0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Attenuation of Progression of Insulin Resistance in Patients With Coronary Artery Disease by Bezafibrate FREE

Alexander Tenenbaum, MD, PhD; Enrique Z. Fisman, MD; Valentina Boyko, MS; Michal Benderly, PhD; David Tanne, MD; Moti Haim, MD; Zipora Matas, PhD; Michael Motro, MD; Solomon Behar, MD
[+] Author Affiliations

Author Affiliations: Cardiac Rehabilitation Institute (Drs Tenenbaum, Fisman, and Motro) and Bezafibrate Infarction Prevention Study Coordinating Center, Neufeld Cardiac Research Institute, Chaim Sheba Medical Center (Ms Boyko and Drs Benderly, Tanne, Haim, and Behar), Tel-Hashomer, Israel; and Biochemistry Laboratory, Wolfson Medical Center, Holon, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel (Dr Matas).


Arch Intern Med. 2006;166(7):737-741. doi:10.1001/archinte.166.7.737.
Text Size: A A A
Published online

Background  Development of insulin resistance (IR) may be important in the pathogenesis of both metabolic syndrome and type 2 diabetes mellitus. Few data are available regarding the short-term efficacy of the peroxisome proliferator–activated receptor ligand bezafibrate on IR, and its long-term effect is unknown. The present analysis aimed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention Study.

Methods  Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from patients who completed a 2-year, randomized, double-blind, placebo-controlled study. The homeostatic indexes of IR (HOMA-IRs) were calculated according to the homeostasis model of assessment.

Results  Both the patients taking bezafibrate (n = 1262) and those taking placebo (n = 1242) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose (r = 0.35 and 0.31, respectively) and triglycerides (r = 0.16 and 0.19, respectively). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88% higher than in their counterparts with normal glucose levels (P<.001). In the placebo group, during follow-up there was a significant 34.4% rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6% change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate (P<.001).

Conclusions  In patients with coronary artery disease enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of the follow-up, bezafibrate significantly attenuated this process.

Development of insulin resistance (IR) has been considered an important stage in the pathogenesis of metabolic syndrome, diabetes, and probably coronary artery disease (CAD), in which its effect is partially mediated by traditional cardiovascular risk factors.15 Moreover, IR has several possible pleiotropic effects, including dyslipidemia and direct promotion of atherogenesis.6,7

The fibric acid derivative bezafibrate is a nonselective ligand for peroxisome proliferator–activated receptor α (PPAR-α) with triglyceride-lowering and high-density lipoprotein cholesterol (HDL-C)–raising effects, resulting in decreased systemic availability of fatty acid and diminished fatty acid uptake by muscle.810 We have recently shown that the long-term use of bezafibrate in patients with CAD can reduce the incidence of diabetes.8,11 We hypothesized that this effect may be based on an improvement in insulin sensitization. Currently, few data are available regarding the short-term efficacy of bezafibrate on IR in clinical settings,1214 and its long-term effect is unknown. The present study aimed to investigate the effect of bezafibrate on IR in patients with CAD enrolled in the Bezafibrate Infarction Prevention (BIP) Study.15

PATIENTS

Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from patients who completed a 2-year, randomized, double-blind, placebo-controlled prospective study. The major inclusion and exclusion criteria for the BIP study, as well as the ethical guidelines, have been previously reported.15 In brief, inclusion criteria for men and women included the following: age 45 to 74 years, history of myocardial infarction no less than 6 months and not more than 5 years before enrollment into the study, and/or stable angina supported by coronary angiography and/or radionuclear studies or standard exercise tests. In addition, a lipid profile of serum total cholesterol level between 180 and 250 mg/dL (4.66-6.48 mmol/L), low-density lipoprotein cholesterol (LDL-C) level of 180 mg/dL or less (≤4.66 mmol/L) (≤160 mg/dL [4.14 mmol/L] for patients younger than 50 years), HDL-C level of 45 mg/dL or less (≤1.17 mmol/L), and triglyceride level of 300 mg/dL or less (≤3.39 mmol/L) was required. The major exclusion criteria for the BIP study were as follows: permanent pacemaker implantation, cerebrovascular disease, chronic hepatic or renal disease, peripheral vascular disease, malignant diseases, estrogen replacement therapy, type 1 diabetes mellitus, and current use of a lipid-modifying drug. The study was a multicenter prospective trial, performed in 18 university-affiliated hospitals. The trial was approved by the Helsinki Committee of each center and the central national Helsinki Committee. There were 3122 eligible patients who were included in the main BIP study. Among them, 81 died during the 2-year follow-up, and in 537, data were missing regarding baseline and/or follow-up level of fasting blood glucose (FBG) and/or insulin; all of these patients were excluded from this analysis. Thus, the final study sample for the current analysis included 2504 patients.

