetimibe and fish oil.

Abbott’s Cholesterol Drug Deal with AstraZeneca

AstraZeneca is to co-promote Abbott’s Trilipix® (fenofibric acid) for the treatment of lipid disorders, which will increase the exposure of Trilipix in the cholesterol market. The two companies filed an NDA for the combination of Trilipix with Crestor® (rosuvastatin), known as Certriad®.

Dyslipidemia and the Treatment of Lipid Disorders in African Americans

Background Despite the high prevalence of cardiovascular disease documented among the African-American population, there has been little emphasis on the role of dyslipidemia as a prominent risk factor in this large subpopulation. Questions of medication efficacy also have been raised. Together, these factors may have affected awareness, diagnosis, and treatment rates. Methods and Results Dyslipidemia was defined as the presence of either hypercholesterolemia or hypertriglyceridemia using National Cholesterol Education Program III criteria and the fasting lipid measurements, self-reported treatment history, and medication survey available from 5302 Jackson Heart Study participants. Dyslipidemia was more common in men (compared with women) aged less than 50 years and increased with age in both genders. Hypercholesterolemia prevalence rates approached 50% in women aged more than 65 years. The lifestyle-related attributes found to be related to prevalence were being overweight and less physically active, and all disease status variables exhibited significant ( P < .05) associations. Awareness of hypercholesterolemia is approximately 55% or more in both men and women aged more than 35 years. Treatment rates lag far behind awareness, particularly in younger adult men, and less than 50% of women and men aged less than 65 years were treated for hypercholesterolemia. Conclusion Higher rates of identification and effective treatment of dyslipidemia are clearly needed in this, and probably other African-American communities. Despite the less than optimal treatment, the identification and importance of the known cardiovascular disease states and risk factors in these analyses suggest the adoption of National Cholesterol Education Program III “high-risk strategy” algorithms in treatment recommendations and decisions by providers is occurring.

The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist

Nicotinic acid has been used for several decades to treat dyslipidemia. In mice, the lipid-lowing effect of nicotinic acid is mediated by the Gi coupled receptor PUMA-G. In humans, high (GPR109A) and low (GPR109B) affinity nicotinic acid receptors have been characterized. Here we identify monomethylfumarate as a GPR109A agonist. Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. We show that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrate competitive binding with nicotinic acid. We show that GPR109A is highly expressed in neutrophils and epidermal keratinocytes, and that its expression is increased in human psoriatic lesions. Our findings provide evidence that GPR109A is a target for the drug Fumaderm and suggest that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders.

Effects of Thyroid Hormone Analogs on Lipid Metabolism and Thermogenesis

Thyroid hormone affects in a myriad of biological processes such as development, growth, and metabolic control. Triiodothyronine (T3) is the biologically active form of thyroid hormone that acts through nuclear receptors, TRalpha and TRbeta, regulating gene expression. Given that the distribution of these receptors is heterogeneous amongst the different tissues, it is not surprising that some physiological effects of T3 are isoform specific. For example, while TRalpha is the dominant receptor in the brain and skeletal system and mediates most of the synergism between T3 and the sympathetic signaling pathway in the heart, TRbeta is abundant in liver and is probably the isoform that mediates most of the T3 effects on lipid metabolism. Thus, it makes sense to develop compounds that selectively act on either one of the TRs, allowing for the activation of specific T3-dependent pathways. This article reviews the recent progress made in this area, focusing on the physiological effects of compounds that lower serum cholesterol and decrease fat mass, as they spare skeletal muscle and bone masses, as well as the heart. The available studies indicate that achieving selective activation of different TR-mediated pathways is a promising strategy for treating lipid disorders and obesity.

Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio?

Statins effectively lower low-density lipoprotein cholesterol levels and the risk of cardiovascular disease (CVD) events, and because of this they have become a standard treatment for dyslipidemia and atheroprevention. Unfortunately, statin monotherapy may fail to normalize high triglycerides and low high-density lipoprotein cholesterol, and it prevents only a minority of CVD events. Further treatment of lipid disorders that remain after statin monotherapy should help reduce the residual CVD risk. Fibrate monotherapy lowers high triglyceride levels, raises low high-density lipoprotein cholesterol, and reduces CVD risk; therefore, fibrates are recommended as an adjunct to statins for treatment of residual dyslipidemia and residual CVD risk. This review provides an update on the benefits and risks of fibrate monotherapy and addresses the benefits and risks of adding fibrates to statins.

