Novel Indices of Cognitive Impairment and Incident Cardiovascular Outcomes in the REWIND Trial.

CONTEXT: Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown. METHODS: Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST ≥ 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was ≥ 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed. RESULTS: Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors. CONCLUSION: Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.

Expert Opinion: A Call for Basal Insulin Titration in Patients with Type 2 Diabetes in Daily Practice: Southeast European Perspective.

Therapeutic inertia related to insulin treatment, i.e. delays in initiation, especially titration of basal insulin, is a significant problem in daily practice in Southeast European countries. This phenomenon can be traced back to several patient-, physician- and health system-related factors. In recognition of the issue of inadequate insulin titration, 11 leading experts from countries in this region held a consensus-seeking meeting to review the current status of insulin initiation after non-insulin treatment and the potential barriers to insulin titration to provide an algorithm and tools for outpatient physicians and for patients aimed at optimizing basal insulin titration. The experts reached a consensus on the majority of the topics and proposed recommendations on how clinical inertia can be overcome. The outcomes of the meeting have been summarized in this paper.

The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.

BACKGROUND: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. INTERPRETATION: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity. FUNDING: Eli Lilly and Company.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Background Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods REWIND was a multicenter, randomized, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m² (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1­5·9) comprising 51 820 person years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77­0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68­0·87; p<0·0001), with HRs of 0·89 (0·78­1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39­1·44; p=0·39) for chronic renal replacement therapy. (AU)

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

Prevalence of dyslipidemia and its association with cardiometabolic factors and kidney function in the adult Romanian population: The PREDATORR study.

The aims were to assess the prevalence and characteristics of dyslipidemia phenotypes in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological study with a cross-sectional, cluster random sampling design. Participants were classified into four dyslipidemia phenotypes based on the NCEP ATP III criteria: isolated hypertrigliceridemia, isolated hypoHDL-C, isolated hyperLDL-C and mixed dyslipidemia (≥2 standard lipid abnormalities). Overall, 2656 were included in the analysis by dyslipidemia phenotypes. RESULTS: An estimated 67.1% of Romanian adults have at least one lipid abnormality: 27.5% (95%CI26.0-28.9%) have elevated TG, 29.4% (95%CI27.9-30.8%) have low HDL-C and 47.8% (95%CI46.3-49.2%) have elevated LDL-C (26.2% had LDL-C levels ≥2.58 mmol/l associated with CHD or CHD risk equivalent). Also, 30% Romanian adults have mixed dyslipidemia with 7.6% (95%CI6.1-9.0%) having all three lipid abnormalities. THE AGE: and sex-adjusted prevalence of isolated dyslipidemia phenotypes in Romanian adult population was 23.7% (95%CI22.2-25.1%) for hyperLDL-Cholesterolemia, 9.3% (95%CI7.8-10.7%) for hypoHDL-Cholesterolemia and 4.1% (95%CI2.6-5.5%) for hypertriglyceridemia. Among participants with triglycerides ≥2.25 mmol/l, 15.2% (95%CI13.7-16.6%) of Romanian adults have non-HDL-C levels ≥3.36 mmol/l. CONCLUSIONS: The PREDATORR survey indicated a high prevalence of dyslipidemia phenotypes in the Romanian population aged 20-79 years, providing data on its association with several cardiometabolic risk factors.

Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study.

BACKGROUND: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. OBJECTIVES: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer-administered questionnaires. RESULTS: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 ± 50.4 versus 213.9 ± 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 ± 45.2 versus 130.7 ± 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 ± 16.8 versus 90.7 ± 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 ± 129.8 versus 144.3 ± 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 ± 17 versus 90.3 ± 18 ml/min/1.73 m2, P < 0.001) and lower HDL-cholesterol (48 ± 15.5 versus 50.4 ± 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01-1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01-1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48-0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. CONCLUSION: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits.

Prevalence and predictors of non-alcoholic fatty liver disease as defined by the fatty liver index in a type 2 diabetes population.

