Predictors of early-stage left ventricular dysfunction in type 2 diabetes: results of DYDA study.

BACKGROUND: Better knowledge of prevalence and early-stage determinants of subclinical left ventricular dysfunction (LVD) in type 2 diabetes would be useful to design prevention strategies. The objective of the LVD in Diabetes (DYDA) study was to assess these points in patients without established cardiac disease. METHOD: Baseline clinical, ECG, laboratory and echocardiographic data from 751 patients (61 ± 7 years, 59% hypertensive) recruited by 37 Italian diabetes clinics were analysed. Clinical history, life habits, laboratory data (NT-proBNP, HsCRP, HbA1c, serum glucose, lipids and creatinine, liver enzymes, microalbuminuria, glomerular filtrate) and data on microvascular complications and drug therapy were collected. RESULTS: LVD was present in 59.9% of patients. Age (OR 1.05, 95% CI [1.02-1.07]), HbA1c (OR 1.27, 95% CI [1.09-1.49]), triglycerides (OR 1.003, 95% CI [1.001-1.006]), treatment with metformin (OR 1.62, 95% CI [1.09-2.40]) and doxazosine (OR 2.48, 95% CI [1.10-5.55]) were independent predictors of LVD. Glitazones were associated with reduced risk of diastolic dysfunction (OR 0.44, 95% CI [0.22-0.87]) whereas waist circumference and metformin were adversely associated with systolic dysfunction (OR 1.02, 95% CI [1.01-1.04] and 1.57, 95% CI [1.01-2.43], respectively). CONCLUSION: In asymptomatic and fairly controlled diabetic patients, age, worse HbA1c, traits of insulin resistance, such as visceral adiposity and triglycerides or treatment with metformin, and use of doxazosin indicate greater risk of LVD. Glitazones, at this stage, seem to be associated with better diastolic performance.

Incidence and risk factors for stroke in type 2 diabetic patients: the DAI study.

BACKGROUND AND PURPOSE: Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations. METHODS: We prospectively followed-up 14,432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables. RESULTS: During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes. CONCLUSIONS: Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.

Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria.

Type 2 diabetic patients often die because of end-stage renal failure, but no definitive reliable factor predicting long-term renal outcome has been identified. We tested whether a renal arterial resistance index (R/I) > or =80, using Doppler ultrasound technique, was predictive of worsening renal function. The primary end points of the study were 1) the course of glomerular filtration rate (GFR) and 2) the albumin excretion rate in 157 microalbuminuric, hypertensive, type 2 diabetic patients after a 7.8-year follow-up period (range 7.1-9.2). Kaplan-Meier curves for the primary end point (decrease of GFR > or = -3.0 ml/min per 1.73 m(2) per year) was two to three times more frequently observed in patients with R/I > or =80. Four- to fivefold fewer patients showed a regression to normoalbuminuria during the follow-up period from baseline microalbuminuria in the cohort with R/I > or =80. Overt proteinuria did develop in 24% of patients with R/I > or =80 and in 5% of patients with R/I <80 (P < 0.01). In conclusion, intrarenal arterial resistance appears to play a nontrivial role in deteriorating renal function in type 2 diabetic patients. R/I is a noninvasive diagnostic procedure, which strongly predicts the outcome of renal function in type 2 diabetic patients, even when GFR patterns are still normal.

The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy.

BACKGROUND AND AIMS: The greatest decrease in mortality from cardiovascular disease (CAD) that can be achieved with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is seen in patients with the highest risk for CAD, such as diabetics. Yet, there is evidence for inadequate use of drug therapies to achieve lipid goals. Our aims were to: (1) assess the prevalence of statin use in patients attending diabetic clinics and (2) correlate the use of statins with their risk and clinical status. METHODS AND RESULTS: Of 9921 patients included, only 20.4% of them were receiving statin therapy. Statins were more progressively prescribed in those with risk factors additional to that of diabetes. Patients under statin treatment were older, mostly type 2 diabetics, more hypertensive and hyperlipidemic, had a higher prevalence of both macro- and microvascular disease. Among those with a total cholesterol concentration above 252 mg/dl, statin treatment was given only to 60% of diabetic patients with prior myocardial infarction, 56% of those with angina, 66% of those having had prior revascularization procedure, 54% of those with cerebrovascular disease and 51% of those with peripheral artery disease. CONCLUSIONS: At least in Italy, statins are not prescribed to the majority of diabetic patients, and a substantial proportion of patients not treated with statins present significant macro- and microvascular complications.

