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.
Cardiovascular risk; Cholesterol; Fibrates; Hypertriglyceridemia; Insulin resistance; Metabolic syndrome; Obesity; Statins; Triglycerides; Type 2 diabetes
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.
Adipokines; Adiponectin; Atherosclerosis; Coronary artery disease; Diabetes mellitus; Metabolic syndrome; Obesity; T-cadherin
The Editors of Cardiovascular Diabetology wish to thank all reviewers, both Editorial Board Members and external referees, who contributed to the journal in 2013 (Volume 12), and whose enthusiastic support in providing the essential service of peer review continues to improve the scientific quality of the journal and enable its goals to be achieved.
Coronary artery calcification (CAC) is closely related to coronary atherosclerosis. However, less is known about the clinical significance of extensive CAC (ECAC) in regard to types of first coronary events (acute vs. chronic). Diabetes mellitus (DM) represents a strong risk factor for CAD although its association with CAC is controversial. Aiming to elucidate these controversies we investigated the long-term outcome of coronary artery disease (CAD) in relation to degree of CAC in patients with and without DM from our annual cheek-up outpatient clinic.
Coronary artery computed tomography (CT) was performed in 667 patients who were yearly evaluated during a mean follow-up period of 6.3 ±3.4 year. The following 4 CAC categories were established: calcium absence; total calcium score (TCS): 1–100 AU; TCS: 101–600 AU and ECAC: TCS above 600 AU. Acute event was defined as first acute myocardial infarction (MI) or a new unstable angina. First chronic event was defined as a positive stress test with a consequent elective percutaneous coronary intervention or coronary artery bypass grafting.
628 subjects (94%) were free from any cardiac events, 39 (6%) experienced first cardiac event: 18 of them suffered acute and 21 chronic events. There were 67 patients with and 600 patients without DM: 78% of patients with DM presented CAC vs. 50% of patients without DM (p < 0.001).The mean TCS was 17 times higher in the chronic than in the acute events group: 914 vs. 55 AU, p < 0.001. In 95% of the patients with chronic events more than one calcified vessel was found, compared to 67% of the patients with acute events and only 30% of those without events (p < 0.001). Incidence of CAD events (all types pooled together) rose consequently from 2% in subjects without CAC to 34% in subjects with ECAC (p < 0.001). However, among the 32 subjects with ECAC, 11 (34%) developed chronic event while none of them had acute event. In contrast, none of subjects with TCS =0 or TCS 1–100 AU presented with chronic events. Subjects with TCS 101–600 AU presented 10 (9%) chronic and 5 (4.5%) acute events (p < 0.001).
Asymptomatic subjects with ECAC are not firstly manifested as acute coronary events but presented a high level of chronic CAD-related events during the 6.3 ±3.4 year follow-up. In contrast, first acute CAD-related events occurred mostly in subjects with mild and moderate CAC score.
Angina pectoris; Atherosclerosis; Coronary calcification; Coronary artery disease; Coronary computed tomography; Diabetes mellitus; Myocardial infarction
The Editors of Cardiovascular Diabetology wish to thank all reviewers, both Editorial Board Members and external referees, who contributed to the journal in 2012 (Volume 11), and whose enthusiastic support in providing the essential service of peer review continues to improve the scientific quality of the journal and enable its goals to be achieved.
We report the variation with temperature of the ensemble distribution of conformations spanned by the tau protein in its dynamical states measured by small-angle X-ray scattering (SAXS) using synchrotron radiation. The SAXS data show a clear temperature variation of the distribution of occupied protein conformations from 293 to 318 K. More conformations with a smaller radius of gyration are occupied at higher temperature. The protein–solvent interactions are shown by computer simulation to be essential for controlling the dynamics of protein conformations, providing evidence for the key role of water solvent in the protein dynamics, as proposed by Giorgio Careri.
Protein conformations; Intrinsic disordered proteins; Water effect in conformational landscape; Temperature effects in protein fluctuations
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.
