Is statin-induced diabetes clinically relevant? A comprehensive review of the literature.

In those predisposed to the development of diabetes (the insulin resistant, obese and older patients) statins may increase the risk of developing diabetes. Despite the fact that the conversion to diabetes is generated from post hoc analyses, it seems to be a class effect with a dose-response relationship. However, statins have not been clearly shown to increase diabetic microvascular complications (retinopathy, nephropathy and neuropathy). Thus, the clinical significance of increased glucose levels in patients treated on statins is uncertain. While the exact mechanism for how statins increase the risk of diabetes is unknown, a possible explanation is through a reduction in adiponectin levels. Despite the fact that higher statin doses are more likely to lead to new-onset diabetes, for every case of diabetes caused, there are approximately three cardiovascular events reduced with high dose versus moderate dose statin therapy. Overall, the small risk of developing type 2 diabetes with statin therapy is far outweighed by the potential of statins to decrease cardiac events.

Therapies for diabetic dyslipidaemia.

Correction of diabetic dyslipidaemia in diabetic patients is the most important factor in reducing cardiac risk. Diabetic dyslipidaemia is characterized by elevated triglycerides, low total high-density lipoprotein (HDL) and small dense low-density lipoprotein (LDL) particles. The most important therapeutic goal in diabetic dyslipidaemia is correction of the non-HDL-cholesterol (HDL-C) level. Glycaemic control with particular attention to postprandial glucose control plays a role not only in improving dyslipidaemia but also in lowering cardiac events. Pioglitazone is particularly effective for improving the manifestations of diabetic dyslipidaemia, in addition to its favorable effects on systemic inflammation and hyperglycaemia. Use of statins in addition to lifestyle change is recommended in most if not all type 2 diabetic patients and the goal should be to lower the LDL to a level recommended for the patient with existing cardiovascular disease (CVD) (non-HDL-C level <100 mg/dl). In addition, therapies for normalization of HDL and triglyceride levels should be deployed. Most patients with type 2 diabetes (T2D) will require combining a lipid-lowering therapy with therapeutic lifestyle changes to achieve optimal lipid levels. Combinations usually include two or more of the following: a statin, nicotinic acid, omega-3 fats and bile acid sequestrants (BASs). Fibrates may also be of use in diabetic patients with persistently elevated triglycerides and depressed HDL-C levels, although their role in lowering adverse CV events is questionable.

Eplerenone improves prognosis in postmyocardial infarction diabetic patients with heart failure: results from EPHESUS.

BACKGROUND: The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that selective aldosterone blockade with eplerenone significantly reduced total mortality by 15%, combined cardiovascular (CV) mortality/CV hospitalization by 13%, CV mortality by 17% and sudden cardiac death by 21%, vs. placebo when added to standard care in patients with left ventricular systolic dysfunction (LVSD) and signs of congestive heart failure (CHF) following acute myocardial infarction (AMI). We retrospectively evaluated the effect of eplerenone vs. placebo in a subset of 1483 diabetic patients with LVSD and signs of CHF following AMI. METHODS: Diabetic status was determined from medical histories at screening. Analyses were based on time to first occurrence of an event. Results were based on a Cox's proportional hazards regression model stratified by region with treatment, subgroup and treatment-by-subgroup interaction as factors. The 95% confidence intervals for the risk ratios were based on the Wald's test. RESULTS: Treatment with eplerenone in diabetic patients with CHF following AMI reduced the risk of the primary endpoint, a composite of CV mortality or CV hospitalization, by 17% (p = 0.031). The absolute risk reduction of the primary endpoint was greater in the diabetic cohort (5.1%) than in the non-diabetic cohort (3%). Hyperkalaemia occurred more often with eplerenone than with placebo (5.6 vs. 3%, p = 0.015). Among the diabetic cohorts, the prespecified endpoint of 'any CV disorder' occurred in 28% of the eplerenone group and 35% of the placebo group (p = 0.007). CONCLUSION: Eplerenone treatment may reduce adverse CV events in diabetic patients with LVSD and signs of CHF following AMI.

Frequency of undiagnosed and untreated diabetes mellitus in patients with acute coronary syndromes.

The current epidemic of obesity warrants aggressive screening for associated comorbid conditions; namely, the metabolic syndrome and diabetes mellitus. Approximately 25-30% of patients with acute coronary syndrome have diabetes. Of the remaining patients, most have a spectrum of abnormal glucose metabolism, including previously undiagnosed impaired fasting glucose and diabetes mellitus. This article reviews the current literature and the author's own experience of this subject, as well as highlighting effective new agents in treating diabetes.

Should an angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease?

