| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:2197-2202.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Cardiac Rehabilitation Institute (A.T., M.M., E.Z.F., E.S., Y.A.) and Bezafibrate Infarction Prevention Study Coordinating Center (I.G., J.L., V.B., L.M., S.B.), Neufeld Cardiac Research Institute, Chaim Sheba Medical Center, Tel-Hashomer, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Correspondence to Alexander Tenenbaum, MD, PhD, Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel. E-mail altenen{at}post.tau.ac.il or altenen{at}yahoo.com
Received November 14, 2002; de novo received November 5, 2003; revision received February 3, 2004; accepted February 6, 2004.
| Abstract |
|---|
|
|
|---|
Methods and Results The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). The patients received either 400 mg bezafibrate retard (156 patients) or placebo (147 patients) once a day. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. During follow-up, development of new-onset diabetes was recorded in 146 patients: in 80 (54.4%) from the placebo group and 66 (42.3%) from the bezafibrate group (P=0.04). The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo: 4.6±2.3 versus 3.8±2.6 years (P=0.004). Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development (hazard ratio, 0.70; 95% CI, 0.49 to 0.99). Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level (hazard ratio, 1.22; 95% CI 1.0 to 1.51) and body mass index (hazard ratio, 1.10; 95% CI, 1.05 to 1.16).
Conclusions Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination of bezafibrate with other recommended drugs for secondary prevention (statins and ACE inhibitors) would be as efficacious as suggested by our results remains to be determined.
Key Words: bezafibrate coronary disease diabetes mellitus glucose prevention
| Introduction |
|---|
|
|
|---|
In 1997, the American Diabetes Association (ADA) adopted new criteria for the detection of diabetes10 by establishing a single fasting blood glucose of at least 126 mg/dL (7 mmol/L) for the diagnosis of overt diabetes and glucose levels of 110 to 125 mg/dL (6.1 to 6.9 mmol/L) for impaired fasting glucose. People who develop type 2 diabetes usually pass through the phases of excessive adipogenesis, nuclear peroxisome proliferatoractivated receptor (PPAR) modulation, insulin resistance, hyperinsulinemia, pancreatic ß-cell stress and damage leading to a progressive decrease in insulin secretion, and impaired glucose postprandial and fasting levels.1117 Fasting glucose is presumed to remain normal as long as insulin hypersecretion can compensate for insulin resistance. The profound metabolic (specifically glucose and fatty acids) abnormalities associated with the impaired fasting glucose phase lead to further disturbance of insulin sensitization and secretion. These mechanisms contribute to the conversion of the impaired fasting glucose phase to overt diabetes.1117
Bezafibrate is a potent nonselective ligand/activator for PPAR-
,18 with triglyceride-lowering and HDL cholesterolraising effects resulting in decreased systemic availability of fatty acid, diminished fatty acid uptake by muscle, and improved insulin sensitization.1821 In patients with overt diabetes, bezafibrate reduces plasma glucose concentrations.19,22
Recent studies have shown that type 2 diabetes is preventable by lifestyle interventions and by some medications that influence primary glucose metabolism.2326 Whether pharmacological interventions that influence primary lipid metabolism can also delay or prevent development of type 2 diabetes is unknown.
The goal of the present study was to evaluate the effect of bezafibrate on the progression of the impaired fasting glucose phase to type 2 diabetes in patients with healed myocardial infarction and/or stable angina pectoris over a 6.2-year follow-up period.
| Methods |
|---|
|
|
|---|
After an initial 2 months of a lipid-lowering diet, the 3122 eligible patients were included in the BIP study between May 1990 and January 1993. There was no difference in the distribution of all-cause and cardiac mortality between the bezafibrate and placebo study groups. However, the reduction in the primary end point was impressive in the subgroup of patients with high baseline triglycerides (
200 mg/dL).28
Among the BIP study patients, there were 311 diagnosed diabetics, 141 patients with a fasting blood glucose level of
126 mg/dL (7 mmol/L) (undiagnosed diabetics), 2353 patients with a normal fasting blood glucose level of <110 mg/dL (6.1 mmol/L), and 14 patients with unknown glucose metabolism status. All these patients were excluded from analysis. Thus, the final study sample for this post hoc subgroup analysis comprised 303 nondiabetic patients without any antihyperglycemic treatment and with an impaired fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). In accordance with the ADA classification,10 we defined the detection of a fasting blood glucose level
126 mg/dL (7 mmol/L) during the follow-up period as the criterion for new diabetes.