The patients received either 400 mg of bezafibrate retard or placebo once a day. Patients continued their prescribed medications for cardiac and other conditions except for lipid-lowering drugs. Routine visits to the clinics were scheduled bimonthly for study medication distribution and compliance assessment by tablet count, every 4 months for clinical evaluation, and every year for blood analyses.

CRITERIA OF DIABETES AND IMPAIRED FBG

The diagnosis of diabetes at baseline was made by the referring physician and confirmed in the framework of a university hospital based on the reported history and medical records. In addition, in accordance with the American Diabetes Association classification,16 we classified all patients with FBG levels at baseline of 126 mg/dL or higher (≥7 mmol/L) or receiving any type of pharmacologic antidiabetic treatment as diabetic patients. In patients without diabetes at baseline, we defined glucose levels of 110 to 125 mg/dL (6.1-6.9 mmol/L) as impaired fasting glucose (IFG). There were 351 patients with diabetes, 247 patients with IFG, and 1906 patients without diabetes or IFG at baseline.

LABORATORY ANALYSIS

Detailed data on laboratory methods were given in a previous report.15 A central laboratory performed all biochemical determinations. For the purpose of the present study, plasma citrate samples, which had been obtained at baseline from each study participant and stored at −70°C, were thawed and assayed for insulin level (Immulite 2000 analyzer, Diagnostic Products Corporation, Los Angeles, Calif) with the manufacturer's reagents–solid-phase, 2-site, chemiluminescent enzyme–labeled immunometric assay. This assay uses monoclonal and polyclonal antibodies for the capture and detection, respectively, of insulin. The interobserver and intraobserver variabilities of the insulin test in our study were 6.1% and 7.9%, respectively.

The homeostatic index of IR (HOMA-IR) and the homeostatic index of percentage of β-cell function (HOMA-BCF) were calculated according to the homeostasis model of assessment as follows17:

STATISTICAL ANALYSIS

Data were analyzed using SAS statistical software (SAS Institute Inc, Cary, NC). Continuous variables at baseline were presented as mean ± SD. Comparisons between groups were made using χ2 tests for discrete variables and the t test or Wilcoxon rank sum test for continuous variables.

Pearson correlation coefficients were calculated to examine the relationships between metabolic and inflammatory analytes at baseline and changes during follow-up for the study population as a whole. Log-transformed data were used for determination of Pearson correlation coefficients.

Because of their skewed distribution, insulin, HOMA-IR, and HOMA-BCF were presented as geometric mean (GM) and 95% confidence interval (CI). For the assessment of differences after 2 years between the bezafibrate and placebo groups, an analysis of covariance with terms for treatment and baseline values was used based on log-transformed data. Percent changes from baseline to 2 years were presented as GM and interquartile range and compared using the Wilcoxon rank sum test. P<.05 (2-sided) was considered statistically significant.

BASELINE DATA

Our population included 2 groups: the bezafibrate group (1262 patients) and the placebo group (1242 patients). Patients in the placebo and bezafibrate groups were well balanced in terms of clinical and laboratory baseline characteristics and concomitant medications (Table 1). The study groups were similar in regard to age, sex, and the prevalence of the most relevant cardiovascular diseases and risk factors (myocardial infarction in the past, hypertension, heart failure, peripheral vascular disease, anginal syndrome, and chronic obstructive pulmonary disease). No significant differences between the groups were found for the following values: all types of cholesterol, apolipoproteins, blood pressure, heart rate, FBG, triglycerides, fibrinogen, C-reactive protein, creatinine, fasting insulin, HOMA-IR, HOMA-BCF, and body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters). There were no differences between the placebo and bezafibrate groups in the proportion of patients receiving all types of cardiovascular drugs. Nitrates (50%), calcium antagonists (51%), β-blockers (39%), antiplatelet drugs (70%), diuretics (13%), and angiotensin-converting enzyme inhibitors (12%) were the most commonly used medications. The use of all types of cardiovascular drugs did not change significantly during the 2-year follow-up period.

