Publications by authors named "Enrique Z Fisman"

97 Publications

Type 2 diabetes mellitus increases the mortality risk after acute coronary syndrome treated with coronary artery bypass surgery.

Cardiovasc Diabetol 2020 06 13;19(1):86. Epub 2020 Jun 13.

Department of Cardiac Surgery, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, 52621, Tel Hashomer, Israel.

Background: Type 2 diabetes mellitus (DM) is a risk factor for cardiovascular diseases and is common among patients undergoing coronary artery bypass grafting (CABG) surgery. The main objective of our study was to investigate the impact of DM type 2, and its treatment subgroups, on short- and long-term mortality in patients with acute coronary syndrome (ACS) who undergo CABG.

Methods: The study included 1307 patients enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for ACS and underwent CABG. Of them, 527 (40%) patients were with and 780 (60%) were without DM.

Results: Compared with the non-diabetic group, the diabetic group of patients comprised more women and had more comorbidities such as hypertension, dyslipidemia, renal impairment, peripheral vascular disease and prior ischemic heart disease. Overall 30-day mortality rate was similar between DM and non-DM patients (4.2% vs. 4%, p = 0.976). Ten-year mortality rate was higher in DM compared with non-diabetic patients (26.6% vs. 17.7%, log-rank p < 0.001), and higher in the subgroup of insulin-treated patients compared to non-insulin treated patients (31.5% vs. 25.6%, log-rank p = 0.019). Multivariable analysis showed that DM increased the mortality hazard by 1.61-fold, and insulin treatment among the diabetic patients increased the mortality hazard by 1.57-fold.

Conclusions: While type 2 DM did not influence the in-hospital mortality hazard, we showed that the presence of DM among patients with ACS referred to CABG, is a powerful risk factor for long-term mortality, especially when insulin was included in the diabetic treatment strategy.
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http://dx.doi.org/10.1186/s12933-020-01069-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293781PMC
June 2020

Hypomagnesemia is associated with new-onset diabetes mellitus following heart transplantation.

Cardiovasc Diabetol 2019 10 11;18(1):132. Epub 2019 Oct 11.

Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, Israel.

Background: Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT).

Methods: Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association.

Results: Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15-32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02-6.77, p = 0.05).

Conclusions: Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.
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http://dx.doi.org/10.1186/s12933-019-0939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787962PMC
October 2019

Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents.

Cardiovasc Diabetol 2019 09 25;18(1):124. Epub 2019 Sep 25.

Internal Medicine D and Hypertension Unit, Sheba Medical Center, 2 Derech Sheba, Migdal Ishpuz, 1st Floor, Tel Hashomer, 5265601, Ramat Gan, Israel.

Background: Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values.

Methods: Medical and socio-demographic data were collected from the Israeli Defense Force's conscription center's database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used.

Results: The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50-0.87) and 0.62 (95% CI 0.43-0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130-139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60-0.90).

Conclusions: Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.
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http://dx.doi.org/10.1186/s12933-019-0929-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760097PMC
September 2019

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation.

Cardiovasc Diabetol 2019 09 16;18(1):118. Epub 2019 Sep 16.

Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Tel Hashomer, 52621, Ramat Gan, Israel.

Background: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT.

Methods: The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality.

Results: Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p = 0.003) in the risk for CAV or cardiovascular mortality.

Conclusions: In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.
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http://dx.doi.org/10.1186/s12933-019-0925-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747732PMC
September 2019

Type 2 diabetes mellitus increases long-term mortality risk after isolated surgical aortic valve replacement.

Cardiovasc Diabetol 2019 03 15;18(1):31. Epub 2019 Mar 15.

Department of Cardiac Surgery, Tel Aviv University, Tel Aviv, Israel.

Background: Diabetes mellitus (DM) adversely affects morbidity and mortality for major atherosclerosis-related cardiovascular diseases and is associated with increased risk for the development of aortic stenosis. Clinical data regarding the impact of DM on outcomes of patients undergoing aortic valve replacement (AVR) have revealed inconsistent results. The aim of the current study was to investigate and compare the impact of type 2 DM on short-, intermediate- and long-term mortality between DM and non-DM patients who undergo isolated AVR.

