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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.

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.We analyzed baseline data from 708 patients (61 ± 7 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.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.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.

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.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.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.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.

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.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.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).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.

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.

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.

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.

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.

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.

Although diabetes is a major risk factor for ischemic heart disease or heart failure (HF), and despite the fact that echocardiography has revealed a high prevalence of left ventricular (LV) diastolic and systolic dysfunctions and hypertrophy (1–3), routine screening for cardiovascular disease using echocardiography in asymptomatic patients with type 2 diabetes is not recommended by current guidelines (4). The availability of laboratory markers of cardiovascular risk would substantially contribute to the early and simple screening of patients at increased risk of HF, allowing them to be better targeted with appropriate pharmacological therapies (5). As part of the LV Dysfunction in Diabetes (DYDA) study, we assessed the relations between different laboratory markers, including centrally assayed glycated hemoglobin (HbA1c), N-terminal probrain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), …

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.

A randomized double-blind study of benfluorex (150 mg x 3 daily) versus placebo was conducted over 3 months in 32 type II diabetic patients (24 men and 8 women, aged 52 +/- 8.4 years) with mild stable obesity [body-mass index (BMI) 27 +/- 1.6 kg/ m2], moderate fasting hyperglycemia (fasting blood glucose 9 +/- 0.5 mmol/L, HbA1c 6.7 +/- 0.9%) and moderate hyperinsulinemia (18.6 +/- 3.0 microU/mL) when on treatment with diet alone. After a 1-month placebo run-in period, subjects were randomized to benfluorex or placebo three tablets daily. Inclusion parameters and end-of-study measures were body weight, BMI, fasting blood glucose, glycemic profile, HbA1c, fasting insulinemia, basal and stimulated C-peptide, and an insulin tolerance test (0.1 U/kg). The groups were homogeneous at baseline, except for glycemic profile (higher postprandial glycemia in the group randomized to benfluorex). At the end of the study, the groups did not differ in body weight or BMI; however, HbA1c decreased more with benfluorex (6.0 +/- 1.0% versus 6.8 +/- 0.9%, p = 0.024), as did the mean glycemic profile (7.8 +/- 1.4 versus 8.5 +/- 1.7 mmol/L, p0.001), including a particular decrease in postprandial glycemia. The decreases in fasting blood glucose and insulinemia appeared larger with benfluorex (7.7 +/- 1.3 versus 8.4 +/- 1.6 mmol/L and 13.5 +/- 4.5 versus 16.1 +/- 5.1 microU/mL, respectively), but were not statistically significant. The increase in the insulin sensitivity index (Kitt) was greater with benfluorex (+0.54 +/- 1.4 versus +0.25 +/- 1.3%/mn), but the difference was not statistically significant. The same was observed for the stimulated C-peptide. In type II diabetics with mild obesity and hyperglycemia previously managed with diet alone, benfluorex has significant long-term effect on HbA1c and mean daily blood glucose, and tends to lower insulinemia.