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Population*
PATIENTS WITH DIABETES AND IFG

In the subgroup of 351 patients with diabetes (168 taking bezafibrate and 183 taking placebo), HOMA-IR (presented as GM [95% CI]) was significantly higher (Table 2), whereas HOMA-BCF was lower than in patients with normal glucose levels (<110 mg/dL [<0.26 mmol/L]): 1.49 (1.30-1.71) vs 0.83 (0.78-0.88) and 28.2 (24.4-32.6) vs 46.1 (43.4-48.9), respectively, in the bezafibrate group (P<.001 for both) and 1.62 (1.41-1.86) vs 0.83 (0.78-0.88) and 30.5 (26.6-35.1) vs 45.8 (43.1-48.6), respectively, in the placebo group (P<.001 for both). In 247 patients with IFG (glucose level, 110-125 mg/dL [6.11-6.94 mmol/L]), HOMA-IR and HOMA-BCF presented intermediate values: 1.27 (1.09-1.49) and 30.5 (26.1-35.7), respectively, in the bezafibrate group and 1.52 (1.29-1.78) and 36.6 (31.2-43.1), respectively, in the placebo group. Pooling the bezafibrate and placebo groups together, in patients with diabetes, HOMA-IR was 88% higher and HOMA-BCF was 36% lower than in their counterparts with normal glucose levels (P<.001 for both).

Table Graphic Jump LocationTable 2. Insulin, HOMA-IR, and HOMA-BCF at Baseline in Accordance With Glucose Level or Presence of Diabetes*
INTERRELATIONSHIP OF BASELINE METABOLIC AND INFLAMMATORY VALUES

The natural logarithm (ln) of HOMA-IR at baseline was significantly positively correlated with ln FBG (r = 0.35), ln BMI (r = 0.30), ln triglycerides (r = 0.16), and ln C-reactive protein (r = 0.13) and inversely correlated with ln HDL-C (r = −0.11). Similar correlations were shown for insulin. Baseline ln HOMA-BCF was correlated positively with BMI (r = 0.20) and negatively with ln FBG (r = −0.27).

CORRELATIONS BETWEEN CHANGES IN METABOLIC AND INFLAMMATORY VALUES DURING FOLLOW-UP

The change in ln HOMA-IR from baseline to 2 years of follow-up was significantly positively correlated with changes in ln HOMA-BCF (r = 0.82), ln FBG (r = 0.31), ln triglycerides (r = 0.19), ln fibrinogen (r = 0.17), ln total cholesterol (r = 0.13), and ln BMI (r = 0.11) and inversely correlated with changes in ln HDL-C (r = −0.13). The change in ln HOMA-BCF was positively correlated with changes in ln insulin (r = 0.90) and inversely correlated with changes in ln FBG cholesterol (r = −0.26). There was a relatively weak but significant correlation between the percent changes in ln BMI, ln insulin, ln total cholesterol, and ln triglycerides.

EFFECT OF TREATMENT ON CHANGES OF INSULIN, FBG, HOMA-IR, HOMA-BCF, AND BMI

Changes in insulin, HOMA-IR, and HOMA-BCF from baseline to 2 years of follow-up (bezafibrate vs placebo) are given in Table 3 and Table 4. No significant differences between the groups were found for these parameters at baseline. During follow-up, in the placebo group there was a significant 30.3% rise in GM of percentage change in insulin level, 15.2% in FBG, and 34.4% in HOMA-IR. In contrast, changes in the bezafibrate group were nonsignificant (7.8%, 2.1%, and 6.6%, respectively). The intergroup differences in percentage changes were in favor of bezafibrate (P<.001 for all). The HOMA-BCF values have increased during follow-up in patients of both groups but were more pronounced in patients taking placebo (P = .02). The BMI during 2-year follow-up increased significantly and similarly in patients taking bezafibrate and those taking placebo (1.4% and 1.2%, respectively; P<.001 for both).

Table Graphic Jump LocationTable 3. Insulin Level, HOMA-IR, and HOMA-BCF at Baseline and After 2-Year Follow-up (Bezafibrate vs Placebo)*
Table Graphic Jump LocationTable 4. Percentage Changes in Insulin Level, HOMA-IR, and HOMA-BCF From Baseline to 2-Year Follow-up (Bezafibrate vs Placebo)*

There are 2 major findings in our study. First, the obtained data demonstrated that in patients with CAD, as represented by the placebo group, HOMA-IR increases over time. Second, the PPAR ligand bezafibrate can significantly attenuate this process. These data, derived from a large-scale, prospective, randomized, double-blind, placebo-controlled study, are in line with 3 previous short-term, small observations that showed beneficial effects of bezafibrate on glucose and insulin metabolism.1214