Methods: We performed an observational study in a large tertiary medical center over a 14-year period (2004-2018), which included all patients who had undergone isolated AVR surgery for the first time. Of the 1053 study patients, 346 patients (33%) had type 2 DM (DM group) and were compared with non-DM (non-DM group) patients (67%). Short-term (in-hospital), intermediate (1- and 3-years), and late (5- and 10-years) mortality were evaluated. Mean follow-up of was 69 ± 43 months.

Results: Short-term (in-hospital) mortality was similar between the DM compared with the non-DM group: 3.5% and 2.5% (p = 0.517). Intermediate-term mortality (1- and 3-year) was higher in the DM group compared with the non-DM group, but did not reach statistical significance: 8.1% vs. 5.7% (p = 0.169) and 12.1% vs. 8.3% (p = 0.064) respectively. Long-term (5- and 10-year) mortality was significantly higher in the DM group, compared to the non-DM group: 19.4% vs. 12.9% (p = 0.007) and 30.3% vs. 23.5% (p = 0.020) respectively. Among the 346 DM patients, 55 (16%) were treated with insulin and 291 (84%) with oral antiglycemic medication only. Overall in-hospital mortality among insulin-treated DM patients was 7.3% compared with 2.7% among non insulin-treated DM patients (p = 0.201). Long-term mortality was higher in the subgroup of insulin-treated DM patients compared with the subgroup of non-insulin treated DM patients with an overall mortality rate of 36.4% vs. 29.2% (p = 0.039). Furthermore, predictors for late mortality included DM (HR 1.39 CI 1.03-1.86, p = 0.031) and insulin treatment (HR 1.76 CI 1.05-2.94, p = 0.033), as demonstrated after adjustment for confounders by multivariable analysis.

Conclusions: Type 2 DM is an independent predictor for long-term mortality after isolated AVR surgery.
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http://dx.doi.org/10.1186/s12933-019-0836-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419403PMC
March 2019

Impact of type 2 diabetes mellitus on short- and long-term mortality after coronary artery bypass surgery.

Cardiovasc Diabetol 2018 11 29;17(1):151. Epub 2018 Nov 29.

Department of Cardiac Surgery, Sheba Medical Center, Tel Hashomer, Affiliated to the Sackler School of Medicine, Tel Aviv University, 52621, Tel Aviv, Israel.

Background: Type 2 diabetes mellitus (DM) is a frequent co-morbidity among patients undergoing coronary artery bypass grafting (CABG) surgery. The aim of this study was to evaluate the impact of DM on the early- and long-term outcomes of patients who underwent isolated CABG.

Methods: We performed an observational cohort study in a large tertiary medical center over a period of 11 years. All data from patients who had undergone isolated CABG surgery between 2004 and 2014 were obtained from our departmental database. The study population included 2766 patients who were divided into two groups: Group I (1553 non-diabetic patients), and Group II (1213 patients suffering from type 2 DM). Group II patients were then divided into two subgroups: subgroup IIA (981 patients treated with oral antihyperglycemic medications) and subgroup IIB (232 insulin-treated patients with or without additional oral antihyperglycemic drugs). In-hospital, 1-, 3-, 5- and 10-year mortality outcome variables were evaluated. Mean follow-up was 97 ± 41 months.

Results: In-hospital mortality was similar between Group I and Group II patients (1.87% vs. 2.31%, p = 0.422) and between the subgroups IIA and IIB (2.14% vs. 3.02%, p = 0.464). Long-term mortality (1, 3, 5 and 10 years) was higher in Group II (DM type 2) compared with Group I (non-diabetic patients) (5.3% vs. 3.6%, p = 0.038; 9.3% vs. 5.6%, p < 0.001; 15.3% vs. 9.3%, p < 0.001 and 47.3% vs. 29.6% p < 0.001). Kaplan-Meier analysis demonstrated that all-cause mortality was higher in Group II compared with Group I (p < 0.001) and in subgroup IIB compared with subgroup IIA (p = 0.001). Multivariable analysis showed that DM increased the mortality hazard by twofold, and among diabetic patients, insulin treatment increased the mortality hazard by twofold.