Altered transcapillary escape of albumin and microalbuminuria reflects two different pathogenetic mechanisms.

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of (125)I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.

Nitric oxide modulation of renal and cardiac hemodynamics in type 2 diabetes.

OBJECTIVE: To evaluate endothelial function in type 2 diabetic patients with and without diabetic nephropathy. METHODS: We studied the effects of systemic infusion of the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine (L-NMMA) on cardiovascular and renal hemodynamics in six type 2 diabetic patients with microalbuminuria (D2-MA), six type 2 diabetic patients with normoalbuminuria (D2-NA) and five control subjects. Both type 2 diabetic patients and control subjects had mild arterial hypertension. RESULTS: L-NMMA infusion decreased the cardiac index in all groups. A reduction in glomerular filtration rate (GFR) and an increase in filtration fraction were observed only in controls. Renal plasma flow decreased in controls and D2-NA patients and renal vascular resistance increased in all groups. CONCLUSIONS: The effect of L-NMMA on cardiac output was similar in controls and type 2 diabetic patients with and without diabetic nephropathy. In contrast, the effect on GFR was impaired in both diabetic groups, suggesting that glomerular NO homeostasis is altered in type 2 diabetes. Moreover the discrepancy, in diabetic patients, between cardiac and renal effects during L-NMMA infusion suggests that the modulation of glomerular hemodynamics is independent from NO-regulated cardiac output.

[Diabetes mellitus, left ventricular dysfunction and congestive heart failure]. / Diabete mellito, disfunzione ventricolare sinistra e scompenso cardiaco.

Diabetes is a well known risk factor for the development of congestive heart failure. Epidemiological evidence in the community underscores the prevalence of left ventricular systolic dysfunction in diabetic patients as 2-fold with respect to non-diabetic ones, with half of them completely asymptomatic. Diastolic dysfunction in diabetic hearts, in comparison with non-diabetic, is even more frequent. The high prevalence has been explained by the frequent coexistence of an underlying diabetic cardiomyopathy, hypertension and ischemic heart disease. In these patients, the diabetic metabolic derangement, together with the early activation of sympathetic nervous system, induce a decrease of myocardial function. The activation of renin-angiotensin system results in an unfavorable cardiac remodeling. The progression from myocardial damage to overt dysfunction and heart failure is often asymptomatic for a long time and frequently undiagnosed and untreated. Currently, the widespread availability of echocardiography and possibly the use of cardiac natriuretic peptides, may allow for an earlier recognition of most of such patients. In heart failure, diabetic patients have a worse prognosis than non-diabetics. The available pharmacological treatments, such as ACE-inhibitors, beta-blockers and possibly angiotensin receptor blockers, togheter with a tight glycemic control, may be effective to reverse the remodeling process and prevent cardiovascular events. In order to identify most of the diabetic patients at risk of development of left ventricular dysfunction and to prevent its progression to overt heart failure, it seems important to elaborate a screening strategy in order to diagnose and treat most of diabetic patients with myocardial damage.

Left ventricular dysfunction and outcome at two-year follow-up in patients with type 2 diabetes: The DYDA study.

AIMS: Left ventricular dysfunction (LVD) in type 2 diabetes mellitus (DM) (DYDA) study is a prospective investigation enrolling 960 with DM without overt cardiac disease. At baseline, a high prevalence of LVD was detected by analysing midwall shortening. We report here the incidence of clinical events in DYDA patients after 2-year follow-up and the frequency of LVD detected at baseline and 2-year evaluation. METHODS: Systolic LVD was defined as midwall shortening ≤15%, diastolic LVD as any condition different from "normal diastolic function" identified as E/A ratio on Doppler mitral flow between 0.75 and 1.5 and deceleration time of E wave >140 ms. Major outcome was a composite of major events, including all-causes death and hospital admissions. RESULTS: During the study period, any systolic/diastolic LVD was found in 616 of 699 patients (88.1%) in whom LVD function could be measured at baseline or at 2 years. Older age and high HbA1c predicted the occurrence of LVD. During the follow-up 15 patients died (1.6%), 3 for cardiovascular causes, 139 were hospitalized (14.5%, 43 of them for cardiovascular causes, 20 for a new cancer). CONCLUSIONS: During a 2-year follow-up any LVD is detectable in a large majority of patients with DM without overt cardiac disease. Older age and higher HbA1c predict LVD. All-cause death or hospitalization occurred in 15% of patients, cardiovascular cause was uncommon. Independent predictors of events were older age, pathologic lipid profile, high HbA1c, claudicatio and repaglinide therapy. Echo-assessed LVD at baseline was not prognosticator of events.

