Richard W. Nesto

Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure A Consensus Statement From the American Heart Association and American Diabetes Association

Diabetes is a chronic, progressively worsening disease associated with a variety of microvascular and macrovascular complications. Cardiovascular disease (CVD) is the main cause of death in these patients.1,2 During the past decade, numerous drugs have been introduced for the treatment of type 2 diabetes that, used in monotherapy or in combination therapy, are effective in lowering blood glucose to achieve glycemic goals and in reducing diabetes-related end-organ disease. Two such drugs, rosiglitazone and pioglitazone, belong to the class called thiazolidinediones (TZDs).3 Troglitazone, the first agent of this class to be approved, was effective in controlling glycemia but was removed from the market because of serious liver toxicity. Both rosiglitazone and pioglitazone are indicated either as monotherapy or in combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control4 (package insert Avandia [rosiglitazone maleate; GlaxoSmithKline] and Actos5 [pioglitazone hydrochloride; Takeda Pharmaceuticals]). In addition to lowering blood glucose, both drugs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function, and fibrinolytic status.6,7 These beneficial effects of TZDs on glycemia and cardiovascular risk factors have made them attractive agents in patients with type 2 diabetes who are at high risk for CVD. There is a growing recognition, however, that edema can occur in patients treated with either drug. Because people with diabetes are at increased risk for CVD and many have preexisting heart disease, the edema that sometimes accompanies the use of a TZD can be cause for concern, as it may be a harbinger or sign of congestive heart failure (CHF). An analysis of Medicare beneficiaries hospitalized with the diagnosis of diabetes and CHF indicated that the number of these patients discharged on TZDs had increased from 7.2% to 16.2% over a …

Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus A Scientific Statement From the American Heart Association and the American Diabetes Association

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial

CONTEXT No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225277.

Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials

BACKGROUND The overall clinical benefit of thiazolidinediones (TZDs) as a treatment for hyperglycaemia can be difficult to assess because of the risk of congestive heart failure due to TZD-related fluid retention. Since prediabetic and diabetic patients are at high cardiovascular risk, the outcome and natural history of such risks need to be better understood. We aimed to examine the risk of congestive heart failure and of cardiac death in patients given TZDs. METHODS We used a search strategy to identify 3048 studies. 3041 were excluded, and we did a systematic review and meta-analysis of the seven remaining randomised double-blind clinical trials of drug-related congestive heart failure in patients given TZDs (either rosiglitazone or pioglitazone). We calculated pooled random-effects estimates of the risk ratios for development of congestive heart failure in patients given TZDs compared with controls. The main outcome measures were development of congestive heart failure and the risk of cardiovascular death. FINDINGS 360 of 20 191 patients who had either prediabetes or type 2 diabetes had congestive heart failure events (214 with TZDs and 146 with comparators). Results showed no heterogeneity of effects across studies (I2=22.8%; p for interaction=0.26), which indicated a class effect for TZDs. Compared with controls, patients given TZDs had increased risk for development of congestive heart failure across a wide background of cardiac risk (relative risk [RR] 1.72, 95% CI 1.21-2.42, p=0.002). By contrast, the risk of cardiovascular death was not increased with either of the two TZDs (0.93, 0.67-1.29, p=0.68). INTERPRETATION Congestive heart failure in patients given TZDs might not carry the risk that is usually associated with congestive heart failure which is caused by progressive systolic or diastolic dysfunction of the left ventricle. Longer follow-up and better characterisation of such patients is needed to determine the effect of TZDs on overall cardiovascular outcome.

Effect of valsartan on the incidence of diabetes and cardiovascular events

BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

The ischemic cascade: Temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia

The development of an ischemic event, whether silent or painful, represents the cumulative impact of a sequence of pathophysiologic events. Each ischemic episode is initiated by an imbalance between myocardial oxygen supply and demand that may ultimately be manifested as angina pectoris. This sequence of events can be termed the ischemic cascade. The significance of this concept resides in the fact that it redirects the focus from the end result--angina--to the more fundamental, underlying pathophysiologic factors that precede it. Specifically, these events include diminished left ventricular compliance, decreased myocardial contractility, increased left ventricular end-diastolic pressure, ST-segment changes and, occasionally, angina pectoris.