In our study, in patients with diabetes, HOMA-IR was 88% higher and HOMA-BCF was 36% lower than in their counterparts without diabetes. People who develop type 2 diabetes mellitus usually pass through the phases of PPAR modulation, progression of IR, hyperinsulinemia, and pancreatic β-cell stress and damage, leading to a progressive decrease in insulin secretion and impaired postprandial and FBG levels.18 Emerging evidence supports the potentially unifying hypothesis that IR and progression to hyperglycemia are caused by mitochondrial dysfunction.19

Methods to assess insulin sensitivity and secretion directly (mainly, the hyperinsulinemic euglycemic glucose clamp technique) are complicated and are not easily implemented in large studies.20 It has been suggested that HOMA is a method to assess IR and secretion from the FBG and insulin concentrations and provides a useful model to assess IR and β-cell function in epidemiologic studies.17

Whether HOMA-IR in patients with established CAD increases progressively over time, as observed in our study, has not been previously demonstrated with certainty. The exact explanation of this observation remains unclear. Several mechanisms are likely to be involved. First, the close relationship between increased BMI and IR is well established.21 Also, in our study there was a significant correlation between BMI, both at baseline and during follow-up with HOMA-IR. Because BMI values during the 2-year follow-up have increased slightly but significantly in patients taking bezafibrate (1.4%) and those taking placebo (1.2%), this mechanism should be taken into consideration. Second, the BIP study population was characterized by a low baseline HDL-C level (since it was one of the inclusion criteria). Consistent with previous reports,21 our study has shown that HDL-C and its longitudinal changes are inversely associated with IR and hyperinsulinemia. These observations may partially explain HOMA-IR increase over time in patients from the placebo group. Third, it has been shown that the use of β-blockers and diuretics, cardiovascular drugs widely used in patients with CAD, may be associated with impaired insulin sensitivity.22 In the current analysis, 39% of the patients were taking β-blockers and 13% were taking diuretics, and their use did not change significantly during the 2-year follow-up period. One could presume that long-term metabolic effects of β-blockers and diuretics may be reflected by longitudinal changes in HOMA-IR.

Some of the patients with CAD, particularly those with more advanced myocardial dysfunction, diminish their exercise activity and are prone to development of IR. Moreover, impaired myocardial performance results in activation of the neurohormonal (mainly sympathetic) systems. Therefore, higher catecholamine levels can be another reason for the progression of IR in some of the patients with CAD.

Fibrates are the pharmacologic ligands for PPAR-α, which controls primarily the expression of genes involved in lipid metabolism. However, PPAR-α (in addition to PPAR-γ) also plays a role in glucose homeostasis and in the development of IR.9,10,18 On a whole-body level, lipid and glucose metabolisms interact intimately.23

In our study, HOMA-IR was significantly correlated with triglycerides both at baseline and during follow-up. Triglyceride-lowering and HDL-C–raising effects of fibrates lead to decreased systemic availability of fatty acid, diminished fatty acid uptake by muscle with improvement of insulin sensitization, and reduced plasma glucose level.1014

In animal models, selective PPAR-α compounds (fibrates) markedly lowered hyperinsulinemia and reduced IR.24 However, in humans gemfibrozil did not affect25 or even decrease insulin sensitivity,26 despite its significant beneficial effect on triglyceride concentrations. The reported results regarding effect of fenofibrate on insulin sensitivity were beneficial27 or neutral.28 The data regarding favorable effects of bezafibrate on glucose metabolism are consistent.8,1114 We reported earlier that bezafibrate reduces the incidence of myocardial infarction in subgroups of patients with metabolic syndrome during long-term follow-up.29 This may be explained by observations that bezafibrate operated as a pan-agonist for all 3 PPARs (α, β/δ, and γ) isoforms. Therefore, it has the potential to directly improve insulin sensitization via PPAR-γ activation.30

To the best of our knowledge, the present study is the first large-scale report regarding the long-term effect of bezafibrate on IR. Moreover, our placebo group (1242 patients) represents one of the first large populations in which long-term changes of IR in patients with CAD were evaluated. However, whether our results could be generalized to other populations of patients with CAD remains to be determined. Furthermore, our work was the secondary analysis of the BIP study, which was not designed to evaluate longitudinal changes in IR. Therefore, further studies are required to confirm our observation that IR in patients with CAD increases over time.

In conclusion, in patients with CAD enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of follow-up, bezafibrate significantly attenuated this process.

Correspondence: Alexander Tenenbaum, MD, PhD, Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.