BACKGROUND AND AIMS: We aimed to study the prevalence and the predictive factors of non-alcoholic fatty liver disease (NAFLD) defined by the fatty liver index (FLI) in type 2 diabetic patients (T2DM). METHODS: Three hundred and eighty-one T2DM outpatients who regularly attended a Consulting Clinic in Cluj were retrospectivelly included. FLI, a surrogate steatosis biomarker based on body mass index (BMI), waist circumference (WC), triglycerides (TGL) and gammaglutamyl-transferase (GGT) was used to assess NAFLD in all patients. Anthropometric and biochemical parameters were measured. Hepatic steatosis (HS) was evaluated by ultrasonography. RESULTS: NAFLD-FLI (defined as FLI>60) was correlated with HS evaluated by ultrasound (r=0.28; p<0.001). NAFLD-FLI was detected in 79% of T2DM. The prevalence of obesity in NAFLD-FLI patients was 80%. Of the patients with normal alanine aminotransferase (ALAT), 73.8 % had NAFLD. At univariate analysis, NAFLD-FLI was correlated with age (r= -0.14; p=0.007), sex (r=0.20; p<0.001), LDL cholesterol (r=0.12; p=0.032), HDL cholesterol (r = -0.13; p=0.015), ALAT (r=0.20; p<0.001) and ASAT (r=0.19; p<0.001). At multiple regression analysis, sex, ALAT and LDL-cholesterol were independent predictors of NAFLD-FLI. After logistic regression model, ALAT, LDL-cholesterol, HOMA-IR were good independent predictors of NAFLD-FLI. CONCLUSIONS: NAFLD-FLI could be useful to identify NAFLD in T2DM patients. Subjects with T2DM had a high prevalence of NADLD-FLI even with normal ALAT levels. Our findings showed that sex, ALAT, LDL cholesterol and IR were significant and independent factors associated with the presence of NAFLD in T2DM subjects.

Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study.

BACKGROUND: The PREDATORR (PREvalence of DiAbeTes mellitus, prediabetes, overweight, Obesity, dyslipidemia, hyperuricemia and chronic kidney disease in Romania) study is the first national study analyzing the prevalence of diabetes mellitus (DM) and prediabetes, and their association with cardiometabolic, sociodemographic, and lifestyle risk factors in the Romanian population aged 20-79 years. METHODS: This was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Sociodemographic, lifestyle, and anamnestic data were collected through self- and interviewer-administered questionnaires, and biochemical assays and oral glucose tolerance tests were performed. RESULTS: In all, 2728 participants from 101 clinics of general practitioners were randomly selected, with a probability proportional to population size according to the 2002 Romanian Census. The participation rate was 99.6%. Impaired glucose regulation (prediabetes, known and unknown DM) was found in 28.1% of the study population. The overall age- and sex-adjusted prevalence of DM was 11.6% (95% CI 9.6%-13.6%), of which 2.4% (95% CI 1.7%-3.1%) had unknown DM. The prevalence of DM increased with age and was higher in men than in women. The age- and sex-adjusted prevalence of prediabetes was 16.5% (95%CI 14.8%-18.2%), with the highest percentage in the 60-79 year age group and in women. Obesity, abdominal obesity, dyslipidemia, low education level, and a family history of diabetes were associated with glucose metabolism disorders. CONCLUSIONS: The PREDATORR study shows a high prevalence of impaired glucose regulation in the adult Romanian population, providing data on the prevalence of DM and prediabetes and their association with several risk factors.

Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia.