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Metabolic syndrome; PPAR; Prevention; Residual cardiovascular risk; Type 2 diabetes
Currently the world faces epidemic of several closely related conditions: obesity, metabolic syndrome and type 2 diabetes (T2DM). The lipid profile of these patients and those with metabolic syndrome is characterized by the concurrent presence of qualitative as well as quantitative lipoprotein abnormalities: low levels of HDL, increased triglycerides, and prevalence of LDL particles that are smaller and denser than normal. This lipid phenotype has been defined as atherogenic dyslipidemia. Overwhelming evidences demonstrate that all components of the atherogenic dyslipidemia are important risk-factors for cardiovascular diseases. Optimal reduction of cardiovascular risk through comprehensive management of atherogenic dyslipidemias basically depends of the presence of efficacious lipid-modulating agents (beyond statin-based reduction of LDL-C). The most important class of medications which can be effectively used nowadays to combat atherogenic dyslipidemias is the fibrates. From a clinical point of view, in all available 5 randomized control trials beneficial effects of major fibrates (gemfibrozil, fenofibrate, bezafibrate) were clearly demonstrated and were highly significant in patients with atherogenic dyslipidemia. In these circumstances, the main determinant of the overall results of the trial is mainly dependent of the number of the included appropriate patients with atherogenic dyslipidemia. In a meta-analysis of dyslipidemic subgroups totaling 4726 patients a significant 35% relative risk reduction in cardiovascular events was observed compared with a non significant 6% reduction in those without dyslipidemia. However, different fibrates may have a somewhat different spectrum of effects. Currently only fenofibrate was investigated and proved to be effective in reducing microvascular complications of diabetes. Bezafibrate reduced the severity of intermittent claudication. Cardinal differences between bezafibrate and other fibrates are related to the effects on glucose metabolism and insulin resistance. Bezafibrate is the only clinically available pan - (alpha, beta, gamma) PPAR balanced activator. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C. Current therapeutic use of statins as monotherapy is still leaving many patients with atherogenic dyslipidemia at high risk for coronary events because even intensive statin therapy does not eliminate the residual cardiovascular risk associated with low HDL and/or high triglycerides. As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the specific case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. Though muscle pain and myositis is an issue in statin/fibrate treatment, adverse interaction appears to occur to a significantly greater extent when gemfibrozil is administered. However, bezafibrate and fenofibrate seems to be safer and better tolerated. Combined fibrate/statin therapy is more effective in achieving a comprehensive lipid control and may lead to additional cardiovascular risk reduction, as could be suggested for fenofibrate following ACCORD Lipid study subgroup analysis and for bezafibrate on the basis of one small randomized study and multiple observational data. Therefore, in appropriate patients with atherogenic dyslipidemia fibrates- either as monotherapy or combined with statins – are consistently associated with reduced risk of cardiovascular events. Fibrates currently constitute an indispensable part of the modern anti-dyslipidemic arsenal for patients with atherogenic dyslipidemia.
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Fenofibrate; Metabolic syndrome; Residual cardiovascular risk; Type 2 diabetes
Diabetic patients present with an accelerated atherosclerotic process and an increased risk for future cardiovascular events. In addition to the risk imposed by the disease itself, pharmacological treatment adds also a sizable risk, especially if certain classes of antidiabetic drugs are employed. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors have anti-atherosclerotic effects, yet clinical data are scarcely available.
We plan to prospectively investigate the effects of dipeptidyl peptidase-4 inhibition with vildagliptin on a number of atherothrombotic markers and adipokines in patients with proven atherosclerosis and type 2 diabetes. The selected markers are: interleukin-6, high sensitivity C reactive protein, interleukin 1-beta, total adiponectin levels, matrix metallo-proteinase 9 and platelet reactivity testing. Sixty eligible patients will be randomized in a 2:1 ratio to vildagliptin/metformin or metformin only treatment, for a 3-month duration treatment. Blood sampling for the proposed investigations will be taken at enrollment and immediately after completion of the study period.
Demonstrating antiatherothrombotic properties of dipeptidyl peptidase-4 inhibitors on proven markers is of substantial clinical significance. Coupled with their proven good safety profile these findings could translate into a significant clinical benefit.
Type 2 diabetes; Vildagliptin; Metformin; Atherosclerosis; Inflammation; Interleukin-6; TNF; Atherothrombosis; Adiponectin; MMP-9; hs-CRP
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.
The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol - presumably low density lipoprotein - cholesterol (LDL-C) - levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.