Analysis of midwall shortening reveals high prevalence of left ventricular myocardial dysfunction in patients with diabetes mellitus: the DYDA study.

BACKGROUND: Individuals with diabetes mellitus (DM) have a higher risk to develop heart failure. Clinical guidelines emphasize the importance of early diagnosis of left ventricular dysfunction (LVD) and preventive interventions in these patients. In this study we assessed the prevalence of LVD, systolic or diastolic, in DM patients without known cardiac disease recruited in the 'left ventricular DYsfunction in DiAbetes (DYDA)' study. DESIGN AND METHODS: We performed clinical, ECG, laboratory, and echocardiographic exams in 960 patients (61 ± 8 years, 59% hypertensive) recruited in the DYDA study from 37 Italian diabetes referral centres. ECG and echo exams were read in central facilities. Systolic LVD was defined as ejection fraction ≤ 50% or midwall shortening (MFS) ≤ 15%. Diastolic LVD was identified when transmitral E/A was out of the range of 0.75-1.5 or deceleration time of mitral E wave ≤ 140 msec. RESULTS: Echocardiographic data were obtained in 751 patients (78.2%). Isolated systolic LVD was detected in 22.0% of patients, isolated diastolic LVD in 21.5%, and combined systolic and diastolic LVD in 12.7%. All patients with systolic LVD had MFS ≤ 15%, while only 9% had an ejection fraction ≤ 50%. Higher LV mass, relative wall thickness, prevalence of concentric geometry, and LV hypertrophy characterized the patients with LVD. CONCLUSIONS: LVD is present in more than half of DM patients without clinically detectable cardiac disease and is associated with LV hypertrophy and concentric LV geometry. One-third of patients exhibits systolic LVD detectable at the midwall level.

Inappropriately high left ventricular mass in patients with type 2 diabetes mellitus and no overt cardiac disease. The DYDA study.

BACKGROUND: An inappropriately high left ventricular mass (iLVM) may be detected in patients with diabetes mellitus. Several hemodynamic and nonhemodynamic factors stimulating LVM growth may actively operate in these patients. In this study, we assessed prevalence and factors associated with iLVM in patients with diabetes mellitus. METHODS: We analyzed baseline data from 708 patients (61 ±â€Š7 years, 57% treated for hypertension) with type 2 diabetes mellitus without evidence of cardiac disease enrolled in the left ventricular dysfunction in diabetes study. iLVM was diagnosed by Doppler echocardiography as LVM more than 28% of the expected LVM predicted from height, sex and stroke work. RESULTS: iLVM was detected in 166 patients (23%), irrespective of concomitant hypertension. Patients with iLVM were more frequently women, had higher BMI and prevalence of metabolic syndrome, higher serum triglyceride levels and were treated more frequently with metformin and diuretics. In a multivariate model, female sex [odds ratio (OR) 1.502 (95% confidence interval (CI) 1.010-2.231), P = 0.04], higher serum triglyceride levels [OR 1.007 (95% CI 1.003-1.012), P < 0.001] and BMI [OR 1.220 (95% CI 1.116-1.335), P < 0.001] emerged independently related to iLVM. CONCLUSION: iLVM is detectable in about a quarter of patients with type 2 diabetes mellitus without evidence of cardiac disease and is unrelated to blood pressure levels. The association between LVM and some components of metabolic syndrome in these patients may have important practical implications.

Exploring the gap between National Cholesterol Education Program guidelines and clinical practice in secondary care: results of a cross-sectional study involving over 10 000 patients followed in different specialty settings across Italy.