A panel of European experts on lipids and cardiovascular disease discussed clinical approaches to managing cardiovascular risk in clinical practice, including residual cardiovascular risk associated with lipid abnormalities, such as atherogenic dyslipidaemia (AD). A simplified definition of AD was proposed to enhance understanding of this condition, its prevalence, and its impact on cardiovascular risk. Atherogenic dyslipidaemia can be defined by high fasting triglyceride levels (≥2.3 mmol/L) and low high-density lipoprotein cholesterol (HDL-c) levels (≤1.0 and ≤1.3 mmol/L in men and women, respectively) in statin-treated patients at high cardiovascular risk. The use of a single marker for the diagnosis and treatment of AD, such as non-HDL-c, was advocated. Interventions including lifestyle optimization and low-density lipoprotein (LDL)-lowering therapy with statins (±ezetimibe) are implemented by all experts. Treatment of residual AD can be performed with the addition of fenofibrate, since it can improve the complete lipoprotein profile and reduce the risk of cardiovascular events in patients with AD. Specific clinical scenarios in which fenofibrate may be prescribed are discussed, and include patients with very high triglycerides (≥5.6 mmol/L), patients who are intolerant or resistant to statins, and patients with AD and at high cardiovascular risk. The fenofibrate-statin combination was considered by the experts to benefit from a favourable benefit-risk profile. Cardiovascular experts adopt a multifaceted approach to the prevention of atherosclerotic cardiovascular disease, with lifestyle optimization, LDL-lowering therapy, and treatment of AD with fenofibrate routinely used to help reduce a patient's overall cardiovascular risk.

Effect of the early intensive multifactorial therapy on the cardiovascular risk in patients with newly diagnosed type 2 diabetes: an observational, prospective study.

BACKGROUND AND AIMS: We assessed if early intensive interventions improve the glycemic control and the modifiable cardiovascular diseases risk factors in Romanian patients with newly diagnosed type-2 diabetes during the first year follow-up period. PATIENTS AND METHODS: This was an observational, prospective study: 69 subjects were included in the analysis; each of them received intensive multi-factorial pharmacologic treatment and therapeutic education targeting hyperglycemia, weight, hypertension and dyslipidemia. Disease monitoring was done at months 0, 1, 3, 6 and 12 by assessment of anthropometric measurements, arterial blood pressure and biochemical parameters. The cardiovascular diseases risk factors were calculated using the United Kingdom Prospective Diabetes Study Risk Engine. RESULTS: The mean age at diagnosis was 53.61±10.66 years. All anthropometric variables (body weight, body mass index, waist circumference, visceral fat area, percentage of body fat), except for skeletal muscle mass, significantly decreased overtime. The majority of the biochemical parameters significantly decreased overtime. The non-fatal/fatal coronary heart disease risk significantly decreased at month 12 (9.74 [p<0.05] and 4.84 [p<0.05], respectively) compared to month 0 (19.66 and 11.10, respectively); a similar trend of the non-fatal/fatal stroke (risk at month 12, 8.30 [p<0.05] and 1.04 [p<0.05], respectively, while at month 0, 7.89 and 1.38, respectively) was recorded. CONCLUSIONS: Early multi-factorial treatment and intensive lifestyle interventions in patients newly diagnosed with type-2 diabetes could decrease with approximately 50% the rate of cardiovascular disease risk.

Age, abdominal obesity, and glycated hemoglobin are associated with carotid atherosclerosis in type 2 diabetes patients with nonalcoholic fatty liver disease.

AIM: The aim of this study was to evaluate the impact of clinical parameters and indices of body composition on the relation between non-alcoholic fatty liver disease (NAFLD) and carotid intima-media thickness (cIMT), in a type 2 diabetes mellitus population (T2DM). MATERIAL AND METHODS: We retrospectively enrolled 336 T2DM outpatients who regularly attended Regina Maria Clinic in Cluj. Clinical, anthropometric and biochemical parameters were measured. Ultrasonography (US) was used to assess hepatic steatosis (HS) in all patients and cIMT in 146 subjects. Body composition was assessed by bioelectric impedance (BIA, InBody 720) in all patients. RESULTS: cIMT was correlated with age (r=0.25; p=0.004), systolic blood pressure (r=0.18; p=0.041), glycated haemoglobin A1C (HbA1C, r=0.20; p=0.04), and with coronary artery disease (r=0.20; p=0.007). HS did not correlate with cIMT (r=0.04; p=0.64). cIMT was correlated with visceral fatty area (VFA, r=0.18; p=0.014) but not with other indices of body composition. Homeostasis model assessment for insulin resistance (HOMA-IR) was not correlated with cIMT (r=0.17; p=0.086). After multivariate analysis, age, HbA1c, and VFA were good independent predictors of cIMT (r=0.45; p < 0.001). CONCLUSIONS: These results are suggestive that in T2DM patients, fatty liver is not a direct mediator of early carotid atherosclerosis. Our data indicate that visceral fat accumulation and HbA1C are determinant factors of cIMT sugesting that controlling abdominal obesity and hyperglicemia might reduce atherosclerotic disease risk in NAFLD-T2DM subjects.