Interleukin-6 (IL-6) is a multifunctional cytokine regulating humoral and cellular responses and playing a central role in inflammation and tissue injury. Its effects are mediated through interaction with its receptor complex, IL-6Rβ (also known as gp130). It plays an important role in the pathogenesis of coronary artery disease and large quantities of IL-6 are found in human atherosclerotic plaques. IL-6 levels positively correlate with higher all-cause mortality, unstable angina, left ventricular dysfunction, propensity to diabetes and its complications, hypertension, obesity and several types of cancer. IL-6 levels augmentation demonstrates a remarkable parallel with another biomarkers reflecting harmful processes, like tumor necrosis factor alpha, interleukins 8 and 18, YKL-40, C reactive protein and resistin. Due to these facts, IL-6 was classified as a noxious interleukin. Nonetheless, there are several facts that challenge this usually accepted point of view. Since IL-6 has also anti-inflammatory activity, it seems reasonable to assume that favorable aspects exist. These aspects are two: 1. protection against bacterial infections, inactivating proinflammatory mediators, mitigating the course of septic shock and inducing the production of cortisol; and 2. influence on insulin sensitivity during exercise; this aspect is even more important. During exercise IL-6 is synthesized and released by muscles, with enhanced insulin action immediately at early recovery. Skeletal muscle may be considered as an endocrine organ; contracting muscles produce IL-6 and release it into the blood exerting its effects on other organs. The increase in circulating levels of IL-6 after exercise is consistent and proportional to exercise duration, intensity, muscle mass involved and endurance capacity. Thus, the fascinating possibility that the plenteous beneficial health effects of exercise could be ultimately mediated by IL-6 merits further elucidation. Interleukins were termed "good" or "bad", probably due to a tendency to see things in black and white, with no gray area in between. Calling IL-6 "a molecule with both beneficial and destructive potentials" would be a more equitable approach. In the literary creatures of Dr. Jekyll and Mr. Hyde, a good and an evil personality are found in the same individual. IL-6 playing the role of Dr. Jekyll is emerging; the time for IL-6 reappraisal is coming.
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.
Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM.
Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors – while usually inadequate as monotherapy – appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
The effects of pan-peroxisome proliferator-activated receptor (PPAR) ligand bezafibrate on N-terminal pro-B type natriuretic peptide (ProBNP) level in patients with coronary artery disease (CAD) is unknown. The current study aimed to investigate the long-term effects of bezafibrate on ProBNP level in patients with pre-existing CAD and advanced functional capacity impairment.
Metabolic and inflammatory parameters were analyzed from stored frozen serum samples obtained from 108 patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. They presented with New York Heart Association (NYHA) functional class III, comprising 58 patients in the bezafibrate group and 50 in the placebo groups, and completed a 2-year prospective, double-blind, placebo-controlled follow-up.
During follow-up ProBNP level did not change significantly in the placebo group, whereas it increased slightly in the bezafibrate group, which was older and with lower baseline ProBNP values. No significant differences between the groups were found for ProBNP levels after 2 year of follow-up. Analysis-of-covariance (ANCOVA) -taking into account age and baseline ProBNP level- showed that bezafibrate was not associated with longitudinal ProBNP changes during the follow-up period (p = 0.3).
Long-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment.
Epidemiologic studies have suggested that hypertriglyceridemia and insulin resistance are related to the development of colon cancer. Nuclear peroxisome proliferator-activated receptors (PPAR), which play a central role in lipid and glucose metabolism, had been hypothesized as being involved in colon cancerogenesis. In animal studies the lipid-lowering PPAR ligand bezafibrate suppressed colonic tumors. However, the effect of bezafibrate on colon cancer development in humans is unknown. Therefore, we proposed to investigate a possible preventive effect of bezafibrate on the development of colon cancer in patients with coronary artery disease during a 6-year follow-up.
Our population included 3011 patients without any cancer diagnosis who were enrolled in the randomized, double blind Bezafibrate Infarction Prevention (BIP) Study. The patients received either 400 mg of bezafibrate retard (1506 patients) or placebo (1505 patients) once a day. Cancer incidence data were obtained by matching a subject's identification numbers with the National Cancer Registry. Each matched record was checked for correct identification.
Development of new cancer (all types) was recorded in 177 patients: in 79 (5.25%) patients from the bezafibrate group vs. 98 (6.51%) from the placebo group. Development of colon cancer was recorded in 25 patients: in 8 (0.53%) patients from the bezafibrate group vs. 17 (1.13%) from the placebo group, (Fisher's exact test: one side p = 0.05; two side p = 0.07).
A difference in the incidence of cancer was only detectable after a 4 year lag and progressively increased with continued follow-up. On multivariable analysis the colon cancer risk in patients who received bezafibrate tended to be lower with a hazard ratio of 0.47 and 95% confidence interval 0.2–1.1.
Our data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.
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.
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.