Angiotensin-converting enzyme (ACE) inhibitors appear to possess unique cardioprotective benefits, even when used in patients without high blood pressure or left ventricular dysfunction (the traditional indications for ACE inhibitor therapy). The ACE inhibitors improve endothelial function and regress both left ventricular hypertrophy and arterial mass better than other antihypertensive agents that lower blood pressure equally as well. These agents promote collateral vessel development and improve prognosis in patients who have had a coronary revascularization procedure (i.e., percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery). Insulin resistance, present not only in type 2 diabetes but also commonly in patients with hypertension or coronary artery disease, or both, sensitizes the vasculature to the trophic effects of angiotensin II and aldosterone. This may partly explain the improvement in prognosis noted when patients who have atherosclerosis or diabetes are treated with an ACE inhibitor. Therapy with ACE inhibitors has also been shown, in two large, randomized trials, to reduce the incidence of new-onset type 2 diabetes through largely unknown mechanisms. The ACE inhibitors are safe, well tolerated and affordable medications. The data suggest that most people with atherosclerosis should be considered candidates for ACE inhibitor therapy, unless they are intolerant to the medication, or have systolic blood pressures consistently <100 mm Hg. Patients who show evidence of insulin resistance (with or without overt type 2 diabetes) should also be considered as candidates for prophylactic ACE inhibitor therapy. Although angiotensin receptor blockers should not be considered equivalent to ACE inhibitors for this indication, they may be a reasonable alternative for patients intolerant of ACE inhibitors.

From Inuit to implementation: omega-3 fatty acids come of age.

During the past 25 years, the cardiovascular effects of marine omega-3 (omega-3) fatty acids have been the subject of increasing investigation. In the late 1970s, epidemiological studies revealed that Greenland Inuits had substantially reduced rates of acute myocardial infarction compared with Western control subjects. These observations generated more than 4,500 studies to explore this and other effects of omega-3 fatty acids on human metabolism and health. From epidemiology to cell culture and animal studies to randomized controlled trials, the cardioprotective effects of omega-3 fatty acids are becoming recognized. These fatty acids, when incorporated into the diet at levels of about 1 g/d, seem to be able to stabilize myocardial membranes electrically, resulting in reduced susceptibility to ventricular dysrhythmias, thereby reducing the risk of sudden death. The recent GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study of 11,324 patients showed a 45% decrease in risk of sudden cardiac death and a 20% reduction in all-cause mortality in the group taking 850 mg/d of omega-3 fatty acids. These fatty acids have potent anti-inflammatory effects and may also be antiatherogenic. Higher doses of omega-3 fatty acids can lower elevated serum triglyceride levels; 3 to 5 g/ d can reduce triglyceride levels by 30% to 50%, minimizing the risk of both coronary heart disease and acute pancreatitis. This review summarizes the emerging evidence of the use of omega-3 fatty acids in the prevention of coronary heart disease.

Predictors of improvement in left ventricular ejection fraction with carvedilol for congestive heart failure.

BACKGROUND: Beta-blocker therapy has been reported to improve survival and left ventricular ejection fraction (LVEF) in the setting of congestive heart failure (CHF). The magnitude and predictors of improved LVEF are unclear. METHODS: A total of 295 patients were enrolled in the study. Inclusion criteria were LVEF <35% at baseline and symptomatic (New York Heart Association class II to IV) CHF despite treatment with at minimum an angiotensin-converting enzyme inhibitor. Carvedilol was initiated at 3.125 mg twice daily and titrated to a target dose of 25 or 50 mg twice daily, depending on the patient's weight. Paired pretreatment baseline and 9 months with treatment follow-up quantitative LVEFs (assessed by resting radionuclide ventriculograms) were obtained in 161 (55 %) of the patients. RESULTS: LVEF improved from 25% +/- 6% at baseline to 36%+/-12% at follow-up (P<.001). Mean change in LVEF (deltaLVEF) was greater for nonischemic cardiomyopathy (NICM) (+14.5+/-2 LVEF points) than ischemic cardiomyopathy (deltaLVEF +/- 7.6+/-10 EF points, P = .001). The deltaLVEF was > or =21 LVEF points in 30% of the NICM group versus 10% of the ischemic cardiomyopathy group. Conversely, the deltaLVEF was unchanged to minimally improved (< or =5 LVEF points) in 21% of the NICM group versus 52% of the ischemic cardiomyopathy group. Multivariable analysis identified NICM and recent onset of congestive heart failure as correlates of improved LVEF. CONCLUSIONS: Carvedilol significantly improved LVEF, especially in patients with NICM and those with recent onset of CHF.

Lipid risk factor correlates of ischemic heart disease as diagnosed by myocardial perfusion scintigraphy.