The Anti-tumor Activities of Statins

Abnormally elevated levels of serum cholesterol have been demonstrated to contribute to atherosclerosis and coronary artery disease. Statins, inhibitors of 3-hy-droxy-3-methylglutaryl coenzyme A (hmg-Coa) re-ductase, are efficient and widely used drugs in the treatment of lipid disorders, especially hypercholes-terolemia. In addition to their cholesterol-lowering effects, statins are reported to inhibit tumour cell growth 1,2. Statins are also known to synergistically enhance the effects of chemotherapy 3,4 and to overcome chemoresistance 5. Accordingly, statins prolong the survival of patients with hepatocellular carcinoma4, and they reduce the risk of colorectal cancer6 and breast cancer7. Statins induce apoptosis and reduce cell invasiveness in various cell lines, including malignant glioma8, neuroblastoma9, myeloid leukemia10, and breast carcinoma11. Cancer cells overexpress hmg coa reductase 12. The chemopreventive activity of statins against cancer is suggested to depend on inhibition of hmg-Coa reductase in cholesterol synthesis and, thereby, cell growth 13. The Ras protein is important in the regulation of cell differentiation and proliferation. Statins are reported to inhibit the activation of ras 14. The products of the mevalonate pathway are necessary for diverse cellular functions, including the G1–S phase transition of cell proliferation and the formation of cell membranes 15. Statins may therefore inhibit cancer cell growth and lead to apoptotic cell death through their inhibition of the mevalonate pathway, although other mechanisms also have been suggested. Interleukin-18 (il-18), a monocyte-derived cyto-kine, is upstream of the production of interferon γ from T cells and natural killer cells 16,17. Interleukin-18 is known to play an important role in regulating immune responses, exhibiting significant antitumour activity 18. The antitumour effects of il-18 are mediated by activation of natural killer cells and cytotoxic T lymphocytes 19. In a previous study, we found that the statins pravastatin, fluvastatin, and simvastatin induced production of il-18 by human monocytes 20,21. The effects of pravastatin, fluvastatin, and simvastatin were abolished by the addition of mevalonate, indicating the involvement of hmg-Coa reductase in the action of the tested statins. Angiogenesis is characterized by the formation of new capillaries from existing vessels. It is well known that tumour growth and metastasis both require growth of new blood vessels 22,23. The statins lovastatin and cerivastatin are reported to inhibit tumour-induced angiogenesis by reducing metabolites of the mevalonate pathway that are pivotal in angio-genesis 24,25. The foregoing observations suggest that the an-ticancer effect of statins depends on the apoptosis of cancer cells, the production of il-18 by monocytes, and the inhibition of angiogenesis. However, the effects of statins on cancer are not completely understood. Further experimental research will be useful in clarifying this complex relationship.

Screening and Treatment for Lipid Disorders in Children and Adolescents: Systematic Evidence Review for the US Preventive Services Task Force

This was a systematic evidence review for the US Preventive Services Task Force, intended to synthesize the published evidence regarding the effectiveness of selecting, testing, and managing children and adolescents with dyslipidemia in the course of routine primary care. Literature searches were performed to identify published articles that addressed 10 key questions. The review focused on screening relevant to primary care of children without previously identified dyslipidemias, but included treatment trials of children with dyslipidemia because some drugs have only been tested in that population. Normal values for lipids for children and adolescents are defined according to population levels (percentiles). Age, gender, and racial differences and temporal trends may alter these statistical cut points. Approximately 40% to 55% of children with elevated total cholesterol and low-density lipoprotein levels will continue to have elevated lipid levels on follow-up. Current screening recommendations based on family history will fail to detect substantial numbers (30%-60%) of children with elevated lipid levels. Drug treatment for dyslipidemia in children has been studied and shown to be effective only for suspected or proven familial monogenic dyslipidemias. Intensive dietary counseling and follow-up can result in improvements in lipid levels, but these results have not been sustained after the cessation of the intervention. The few trials of exercise are of fair-to-poor quality and show little or no improvements in lipid levels for children without monogenic dyslipidemias. Although reported adverse effects were not serious, studies were generally small and not of sufficient duration to determine long-term effects of either short or extended use. Several key issues about screening and treatment of dyslipidemia in children and adolescents could not be addressed because of lack of studies, including effectiveness of screening on adult coronary heart disease or lipid outcomes, optimal ages and intervals for screening children, or effects of treatment of childhood lipid levels on adult coronary heart disease outcomes.