Little information is available on the hemodynamic response (renal reserve) of the diabetic kidney during an acute amino acid infusion, which has been shown to increase glomerular filtration rate (GFR) in normal humans. We recently found that the infusion of ketone bodies is able to raise GFR in both normal subjects and insulin-dependent diabetes mellitus (IDDM) patients. The aim of this study was to evaluate the renal reserve in 15 IDDM patients with a duration of diabetes of >9 yr [8 with albumin excretion rate 100 μg/min (group 2)] and in 8 normal subjects during amino acid infusion (33 μmol · kg−1 · min−1 , Travasol 10% wt/vol solution containing 0.154 mM sodium chloride concentration; Travenol, Savage, MD) and during acetoacetic sodium salt (25 μmol · kg−1 · min−1) infusion. Blood glucose was clamped at euglycemic levels. The infusion of sodium acetoacetate resulted in a 10- to 15-fold increase in circulating concentrations of ketone bodies, which were similar in magnitude in normal subjects and diabetic patients. The GFR peak increase above baseline after sodium acetoacetate infusion was 28% in normal subjects and 27% in group 1 and 19% in group 2 diabetic patients. The infusion of amino acid solution produced a three- to fivefold increase in plasma concentrations of amino acids in both normal subjects and diabetic patients. The GFR peak increase above baseline after amino acid infusion was significantly lower in diabetic patients (IDDM group 1: 5%, P < .01; IDDM group 2: 6%, P < .01) than in normal subjects (38%). During sodium acetoacetate infusion, proximal sodium reabsorption increased as well as distal sodium delivery in normal subjects and group 1 and group 2 IDDM patients. During amino acid infusion, only normal subjects showed a significant increase in proximal sodium reabsorption and distal sodium delivery, whereas no change was found in group 1 and group 2 IDDM patients. Amino acid infusion resulted in a marked increase in the albumin fractional clearance rate in both normal subjects and diabetic patients. On the contrary, ketone body infusion slightly increased the albumin fractional clearance rate in group 2 diabetic patients but not in group 1 diabetic patients and normal subjects. This study demonstrates that long-standing diabetic patients, irrespective of the presence of impaired renal function, show a peculiar defect in the kidney hemodynamic response to amino acid but not to ketone body infusion. These results question the use of an amino acid load to test for glomerular filtration reserve in diabetic patients, because a lack of response may simply be related to an altered response of the kidney to amino acids. A macula densa feedback mechanism could not account for the increase in GFR after both amino acid and ketone body infusion, because these compounds increase the sodium distal delivery. Amino acids increase albumin excretion rate with a mechanism independent of GFR and renal plasma flow changes, in that this effect occurs even in diabetic patients who showed no changes in these variables.

Diabetes mellitus is associated with important changes in renal hemodynamics. The purpose of this study was to determine whether an increase in blood concentration patterns of ketone bodies and lactic acid, organic acids often elevated in poorly controlled insulin-dependent diabetes mellitus (IDDM), could contribute to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) regardless of changes in circulating levels of glucose and insulin. Six IDDM patients and six normal subjects were given a saline infusion (15 μmol · min−1 · kg−1) for 2 h, an acetoacetic acid infusion (15 μmol · min−1 · kg−1) for another 2 h, and then a saline infusion after an overnight fast during euglycemic insulin-glucose clamp. Acetoacetic acid infusion resulted in an increase of blood ketone bodies in the range of 0.7–1.5 mM from a basal value of 0.1–0.3 mM. GFR was 125 ± 16 and 136 ± 17 ml · min−1 · 1.73 m−2 in normal and IDDM subjects, respectively, during baseline saline infusion and 138 ± 21 (P < .01 vs. basal level) and 158 ± 15 ml · min−1 · 1.73 m−2 (P < .001 vs. basal level) during acetoacetic acid infusion. During the last saline infusion, renal hemodynamic patterns decreased again to baseline levels. Another six IDDM patients and six normal subjects were given saline, lactic acid, and saline infusions at the same rates of infusion after an overnight fast during euglycemic insulin-glucose clamp. Lactic acid concentration increased from ∼0.5–0.8 to 1.0–1.5 mM in both groups. GFR was 125 ± 9 and 144 ± 18 ml · min−1 · 1.73 m−2 in normal and IDDM subjects, respectively, during baseline saline infusion and 135 ± 8 and 158 ± 16 ml · min1 · 1.73 m−2 during lactic acid infusion (P < .01 vs. basal level). Acetoacetic acid and lactic acid infusion resulted in a 14.7 and 7.6% increase, respectively, in RPF compared with baseline values in normal subjects and in a 12.6 and 6.9% increase, respectively in IDDM subjects. With the same protocol of the previous organic acid infusion, another five normal and six IDDM patients were given an acetic acid infusion (15 μmol · kg−1 · min−1), resulting in an increase of plasma circulating levels of acetic acid from 0.1–0.2 to 0.3–0.4 mM, which was associated with negligible changes in ketone body and lactic acid concentrations. Neither GFR nor RPF were influenced by acetic acid administration. During acetoacetic acid and lactic acid infusion, both lactic and ketone body acid tubular reabsorption rates were three to five times higher than during saline infusion. In conclusion, lactic acid and acetoacetic acid infusion resulting in circulating patterns of these intermediate metabolites comparable with those often found in poorly controlled IDDM subjects induced a significant increase in GFR and RPF in normal and IDDM subjects. The increased GFR was associated with stimulation of organic acid tubular reabsorption rate and was not related to sodium and liquid overload, because it returned to basal value when saline alone was administered again.