OBJECTIVES: To evaluate implementation of low-density lipoprotein cholesterol (LDL-C) control recommendations in secondary care and explore key points in the decisional workup. METHODS AND RESULTS: In a nationwide survey of secondary-care outpatients (n=11,124), we studied prevalence/predictors of (1) LDL-C value availability; (2) ongoing treatment with statins; (3) achievement of US National Cholesterol Education Program III target LDL-C values. Agreement between US National Cholesterol Education Program III risk category and physicians' personal risk assessments was also studied. LDL-C values were available for 78% evaluable patients; 71% of the patients with dyslipidema were undergoing treatment with statins; 34% patients undergoing treatment had target LDL-C values. At regression analysis, non-availability of LDL-C values was predicted by absence of diabetes, presence of normotension, and advancing age; lack of statins treatment by female sex, diabetes, overweight and northern location (southern location predicted treatment); non-achievement of target LDL-C values by age, diabetes, attending a diabetic clinic, cigarette smoking, history of cardiovascular disease, and taking less than six pills per day. Physicians provided underestimates of patients' risk (39% high-risk patients were rated as intermediate-risk patients and a further 10% as low-risk patients). CONCLUSION: Suboptimal prevention practice seems to be associated with various factors acting at different levels within the complex process running from individual risk-level ascertainment to LDL-C target achievement. Multicomponent interventions that target the different key steps need to be considered.

Recurrence of cardiovascular events in patients with type 2 diabetes: epidemiology and risk factors.

OBJECTIVE: The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: We estimated the incidence of recurrent cardiovascular events in type 2 diabetic patients, aged 40-97 years, followed by a network of diabetes clinics. The analysis was conducted separately for 2,788 patients with CVD at enrollment (cohort A) and for 844 patients developing the first episode during the observation period (cohort B). RESULTS: During 4 years of follow-up, in cohort A the age-adjusted incidence of a recurrent event (per 1,000 person-years) was 72.7 (95% CI 58.3-87.1) in men and 32.5 (21.2-43.7) in women, whereas in cohort B it was 40.1 (17.4-62.9) in men and 22.4 (12.9-32.0) in women. After controls were included for potential predictors (familial CVD, obesity, smoking, diabetes duration, glycemic control, microvascular complications, geographic area, and antihypertensive and lipid-lowering treatment), male sex, older age, and insulin use were significant independent risk predictors (cohort A) and serum triglyceride levels >/=1.69 mmol/l emerged as the only metabolic (negative) prognostic factor (cohort B). In both cohorts, a prior CVD episode, especially myocardial infarction, was by far the strongest predictor of recurrent CVD. CONCLUSIONS: Approximately 6% of unselected diabetic patients in secondary prevention develop recurrent major CVD every year. Those with long-standing previous CVD show a higher incidence of recurrence. Male sex, age, high triglyceride levels, and insulin use are additional predictors of recurrence.

Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location.

OBJECTIVE: Cardiovascular disease (CVD) is the main cause of morbidity/mortality in diabetes. We set forth to determine incidence and identify predictors (including microvascular complications and treatment) of first coronary heart disease (CHD) event in CVD-free type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cohort of 6,032 women and 5,612 men, sampled from a nationwide network of hospital-based diabetes clinics, was followed up for 4 years. Baseline assessment included retinopathy, nephropathy, and foot ulcers. First CHD events (myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and electrocardiogram-proven angina) were analyzed for 29,069 person-years. RESULTS: The age-standardized incidence rate (per 1,000 person-years) of first CHD event (n = 881) was 28.8 (95% CI 5.4-32.2) in men and 23.3 (20.2-26.4) in women. Major CHD (myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty) was less frequent in women (5.8 [4.3-7.2]) than in men (13.1 [10.9-15.4]; a sex ratio of 0.5 [0.4-0.6]). Incidence rates of all outcomes were higher in patients with microvascular complications (for major CHD, age-adjusted rate ratios were 1.6 [1.2-2.21] in men and 1.5 [1.0-2.2] in women). By multivariate Cox analysis, age and diabetes duration were risk predictors common in both sexes. In men, glycemic control and treated hypertension were additional independent risk factors, but residing in the south was associated with a significant 29% risk reduction. In women, higher triglycerides/lower HDL cholesterol and microvascular complications were independent risk factors. CONCLUSIONS: In CVD-free patients with type 2 diabetes, risk of first CHD event depends on sex, geographic location, and presence of microvascular disease. Hyperglycemia and hypertension, particularly in men, and diabetic dyslipidemia, especially in women, are risk factors amenable to more aggressive treatment.