No physical activity or exercise is not an option

the incidence of coronary artery disease (CAD) increases with increasing plasma low-density lipoprotein-cholesterol concentrations and decreases with increasing high-density lipoprotein-cholesterol (HDL-C) concentrations. Plasma triglycerides levels are an accepted risk factor for peripheral

Effect of niacin on lipoproteins and atherosclerosis

Niacin has been in use for the past 50 years to treat lipid disorders and atherosclerotic cardiovascular disease. We have recently demonstrated that niacin, by selective inhibition of liver diacylglycerol acyltransferae (DGAT)2, a rate-limiting enzyme in triglyceride synthesis, inhibits triglyceride synthesis thereby decreasing the secretion of apolipoprotein (Apo)B-containing very low-density lipoprotein and low-density lipoprotein particles. We have demonstrated that niacin increases ApoAI–high-density lipoprotein (HDL), mainly through the selective inhibition of hepatic uptake and removal of ApoAI–HDL (but not HDL-cholesterol ester). Emerging data from our laboratory provide evidence for the nonlipid-related effects of niacin on vascular oxidative and inflammatory processes involved in atherosclerosis. Although decreased free fatty acid mobilization from adipose tissue via a newly described niacin receptor (HM74A) is reported as a mechanism by which niacin decreases triglycerides, both physiologically ...

Impact of rosuvastatin use on costs and outcomes in patients at high risk for cardiovascular disease in US managed care and medicare populations: A data analysis

Background: High blood cholesterol is a major modifiable risk factor for coronary heart disease (CHD) and stroke. Objective: The aim of this study was to estimate the economic impact of rosuvastatin calcium use in patients at high risk for CHD and stroke, according to the National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines. Methods: An economic simulation model was developed that used a Markov process to project the number of cardiovascular events and associated costs in a high-risk population in various treatment scenarios. According to the ATP III, high-risk patients are those with CHD, atherosclerosis of peripheral and/or cerebral arteries, diabetes, and/or multiple other risk factors conferring a risk of at least 20% within 10 years. Data on population characteristics and costs of cardiovascular disease (CVD) were obtained from claims data sets from employer-funded commercial and Medicare health plans in the United States. Treatment of lipid disorders was translated into CVD risk reduction based on results from the Heart Protection Study. The estimated efficacies of individual lipid-lowering drugs were based on data published in package inserts. The model generated costs at the health plan level of lipid-lowering therapy in high-risk patients and the number and total costs of cardiovascular events. Estimates were compared for scenarios representing the mix of treatments used before and after the introduction of rosuvastatin. Estimates were generated separately for commercial and Medicare health plans. Results: For every 1 million members of a commercial health plan, an estimated 44,457 met ATP III criteria for high-risk status. Use of rosuvastatin in place of other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”) by 11 % of these patients over a period of 5 years was estimated to result in 36 fewer cardiovascular events and a net savings of US $4.03 million. A Medicare plan of 1 million members with an estimated 433,268 high-risk patients and 7% rosuvastatin use was estimated to avoid 727 events and save US $34.32 million. Conclusions: The results of this data analysis suggest that increasing the use of rosuvastatin can result in cardiovascular event reduction and cost savings. Because the impact of lipid-modifying therapy on cardiovascular risk has not been thoroughly documented in controlled clinical studies, our model assumed that incremental lipid changes had effects in proportion to the magnitude of change.

Thia fatty acids with the sulfur atom in even or odd positions have opposite effects on fatty acid catabolism

As tools for mechanistic studies on lipid metabolism, with the long-term goal of developing a drug for the treatment of lipid disorders, thia FA with the sulfur atom inserted at positions 3-9 from the carboxyl group were fed to male Wistar rats for 1 wk to determine their impact on key parameters in lipid metabolism and hepatic levels of thia FA metabolites. Thia FA with the sulfur atom in even positions decreased hepatic and cardiac mitochondrial beta-oxidation and profoundly increased hepatic and cardiac TAG levels. The plasma TAG level was unchanged and the hepatic acyl-CoA oxidase activity increased. In contrast, thia FA with the sulfur atom in odd positions, especially 3-thia FA, tended to increase hepatic and cardiac FA oxidation and acyl-CoA oxidase and carnitine palmitoyltransferase-II activities, and decreased the plasma TAG levels. The effects seem to be related to differences in the catabolic rate of the thia FA. Differences between the two groups of acids were also observed with respect to the regulation of genes involved in FA transport and catabolism. Feeding experiments with 3- and 4-thia FA in combination indicated that the 4-thia FA partly attenuated the effects of the 3-thia FA on mitochondrial FA oxidation and the hepatic TAG level. In summary, the position of the sulfur atom in the alkyl chain, especially whether it is placed in the even or odd position, is crucial for the biological effect of the thia FA.