The patients received either 400 mg bezafibrate retard or placebo once a day, in addition to dietary advice. Patients continued to take prescribed medications for cardiac and other conditions except 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. In July 1994, after the publication of the Scandinavian Simvastatin Survival Study (4S) results,29 the International Review and Advisory Board approved the recommendation of the Steering Committee to add colestipol for patients on study medication if their LDL cholesterol was >180 mg/dL in 2 separate laboratory examinations after reinforcement of dietary advice.
The study was a multicenter prospective trial performed in 18 university-affiliated hospitals. The follow-up period lasted until May 1998 (mean, 6.2±0.8 years; range, 4.7 to 7.6 years).
Laboratory Methods
Detailed data on laboratory methods were given in a previous report.28 Briefly, blood samples, collected in the 18 participating medical centers using standardized equipment and procedures, were transferred in cooled containers to a central laboratory. Blood samples were drawn after at least 12 hours of fasting for determination of serum levels of cholesterol, HDL cholesterol, and triglycerides. Laboratory measurements were carried out by use of standard automated procedures with commercially available kits (Roche Diagnostics). Fasting blood glucose values were determined by the GOD-PAPP method with a BM/Hitachi 717/911 analyzer.28 For the purposes of this study, serum samples, which had been taken at baseline from each study participant and stored at 70°C, were thawed and assayed for insulin level by routine radioimmunoassay (Insik 5, Sorin Biomedica). The homeostatic indexes of insulin resistance (HOMA IR and QUICKI) were calculated according to the homeostasis model of assessment as follows2932: Homeostasis Assessment of Insulin Resistance (HOMA IR)=fasting insulin (µU/mL)xfasting glucose (mmol/L)/22.5, and Quantitative Insulin Sensitivity Check Index (QUICKI)=1/[log fasting insulin (µU/mL)+ log fasting glucose (mg/100 mL)].
Determination of Additional Variables
Criteria for the diagnosis of myocardial infarction, anginal syndrome, hypertension, and congestive heart failure have previously been reported.28 Briefly, the diagnosis of ischemic heart disease was made in patients with documented myocardial infarction or typical angina pectoris in whom there was also a positive exercise test, evidence of myocardial ischemia revealed by radionuclide studies, or at least 60% stenosis of 1 major coronary artery. Functional capacity classes were evaluated according to the New York Heart Association classification. Smoking habits were determined on the basis of self-report during an interview held with a study physician.
Statistical Analysis
Data were analyzed with the SAS software.33 Continuous variables were presented as mean±SD. Comparisons between groups were made by use of
2 tests for discrete variables and a t test for continuous variables. Kaplan-Meier curves were produced with the LIFETEST procedure.34 The log-rank test was used to compare curves.
Repeated-measures ANOVA was used to evaluate the treatment effect (placebo versus bezafibrate) and changes in mean levels of glucose over time. Multivariate analysis of incidence of new diabetes was performed with the Cox proportional-hazards model (PHREG procedure) to account for different lengths of follow-up and correlation with covariates.34 Variables included in the model were age, gender, total cholesterol, triglycerides, hypertension, previous myocardial infarction, heart failure, peripheral vascular disease, anginal syndrome, chronic obstructive pulmonary disease, smoking status, BMI, and use of ACE inhibitors.
| Results |
|---|
|
|
|---|
|
|
Cardiovascular Drugs
Data on treatment with cardiovascular drugs among the study groups are presented in Table 2. At baseline, nitrates, calcium antagonists, ß-blockers, and antiplatelet drugs (mainly aspirin) were the most commonly used medications. Use of ACE inhibitors at baseline was low. It increased significantly during the follow-up period. In addition, we observed during follow-up a relatively decreased use of calcium antagonists and nitrates, whereas use of antiplatelet drugs and diuretics was augmented. There were no significant differences in the proportion of patients receiving the other cardiovascular drugs.