Accepted for Publication: September 29, 2005.

Author Contributions: Dr Tenenbaum had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None.

Zethelius  BLithell  HHales  CNBerne  C Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease: a population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 2005;48862- 867
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [executive summary]. Circulation 2005;1122735- 2752
PubMed Link to Article
Hanley  AJWilliams  KStern  MPHaffner  SM Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002;251177- 1184
PubMed Link to Article
Nesto  RW Correlation between cardiovascular disease and diabetes mellitus: current concepts. Am J Med 2004;116 ((suppl 5A)) 11S- 22S
PubMed Link to Article
Kahn  RBuse  JFerrannini  EStern  M The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;282289- 2304
PubMed Link to Article
Reaven  GM Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993;44121- 131
PubMed Link to Article
Jadhav  SPetrie  JFerrell  WCobbe  SSattar  N Insulin resistance as a contributor to myocardial ischaemia independent of obstructive coronary atheroma: a role for insulin sensitisation? Heart 2004;901379- 1383
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZ  et al.  Peroxisome proliferator-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease. Circulation 2004;1092197- 2202
PubMed Link to Article
Despres  JPLemieux  IRobins  SJ Role of fibric acid derivatives in the management of risk factors for coronary heart disease. Drugs 2004;642177- 2198
PubMed Link to Article
Fruchart  JCStaels  BDuriez  P The role of fibric acids in atherosclerosis. Curr Atheroscler Rep 2001;383- 92
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZ  et al.  Effect of bezafibrate on incidence of type 2 diabetes mellitus in obese patients. Eur Heart J 2005;262032- 2038
PubMed Link to Article
Taniguchi  AFukushima  MSakai  M  et al.  Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism 2001;50477- 480
PubMed Link to Article
Jonkers  IJMohrschladt  MFWestendorp  RGvan der Laarse  ASmelt  AH Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002;112275- 280
PubMed Link to Article
Kim  JITsujino  TFujioka  YSaito  KYokoyama  M Bezafibrate improves hypertension and insulin sensitivity in humans. Hypertens Res 2003;26307- 313
PubMed Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;10221- 27
PubMed Link to Article
American Diabetes Association, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;201183- 1197
PubMed
Haffner  SMMiettinen  HStern  MP The homeostasis model in the San Antonio Heart Study. Diabetes Care 1997;201087- 1092
PubMed Link to Article
Tenenbaum  AFisman  EZMotro  M Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR). Cardiovasc Diabetol 2003;24
PubMed Link to Article
Lowell  BBShulman  GI Mitochondrial dysfunction and type 2 diabetes. Science 2005;307384- 387
PubMed Link to Article
DeFronzo  RATobin  JDAndres  R Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237E214- E223
PubMed
Lyssenko  VAlmgren  PAnevski  D  et al.  Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 2005;54166- 174
PubMed Link to Article
Kuperstein  RSasson  Z Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: a randomized, double-blind, controlled study of 21 obese hypertensives. Circulation 2000;1021802- 1806
PubMed Link to Article
Frayn  KN The glucose-fatty acid cycle: a physiological perspective. Biochem Soc Trans 2003;31 ((pt 6)) 1115- 1119
PubMed Link to Article
Guerre-Millo  MGervois  PRaspe  E  et al.  Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000;27516638- 16642
PubMed Link to Article
Whitelaw  DCSmith  JMNattrass  M Effects of gemfibrozil on insulin resistance to fat metabolism in subjects with type 2 diabetes and hypertriglyceridaemia. Diabetes Obes Metab 2002;4187- 194
PubMed Link to Article
Ohrvall  MLithell  HJohansson  JVessby  B A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia. Metabolism 1995;44212- 217
PubMed Link to Article
Idzior-Walus  BSieradzki  JRostworowski  W  et al.  Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest 2000;30871- 878
PubMed Link to Article
Vega  GLCater  NBHadizadeh  DR  IIIMeguro  SGrundy  SM Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome. Clin Pharmacol Ther 2003;74236- 244
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZTanne  DBoyko  VBehar  S Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005;1651154- 1160
PubMed Link to Article
Willson  TMBrown  PJSternbach  DDHenke  BR The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43527- 550
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Population*
Table Graphic Jump LocationTable 2. Insulin, HOMA-IR, and HOMA-BCF at Baseline in Accordance With Glucose Level or Presence of Diabetes*
Table Graphic Jump LocationTable 3. Insulin Level, HOMA-IR, and HOMA-BCF at Baseline and After 2-Year Follow-up (Bezafibrate vs Placebo)*
Table Graphic Jump LocationTable 4. Percentage Changes in Insulin Level, HOMA-IR, and HOMA-BCF From Baseline to 2-Year Follow-up (Bezafibrate vs Placebo)*

