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Lipid Management and 2-Year Clinical Outcomes in Japanese Patients with Acute Coronary Syndrome: EXPLORE-J.
Nakamura, M, Ako, J, Arai, H, Hirayama, A, Nohara, A, Murakami, Y, Ozaki, A, Harada-Shiba, M
Journal of atherosclerosis and thrombosis. 2021;(12):1307-1322
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Abstract
AIM: The prevalence of atherosclerotic cardiovascular (CV) disease has risen in Japan due to increasing metabolic risk factors, including dyslipidemia. A positive linear correlation between low-density lipoprotein cholesterol (LDL-C) levels, incidence of CV events, and preventive effects of lipid-lowering therapy (LLT) is well established; however, data in Japan are limited. This analysis evaluated current lipid management practices and risk of recurrent CV events in Japanese post-acute coronary syndrome (ACS) patients. METHODS EXPLORE-J is a multicenter, 2-year observational study of hospitalized ACS patients in Japan. RESULTS At 2-year follow-up (n=1944, mean age 66 years, 80.3% male), the cumulative incidence of major adverse cardiovascular events (MACE; death associated with myocardial infarction/cerebrovascular accident [CVA] and other CV death, non-fatal ACS, and non-fatal CVA requiring hospitalization during the observation period) was 6.2%; respective incidences of CV death, non-fatal ACS, and CVA were 0.7%, 4.5%, and 1.7%. Statin, intensive statin, and ezetimibe were prescribed for 93.6%, 8.2%, and 3.9% at visit (V)1 (Day[D]1+14), and 92.3%, 10.5%, and 11.6% of patients at V5 (D730±30 days), respectively. Mean LDL-C was reduced from first post-ACS measurement (121.3 mg/dL) to V5 (79.8 mg/dL). A limited number of patients achieved LDL-C <70 mg/dL from V1-V5 (14.4%-34.6%); those with a greater LDL-C reduction by V1 had a lower probability of MACE, indicating the benefits of early LDL-C reduction post ACS. CONCLUSIONS Guideline-recommended LDL-C target achievement post ACS in Japan is suboptimal, suggesting the need for LLT intensification. Additional analyses by risk stratification of the study population and the benefits of lipid management are planned.
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Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management.
Ganda, OP, Bhatt, DL, Mason, RP, Miller, M, Boden, WE
Journal of the American College of Cardiology. 2018;(3):330-343
Abstract
Despite the important role of high-intensity statins in reducing atherosclerotic cardiovascular disease events in secondary and primary prevention, substantial residual risk persists, particularly among high-risk patients with type 2 diabetes mellitus, metabolic syndrome, and obesity. Considerable attention is currently directed to the role that elevated triglycerides (TGs) and non-high-density lipoprotein cholesterol levels play as important mediators of residual atherosclerotic cardiovascular disease risk, which is further strongly supported by genetic linkage studies. Previous trials with fibrates, niacin, and most cholesterol ester transfer protein inhibitors that targeted high-density lipoprotein cholesterol raising, and/or TG lowering, have failed to show conclusive evidence of incremental event reduction after low-density lipoprotein cholesterol levels were "optimally controlled" with statins. Although omega-3 fatty acids are efficacious in lowering TG levels and may have pleiotropic effects such as reducing plaque instability and proinflammatory mediators of atherogenesis, clinical outcomes data are currently lacking. Several ongoing randomized controlled trials of TG-lowering strategies with an optimal dosage of omega-3 fatty acids are nearing completion.
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Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.
Hippe, DS, Phan, BAP, Sun, J, Isquith, DA, O'Brien, KD, Crouse, JR, Anderson, T, Huston, J, Marcovina, SM, Hatsukami, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):673-678
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OBJECTIVE To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (β=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.
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Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes.
Kones, R
Vascular health and risk management. 2013;:617-70
Abstract
Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the "HDL hypothesis", ie, raising HDL cholesterol per se will reduce MCVE. After the equivocal AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) study and withdrawal of two major cholesteryl ester transfer protein compounds, one for off-target adverse effects and the other for lack of efficacy, development continues for two other agents, ie, anacetrapib and evacetrapib, both of which lower LDL cholesterol substantially. The negative but controversial HPS2-THRIVE (the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial casts further doubt on the HDL cholesterol hypothesis. The growing impression that HDL functionality, rather than abundance, is clinically important is supported by experimental evidence highlighting the conditional pleiotropic actions of HDL. Non-HDL cholesterol reflects the cholesterol in all atherogenic particles containing apolipoprotein B, and has outperformed LDL cholesterol as a lipid marker of cardiovascular risk and future mortality. In addition to including a measure of residual risk, the advantages of using non-HDL cholesterol as a primary lipid target are now compelling. Reinterpretation of data from the Treating to New Targets study suggests that better control of smoking, body weight, hypertension, and diabetes will help lower residual risk. Although much improved, control of risk factors other than LDL cholesterol currently remains inadequate due to shortfalls in compliance with guidelines and poor patient adherence. More efficient and greater use of proven simple therapies, such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, combined with statin therapy, may be more fruitful in improving outcomes than using other complex therapies. Comprehensive, intensive, multimechanistic, global, and national programs using primordial, primary, and secondary prevention to lower the total level of cardiovascular risk are necessary.
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Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists.
Fruchart, JC
Cardiovascular diabetology. 2013;:82
Abstract
Dyslipidemia is a major risk factor for cardiovascular (CV) disease - the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARα-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARα-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARα-modulators (SPPARMα) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARα/γ agonist) and GFT505 (a dual PPAR α/δ agonist) have recently entered late-phase development. Although both compounds are more potent PPARα-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARα-agonist (K-877) has emerged with SPPARMα characteristics. Compared to fenofibrate, K-877 has more potent PPARα-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes.
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Dyslipidemia in obesity: mechanisms and potential targets.
Klop, B, Elte, JW, Cabezas, MC
Nutrients. 2013;(4):1218-40
Abstract
Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.
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Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism.
Cariou, B, Zaïr, Y, Staels, B, Bruckert, E
Diabetes care. 2011;(9):2008-14
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OBJECTIVE We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one-sided CI -∞ to -5.3], P = 0.005; S2: -24.8% [-∞ to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [ -∞ to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% [-∞ to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [-∞ to -0.10], P = 0.01) and fructosamine (-3.6% [-∞ to -0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% [-∞ to -12.8], P < 0.0001; S2: -15.1% [-∞ to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.
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"If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study.
Tenenbaum, A, Fisman, EZ
Cardiovascular diabetology. 2010;:24
Abstract
Even using intensive statin monotherapy, many patients fail to achieve all the desired lipid goals and remain at high residual risk of cardiovascular events. In view of the still unproven decisively intensive "statin as monotherapy" strategy and "residual risk" concept, it is logical to ask whether other strategies, particularly fibrate/statin combination therapy, could be more beneficial and safer. A clear benefit of fibrate monotherapy did emerge previously among patients with atherogenic dyslipidemia (particularly high triglycerides and low high density lipoprotein cholesterol [HDL-C]) typically present in the metabolic syndrome and type 2 diabetes. In contrast, in patients without atherogenic dyslipidemia this favorable effect was not demonstrated. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus. However, relevant patients with atherogenic dyslipidemia represented less than 17 percent of the ACCORD Lipid population (941 out of 5518 patients). In this prespecified subgroup, the patients benefited from fenofibrate therapy in addition to simvastatin similar to the previous "fibrate's as monotherapy" trials: the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group (28% crude HR reduction, CI less than 1, e.g. statistically significant findings). Among all other 4548 patients without atherogenic dyslipidemia such rates were 10.1% in both fenofibrate and placebo study groups. Authors concluded that in the overall cohort of patients the combination of fenofibrate and simvastatin did not reduce the rate of the cardiovascular events as compared with simvastatin alone. Thus, their results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the general patients with type 2 diabetes. A recent large meta-analysis regarding effects of fibrates on cardiovascular outcomes noted greater effect sizes in trials that recorded a higher mean baseline triglyceride concentration (p = 0.030). As expected, in a so called "general population", reflecting a blend of effects in patients with and without atherogenic dyslipidemia, a mean "diluted" effect of fibrate therapy was reduced, but still producing a significant 10% relative risk (RR) decrease in major cardiovascular events (p = 0.048) and a 13% RR reduction for coronary events (p < 0.0001). It should be pinpointed that the epidemiological characteristics of the ACCORD Lipid study depart from those seen in real clinical practice: among people with type 2 diabetes, there is a high prevalence of atherogenic dyslipidemia and metabolic syndrome. For example, an analysis of NHANES III data in adults aged >or=50 years showed that approximately 86% of patients with type 2 diabetes also had the metabolic syndrome. Therefore, an important finding of ACCORD Lipid study was the observation that fibrates may lead to cardiovascular risk reduction in patients with atherogenic dyslipidemia not only as monotherapy but in combination with statins as well. In conclusion, in patients with atherogenic dyslipidemia (high triglycerides and low HDL-C, fibrates -- either as monotherapy or combined with statins - were associated with reduced risk of cardiovascular events. In patients without dyslipidemia this favorable effect - as expected - was absent.
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Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome.
Belfort, R, Berria, R, Cornell, J, Cusi, K
The Journal of clinical endocrinology and metabolism. 2010;(2):829-36
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CONTEXT Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood. OBJECTIVE The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS). DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center. PATIENTS We studied 25 nondiabetic insulin-resistant MetS subjects. INTERVENTION(S): We administered fenofibrate (200 mg/d) and placebo for 12 wk. MAIN OUTCOME MEASURES Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry. RESULTS Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity. CONCLUSIONS In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.
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Fenofibrate and metabolic syndrome.
Kraja, AT, Province, MA, Straka, RJ, Ordovas, JM, Borecki, IB, Arnett, DK
Endocrine, metabolic & immune disorders drug targets. 2010;(2):138-48
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The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as result a of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of -93.7 mg/dL (-39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by -17.9 mg/dL (-12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TGs including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF's basic mechanism of action is known to involve PPAR-alpha agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5- rs662799, rs3135506; APOC3- rs5128, rs2854117, rs4520); APOA4- rs5104; PPARA- rs9626730, rs135543, rs11703495; LPL- rs1801177), after treatment PPARA- rs11708495; LPL- rs1801177, and appeared to modulate overall response to FF treatment (NOS3- rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not - particularly in the context of type 2 diabetes.