Changes in Glucose Level and BMI During Follow-Up
No significant differences between groups were found for fasting glucose levels on baseline. In the first year, there was a reduction in the mean level of fasting blood glucose in the bezafibrate group, whereas it was unchanged in the placebo group (Figure 1A). The values rose in parallel in both groups in subsequent years. In total, there was a significant difference in glucose levels over time between bezafibrate and placebo groups (P=0.02). There was no significant change in mean BMI values in either the bezafibrate or placebo group during follow-up (Figure 1B).
|
Effect of Treatment on Lipid Levels
Average changes in mean HDL cholesterol and triglyceride levels are shown in Figure 2A and 2B. The most marked changes were an increase of 16% (P=0.0.001) in mean HDL cholesterol (Figure 2A) and a reduction of 24% (P=0.0001) in mean triglyceride values (Figure 2B) in the bezafibrate group after the first year of treatment (corresponding to the reduction in mean levels of fasting blood glucose). There were no significant changes in mean HDL cholesterol and triglyceride levels in the placebo group during follow-up
|
Development of New Diabetes
Per the definition, there were no patients with diabetes among the study groups at the beginning of follow-up. Patients were followed up from 4.7 to 7.6 years (mean follow-up, 6.2±0.8 years). During this period, development of new diabetes was recorded in 146 patients: in 80 patients (54.4%) in the placebo group compared with 66 patients (42.3%) in the bezafibrate group (P=0.04). In addition to a reduction in the incidence of disease, the mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo: 4.6±2.3 versus 3.8±2.6 years (P=0.004). The mean delay was
10 months.
All patients in whom diabetes was diagnosed during the study were initially on an antihyperglycemic diet. In addition, 49 of 146 patients (33.6%) with new diabetes thereafter received oral antihyperglycemic drugs. There was no difference in the proportion of patients receiving these drugs between study groups (Table 2).
Kaplan-Meier curves of diabetes incidence (in accordance with the time of diagnosis after annual fasting blood glucose level measurements) for the 2 study groups are presented in Figure 3. The incidence rate of the patients on placebo was significantly worse than in their bezafibrate-treated counterparts (log-rank P=0.009). Age-adjusted analysis demonstrated that the rate of diabetes incidence was reduced by 36% among patients on bezafibrate (hazard ratio [HR], 0.64; 95% CI, 0.46 to 0.89).
|
To assess whether the association between bezafibrate treatment and the reduced rate of new diabetes persisted in diverse categories of metabolic status, diabetes mellitus incidence was determined in patients according to level of BMI, LDL cholesterol, and triglycerides and the presence of ACE inhibitors (Table 3). A lower incidence of diabetes mellitus was found in the patients on bezafibrate regardless of the use of ACE inhibitors and for different levels of BMI, LDL cholesterol, and triglycerides.
|
Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development (HR, 0.70; 95% CI, 0.49 to 0.99).
Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level (20-mg/dL increment) (HR, 1.22; 95% CI, 1.0 to 1.51) and BMI (1-kg/m2 increment) (HR, 1.10; 95% CI, 1.05 to 1.16).
| Discussion |
|---|
|
|
|---|
The Diabetes Prevention Program (DPP) results have shown that individualized, systematic, and intensive lifestyle interventions (including dietary changes, increased physical activity, and weight loss) are the most effective means of preventing type 2 diabetes in general high-risk populations.23 Unfortunately, they are not easily applied in general practice. Pharmacological interventions by some medications that influence primary glucose metabolism (metformin and acarbose) can also effectively delay progression to type 2 diabetes,23,26 but the magnitude of the benefit seems to be somewhat less (58% for DPP lifestyle changes versus 31% for metformin and 25% for acarbose). However, it should be stressed that the DPP was in part related to individualized lifestyle interventions (in contrast to pharmacological studies) and by definition was a randomized but not double-blind trial. Data from our study have shown that a pharmacological intervention (bezafibrate) that influences primary lipid metabolism can also delay the development of type 2 diabetes with a magnitude of benefit similar to that for metformin and acarbose (30%).