Treatment of lipid disorders in patients with diabetes

The use of lipid-lowering drugs in diabetes is aimed primarily at reducing the large cardiovascular disease (CVD) risk burden experienced by this group of patients. Statin therapy has been shown to be highly efficacious in reducing CVD risk, both in those with and without prior CVD. Therefore, statins are the first-line lipid-lowering therapy in patients with diabetes. Patients with diabetes and established CVD should have low-density lipoprotein cholesterol (LDLC) lowered to at least 2.6 mmol/L (100 mg/dL) and, if possible, to 1.8 mmol/L (70 mg/dL). Those without prior CVD should have LDLC lowered to 2.6 mmol/L. Triglycerides should be kept less than 1.7 mmol/L (150 mg/dL) and high-density lipoprotein cholesterol (HDLC) above 1.15 mmol/L (40 mg/dL) in men and 1.2 mmol/L (46 mg/dL) in women. Additional therapy with fibrates or nicotinic acid may be needed to achieve these goals; the choice is determined by tolerance and side-effect profile. The use of nicotinic acid or fibrates on their own to achieve triglyceride or HDLC levels should be limited to those patients already at or near LDLC goals. Caution is warranted with combination therapy because muscle side effects, in particular, can increase. In type 1 diabetes, CVD risk is high but trial data are sparse. Where there is nephropathy, and where glycemic control is poor, there will often be a need for triglyceride and HDLC raising interventions as above. In the absence of these, lipid profile is often normal and focus should be on reducing CVD risk by statin therapy. If uncertainty about CVD risk status exists, consideration should be given to using CVD imaging modalities to inform intervention choice in younger patients.

Fenofibrate: a novel formulation (Triglide) in the treatment of lipid disorders: a review.

Cardiovascular disease is the major cause of mortality worldwide and accounts for approximately 40% of all deaths. Dyslipidemia is one of the primary causes of atherosclerosis and effective interventions to correct dyslipidemia should form an integral component of any strategy aimed at preventing cardiovascular disease. Fibrates have played a major role in the treatment of hyperlipidemia for more than two decades. Fenofibrate is one of the most commonly used fibrates worldwide. Since fenofibrate was first introduced in clinical practice, a major drawback has been its low bioavailability when taken under fasting conditions. Insoluble Drug Delivery-Microparticle fenofibrate is a new formulation that has an equivalent extent of absorption under fed or fasting conditions. In this review, we will discuss the clinical pharmacology of fenofibrate, with particular emphasis on this novel formulation, as well as its lipid-modulating and pleiotropic actions. We will also analyze the major trial that evaluated fibrates for primary and secondary prevention of cardiovascular disease, the safety and efficacy profile of fibrate-statin combination treatment, and the current recommendations regarding the use of fibrates in clinical practice.

GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing

Nicotinic acid (niacin) has long been used as an antidyslipidemic drug. Its special profile of actions, especially the rise in HDL-cholesterol levels induced by nicotinic acid, is unique among the currently available pharmacological tools to treat lipid disorders. Recently, a G-protein-coupled receptor, termed GPR109A (HM74A in humans, PUMA-G in mice), was described and shown to mediate the nicotinic acid-induced antilipolytic effects in adipocytes. One of the major problems of the pharmacotherapeutical use of nicotinic acid is a strong flushing response. This side effect, although harmless, strongly affects patient compliance. In the present study, we show that mice lacking PUMA-G did not show nicotinic acid-induced flushing. In addition, flushing in response to nicotinic acid was also abrogated in the absence of cyclooxygenase type 1, and mice lacking prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)) receptors had reduced flushing responses. The mouse orthologue of GPR109A, PUMA-G, is highly expressed in macrophages and other immune cells, and transplantation of wild-type bone marrow into irradiated PUMA-G-deficient mice restored the nicotinic acid-induced flushing response. Our data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE(2) and PGD(2), most likely from immune cells of the skin.