Patients with known coronary artery disease frequently change their lifestyles (e.g., diet, exercise, and smoking habit) after the diagnosis is made. Such changes can alter lipid risk factor levels and obscure etiologic risk factor associations with the presence of coronary artery disease. It is therefore preferable to determine the contribution of potential risk factors before the diagnosis of coronary artery disease has been established. In this trial, we used stress nuclear myocardial perfusion imaging to diagnose coronary artery disease in patients presenting for evaluation of chest pain. Two groups of age- and sex-matched patients were identified: a normal group (patients with no evidence of coronary artery disease), and an abnormal group (patients whose scans indicated the presence of significant coronary artery disease due to either fixed or reversible perfusion defects). Blood samples were drawn before scanning and analyzed for lipid risk factors. Compared to the normal group, the abnormal group had higher levels of triglycerides (189±91 vs. 135±51 mg/dL, p=0.003), lower levels of high-density lipoprotein cholesterol (39±9 vs. 45±14 mg/dL, p=0.037), and higher levels of small, dense low-density lipoprotein (LDL(3)) (42±18 vs. 32±13 mg/dL, p=0.007). Total cholesterol, low-density lipoprotein, and lipoprotein(a) levels were similar between groups. These findings suggest that ischemic heart disease, as assessed by myocardial perfusion scintigraphy, is more closely associated with the low high-density lipoprotein/high triglyceride syndrome than with increased low-density lipoprotein or total cholesterol levels. (c) 2000 by CHF, Inc.

Isolated left anterior descending coronary artery disease: percutaneous transluminal coronary angioplasty versus stenting versus left internal mammary artery bypass grafting.

BACKGROUND: Single-vessel coronary artery disease is usually treated with PTCA; however, this approach when applied to the left anterior descending coronary artery (LAD) is hampered by high restenosis rates, often approaching 50%. Coronary stenting (STENT) and left internal mammary artery bypass grafting of the LAD (LIMA-LAD) are other options that have been successfully used for single-vessel LAD disease. The optimal mode of revascularization for patients with isolated single-vessel LAD disease is unclear. The purpose of the present study was to examine PTCA versus STENT versus LIMA-LAD with respect to short- and intermediate-term outcomes. METHODS AND RESULTS: This was an observational retrospective cohort study comparing in-hospital and intermediate-term outcomes and functional class among patients with isolated single-vessel LAD disease revascularization. Consecutive eligible patients were grouped according to their initial revascularization procedure and systematically followed up. A total of 704 patients qualified for the study: 469 in the PTCA group, 137 in the STENT group, and 98 in the LIMA-LAD group. Follow-up data were complete for 97% of patients and averaged 27+/-13 months. In-hospital mortality for the PTCA, STENT, and LIMA-LAD groups was 1.1%, 0%, and 0% (P=0.51), respectively. Median hospital stays after the procedure for the respective treatment groups were 1, 1, and 5 days (P<0.001), and occurrences of in-hospital myocardial infarction were 0.9%, 1.5%, and 1.0% (P=NS). Repeat revascularization procedures were performed in 30%, 24%, and 5% of the PTCA, STENT, and LIMA-LAD groups (P=<0. 001 for LIMA-LAD versus other groups, P=0.11 for PTCA versus STENT). Actuarial 2-year mortality was 3.9%, 2.6%, and 1% in the PTCA, STENT, and LIMA-LAD groups (P=0.33). CONCLUSIONS: Revascularization for isolated LAD disease using PTCA, STENT, or LIMA-LAD results in low in-hospital adverse event rates and good long-term results. Repeat procedures are required less often after LIMA-LAD than after either PTCA or STENT. Long-term mortality was not statistically different, but the trend was for the lowest mortality with LIMA-LAD, a somewhat higher mortality with STENT, and the highest mortality with PTCA.

A randomized, controlled trial of the effects of remote, intercessory prayer on outcomes in patients admitted to the coronary care unit.

CONTEXT: Intercessory prayer (praying for others) has been a common response to sickness for millennia, but it has received little scientific attention. The positive findings of a previous controlled trial of intercessory prayer have yet to be replicated. OBJECTIVE: To determine whether remote, intercessory prayer for hospitalized, cardiac patients will reduce overall adverse events and length of stay. DESIGN: Randomized, controlled, double-blind, prospective, parallel-group trial. SETTING: Private, university-associated hospital. PATIENTS: Nine hundred ninety consecutive patients who were newly admitted to the coronary care unit (CCU). INTERVENTION: At the time of admission, patients were randomized to receive remote, intercessory prayer (prayer group) or not (usual care group). The first names of patients in the prayer group were given to a team of outside intercessors who prayed for them daily for 4 weeks. Patients were unaware that they were being prayed for, and the intercessors did not know and never met the patients. MAIN OUTCOME MEASURES: The medical course from CCU admission to hospital discharge was summarized in a CCU course score derived from blinded, retrospective chart review. RESULTS: Compared with the usual care group (n = 524), the prayer group (n = 466) had lower mean +/- SEM weighted (6.35 +/- 0.26 vs 7.13 +/- 0.27; P=.04) and unweighted (2.7 +/- 0.1 vs 3.0 +/- 0.1; P=.04) CCU course scores. Lengths of CCU and hospital stays were not different. CONCLUSIONS: Remote, intercessory prayer was associated with lower CCU course scores. This result suggests that prayer may be an effective adjunct to standard medical care.