Bezafibrate is a potent nonselective pharmacological ligand for PPAR-
, which controls primarily the expression of genes involved in lipid metabolism. However, PPAR-
(in addition to PPAR-
) also plays a role in glucose homeostasis and in the development of insulin resistance.18,35,36 It is important to note that on a whole-body level, lipid and glucose metabolisms interact intimately. In summary, PPAR-
is activated by fibric acids (eg, bezafibrate) and form heterodimers with the 9-cis retinoic acid receptor. These heterodimers bind to peroxisome proliferator response elements, which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR-
target genes. Bezafibrate reduces triglyceride plasma levels through increases in the expression of genes involved in fatty acid-ß oxidation and a decrease in apolipoprotein C-III gene expression. Fibric acids increase HDL cholesterol partly by increasing apolipoprotein A-I and A-II gene expression. Their triglyceride-lowering and HDL cholesterolraising effects lead to decreased systemic availability of fatty acid, diminished fatty acid uptake by muscle, improved insulin sensitization, and reduced plasma glucose level.1824
Moreover, compared with other fibrates, bezafibrate has a unique characteristic profile of action. Clofibrate, fenofibrate, and bezafibrate were developed as hypolipidemic agents through optimization of their lipid-lowering activity in rodents before the discovery of the PPARs. Clofibric acid and fenofibric acid, the active metabolites of clofibrate and fenofibrate, are dual activators of PPAR-
and PPAR-
, with
10-fold selectivity for PPAR-
, whereas bezafibrate activates all 3 PPAR subtypes (
,
, and
) at comparable doses.37,38 Therefore, bezafibrate operated as a panagonist for all 3 PPAR isoforms with the potential to directly improve insulin sensitization via PPAR-
activation.
In the BIP study,28 rates of adverse events, hospitalization, and mortality were similar in both study groups. Thus, bezafibrate treatment was safe and effective in diabetes prevention.
Study Limitations
Our study has several important limitations. First, BMI was slightly but significantly lower among patients on bezafibrate, which could have contributed to their lower diabetes incidence. On the other hand, no significant differences at baseline were found between groups in fasting insulin level and indexes of insulin sensitivity (HOMA IR and QUICKI). Second, most of the bezafibrate effects in relation to fasting glucose level and cumulative incidence of diabetes (Figures 1A and 3
) were achieved during the first year of treatment, but these favorable effects compared with the placebo group were maintained throughout the whole follow-up period. It is interesting that the same phenomenon was observed for both metformin and lifestyle interventions.23 Third, our study was initiated in 1990. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence,39 was relatively low. Therefore, whether the combination of the bezafibrate with drugs already recommended for secondary prevention (statins and angiotensin converting enzyme inhibitors) would be as efficacious as suggested by our results remains to be determined.
A partial answer to these unresolved questions is presented in a subgroup analysis (Table 3). To assess whether the association between bezafibrate treatment and the reduced rate of new diabetes persisted in diverse categories of metabolic status, diabetes mellitus incidence was determined in patients according to level of BMI, LDL cholesterol, and triglycerides and the presence of ACE inhibitors. The lower diabetes mellitus incidence was found in patients on bezafibrate regardless of use of ACE inhibitors and for different levels of BMI, LDL cholesterol, and triglycerides. However, the number of participants with new diabetes in the study was too small to make this type of analysis really significant.
Our data suggest that bezafibrate can slow down the progression of impaired fasting glucose to overt type 2 diabetes. Therefore, pharmacological interventions that influence primary lipid metabolism probably can be effective in this context. However, caution should be used in interpreting our finding because it was identified in post hoc subgroup analysis.
| Conclusions |
|---|
|
|
|---|
| References |
|---|
|
|
|---|
2. Burke JP, Williams K, Gaskill SP, et al. Rapid rise in the incidence of type 2 diabetes from 1987 to 1996: results from the San Antonio Heart Study. Arch Intern Med. 1999; 159: 14501456.
3. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999; 100: 11341146.
4. Mokdad AH, Ford ES, Bowman BA, et al. The continuing increase of diabetes in the US. Diabetes Care. 2001; 24: 412.
5. Tenenbaum A, Motro M, Fisman EZ, et al. Clinical impact of borderline and undiagnosed diabetes mellitus in patients with coronary artery disease. Am J Cardiol. 2000; 86: 13631366.[CrossRef][Medline] [Order article via Infotrieve]
6. Burchfiel CM, Curb JD, Rodriguez BL, et al. Incidence and predictors of diabetes in Japanese-American men: the Honolulu Heart Program. Ann Epidemiol. 1995; 5: 3343.[CrossRef][Medline] [Order article via Infotrieve]
7. von Eckardstein A, Schulte H, Assmann G. Risk for diabetes mellitus in middle-aged Caucasian male participants of the PROCAM study: implications for the definition of impaired fasting glucose by the American Diabetes Association: Prospective Cardiovascular Munster. J Clin Endocrinol Metab. 2000; 85: 31013108.
