Faculty Bibliography

Despite a better understanding of cardiovascular risk factors and attempts at optimal management, diabetes-related macrovascular events remain a significant cause of morbidity and mortality in the United States and worldwide. The trials to date have validated strict glycemic control as a method to achieve sustained reductions in the rate of nephropathy, neuropathy, and retinopathy due to diabetes. For these microvascular complications, the closer hemoglobin A1c is to normal levels, the better the outcome. Although reducing hemoglobin A1c levels to 7% has been shown to reduce macrovascular events, demonstrating an additional reduction in macrovascular events with tighter glycemic control has been more difficult to achieve. A careful review of recent trials, however, has demonstrated that treatment early in the disease course and the ability to safely maintain lower hemoglobin A1c levels might be critical factors in further reducing macrovascular events. In conclusion, with the introduction of novel antidiabetic agents, future trials using these drugs might be able to definitively establish the safety and efficacy of reducing cardiovascular events with stringent glycemic control; however, the current evidence is inconsistent.

OPINION STATEMENT: Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events.

The ability for statins to reduce major cardiovascular events and mortality has lead to this drug class being the most commonly prescribed in the world. In particular, the benefit of these drugs in type 2 diabetes (T2D) is well established. In February 2012, the Food and Drug Administration released changes to statin safety label to include that statins have been associated with increases in hemoglobin A1C and fasting serum glucose levels. This has stirred much debate in the medical community. Estimate for new onset diabetes from statin treatment is approximately one in 255 patients over four years. The number needed to treat for statin benefit is estimated at one in 40 depending on the population. The mechanism of this link remains unknown. Statins may accelerate progression to diabetes via molecular mechanisms that impact insulin resistance and cellular metabolism of carbohydrates. It remains clear that the benefit of statin therapy outweighs the risk of developing diabetes.

OBJECTIVES: The purpose of this study was to assess the impact of rosiglitazone on survival in patients with diabetes mellitus (DM) and coronary artery disease (CAD). METHODS: We carried out a drug-exposure analysis in 801 patients with DM and CAD in a cardiac catheterization laboratory registry (490 patients treated with a percutaneous coronary intervention, 224 patients treated with coronary artery bypass grafting, and 87 patients treated with medication alone). RESULTS: A total of 193 patients (24.1%) were exposed to rosiglitazone. The median survival from the date of cardiac catheterization in the rosiglitazone group was 146.7 months versus 109.1 months in the unexposed group (P<0.001). At 5 years, the unadjusted survival was 82% in the rosiglitazone-exposed group versus 69% in the unexposed group (P<0.001). There was no difference in survival between rosiglitazone-exposed and rosiglitazone-unexposed patients in the groups treated with coronary artery bypass grafting or medical therapy (P=0.37 and 0.11, respectively). In a multivariable model, rosiglitazone exposure had no effect on mortality (hazard ratio=0.737; 95% confidence interval: 0.521-1.044, P=0.86). CONCLUSION: We conclude that exposure to rosiglitazone is not associated with increased mortality in diabetics who are treated for CAD. These findings support the notion that insulin sensitization with a thiazolidinedione is safe in carefully selected and treated patients with DM and CAD.

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of "intermediate-risk" patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.

Previous studies have shown that 3% to 4% of African Americans carry an amyloidogenic allele of the human serum protein transthyretin (TTR V122I). The allele appears to have an absolute anatomic risk for cardiac amyloid deposition after 65 years of age. In this study, a case-control comparison was performed of clinical, echocardiographic, and electrocardiographic characteristics of 23 age at risk carriers of the amyloidogenic allele and 46 age-, gender-, and ethnically matched noncarriers being evaluated for cardiac disease using standard clinical testing. The 2 groups were matched for blood pressure and the cardiac ejection fraction. None of the subjects had a prestudy diagnosis of cardiac amyloidosis. Carriers of the amyloidogenic allele were found to have statistically significant increases in the occurrence of many of the echocardiographic features of cardiac amyloidosis relative to the noncarriers and a higher frequency of congestive heart failure and atrial fibrillation. The observations suggest that TTR V122I represents a substantial risk for clinically significant cardiac amyloidosis in elderly African American men, behaving as an age-dependent autosomal dominant disease-associated allele. The diagnosis is difficult to make but can be suspected in African Americans aged >60 years on the basis of age, echocardiographic evidence of diastolic dysfunction, and interventricular septal thickening, even in the absence of more recently available sophisticated echocardiographic techniques for evaluating long-axis function and cardiac magnetic resonance imaging. Positive results for the amyloidogenic TTR V122I allele support the diagnosis and define the origin of the disease, which can be confirmed by endomyocardial biopsy

OPINION STATEMENT: The pathogenesis of cardiovascular disease is a complex and dynamic process. The renin-angiotensin-aldosterone system (RAAS) is a potent and powerful mediator in the homeostasis of the cardiovascular and renal systems. RAAS blockade via angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been consistently proven to be an effective and safe strategy for the primary and secondary prevention of cardiovascular disease in patients across a wide spectrum of risk. Although the beneficial effects of RAAS blockade may be due to its effects on central and peripheral blood pressure, there are many additional mechanisms to consider that may contribute additional protection. While a combination of ACE inhibitors and ARBs has not yielded significantly positive results, the newer class of direct renin inhibitors (DRIs) may offer a novel and effective strategy for monotherapy as well as in combination