Improving the adverse cardiovascular prognosis of type 2 diabetes.

Approximately 80% of all patients with diabetes die of cardiovascular disease. The traditional management of type 2 diabetes has been ineffective in altering this dismal prognosis. Insulin resistance is the fundamental defect of type 2 diabetes. Insulin resistance often leads to hyperinsulinemia, which is associated with hypertension, atherogenic dyslipidemia, left ventricular hypertrophy, impaired fibrinolysis, visceral obesity, and sedentary lifestyle. Although all these conditions are associated with atherosclerosis and adverse cardiovascular events, the therapeutic efforts in patients with diabetes have focused predominantly on normalizing glucose levels. Improved insulin sensitivity through lifestyle modifications or pharmacologic therapy (troglitazone and metformin) will lower both insulin and glucose levels as well as diminish dyslipidemia and hypertension. In contrast, sulfonylurea agents lower glucose by increasing insulin levels and may increase the risk of cardiovascular events. Therapy including aspirin, lipid agents (for example, statins), angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, postmenopausal estrogen replacement, and vitamin E should be considered for patients with type 2 diabetes. In most patients with diabetes who have multivessel coronary artery disease, coronary artery bypass grafting is superior to coronary angioplasty for improving long-term cardiovascular prognosis. This superiority is mediated in part by the use of a left internal mammary graft to the left anterior descending coronary artery. Urgent coronary angioplasty or thrombolytic therapy should be considered for all patients with diabetes who have acute myocardial infarction.

Combination drug therapy for dyslipidemia.

Effective treatment of dyslipidemia improves prognosis. Statin therapy has been documented to decrease the cardiovascular event rate in the setting of elevated low-density lipoprotein (LDL) cholesterol levels and coronary heart disease, but most patients are not treated to the target (LDL

The optimal mode of coronary revascularization for diabetics. A risk-adjusted long-term study comparing coronary angioplasty and coronary bypass surgery.

AIMS: Some recent studies have reported-superior outcomes for diabetic patients following coronary bypass surgery compared with coronary angioplasty. However, the available data are conflicting, are based on relatively small numbers of diabetic patients, and have limited duration of follow-up. The aims of this study were to compare risk adjusted long-term survival in diabetic patients following first-time revascularization via either coronary bypass surgery or coronary angioplasty; and, to identify variables independently associated with mortality. METHODS AND RESULTS: This was a two centre database project involving 15809 patients undergoing either coronary angioplasty or coronary bypass surgery as their initial revascularization procedure. Diabetes was present in 1938 (12%). Mean follow-up was 4.6+/-2.7 years for angioplasty and 6.6+/-4.3 years surgery diabetic patients. Multivariable time-related analyses in the hazard function domain for death were performed. Overall ten-year survival for pharmacologically treated diabetics was better after coronary bypass surgery (60%) than angioplasty (46%, <0.0001). However, the risk-adjusted survival advantage conferred by bypass surgery over angioplasty was strongest for patients receiving oral agents for diabetic control (75% vs 62%) and less impressive for diet (84% vs 81%) and insulin-treated diabetics (63% vs 64%). The major factors independently associated with worse outcome after angioplasty were incomplete revascularization, and the use of a sulfonylurea agent. The use of the left internal mammary graft improved survival in surgical patients. CONCLUSIONS: In general, diabetic patients had better long-term survival after bypass surgery than angioplasty. Incomplete revascularization and sulfonylurea therapy worsened outcome after angioplasty, and use of the left internal mammary improved outcome after bypass surgery.

Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction.

In this multicenter study, 249 patients who underwent tomographic technetium-99m sestamibi infarct size measurement at hospital discharge were followed up for a median duration of 7 months. Infarct size was significantly associated with mortality (chi-square = 5.8, p = 0.02) and could stratify patients into lower and higher risk subsets: 1-year mortality 2% for infarct size < 14% versus 8% for infarct size > or = 14% of the left ventricle.