8. Mykkanen L, Kuusisto J, Pyorala K, et al. Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects. Diabetologia. 1993; 36: 553559.[Medline] [Order article via Infotrieve]
9. Moore LL, Visioni AJ, Wilson PW, et al. Can sustained weight loss in overweight individuals reduce the risk of diabetes mellitus? Epidemiology. 2000; 11: 269273.[CrossRef][Medline] [Order article via Infotrieve]
10. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997; 20: 11831197.[Medline] [Order article via Infotrieve]
11. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of noninsulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med. 1993; 329: 19881992.
12. Groop LC. Insulin resistance: the fundamental trigger of type 2 diabetes. Diabetes Obes Metab. 1999; 1 (suppl 1): S1S7.
13. Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999; 42: 10331049.[CrossRef][Medline] [Order article via Infotrieve]
14. Vamecq J, Latruffe N. Medical significance of peroxisome proliferatoractivated receptors. Lancet. 1999; 10, 354: 141148.
15. Hayden MR, Tyagi SC. Intimal redox stress: accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus: atheroscleropathy. Cardiovasc Diabetol. 2002; 1: 3.[CrossRef][Medline] [Order article via Infotrieve]
16. Porte D Jr, Kahn SE. ß-Cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001; 50 (suppl 1): S160S163.
17. Aronson D, Rayfield E. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol. 2002; 1: 1.[CrossRef][Medline] [Order article via Infotrieve]
18. Fruchart JC, Staels B, Duriez P. The role of fibric acids in atherosclerosis. Curr Atheroscler Rep. 2001; 3: 8392.[Medline] [Order article via Infotrieve]
19. Rovellini A, Sommariva D, Branchi A, et al. Effects of slow release bezafibrate on the lipid pattern and on blood glucose of type 2 diabetic patients with hyperlipidaemia. Pharmacol Res. 1992; 25: 237245.[CrossRef][Medline] [Order article via Infotrieve]
20. Taniguchi A, Fukushima M, Sakai M, et al. Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism. 2001; 50: 477480.[CrossRef][Medline] [Order article via Infotrieve]
21. Jonkers IJ, Mohrschladt MF, Westendorp RG, et al. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med. 2002; 112: 275280.[CrossRef][Medline] [Order article via Infotrieve]
22. Jones IR, Swai A, Taylor R, et al. Lowering of plasma glucose concentrations with bezafibrate in patients with moderately controlled NIDDM. Diabetes Care. 1990; 13: 855863.[Abstract]
23. Knowler WC, Barrett-Connor E, Fowler SE, et al, for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002; 346: 393403.
24. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care. 1997; 20: 537544.[Abstract]
25. Tuomilehto J, Lindstrom J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344: 13431350.
26. Chiasson JL, Josse RG, Gomis R, et al, for the STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002; 359: 20722077.[CrossRef][Medline] [Order article via Infotrieve]
27. Goldbourt U, Behar S, Reicher-Reiss H, et al. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial). Am J Cardiol. 1993; 71: 909915.[CrossRef][Medline] [Order article via Infotrieve]
28. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102: 2127.
29. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 13831389.[CrossRef][Medline] [Order article via Infotrieve]
30. Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care. 1997; 20: 10871092.[Abstract]
31. Katz A, Nambi SS, Mather K, et al. Quantitative Insulin Sensitivity Check Index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000; 85: 24022410.
32. Lichnovska R, Gwozdziewiczova S, Hrebicek J. Gender differences in factors influencing insulin resistance in elderly hyperlipidemic non-diabetic subjects. Cardiovasc Diabetol. 2002; 1: 4.[CrossRef][Medline] [Order article via Infotrieve]
33. SAS/STAT: Users Guide, Version 6, Volume 2. 4th ed. Cary, NC: SAS Institute Inc; 1987.
34. SAS/STAT Software: Changes and Enhancements, Release 6.07. Cary, NC: SAS Institute Inc; 1992. SAS Technical Report P-229.
35. Guerre-Millo M, Rouault C, Poulain P, et al. PPAR-alphanull mice are protected from high-fat dietinduced insulin resistance. Diabetes. 2001; 50: 28092814.
36. Tenenbaum A, Fisman EZ, Motro M. Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR). Cardiovasc Diabetol. 2003; 2: 4.[CrossRef][Medline] [Order article via Infotrieve]
37. Willson TM, Brown PJ, Sternbach DD, et al. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000; 43: 527550.[CrossRef][Medline] [Order article via Infotrieve]
38. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002; 53: 409435.[CrossRef][Medline] [Order article via Infotrieve]
39. Yusuf S, Gerstein H, Hoogwerf B, et al, for the HOPE Study Investigators. Ramipril and the development of diabetes. JAMA. 2001; 286: 18821885.