Conclusions: Diabetic and non-diabetic patients have similar in-hospital mortality rates. Survival rates of diabetic patients start to deteriorate 3 year after surgery. Type 2 DM is an independent predictor for long-term mortality after isolated CABG surgery. Mortality is even higher when the diabetes treatment strategy included insulin.
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http://dx.doi.org/10.1186/s12933-018-0796-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264047PMC
November 2018

Omega-3 polyunsaturated fatty acids supplementation in patients with diabetes and cardiovascular disease risk: does dose really matter?

Cardiovasc Diabetol 2018 08 28;17(1):119. Epub 2018 Aug 28.

Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel.

There is a vast disagreement in relation to the possible beneficial effects of omega-3 polyunsaturated fatty acids (omega-3 PUFA) supplementation in patients with diabetes and cardiovascular disease. The conflicting results between the various original studies and meta-analyses could be partially explained as a result of variable supplementation dosage and duration, either of which may modify the effects of omega-3 PUFA on cardio-metabolic biomarkers. Meta-analyses are limited usually by the inability to draw inferences regarding dosage, duration and the interaction of dosage and duration of omega-3 PUFA intake. Even so, almost all endpoints in the so-called "negative" meta-analyses leaned toward a trend for benefit with a near 10% reduction in cardiovascular outcomes and a borderline statistical significance. Many trials included in these meta-analyses tested an insufficient daily dose of omega-3 PUFA of less than 1000 mg. Probably, the consistent cardiovascular effects of omega-3 PUFA supplements could be expected only with daily doses above 2000 mg.
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http://dx.doi.org/10.1186/s12933-018-0766-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112138PMC
August 2018

Admission blood glucose and 10-year mortality among patients with or without pre-existing diabetes mellitus hospitalized with heart failure.

Cardiovasc Diabetol 2017 08 14;16(1):102. Epub 2017 Aug 14.

Department of Cardiology, Rabin Medical Center, 39 Jabotinski St., Petah Tikva, Israel.

Background: High admission blood glucose (ABG) level has been associated with a poor short-term outcome among non-diabetic patients with heart failure (HF). We aimed to investigate the association between ABG levels and long-term (10 years) mortality in patients with or without pre-existing diabetes mellitus (DM) admitted with HF.

Methods: We analyzed data on 1811 patients with DM and 2182 patients without pre-existing DM who were hospitalized with HF during a prospective national survey. The relationship between ABG and 10-year mortality was assessed using the Cox proportional hazard model adjusting for multiple variables. ABG was analyzed both as a categorical (<110, 110-140, 140-200, and >200 mg/dL) and as a continuous variable.

Results: At 10 years of follow-up the cumulative probability of mortality was 85 and 78% among patients with DM and patients with no pre-existing DM (p < 0.001), respectively. Among patients with no pre-existing DM, glucose levels of 110-140, 140-200 and ≥200 mg/dL were associated with 9% (p = 0.140), 16% (p = 0.031) and 53% (p < 0.001) increased mortality risk compared to ABG < 110 mg/dL. Each 18-mg/dL (1-mmol/L) increase in glucose level was associated with a 5% increased risk of mortality (p < 0.001) among patients with no-pre-existing DM. In contrast, among patients with DM, only those with glucose levels >200 mg/dL had an increased mortality risk (>200 mg/dL versus <110 mg/dL; HR = 1.20, p = 0.032).

Conclusion: Among hospitalized HF patients with no pre-existing DM there is a linear relationship between ABG level and long-term mortality, whereas among patients with DM only ABG level >200 mg/dL is associated with increased mortality risk.
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http://dx.doi.org/10.1186/s12933-017-0582-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557317PMC
August 2017

Mirroring the CANTOS revolution: is anti-inflammatory therapy for diabetes just around the corner?

Cardiovasc Diabetol 2017 07 19;16(1):91. Epub 2017 Jul 19.

Cardiovascular Diabetology Research Foundation, 5848407, Holon, Israel.

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http://dx.doi.org/10.1186/s12933-017-0573-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517949PMC
July 2017

The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study.

Cardiovasc Diabetol 2017 05 22;16(1):69. Epub 2017 May 22.

The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620, Ramat Gan, Israel.

Background: Patients with type 2 diabetes present with an accelerated atherosclerotic process. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors (gliptins) have anti-inflammatory and anti-atherosclerotic effects, yet clinical data are scarcely available.