Triggers, acute risk factors and vulnerable plaques: The lexicon of a new frontier

A neglected area of cardiovascular research--study of the mechanisms of acute disease onset-is receiving increased attention. The new interest is based on the undisputed findings that onset of myocardial infarction and sudden cardiac death are more likely soon after awakening, indicating that activities of the patient frequently trigger the diseases. Triggering may occur when stressors produce hemodynamic, vasoconstrictive and prothrombotic forces--acute risk factors--that, in the presence of a vulnerable atherosclerotic plaque, cause plaque disruption and thrombosis. Triggering research may clarify mechanisms and suggest measures to sever the linkage between a potential trigger and its pathologic consequence.

Impact of Glucose Intolerance and Insulin Resistance on Cardiac Structure and Function Sex-Related Differences in the Framingham Heart Study

Background—Although insulin resistance has been implicated in the pathogenesis of left ventricular (LV) hypertrophy, previous studies have yielded inconsistent results and are limited by referral bias. Methods and Results—We examined the relations between echocardiographic LV measurements and glucose tolerance status in 2623 Framingham Study subjects (1514 women, mean age 53 years) free of myocardial infarction and heart failure. We also evaluated the relations of insulin resistance (homeostasis model, HOMA-IR) and LV and left atrial (LA) measures within the normal and abnormal glucose tolerance categories (the latter included impaired glucose tolerance, impaired fasting glucose, and newly diagnosed diabetes). LV mass (adjusted for age, height, heart rate, and systolic blood pressure) increased across categories of worsening glucose tolerance; the trend was more striking in women (P <0.001) compared with men (P =0.054). In subjects with normal (n=2022) and abnormal glucose tolerance (n=327), covariate-adjusted LV mass and LV wall thickness increased across HOMA-IR quartiles in women (P <0.001) but not men. In contrast, covariate-adjusted LA size increased with worsening glucose tolerance and across HOMA-IR quartiles in the normal and abnormal glucose tolerance groups in both sexes. Adjustment for body mass index considerably attenuated the relations of LV/LA measures and HOMA-IR, rendering them statistically nonsignificant in the normal glucose tolerance group. Conclusions—In our large community-based sample, LV mass and wall thickness increased with worsening glucose intolerance, an effect that was more striking in women compared with men. Insulin resistance was associated with increased LV mass in women alone, but this relation was largely accounted for by obesity.

The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes ☆

OBJECTIVES The purpose of this study was to assess safety and efficacy of enhanced external counterpulsation (EECP). BACKGROUND Case series have shown that EECP can improve exercise tolerance, symptoms and myocardial perfusion in stable angina pectoris. METHODS A multicenter, prospective, randomized, blinded, controlled trial was conducted in seven university hospitals in 139 outpatients with angina, documented coronary artery disease (CAD) and positive exercise treadmill test. Patients were given 35 h of active counterpulsation (active CP) or inactive counterpulsation (inactive CP) over a four- to seven-week period. Outcome measures were exercise duration and time to > or =1-mm ST-segment depression, average daily anginal attack count and nitroglycerin usage. RESULTS Exercise duration increased in both groups, but the between-group difference was not significant (p > 0.3). Time to > or =1-mm ST-segment depression increased significantly from baseline in active CP compared with inactive CP (p = 0.01). More active-CP patients saw a decrease and fewer experienced an increase in angina episodes as compared with inactive-CP patients (p < 0.05). Nitroglycerin usage decreased in active CP but did not change in the inactive-CP group. The between-group difference was not significant (p > 0.7). CONCLUSIONS Enhanced external counterpulsation reduces angina and extends time to exercise-induced ischemia in patients with symptomatic CAD. Treatment was relatively well tolerated and free of limiting side effects in most patients.

Primary prevention of cardiovascular diseases in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: the ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.