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1.  Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? 
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
PMCID: PMC3502168  PMID: 23150952
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Metabolic syndrome; PPAR; Prevention; Residual cardiovascular risk; Type 2 diabetes
2.  "If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study 
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 than1, 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 ≥50 years showed that approximately 86% of patients with type 2 diabetes also had the metabolic syndrome. Therefore, an importand 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.
PMCID: PMC2893121  PMID: 20550659
3.  Which is the best lipid-modifying strategy in metabolic syndrome and diabetes: fibrates, statins or both? 
Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published.
Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality.
Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy.
PMCID: PMC538252  PMID: 15574199
Diabetes mellitus; Dyslipidemia; Fibrates; Metabolic syndrome; Statins
4.  Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor 
Cardiovascular Diabetology  2014;13(1):159.
The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main difficulty in isolating the effect of hypertriglyceridemia on CV risk is the fact that elevated triglyceride levels are commonly associated with concomitant changes in high density lipoprotein (HDL), low density lipoprotein (LDL) and other lipoproteins. As a result of this problem and in disregard of the real biological role of TG, its significance as a plausible therapeutic target was unfoundedly underestimated for many years. However, taking epidemiological data together, both moderate and severe hypertriglyceridaemia are associated with a substantially increased long term total mortality and CV risk. Plasma TG levels partially reflect the concentration of the triglyceride-carrying lipoproteins (TRL): very low density lipoprotein (VLDL), chylomicrons and their remnants. Furthermore, hypertriglyceridemia commonly leads to reduction in HDL and increase in atherogenic small dense LDL levels. TG may also stimulate atherogenesis by mechanisms, such excessive free fatty acids (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia and high concentrations of TRL as causal risk factors for CV disease. The most common forms of hypertriglyceridemia are related to overweight and sedentary life style, which in turn lead to insulin resistance, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Intensive lifestyle therapy is the main initial treatment of hypertriglyceridemia. Statins are a cornerstone of the modern lipids-modifying therapy. If the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy, and in combination with statin; gemfibrozil only for monotherapy) could be the preferable drugs. Also ezetimibe has mild positive effects in lowering TG. Initial experience with en ezetimibe/fibrates combination seems promising. The recently released IMPROVE-IT Trial is the first to prove that adding a non-statin drug (ezetimibe) to a statin lowers the risk of future CV events. In conclusion, the classical clinical paradigm of lipids-modifying treatment should be changed and high TG should be recognized as an important target for therapy in their own right. Hypertriglyceridemia should be treated.
PMCID: PMC4264548  PMID: 25471221
Cardiovascular risk; Cholesterol; Fibrates; Hypertriglyceridemia; Insulin resistance; Metabolic syndrome; Obesity; Statins; Triglycerides; Type 2 diabetes
5.  Vascular and metabolic effects of treatment of combined hyperlipidemia 
International journal of cardiology  2007;124(2):149-159.
Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARα in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.
PMCID: PMC2758222  PMID: 17658632
Statins; Fibrates; Endothelial function; Insulin resistance; Combined hyperlipidemia; Safety
6.  Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins 
Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B) – emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP – Bezafibrate Infarction Prevention study, HHS – Helsinki Heart Study, VAHIT – Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD – Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy – selected on the basis of their safety and effectiveness – may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.
PMCID: PMC1592077  PMID: 17002798
7.  Combination therapy of statins and fibrates in the management of cardiovascular risk 
Current Opinion in Lipidology  2009;20(6):505-511.
Purpose of review
Despite that statin treatment substantially reduces cardiovascular morbidity and mortality, many treated patients still experience a high residual risk. Statins lower LDL-cholesterol (LDL-C), with limited effects on other lipid parameters. Fibrates improve atherogenic dyslipidemia characterized by high triglyceride and/or low HDL-C levels and elevated concentrations of small dense LDL particles, with or without high LDL-C levels. Fibrates decrease cardiovascular morbidity especially in patients with the metabolic syndrome. The purpose of this review is to provide a rationale for the combined use of statins and fibrates in the management of patients with high residual cardiovascular risk related to atherogenic dyslipidemia and persisting after single therapy.
Recent findings
A meta-analysis from 14 randomised trials conducted in high-risk patients reported that statin therapy is effective in reducing the proportional risk for major vascular events by 21% for each mmol/L lowering of LDL-C. However, on average 14% of patients still experienced an event despite being allocated to statin. Beyond LDL-C, other factors, including triglycerides, non-HDL-C, HDL-C and apolipoprotein B, have been identified as factors determining residual risk, and normalization of these parameters may further decrease cardiovascular disease in patients treated with statins. Data from fibrate trials indicate that these drugs are particularly effective in reducing cardiovascular morbidity in patients with atherogenic dyslipidemia.
Reducing the residual cardiovascular risk in patients treated with statins requires addressing multiple lipid goals. In this context, future therapeutic interventions based on combination therapy, such as statins and fibrates, appears particularly promising.
PMCID: PMC2980504  PMID: 19829109
Antilipemic Agents; therapeutic use; Cardiovascular Diseases; blood; drug therapy; Cholesterol, LDL; blood; Clofibric Acid; therapeutic use; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; therapeutic use; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Cardiovascular risk factors; Residual risk; Statins; Fibrates; Dyslipoproteinemia
8.  Cardiovascular Events in Patients Received Combined Fibrate/Statin Treatment versus Statin Monotherapy: Acute Coronary Syndrome Israeli Surveys Data 
PLoS ONE  2012;7(4):e35298.
The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30-day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone.
The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization.
Patients from the combination group were younger (58.1±11.9 vs. 62.9±12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32–0.94.
A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups.
PMCID: PMC3327654  PMID: 22523582
9.  Role of Colesevelam in Combination Lipid-Lowering Therapy 
Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug–drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.
PMCID: PMC3781306  PMID: 23913404
10.  Reducing Vascular Events Risk in Patients with Dyslipidaemia: An Update for Clinicians 
Reducing the risk of vascular events in patients with dyslipidaemia requires cardiovascular disease risk stratification and lifestyle/pharmacological intervention on modifiable risk factors. Reduction of low-density lipoprotein cholesterol (LDL-C) with statins is highly effective in reducing cardiovascular disease in patients with and without diabetes, but leaves unaddressed a sizeable residual vascular risk (RvR), which is rarely quantified in routine clinical practice. Such RvR may relate to lack of strict target attainment for all atherogenic variables [LDL-C, non-high-density lipoprotein cholesterol (HDL-C) and/or apolipoprotein B100]. Another substantial lipid-related and modifiable RvR component is related to atherogenic dyslipidaemia, especially as global rates of obesity, type 2 diabetes and metabolic syndrome are increasing. Atherogenic dyslipidaemia is associated with insulin-stimulated very-low-density lipoprotein overproduction and reduced reverse cholesterol transport. The hallmark of atherogenic dyslipidaemia is the coexistence of low HDL-C and elevated triglycerides. Therapeutic lifestyle changes and combination lipid-lowering therapy with drugs targeting atherogenic dyslipidaemia (such as fibrates or innovative drugs targeting atherogenic dyslipidaemia and/or apolipoprotein B100 metabolism) on top of background statins, have a potential to reduce RvR in high-risk groups, as shown in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, in which combination therapy with simvastatin plus fenofibrate decreased macrovascular risk in patients with diabetes and atherogenic dyslipidaemia, and retinopathy risk irrespective of baseline lipids.
PMCID: PMC3513890  PMID: 23251757
cardiovascular risk; low-density lipoprotein cholesterol; apolipoprotein B; atherogenic dyslipidaemia; metabolic syndrome; diabetes
11.  Should We Use PPAR Agonists to Reduce Cardiovascular Risk? 
PPAR Research  2008;2008:891425.
Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR-α agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR-γ agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-α/γ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-δ and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.
PMCID: PMC2234387  PMID: 18288293
12.  Is combined lipid-regulating therapy safe and feasible for the very old patients with mixed dyslipidemia? 
To detect the efficacy and safety of combined lipid-regulating therapies in the very old patients with mixed dyslipidemia and determine an appropriate therapy for them.
Four hundred and fifty patients aged over 75 with mixed dyslipidemia were divided into five groups according to different combination therapies. Lipid levels and drug related adverse events were tested during the study.
Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were reduced in every group compared to baseline: statin + ezetimibe: −30.0% and −55.5%; statin + policosanol: −31.1% and −51.2%; statin + fibrates: −23.7% and −44.6%; statin + niacin: −25.2% and −43.0%; and niacin + fibrates: −11.3% and −23.5%. The target achievement rates of LDL-C all exceeded 50%, except in niacin + fibrates (42.0%); statin + ezetimibe: 57.0%; statin + policosanol: 56.0%; statin + niacin: 52.0%; and statin + fibrates: 50.0%. However, overall, the niacin + fibrates group was the most effective in decreasing triglyceride (TG) and increasing high-density lipoprotein cholesterol (HDL-C) as follows: niacin + fibrates: −39.3% and 28.6%; statin + fibrates: −29.3% and 18.4%; statin + niacin: −18.5% and 16.7%; statin + ezetimibe: −17.1% and 7.1%; and statin + policosanol: −15.6% and 9.5%. The achievement rates of TG and HDL-C levels in niacin + fibrates (58.0% and 39.0%) were better than the other four groups: statin + niacin (34.0% and 34.0%), statin + fibrates (43.0% and 28.0%), statin + policosanol (30.0% and 24.0%) and statin + ezetimibe (28.0% and 25.0%). Patients in all five groups experiencing drug adverse events were only 2% and no severe adverse events occurred.
Statin + ezetimibe was the most effective group in lowering TC and LDL-C levels, while niacin + fibrates was the most effective in decreasing TG and increasing HDL-C levels. The commonly used combined lipid-regulating therapies with common dosages in this study were all quite safe and feasible for the very old patients with mixed hyperlipidemia.
PMCID: PMC3888917  PMID: 24454328
Elderly patients; Mixed dyslipidemia; Combination therapies; Safety
13.  Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid 
Cardiovascular disease (CVD) represents the leading cause of mortality worldwide. Lifestyle modifications, along with low-density lipoprotein cholesterol (LDL-C) reduction, remain the highest priorities in CVD risk management. Among lipid-lowering agents, statins are most effective in LDL-C reduction and have demonstrated incremental benefits in CVD risk reduction. However, in light of the residual CVD risk, even after LDL-C targets are achieved, there is an unmet clinical need for additional measures. Fibrates are well known for their beneficial effects in triglycerides, high-density lipoprotein cholesterol (HDL-C), and LDL-C subspecies modulation. Fenofibrate is the most commonly used fibric acid derivative, exerts beneficial effects in several lipid and nonlipid parameters, and is considered the most suitable fibrate to combine with a statin. However, in clinical practice this combination raises concerns about safety. ABT-335 (fenofibric acid, Trilipix®) is the newest formulation designed to overcome the drawbacks of older fibrates, particularly in terms of pharmacokinetic properties. It has been extensively evaluated both as monotherapy and in combination with atorvastatin, rosuvastatin, and simvastatin in a large number of patients with mixed dyslipidemia for up to 2 years and appears to be a safe and effective option in the management of dyslipidemia.
PMCID: PMC2922314  PMID: 20730069
atherogenic dyslipidemia; cardiovascular disease prevention; lipid-lowering treatment; fenofibric acid; statins
14.  The influence of statin-fibrate combination therapy on lipids profile and apolipoprotein A5 in patients with acute coronary syndrome 
Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome (ACS) complicated by elevated triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C). The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 (apoA5) level in patients with ACS.
One hundred and four patients with ACS were recruited and randomly assigned into two groups: one was statin group (n = 52), given atorvastatin (20 mg QN) or other statins with equivalent dosages; the other was combination group (n = 52), given the same dose of statin plus bezafibrate (200 mg BID). Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment. Serum apoA5 levels were determined using a commercial available ELISA kit.
(1) Compared with that of statin monotherapy, statin-bezafibrate combination treatment not only resulted in a significant reduction of TG, TC and LDL-C levels, (all p < 0.05), but also led to increases in HDL-C and apoA5 levels (p < 0.05).
(2) The percentage changes of TC, TG, LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks (all p < 0.05). Similarly, the rates of achieving lipid-control target were higher in statin-bezafibrate combination treatment group than those in statin monotherapy group (all p < 0.05).
(3) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG (r = 0.359, p = 0.009). However, a negative correlation was observed between apoA5 and TG (r = -0.329, p = 0.017) after 12 weeks treatment.
Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients. Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control.
PMCID: PMC3850707  PMID: 24016248
Apolipoprotein A5; Triglyceride; Statin; Fibrate; Acute coronary syndrome
15.  Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons 
There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
PMCID: PMC1236941  PMID: 16168052
16.  Update on the clinical utility of fenofibrate in mixed dyslipidemias: mechanisms of action and rational prescribing 
Mixed dyslipidemia is a common lipid disorder characterized by the presence of an atherogenic lipoprotein phenotype due to abnormalities in various atherogenic and anti-atherogenic lipoproteins. Despite the link between the decrease of LDL-cholesterol by statin treatment and the prevention of cardiovascular disease, a high residual risk is observed in statin trials. This residual risk is partly explained by lipoprotein abnormalities other than LDL. Fenofibrate exerts a favorable effect on the atherogenic lipid profile of mixed dyslipidemia and can effectively reduce cardiovascular disease in patients with mixed dyslipidemia. Fenofibrate may offer important treatment alternatives as a second-line therapy in several circumstances: in combination with a statin for patients with mixed dyslipidemias not at goals on statin mono-therapy; in monotherapy for patients intolerant or with contraindication to statin therapy; and in combination with other drugs (ezetimibe, colesevelam) for patients with mixed dyslipidemias, known intolerance, or contraindication to statin and not at goals on fenofibrate monotherapy. However, the role of fenofibrate-statin therapy and of other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established.
PMCID: PMC2605343  PMID: 19183747
fenofibrate; mixed dyslipidemia; triglycerides; LDL-cholesterol; HDL-cholesterol
17.  Update on the use of fibrates: focus on bezafibrate 
Low-density lipoprotein-cholesterol (LDL-C) is a well established coronary heart disease (CHD) risk factor. However, the ability of this metabolic risk factor alone to identify individuals at rigk for future CHD events is limited. The raised triglycerides-low high-density lipoprotein-cholesterol (HDL-C) dyslipidaemia was shown to be an important cardiovascular risk factor independently of LDL-C levels. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-C levels. Through peroxisome proliferator-activated α-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Data from recent primary and secondary prevention clinical trials demonstrate the efficacy of fibrate therapy in patients with the raised triglycerides-low HDL-C dyslipidaemia. This review summarizes current data regarding mechanism of action and the metbolic effects of fibrates, as well as results from major clinical trials on the efficacy of this mode of lipid lowering therapy. In addition, recent data from subgroup analyses of the Bezafibrate Infarction Prevention trial, demonstrating several important metabolic and long-term cardiovascular effects of bezafibrate therapy, are detailed.
PMCID: PMC2464751  PMID: 18629356
fibrates; high-density lipoprotein-cholsterol; metabolic syndrome; peroxisome proliferator-activated α-receptors; cardiac events
18.  Diabetes: managing dyslipidaemia 
BMJ Clinical Evidence  2008;2008:0610.
Dyslipidaemia is a major contributor to the increased risk of heart disease found in people with diabetes. An increase of 1 mmol/L LDL-C is associated with a 1.57-fold increase in the risk of coronary heart disease (CHD) in people with type 2 diabetes. A diagnosis of diabetic dyslipidaemia requiring pharmacological treatment is determined by the person's lipid profile and level of cardiovascular risk.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for dyslipidaemia in people with diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anion exchange resins, combined treatments (for lipid modification), ezetimibe, fibrates, fish oil (for lipid modification), intensive multiple intervention treatment programmes (for lipid modification), nicotinic acid (for lipid modification), and statins.
Key Points
Dyslipidaemia is characterised by decreased circulating levels of high-density lipoprotein cholesterol (HDL-C) and increased circulating levels of triglycerides and low-density lipoprotein cholesterol (LDL-C). Dyslipidaemia is a major contributor to the increased risk of heart disease found in people with diabetes.An increase of 1 mmol/L LDL-C is associated with a 1.57-fold increase in the risk of CHD in people with type 2 diabetes.A diagnosis of diabetic dyslipidaemia requiring pharmacological treatment is determined by the person's lipid profile and level of cardiovascular risk. The classification of cardiovascular risk and lipid targets for drug treatment differ between the USA and the UK, and the rest of Europe. We used the United Kingdom Prospective Diabetes Study (UKPDS) risk calculator to estimate 10-year cardiovascular risk, and categorised a 15% or more risk as "higher risk", and 15% or less as "lower risk" according to the UK clinical guidelines. We found no RCTs of a solely lower-risk population, although some studies were excluded because of insufficient data to calculate risk. In clinical practice, most people with diabetes are increasingly considered at high cardiovascular risk, regardless of the presence or absence of other risk factors.
Statins are highly effective at improving cardiovascular outcomes in people with diabetes. Statins reduce cardiovascular mortality in people with type 2 diabetes with and without known CVD, and regardless of baseline total and LDL-C concentrations.Different statins seem to have similar efficacy at reducing LDL-C.
Combining statins with other treatments (such as ezetimibe or a fibrate) seems to reduce LDL-C more than statin treatments alone. Combinations could be useful in people with mixed dyslipidaemia where one drug fails to control all lipid parameters.
Fibrates seem to have a beneficial effect on cardiovascular mortality and morbidity by reducing triglyceride levels. In people with mixed dyslipidaemia, statins may also be required.
Intensive-treatment programmes involving multiple interventions (people seen by a nurse every 4-6 weeks) seem better at reducing cholesterol than usual-care programmes.
Fish oils may reduce triglyceride levels, but also seem to increase LDL-C levels, making them of limited benefit to most diabetic patients.
Nicotinic acid seems effective at increasing HDL-C and may reduce triglycerides. However, in clinical practice, nicotinic acid alone is not the preferred treatment for hypertriglyceridaemia, but may be used in combination with a statin in people with mixed dyslipidaemia, or in those unable to tolerate fibrates. Nicotinic acid seems to increase the incidence of flushing, particularly in female patients.
We don't know whether anion exchange resins or ezetimibe are useful in treating dyslipidaemia in people with diabetes, but they could be used in combination with a statin if the statin alone fails to achieve lipid targets.
PMCID: PMC2907966  PMID: 19450295
19.  A review on the rationale and clinical use of concomitant rosuvastatin and fenofibrate/fenofibric acid therapy 
Mixed dyslipidemia, characterized by a lipid triad of elevated triglycerides (TG), elevated low-density lipoprotein-cholesterol (LDL-C) and reduced high-density lipoprotein-cholesterol (HDL-C), is a common and frequently difficult to manage condition. The use of combination medications is often needed to effectively treat the lipid triad. The co-administration of statins and fibrates may provide the desired endpoints but safety issues such as toxicity to the muscles, liver and kidneys are a concern. Given the potency of rosuvastatin to lower LDL-C and fenofibrate’s effectiveness in lowering TG, the use of this specific combination may be desirable in treating mixed dyslipidemia. Pharmacokinetic studies revealed no significant interactions with the concomitant use of rosuvastatin and fenofibrate or its active metabolite fenofibric acid. Clinical studies evaluating the efficacy and safety of this combination therapy demonstrate significant reductions in TG and LDL-C levels, and elevations in HDL-C. Safety data from clinical trials reveal no major adverse reactions. However, case reports of adverse events have been published and monitoring for potential adverse reactions of the individual agents is advised. Overall, current data suggest the combination of rosuvastatin and fenofibrate or fenofibric acid is a safe combination to utilize when managing difficult to treat mixed dyslipidemia patients.
PMCID: PMC3262365  PMID: 22291492
dyslipidemia; rosuvastatin; fenofibrate; fenofibric acid
20.  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 
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.
PMCID: PMC3808150  PMID: 24174878
cardiovascular prevention; low-density lipoprotein; high-density lipoprotein; statin drugs; metabolic syndrome; obesity; diabetes; niacin; AIM-HIGH study; cholesteryl ester transfer protein; endothelial progenitor cells; fibrate drugs
21.  Effect of fibrate treatment on liver function tests in patients with the metabolic syndrome 
SpringerPlus  2014;3:14.
Fibrates are used especially in patients with hypertriglyceridaemia, a feature of the metabolic syndrome. Elevated LFTs are often observed in these patients perhaps related to fatty infiltration.
We wished to study changes seen in LFTs (GGT, ALT and ALP) following fibrate therapy and then determine associated factors.
This was a retrospective observational study in which data was collected from case notes of patients started on fibrates (n = 118, 2002–2008) in the lipid clinic at Good Hope Hospital and pre/post-fibrate lipid and LFT values were obtained. All biochemistry was performed on the Roche P-Unit using supplied reagents. Statistical analyses included t tests and regression analyses (factorised when quartiles were compared).
Of the study population 106 patients were on fenofibrate; the remaining on bezafibrate. Significant lowering of GGT (p < 0.0001), ALT (p = 0.0014) and ALP (p < 0.0001) levels were observed following fibrate treatment. Baseline lipid (cholesterol, triglycerides and HDL) concentrations, alcohol intake, length of treatment, gender, concurrent statin treatment and diabetes did not correlate with these changes in LFT in a multiple regression analysis. Higher pre-fibrate GGT (p < 0.0001), ALT (p < 0.0001) and ALP (p < 0.0001) concentrations were associated with larger decreases in each of these tests respectively with the highest 2 quartiles (GGT > 57 IU/l, ALT > 34 IU/l and ALP > 94 IU/l) significantly different to the lowest quartile. The above associations remained significant even when the regression analyses were corrected for changes in lipid values (which did not show an association).
Fibrate treatment led to improvements in LFT, the greatest benefit seen in patients with higher baseline LFT values. It appears that baseline and changes in lipid values post fibrate treatment were not associated with change in LFT.
PMCID: PMC3893320  PMID: 24455467
Fibrates; GGT; ALT; ALP; PPARα; Metabolic syndrome; Statins
22.  Adherence to Drug Label Recommendations for Avoiding Drug Interactions Causing Statin-Induced Myopathy–A Nationwide Register Study 
PLoS ONE  2013;8(8):e69545.
To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.
Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.
OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60–1.25 and 0.92; 95% CI 0.69–1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56–0.68 and low dose 0.63; CI 0.58–0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55–0.76 and low dose 0.70; CI 0.63–0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001).
Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy.
PMCID: PMC3735530  PMID: 23940522
23.  A comparative study of efficacy of atorvastatin alone and its combination with fenofibrate on lipid profile in type 2 diabetes mellitus patients with hyperlipidemia 
Mixed dyslipidemia is characterized by increased low-density lipoprotein cholesterol (LDL-C) elevated triglycerides (TGs) and decrease high-density lipoprotein cholesterol (HDL-C). It is more common in diabetes and is associated with an increased risk of coronary artery disease. Monotherapy with statins or fibrates may not effectively control all lipid parameters. The atorvastatin-fenofibrate combination has been shown to have highly beneficial effect on lipid parameters in type 2 diabetes associated with combined hyperlipidemia (CHL). In an open-label study, we evaluated the efficacy of atorvastatin alone and in combination with fenofibrate in 60 types 2 diabetes mellitus patients associated with hyperlipidemia. Patients were randomly assigned to receive atorvastatin 10 mg (Group 1) or combination of atorvastatin 10 mg and fenofibrate 145 mg (Group 2) once daily for 12 weeks. The effect of drugs on lipid profile was evaluated before and after treatment. After 12 weeks, the reduction in total cholesterol (TC), TGs, LDL-C, VLDL-C was 28%, 20%, 37% and 20% in Group 1 (P < 0.001 for all) as compared with 31%, 39%, 33% and 40% in Group 2 (P < 0.001 for all). There was insignificant rise in HDL-C in Group 1 (P = 0.71) and insignificant decrease in HDL-C (P = 0.70) in Group 2. During the combination therapy, the decrease in TC, TGs and VLDL-C was greater than atorvastatin alone. The combination of atorvastatin with fenofibrate in type 2 diabetes patients with CHL may have a favorable effect on some major coronary artery disease risk factors.
PMCID: PMC3777308  PMID: 24083205
Atorvastatin; fenofibrate; hyperlipidemia
24.  Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists 
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.
PMCID: PMC3682868  PMID: 23721199
Peroxisome proliferator-activated receptor; Fibrate; SPPARM; K-877; Cardiovascular; Diabetes; Metabolic syndrome
25.  Approach to identifying and managing atherogenic dyslipidemia 
Canadian Family Physician  2013;59(11):1169-1180.
To review the evidence for recognition and management of atherogenic dyslipidemia.
Sources of information
High-quality randomized trials and meta-analyses were available to address most questions. North American and European guidelines were reviewed. Of these, the Canadian Cardiovascular Society lipid guidelines were most congruent with current literature.
Main message
Atherogenic dyslipidemia is characterized by low levels of high-density lipoprotein (HDL), high levels of triglycerides, and a high low-density lipoprotein (LDL) particle number. The condition is highly associated with cardiovascular disease (CVD) and is poorly reflected in Framingham risk score and LDL measurements. Obesity, glucose intolerance, diabetes, and metabolic syndrome are rapidly becoming more common, and are often associated with atherogenic dyslipidemia, affecting long-term CVD risk. Recognition in the office is best achieved by non-HDL or total cholesterol–HDL ratio testing. Treatment success lies in optimizing diet and exercise. Of available medications, statins produce the most benefit and can be titrated to patient tolerance rather than to LDL target levels, which have a poor evidence base. The addition of fenofibrate can be considered in patients with high triglyceride and low HDL levels who have responded poorly to or have not tolerated statins.
Growing obesity prevalence creates a CVD risk that might be missed by LDL cholesterol testing alone. Simple calculations from results of a non-fasting lipid panel produce non-HDL levels and total cholesterol–HDL ratio, both of which are superior for predicting risk in all patients. These metrics should be available in lipid panels.
PMCID: PMC3828092  PMID: 24235189

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