Design And Methods: A prospective, randomized, open-label study was performed in 60 patients with coronary artery disease (CAD) and type 2 diabetes, who participated in a cardiac rehabilitation program. After a washout period of 3 weeks, patients were randomized in a 2:1 ratio to receive combined vildagliptin/metformin therapy (intervention group: n = 40) vs. metformin alone (control group: n = 20) for a total of 12 weeks. Blinded assessment of interleukin-1ß (IL-1ß, the primary endpoint), hemoglobin A1c (HbA1c), and high sensitivity C reactive protein (hsCRP), were performed at baseline and after 12 weeks.

Results: Mean age of study patients was 67 ± 9 years, 75% were males, and baseline HbA1c and inflammatory markers levels were similar between the two groups. At 12 weeks of follow up, levels of IL-1ß, hsCRP, and HbA1c were significantly lower in the intervention group as compared with the control group. There was a continuous elevation of IL-1ß among the control group, which was not observed in the intervention group (49 vs. 4%, respectively; p < 0.001). The hsCRP was lowered by 60% in the vildagliptin/metformin group vs. 23% in the metformin group (p < 0.01). Moreover, a significant relative reduction of the HbA1c was seen in the intervention group (7% reduction, p < 0.03).

Conclusion: The addition of vildagliptin to metformin treatment in patients with type 2 diabetes and CAD led to a significant suppression of the IL-1ß elevation during follow up. A significant relative reduction of hsCRP and HbA1c in the intervention group was also observed. Trial registration NCT01604213.
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http://dx.doi.org/10.1186/s12933-017-0551-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440983PMC
May 2017

Characteristics and outcomes of diabetic patients with an implantable cardioverter defibrillator in a real world setting: results from the Israeli ICD registry.

Cardiovasc Diabetol 2016 12 1;15(1):160. Epub 2016 Dec 1.

Rabin Medical Center, Petah Tikva, Israel.

Aims: There are limited data regarding the effect of diabetes mellitus (DM) on the risks of both appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy. The present study was designed to compare the outcome of appropriate and inappropriate ICD therapy in patients with or without DM.

Methods And Results: The risk of a first appropriate ICD therapy for ventricular tachyarrhythmias (including anti tachycardia pacing and shock) was compared between 764 DM and 1346 non-DM patients enrolled in the national Israeli ICD registry. We also compared the risks of inappropriate ICD therapy, and death or cardiac hospitalization between diabetic and non-diabetic patients. Diabetic patients were older, were more likely to have ischemic cardiomyopathy, lower ejection fraction, atrial fibrillation, and other co-morbidities. The 3-year cumulative incidence of appropriate ICD therapy was similar in the DM and non-DM groups (12 and 13%, respectively, p = 0.983). Multivariate analysis showed that DM did not affect the risk of appropriate ICD therapy (HR = 1.07, 95% CI 0.78-1.47, p = 0.694) or inappropriate therapy (HR = 0.72, 95% CI 0.42-1.23, p = 0.232). However, DM was associated with a 31% increased risk for death or cardiac hospitalization (p = 0.005). Results were similar in subgroup analyses including ICD and defibrillators with cardiac resynchronization therapy function recipients, primary or secondary prevention indication for an ICD.

Conclusions: Despite a significant excess of cardiac hospitalizations and mortality in the diabetic population, there was no difference in the rate of ICD treatments, suggesting that the outcome difference is not related to arrhythmias.
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http://dx.doi.org/10.1186/s12933-016-0478-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134232PMC
December 2016

Metabolic syndrome is independently associated with increased 20-year mortality in patients with stable coronary artery disease.

Cardiovasc Diabetol 2016 Oct 28;15(1):149. Epub 2016 Oct 28.

The Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sheba Road 2, 52620, Ramat Gan, Israel.

Background: Data regarding long-term association of metabolic syndrome (MetS) with adverse outcomes are conflicting. We aim to determine the independent association of MetS (based on its different definitions) with 20 year all-cause mortality among patients with stable coronary artery disease (CAD).

Methods: Our study comprised 15,524 patients who were enrolled in the Bezafibrate Infarction Prevention registry between February 1, 1990, and October 31, 1992, and subsequently followed-up for the long-term mortality through December 31, 2014. MetS was defined according to two definitions: The International Diabetes Federation (IDF); and the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP).

Results: According to the IDF criteria 2122 (14%) patients had MetS, whereas according to the NCEP definition 7446 (48%) patients had MetS. Kaplan-Meier survival analysis showed that all-cause mortality was significantly higher among patients with MetS defined by both the IDF (67 vs. 61%; log rank-p < 0.001) as well as NCEP (67 vs. 54%; log rank-p < 0.001) criteria. Multivariate adjusted mortality risk was 17% greater [Hazard Ratio (HR) 1.17; 95% Confidence Interval (CI) 1.07-1.28] in patients with MetS according to IDF and 21% (HR 1.21; 95% CI 1.13-1.29) using the NCEP definition. Subgroup analysis demonstrated that long-term increased mortality risk associated with MetS was consistent among most clinical subgroups excepted patients with renal failure (p value for interaction < 0.05).

Conclusions: Metabolic syndrome is independently associated with an increased 20-year all-cause mortality risk among patients with stable CAD. This association was consistent when either the IDF or NCEP definitions were used. Trial registration retrospective registered.
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http://dx.doi.org/10.1186/s12933-016-0466-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084328PMC
October 2016

Bezafibrate for the treatment of dyslipidemia in patients with coronary artery disease: 20-year mortality follow-up of the BIP randomized control trial.

Cardiovasc Diabetol 2016 Jan 22;15:11. Epub 2016 Jan 22.

Cardiovascular Diabetology Research Foundation, Holon, Israel.

Background: Recent data support the renewed interest in hypertriglyceridemia as a possible important therapeutic target for cardiovascular risk reduction. This study was designed to address the question of all-cause mortality during extended follow-up of the BIP trial in patients stratified by baseline triglyceride levels.

Methods: In the BIP trial 3090 patients with proven coronary artery disease were randomized to bezafibrate 400 mg/day or placebo. All-cause mortality data after 20 years of follow-up, were obtained from the National Israeli Population Registry. Patients with hypertriglyceridemia (triglycerides ≥200 mg/dL, n = 458) were equally distributed among the study groups (15 % in both placebo and bezafibrate groups).

Results: During follow-up 1869 patients died (952 in placebo vs. 917 in bezafibrate group). Following multivariate adjustment allocation to bezafibrate was associated with small but significant 10 % mortality risk reduction (HR 0.90; 95 % CI 0.82-0.98, p = 0.026). Variables associated with significantly increased mortality risk were history of a past MI, NYHA class, diabetes, age, higher BMI and glucose level. In patients with hypertriglyceridemia multivariate analysis demonstrated a 25 % all-cause mortality risk reduction associated with allocation to bezafibrate (HR 0.75, CI 95 % 0.60-0.94; p = 0.012). In patients without hypertriglyceridemia bezafibrate had no significant effect on long-term mortality.

Conclusions: During long-term follow-up bezafibrate-allocated patients experienced a modest but significant 10 % reduction in the adjusted risk of mortality. This effect of bezafibrate was more prominent among patients with baseline hypertriglyceridemia (25 % mortality risk reduction).
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http://dx.doi.org/10.1186/s12933-016-0332-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722704PMC
January 2016

Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes.

Cardiovasc Diabetol 2015 Sep 29;14:129. Epub 2015 Sep 29.

Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.

The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.
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http://dx.doi.org/10.1186/s12933-015-0294-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587723PMC
September 2015

Impaired fasting glucose and left ventricular diastolic dysfunction in middle-age adults: a retrospective cross-sectional analysis of 2971 subjects.

Cardiovasc Diabetol 2015 Sep 15;14:119. Epub 2015 Sep 15.

Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel.

Background: Left ventricular (LV) diastolic dysfunction (LVDD) is a well-established and early echocardiographic characteristic of diabetic cardiomyopathy. However, there are limited data on the association between impaired fasting glucose (IFG) and LVDD.

Objective: To determine whether IFG is associated with LVDD among middle age adults.

Methods: Amongst 3781 subjects screened in an annual health survey program and referred for an echocardiogram, 2971 individuals without LV systolic dysfunction or valvular heart disease were selected. Mean age of study population was 59 ± 12 years and 75% were men. The subjects were categorized into three groups: euglycemia (N = 2025), IFG (N = 534) and diabetes mellitus (DM; N = 412). Doppler echocardiography readers were blinded to glycemic state. Subjects with impaired LV relaxation, pseudo-normal or restrictive filling patterns were defined as having LVDD.

Results: LVDD was diagnosed in 574 (19 %) of subjects and it was more prevalent among patients with IFG and DM than in euglycemic individuals (27, 30 and 15%, respectively; p < 0.001). Patients with IFG and DM had lower ratios of early (E) to late (A) trans-mitral flow (0.9 ± 0.3 and 0.9 ± 0.3 vs. 1.1 ± 0.4, respectively, p < 0.001). LV hypertrophy (LVH) was also more prevalent among patients with IFG and DM (11 and 18%, respectively, vs. 9%; p < 0.001). Multivariate binary logistic regression model adjusted to age, gender, obesity, LVH, renal function, total, high and low density lipoprotein cholesterol, triglycerides, ischemic heart disease, hypertension and LV ejection fraction showed that patients with IFG were 43% more likely to have LVDD compared with euglycemic subjects (95% confidence interval 1.12-1.83, p = 0.004).

Conclusions: IFG is independently associated with a significant increase in the likelihood for the presence of LVDD in middle aged adults.
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http://dx.doi.org/10.1186/s12933-015-0282-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570240PMC
September 2015

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor.

Cardiovasc Diabetol 2014 Dec 4;13:159. Epub 2014 Dec 4.

Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel.

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.
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http://dx.doi.org/10.1186/s12933-014-0159-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264548PMC
December 2014

Temporal trends in management and outcome of diabetic and non-diabetic patients with acute coronary syndrome (ACS): residual risk of long-term mortality persists: Insights from the ACS Israeli Survey (ACSIS) 2000-2010.

Int J Cardiol 2015 Jan 22;179:546-51. Epub 2014 Oct 22.

Department of Cardiology, Tel Aviv Medical Center, Tel Aviv, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel. Electronic address:

Background/objectives: In the past diabetes was strongly associated with elevated mortality rate after acute coronary syndrome (ACS). Over the past decade a treatment of the ACS has evolved rapidly with major advances in the management techniques. The aim of the present study was to compare temporal trends of the outcomes of diabetic vs. non-diabetic patients using nationwide data.

Methods: We evaluated time-dependent changes in the clinical characteristics, management strategies, and outcomes of diabetic and non-diabetic patients enrolled in the biannual ACS Israeli Surveys (ACSIS) between 2000 and 2010. We divided the survey into early (2000-2005) vs. late (2006-2010) periods.

Results: There were 3964 diabetic and 7322 non-diabetic patients, a total of 11,472 ACS patients. Although diabetic patients were significantly younger, they displayed more advanced coronary artery disease and considerably higher rates of all-cause mortality at 30 days and 1-year. Both diabetic and non-diabetic patients who were enrolled in the late survey period received more evidence-based therapies (primary PCI, guideline-based medications) and experienced a better 1-year survival probability (respectively 88% vs. 84% and 93% vs. 90%; all p-values<0.01). Multivariate analysis demonstrated that diabetes and early survey period were each independently associated with a significantly increased mortality risk (respectively 39% and 25%, p<0.001 for both).

Conclusion: Our data suggest that despite the overall improvement in the management and outcomes of the ACS, diabetic patients are still at increased residual risk of long-term mortality that needs to be further addressed.
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http://dx.doi.org/10.1016/j.ijcard.2014.10.116DOI Listing
January 2015

Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease?

Cardiovasc Diabetol 2014 Jun 23;13:103. Epub 2014 Jun 23.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

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.
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http://dx.doi.org/10.1186/1475-2840-13-103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230016PMC
June 2014

Authors' response.

Cardiol J 2014 ;21(2):210

Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Cardiovascular Diabetology Research Foundation, 5848407 Holon, Israel.

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http://dx.doi.org/10.5603/CJ.2014.0033DOI Listing
January 2016

Coronary calcium in patients with and without diabetes: first manifestation of acute or chronic coronary events is characterized by different calcification patterns.

Cardiovasc Diabetol 2013 Nov 5;12:161. Epub 2013 Nov 5.

Sackler Faculty of Medicine, Tel-Aviv University, 69978 Tel-Aviv, Israel.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1186/1475-2840-12-161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176741PMC
November 2013

Comparison of statin alone versus bezafibrate and statin combination in patients with diabetes mellitus and acute coronary syndrome.

Am J Cardiol 2014 Jan 2;113(1):12-6. Epub 2013 Oct 2.

Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Leviev Heart Institute, Chaim Sheba Medical Center, Tel-Hashomer, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Israeli Society for the Prevention of Heart Attacks, Chaim Sheba Medical Center, Tel-Hashomer, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Cardiovascular Diabetology Research Foundation, Holon, Israel. Electronic address:

Acute coronary syndromes (ACS) in patients with diabetes mellitus (DM) are associated with a high risk for major adverse cardiovascular events (MACEs) despite statin treatment. The impact of combined bezafibrate and statin therapy in patients with DM and ACS has not been specifically investigated. The aim of this study was to evaluate the association of combined therapy with 30-day MACEs in patients with DM participating in the nationwide Acute Coronary Syndrome Israeli Surveys (ACSIS). The study population comprised 3,063 patients with DM from the ACSIS 2000, 2002, 2004, 2006, 2008, and 2010 enrollment waves who were alive at discharge and received statins. Of these, 225 (7.3%) received on discharge combined bezafibrate and statin therapy, and 2,838 (92.7%) were treated with statins alone. MACEs were defined as a composite measure of death, recurrent myocardial infarction, recurrent ischemia, stent thrombosis, ischemic stroke, and urgent revascularization. The development of 30-day MACEs was recorded in 8% patients receiving combination therapy and 14.2% of those receiving statins alone (p = 0.01). Crude 1-year mortality and 30-day rehospitalization rates were also significantly lower in patients receiving combination therapy: 4.0% versus 8.1% (p = 0.03) and 13.3% versus 21.6% (p = 0.003), respectively. Multivariate analysis identified combined therapy as an independent predictor of reduced risk for 30-day MACEs, with an odds ratio of 0.56 (95% confidence interval 0.34 to 0.92), corresponding to a 44% relative risk reduction. In conclusion, a significantly lower risk for 30-day MACEs was observed in statin-treated patients with DM who also received bezafibrate after ACS. Signals regarding improvement of 30-day rehospitalization and 1-year mortality rates emerged as well.
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http://dx.doi.org/10.1016/j.amjcard.2013.08.033DOI Listing
January 2014

Bezafibrate treatment is associated with a reduced rate of re-hospitalization in smokers after acute coronary syndrome.

Cardiol J 2014 21;21(4):364-9. Epub 2013 Oct 21.

Cardiac Rehabilitation Institute, Sackler Faculty of Medicine, Tel-Aviv, Israel Leviev Heart Institute, Sackler Faculty of Medicine, Tel-Aviv, Israel Israeli Society for the Prevention of Heart Attacks, Chaim Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Cardiovascular Diabetology Research Foundation, Holon, Israel.

Background: Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas cardiovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re-hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone.

Methods: The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate.

Results: Thirty-day re-hospitalization rate was significantly lower in patients from the combination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31-0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospitalization rate during the follow-up were female gender (OR 1.43, CI 1.05-1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13-1.95, p = 0.004).

Conclusions: Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS.
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http://dx.doi.org/10.5603/CJ.a2013.0127DOI Listing
April 2016

Optimal revascularization in diabetes after the FREEDOM trial: were the controversies finally settled?

Cardiol J 2013 ;20(4):331-6

Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel.

The prevalence of diabetes mellitus (DM) is growing worldwide. Prothrombotic and proinflammatory states, in adjunct to endothelial dysfunction and metabolic disorders, such as hyperglycemia, dyslipidemia, obesity, insulin resistance, and oxidative stress, are key features of the accelerated atherosclerotic progression observed in patients with DM. Moreover, drug-eluting stents (DES) thrombosis rate was higher in DM than in non-DM patients and DM itself was identifi ed as an independent predictor of stent thrombosis, particularly due to the impaired response to dual antiplatelet therapy. The accumulating data even before the FREEDOM trial provided strong evidence that in patients with DM and complex coronary artery disease, coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) which was based on the first-generation DES. The FREEDOM trial enrolled 1900 patients with DM and multivessel coronary artery disease treated with CABG surgery or PCI with the first-generation DES. The patients were followed for a median 3.8 years; CABG was superior to PCI as it significantly reduced rates of death and myocardial infarction (MI), with a higher rate of stroke. The benefit of CABG was driven by differences in rates of both MI (p < 0.001) and death from any cause (p = 0.049). Following the FREEDOM results, patients with DM ought to be informed before coronary angiography about the potential survival benefit from CABG for the treatment of a complex disease. However, it should be noticed that the second generation DES were associated with better outcomes compared to the first-generation DES. New stent designs are continually being developed, with the aim of further improving the clinical effi cacy and the safety profile of these devices. Therefore, although the results of the FREEDOM trial clearly demonstrated that CABG was superior to PCI in DM, a comparative analysis of the new incoming stents warrants further investigation.
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http://dx.doi.org/10.5603/CJ.2013.0090DOI Listing
August 2014

The metabolic syndrome entanglement: Cutting the Gordian knot.

Cardiol J 2014 15;21(1):1-5. Epub 2013 May 15.

Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Cardiovascular Diabetology Research Foundation, Holon, Israel.

Questions have been raised on the clinical value of the metabolic syndrome (MS). The negative opinion regarding MS is anchored basically on a separate analysis of 4 conditions: obesity, dyslipidemia, hypertension and glucose intolerance. The common denominator of these 4 sets of arguments is that they represent an utterly simplistic view of MS as a solely predictive tool of morbidity or mortality. We believe that it is inequitable to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to one another from the biological point of view. Several recent large meta-analyses - one of them including nearly one million patients - systematically showed that people with MS are at increased risk of cardiovascular (CV) events. MS was associated with a 2-fold increase in CV outcomes and a 1.5-fold increase in all-cause mortality rates. A very important finding was that CV risk still remained high in patients with MS but without diabetes. The presence of MS possesses a definitely predictive value, but above all it is a widely accepted concept regarding a biological condition based on complex and interrelated pathophysiological mechanisms emanating from excess central adiposity and insulin resistance. The risk factors are multiplicative, meaning that the risk of a CV disease from risk factors rises geometrically, not linearly, as the number of risk factors increases. Therefore, currently available evidences strongly support the concept of the MS as a critical clustering of CV risk factors and diabetes, representing a true and solid evolving clinical entity.
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http://dx.doi.org/10.5603/CJ.a2013.0054DOI Listing
January 2016

Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

Cardiovasc Diabetol 2012 Nov 14;11:140. Epub 2012 Nov 14.

Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel.

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.
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http://dx.doi.org/10.1186/1475-2840-11-140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502168PMC
November 2012

Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction.

Cardiovasc Diabetol 2012 Oct 11;11:125. Epub 2012 Oct 11.

Cardiac Rehabilitation Institute, Sheba Medical Center, Tel-Hashomer, Israel.

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.
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http://dx.doi.org/10.1186/1475-2840-11-125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489608PMC
October 2012

Effects of a vildagliptin/metformin combination on markers of atherosclerosis, thrombosis, and inflammation in diabetic patients with coronary artery disease.

Cardiovasc Diabetol 2012 Jun 6;11:60. Epub 2012 Jun 6.

Cardiac Rehabilitation Institute, Leviev Heart Center, Sheba Medical Center, 52621, Tel Hashomer, Israel.

Background: 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.

Design: 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.

Discussion: 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.
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http://dx.doi.org/10.1186/1475-2840-11-60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403890PMC
June 2012

Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: Acute Coronary Syndrome Israeli Surveys data.

PLoS One 2012 16;7(4):e35298. Epub 2012 Apr 16.

Cardiac Rehabilitation Institute, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035298PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327654PMC
August 2012

Fibrate use in the United States and Canada.

JAMA 2011 Jul;306(2):157; author reply 158-9

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http://dx.doi.org/10.1001/jama.2011.945DOI Listing
July 2011