Drugs in the same class are generally thought to be therapeutically equivalent because of similar mechanisms of action (the so-called "class effect"). However, statins differ in multiple characteristics, including liver and renal metabolism, half-life, effects on several serum lipid components, bioavailability and potency. Some are fungal derivatives, and others are synthetic compounds. The percentage absorption of an oral dose, amount of protein binding, degree of renal excretion, hydrophilicity, and potency on a weight basis is variable. These differences may be even greater in diabetic patients, who may present diabetes-induced abnormalities in P450 isoforms and altered hepatic metabolic pathways. Thus, it is obvious that head-to-head comparisons between different statins are preferable than trial-to-trial comparisons. Such assessments are of utmost importance, especially in cases in which specific populations with a distinct lipid profile and altered metabolic pathways, like diabetics, are studied. It should be specially pinpointed that patients with metabolic syndrome and diabetes constitute also a special population regarding their atherogenic dyslipidemia, which is usually associated with low HDL-cholesterol, hypertriglyceridemia and predominance of small dense LDL-cholesterol. Therefore, these patients may benefit from fibrates or combined statin/fibrate treatment. This policy is not accomplished since in the real world things are more complex. Trials would require very large sample sizes and long-term follow-up to detect significant differences in myocardial infarction or death between two different statins. Moreover, the fact that new compounds are under several phases of research and development represents an additional drawback for performing the trials. Ideally, head-to-head trials regarding clinically important outcomes should be conducted for all drugs. Nonetheless, the desirability of performing such trials, which epitomize modern evidence-based medicine, is frequently superseded by the feasibility dictated by pragmatic and economic circumstances. In the latter case, in absence of solid systematic documentation of comparable health benefits and long-term safety, both researchers and practicing physicians should allude to the weight of scientific endorsement behind the arguments and seek for the possible strengths and weaknesses intrinsic to each specific study. In any case, conclusions based on surrogate endpoints cannot completely substitute head-to-head comparisons regarding patients' outcome.
coronary artery disease; diabetes; hyperlipidemia; statins; trials
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.
Diabetes mellitus; Dyslipidemia; Fibrates; Metabolic syndrome; Statins
Left ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.
Five hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.
Mean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.
Type 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.
Diabetes mellitus; Echocardiography; Hypertension; Left ventricular hypertrophy
The impressive correlation between cardiovascular disease and glucose metabolism alterations has raised the likelihood that atherosclerosis and type 2 diabetes may share common antecedents. Inflammation is emerging as a conceivable etiologic mechanism for both. Interleukins are regulatory proteins with ability to accelerate or inhibit inflammatory processes.
Presentation of the hypothesis
A novel interleukins classification is described, based on their role in diabetes and atherosclerosis, hypothesizing that each interleukin (IL) acts on both diseases in the same direction – regardless if harmful, favorable or neutral.
Testing the hypothesis
The 29 known interleukins were clustered into three groups: noxious (the "bad", 8 members), comprising IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-17 and IL-18; protective (the "good", 5 members), comprising IL-4, IL-10, IL-11, IL-12 and IL-13; and "aloof", comprising IL-5, IL-9, IL-14, IL-16 and IL-19 through IL-29 (15 members). Each group presented converging effects on both diseases. IL-3 was reluctant to clustering.
These observations imply that 1) favorable effects of a given IL on either diabetes or atherosclerosis predicts similar effects on the other; 2) equally, harmful IL effects on one disease can be extrapolated to the other; and 3) absence of influence of a given IL on one of these diseases forecasts lack of effects on the other. These facts further support the unifying etiologic theory of both ailments, emphasizing the importance of a cardiovascular diabetologic approach to interleukins for future research. Pharmacologic targeting of these cytokines might provide an effective means to simultaneously control both atherosclerosis and diabetes.
Atherosclerosis; Coronary artery disease; Cytokines; Diabetes mellitus; Interleukins
The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III) guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance), prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR) deactivation (mainly obesity-related) is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2) with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.
Metabolic syndrome; Diabetes mellitus; Peroxisome proliferator activated receptors (PPAR); Obesity; Insulin resistance
The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study is a multinational, double-blind, randomized, placebo controlled trial which was recently published. It was aimed to evaluate the effect of the angiotensin receptor blocker losartan in patients with diabetic nephropathy. The primary efficacy measure was the time to the first event of the composite end point of a doubling of serum creatinine, end-stage renal disease, or death. The conclusion was that losartan led to significant improvement in renal outcomes, that was beyond that attributable to blood pressure control in patients with type 2 diabetes and nephropathy.
The perusal of the report raises concern, regarding to both the patient population as well as the outcome measures. At randomization, the placebo group included more patients with angina, myocardial infarction and lipid disorders than the losartan group. Information on glucose metabolism was disregarded, and data on antihyperglycemic therapy – which may have undesirable influences on cardiac performance – were not included in a multivariate analysis. In addition, only data on first hospitalization were reported, whilst information on total specific-cause hospitalizations was disregarded, thus potentially masking further unfavorable events. Furthermore, creatinine seems not to be a reliable surrogate end point. Based on its mechanism of action, losartan may possess favorable renoprotective properties. However, due to the methodological flaws and the incomplete data in the RENAAL study, the question of the effectiveness and safety of this drug in diabetic nephropathy remains yet unanswered.
Angiotensin receptor blockers; Clinical trials; Diabetes mellitus; Losartan; Nephropathy; RENAAL study