This article has been cited by other articles:
![]() |
J. Petremand, N. Bulat, A.-C. Butty, C. Poussin, S. Rutti, K. Au, S. Ghosh, V. Mooser, B. Thorens, J.-Y. Yang, et al. Involvement of 4E-BP1 in the Protection Induced by HDLs on Pancreatic {beta}-Cells Mol. Endocrinol., October 1, 2009; 23(10): 1572 - 1586. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. G. Drew, S. J. Duffy, M. F. Formosa, A. K. Natoli, D. C. Henstridge, S. A. Penfold, W. G. Thomas, N. Mukhamedova, B. de Courten, J. M. Forbes, et al. High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus Circulation, April 21, 2009; 119(15): 2103 - 2111. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. H. Flory, S. Ellenberg, P. O. Szapary, B. L. Strom, and S. Hennessy Antidiabetic Action of Bezafibrate in a Large Observational Database Diabetes Care, April 1, 2009; 32(4): 547 - 551. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Nakano, Y. Inada, H. Masuzaki, T. Tanaka, S. Yasue, T. Ishii, N. Arai, K. Ebihara, K. Hosoda, K. Maruyama, et al. Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1213 - E1222. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Bergeron, J. Yao, J. W. Woods, E. I. Zycband, C. Liu, Z. Li, A. Adams, J. P. Berger, B. B. Zhang, D. E. Moller, et al. Peroxisome Proliferator-Activated Receptor (PPAR)-{alpha} Agonism Prevents the Onset of Type 2 Diabetes in Zucker Diabetic Fatty Rats: A Comparison with PPAR{gamma} Agonism Endocrinology, September 1, 2006; 147(9): 4252 - 4262. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Lalloyer, B. Vandewalle, F. Percevault, G. Torpier, J. Kerr-Conte, M. Oosterveer, R. Paumelle, J.-C. Fruchart, F. Kuipers, F. Pattou, et al. Peroxisome Proliferator-Activated Receptor {alpha} Improves Pancreatic Adaptation to Insulin Resistance in Obese Mice and Reduces Lipotoxicity in Human Islets Diabetes, June 1, 2006; 55(6): 1605 - 1613. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Okopien, R. Krysiak, and Z. S. Herman Effects of Short-Term Fenofibrate Treatment on Circulating Markers of Inflammation and Hemostasis in Patients with Impaired Glucose Tolerance J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1770 - 1778. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Tenenbaum, E. Z. Fisman, V. Boyko, M. Benderly, D. Tanne, M. Haim, Z. Matas, M. Motro, and S. Behar Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate. Arch Intern Med, April 10, 2006; 166(7): 737 - 741. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Tenenbaum, M. Motro, E. Z. Fisman, Y. Adler, J. Shemesh, D. Tanne, J. Leor, V. Boyko, E. Schwammenthal, and S. Behar Effect of bezafibrate on incidence of type 2 diabetes mellitus in obese patients Eur. Heart J., October 1, 2005; 26(19): 2032 - 2038. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Hypertension, cardiovascular disease, and treatment approaches Diabetes Care, August 1, 2005; 28(8): 2073 - 2080. [Full Text] [PDF] |
||||
![]() |
A. Tenenbaum, M. Motro, E. Z. Fisman, D. Tanne, V. Boyko, and S. Behar Bezafibrate for the Secondary Prevention of Myocardial Infarction in Patients With Metabolic Syndrome Arch Intern Med, May 23, 2005; 165(10): 1154 - 1160. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Padwal, S. R. Majumdar, J. A. Johnson, J. Varney, and F. A. McAlister A Systematic Review of Drug Therapy to Delay or Prevent Type 2 Diabetes Diabetes Care, March 1, 2005; 28(3): 736 - 744. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. M. Flavell, H. Ireland, J. W. Stephens, E. Hawe, J. Acharya, H. Mather, S. J. Hurel, and S. E. Humphries Peroxisome Proliferator-Activated Receptor {alpha} Gene Variation Influences Age of Onset and Progression of Type 2 Diabetes Diabetes, February 1, 2005; 54(2): 582 - 586. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. T. Villareal and J. O. Holloszy Effect of DHEA on Abdominal Fat and Insulin Action in Elderly Women and Men: A Randomized Controlled Trial JAMA, November 10, 2004; 292(18): 2243 - 2248. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2004 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |