Sandeep A. Saha

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus – A pooled meta-analysis of randomized placebo-controlled clinical trials

OBJECTIVE Fibrates are thought to be useful anti-dyslipidemic agents particularly in patients with diabetes mellitus and dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. We conducted a systematic review and meta-analysis of long-term randomized controlled trials to evaluate the role of fibrates in the prevention of cardiovascular events in patients with type 2 diabetes mellitus. DATA SOURCES English-language journals indexed in Index Medicus/MEDLINE and the Cochrane Collaboration databases (through December 2007), unpublished data from selected clinical trials. DATA EXTRACTION AND ANALYSIS A total of 11,590 patients from 6 published randomized placebo-controlled trials were analyzed using pooled meta-analysis techniques. Relative risks were computed for various cardiovascular outcomes and mortality, and statistical significance was tested using the z-test statistic (two-sided alpha error <0.05). RESULTS The use of fibrates did not significantly affect the risk of all-cause mortality or cardiac mortality, and also did not affect the risk of stroke, unstable angina, or invasive coronary revascularization. However, the relative risk of non-fatal myocardial infarction was significantly reduced by about 21% (pooled relative risk 0.79, p=0.006) with the use of fibrates. CONCLUSIONS Long-term use of fibrates in patients with type 2 diabetes mellitus significantly reduces the risk of non-fatal myocardial infarction, but has no significant effect on mortality or on other adverse cardiovascular outcomes.

Glomerular cell death and inflammation with high-protein diet and diabetes

BACKGROUND Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo. METHODS Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold>control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples. RESULTS In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls. CONCLUSIONS High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.

Hyperlipidaemia and cardiovascular disease: do fibrates have a role?

Purpose of review Fibrates continue to be a viable treatment option for mixed atherogenic dyslipidemia, and recent reports from clinical studies have shed new light on the therapeutic utility of fibrates for the prevention of microvascular and macrovascular disease, especially in combination with statins. Recent findings Data from randomized placebo-controlled trials have shown that fibrates reduce nonfatal coronary events but do not confer any benefit on mortality or other adverse cardiovascular outcomes. The ACCORD Lipid trial studied the additive effect of fenofibrate therapy along with low-dose simvastatin therapy in 5518 patients with type 2 diabetes mellitus, and found that fenofibrate did not affect any of the adverse cardiovascular outcomes, either individually or as part of a composite outcome, after 4.7 years of follow-up. An a priori subgroup analysis showed a significant benefit from fenofibrate–simvastatin combination therapy over simvastatin alone in participants with moderate hypertriglyceridemia and low HDL-cholesterol on major cardiovascular events, consistent with post-hoc analyses of previous fibrate trials. The ACCORD-Eye study adds to the sparse clinical data on the effect of fenofibrate on diabetic retinopathy, and showed that fenofibrate may be used to reduce the risk of progression of diabetic retinopathy even in patients with established disease. The combination of statin and fibrate was well tolerated. Summary Fibrate therapy does not reduce mortality but may reduce nonfatal coronary events in patients at risk for cardiovascular disease, including those with type 2 diabetes. The ACCORD Lipid study shows that the combination of low-dose simvastatin and fenofibrate is well tolerated, and is potentially cardioprotective in patients with atherogenic ‘mixed’ dyslipidemia.

Modulation of Advanced Glycation End Products by Candesartan in Patients with Diabetic Kidney Disease—A Dose-Response Relationship Study

Advanced glycation end products (AGEs) are proinflammatory mediators implicated in the pathogenesis of diabetic kidney disease (DKD). In this study, dose-dependent effects of angiotensin receptor blockade on urinary AGEs were evaluated in patients with DKD.Patients with type 2 diabetes and proteinuria ≥500 mg/d (n = 11) were compared with diabetic controls without DKD (n = 10) and normal controls (n = 11). After a 2-week washout period, DKD participants were treated with candesartan doses progressively increasing from 8, 16, 32, to 64 mg/d every 3 weeks for a total of 12 weeks. Other antihypertensive agents were adjusted to maintain stable blood pressure. At baseline and after each dosing period, blood pressure measurements and 24-hour urine collections were obtained.Urinary carboxymethyl lysine, an AGE biomarker, was reduced over the 12-week dose escalation protocol (r = 0.38, P = 0.01) in DKD participants. Creatinine clearance increased slightly, but albuminuria was unaffected by candesartan administration. Baseline urinary transforming growth factor-β1 excretion was lower in DKD participants than in controls and did not change during the study period.Reducing kidney exposure to AGEs may be a mechanism of protection by angiotensin receptor blockade in DKD. AGEs may also impact the diabetic kidney through mechanisms independent of transforming growth factor-β1.

Influence of glycemic control on the development of diabetic cardiovascular and kidney disease.

Diabetes mellitus leads to the development of a host of micro- and macrovascular complications, which collectively lead to substantial morbidity and mortality. Among the microvascular complications of diabetes, diabetic kidney disease is the most common. Macrovascular complications from diabetes lead to a 2- to 4-fold increase in the incidence of cardiovascular disease and up to twice the mortality from cardiovascular causes as compared with nondiabetic individuals. This article discusses the various drug classes used to treat diabetes mellitus, and reviews the current clinical evidence linking glycemic control using these drug classes on diabetic kidney and cardiovascular disease.

Clinical utility of cardiac troponin i in the diagnosis of acute coronary syndrome in patients with renal failure

To analyze sensitivity and specificity of cardiac troponin I (cTnI) in detecting obstructive coronary artery disease in African American population with renal insufficiency presenting with acute coronary syndrome. Retrospective analysis of 108 patients who underwent coronary angiography over a 3-year period in a single institution. A troponin I level of 0.1 ng/mL or higher was considered abnormal troponin I. Renal insufficiency was defined as creatinine of 1.2 mg/dL or higher. Obstructive coronary artery disease (CAD) was defined as luminal diameter reduction of 70% or more (or total occlusion) in at least 1 coronary artery. Patients were divided into group 1 (renal insufficiency without need for hemodialysis, n = 76, mean age = 65) and group 2 (patients requiring hemodialysis, n = 32, mean age = 60). Access Accu TnI method was used to quantitate cTnI where murine monoclonal antibodies specifically bind to the C-terminal end of cTnI. In group 1, 41 (54%) patients had abnormal troponin of whom 37 (90%) had CAD and 4 (10%) had normal angiogram; 35 (46%) patients had normal troponin, of whom 25 (71%) had CAD and 10 (29%) had normal angiogram yielding a sensitivity of 60% and specificity of 71% (P = 0.003; 95% confidence interval). In group 2, 20 (63%) had abnormal troponin of whom 19 (95%) had CAD and 1(5%) had normal angiogram; 12 (38%) had normal troponin of whom 7 (59%) had CAD and 5 (41%) had normal angiogram yielding a sensitivity of 73% and specificity of 83% (P = 0.06; 95% confidence interval). cTnI has a sensitivity of 60% and specificity of 71% in acute coronary syndrome patients with renal insufficiency. In patients on hemodialysis, troponin I has a sensitivity of 73% and specificity of 83% for detection of obstructive CAD.

Sildenafil-associated coronary thrombosis in a patient with angiographically normal coronary arteries: a case report with review of literature.

Sildenafil is widely used as a primary pharmacological treatment of erectile dysfunction in men with and without underlying cardiovascular disease. Although initial reports of adverse cardiac events were reported soon after Food and Drug Administration approval of this agent, a large body of data suggests that sildenafil does not significantly increase the risk of nonfatal myocardial infarction, stroke, or cardiovascular deaths in patients with preexisting ischemic heart disease. We report the case of a 66-year-old man who developed thrombotic occlusion of the left anterior descending artery and presented with acute myocardial infarction after the use of sildenafil. The patient had presented with chest pain syndrome and borderline elevation of serum troponin I levels 1 week before sildenafil use, and a coronary angiogram had demonstrated normal coronary arteries. This case emphasizes the potential of precipitating coronary thrombosis in patients with unstable plaque after sildenafil use, even in patients with angiographically normal coronary arteries.

Fibrates reduce the risk of major cardiovascular and coronary events compared with placebo, but do not affect risk of cardiovascular or all-cause mortality

Commentary on: JunMFooteCLvJ. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875–84.