References

Zethelius  BLithell  HHales  CNBerne  C Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease: a population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 2005;48862- 867
PubMed Link to Article
Grundy  SMCleeman  JIDaniels  SR  et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement [executive summary]. Circulation 2005;1122735- 2752
PubMed Link to Article
Hanley  AJWilliams  KStern  MPHaffner  SM Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002;251177- 1184
PubMed Link to Article
Nesto  RW Correlation between cardiovascular disease and diabetes mellitus: current concepts. Am J Med 2004;116 ((suppl 5A)) 11S- 22S
PubMed Link to Article
Kahn  RBuse  JFerrannini  EStern  M The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;282289- 2304
PubMed Link to Article
Reaven  GM Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993;44121- 131
PubMed Link to Article
Jadhav  SPetrie  JFerrell  WCobbe  SSattar  N Insulin resistance as a contributor to myocardial ischaemia independent of obstructive coronary atheroma: a role for insulin sensitisation? Heart 2004;901379- 1383
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZ  et al.  Peroxisome proliferator-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease. Circulation 2004;1092197- 2202
PubMed Link to Article
Despres  JPLemieux  IRobins  SJ Role of fibric acid derivatives in the management of risk factors for coronary heart disease. Drugs 2004;642177- 2198
PubMed Link to Article
Fruchart  JCStaels  BDuriez  P The role of fibric acids in atherosclerosis. Curr Atheroscler Rep 2001;383- 92
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZ  et al.  Effect of bezafibrate on incidence of type 2 diabetes mellitus in obese patients. Eur Heart J 2005;262032- 2038
PubMed Link to Article
Taniguchi  AFukushima  MSakai  M  et al.  Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism 2001;50477- 480
PubMed Link to Article
Jonkers  IJMohrschladt  MFWestendorp  RGvan der Laarse  ASmelt  AH Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002;112275- 280
PubMed Link to Article
Kim  JITsujino  TFujioka  YSaito  KYokoyama  M Bezafibrate improves hypertension and insulin sensitivity in humans. Hypertens Res 2003;26307- 313
PubMed Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;10221- 27
PubMed Link to Article
American Diabetes Association, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;201183- 1197
PubMed
Haffner  SMMiettinen  HStern  MP The homeostasis model in the San Antonio Heart Study. Diabetes Care 1997;201087- 1092
PubMed Link to Article
Tenenbaum  AFisman  EZMotro  M Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR). Cardiovasc Diabetol 2003;24
PubMed Link to Article
Lowell  BBShulman  GI Mitochondrial dysfunction and type 2 diabetes. Science 2005;307384- 387
PubMed Link to Article
DeFronzo  RATobin  JDAndres  R Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237E214- E223
PubMed
Lyssenko  VAlmgren  PAnevski  D  et al.  Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 2005;54166- 174
PubMed Link to Article
Kuperstein  RSasson  Z Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: a randomized, double-blind, controlled study of 21 obese hypertensives. Circulation 2000;1021802- 1806
PubMed Link to Article
Frayn  KN The glucose-fatty acid cycle: a physiological perspective. Biochem Soc Trans 2003;31 ((pt 6)) 1115- 1119
PubMed Link to Article
Guerre-Millo  MGervois  PRaspe  E  et al.  Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000;27516638- 16642
PubMed Link to Article
Whitelaw  DCSmith  JMNattrass  M Effects of gemfibrozil on insulin resistance to fat metabolism in subjects with type 2 diabetes and hypertriglyceridaemia. Diabetes Obes Metab 2002;4187- 194
PubMed Link to Article
Ohrvall  MLithell  HJohansson  JVessby  B A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia. Metabolism 1995;44212- 217
PubMed Link to Article
Idzior-Walus  BSieradzki  JRostworowski  W  et al.  Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest 2000;30871- 878
PubMed Link to Article
Vega  GLCater  NBHadizadeh  DR  IIIMeguro  SGrundy  SM Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome. Clin Pharmacol Ther 2003;74236- 244
PubMed Link to Article
Tenenbaum  AMotro  MFisman  EZTanne  DBoyko  VBehar  S Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005;1651154- 1160
PubMed Link to Article
Willson  TMBrown  PJSternbach  DDHenke  BR The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43527- 550
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 54

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
PubMed Articles