Prevalence of chronic kidney disease and its association with cardio-metabolic risk factors in the adult Romanian population: the PREDATORR study.

PURPOSE: PREDATORR is the first national study analyzing the prevalence of chronic kidney disease and its prognosis and association with socio-demographic, cardio-metabolic and lifestyle risk factors in the adult Romanian population. METHODS: Chronic kidney disease was defined according to the KDIGO 2012 criteria as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) and/or urinary albumin-to-creatinine ratio ≥30 mg/g. The socio-demographic, lifestyle and anamnestic data were collected through interviewer-administered questionnaires. Physical examination and biochemical assays were also performed. RESULTS: This cross-sectional study conducted between December 2012 and February 2014 in Romania included 2717 adults. The overall age- and sex-adjusted prevalence of chronic kidney disease was 6.74 % (95 %CI 5.60-7.88 %), of which 3.31 % (2.50-4.13 %) had only reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), 2.98 % (2.21-3.76 %) had only albuminuria, and 0.45 % (0.14-0.74 %) had both. The prevalence of chronic kidney disease increased with age and was similar in women and in men. Age, hyperuricemia, impaired glucose regulation (diabetes/prediabetes), hypertriglyceridemia and a family history of renal disease were independent risk factors for the presence of chronic kidney disease. CONCLUSIONS: The PREDATORR study showed a high prevalence of chronic kidney disease in the adult Romanian population providing data on its prognosis and association with several cardio-metabolic risk factors.

A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: A report from an expert consensus meeting on the role of fenofibrate-statin combination therapy.

A meeting of European experts in cardiovascular (CV) disease and lipids was convened in Paris, France, on 10 November 2014 to discuss lipid profile, and in particular atherogenic dyslipidaemia (AD), and associated CV risk. Key points that were raised and discussed during the meeting are summarised in this paper, which also accounts for further discussion and agreement on these points by the group of experts. Elevated levels of low-density lipoprotein cholesterol (LDL-c) are commonly associated with a greater CV risk than low LDL-c levels, and are routinely managed with statins. However, even for patients controlled on statins and achieving low LDL-c levels, abnormal lipid profiles observed in some patients (i.e. elevated triglyceride levels, with/without low levels of high-density lipoprotein cholesterol [HDL-c]) have been linked to the presence of a residual CV risk. Therefore, it is recommended that both triglyceride and HDL-c levels be measured, to allow for the overall CV residual risk to be adequately managed. Favourable safety and clinical data support the combination of statins with other lipid-lowering agents, such as fenofibrate. Patients who have elevated triglyceride levels plus low levels of HDL-c are most likely to achieve clinical benefit from fenofibrate-statin combination therapy. In these patients with AD, achieving target non-HDL-c levels should be a key focus of CV risk management, and the use of non-HDL-c was advocated to provide a better measure of CV risk than LDL-c levels.

Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial.

BACKGROUND: Diabetes and non-diabetic dysglycaemia are risk factors for accelerated cognitive decline. In this planned substudy of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, we assessed whether normalising glucose with insulin glargine or administering omega-3 fatty acids in this population may slow this process or affect the development of cognitive impairment. METHODS: The ORIGIN trial recruited participants older than 50 years with dysglycaemia who were taking either no or one oral glucose-lowering drug, who had additional risk factors for cardiovascular events, whose HbA1c was less than 9%, and who were not taking insulin. Participants were recruited from 573 sites in 40 countries. Participants were randomly assigned to either titrated basal insulin glargine targeting a fasting plasma glucose concentration of 5.3 mmol/L or lower or standard care and to either omega-3 fatty acid (1 g) or placebo by a factorial design. Outcome adjudicators and data analysts were masked to treatment allocation. Cognitive function was assessed by the Mini-Mental State Examination (MMS) and Digit Symbol Substitution (DSS). The effect of insulin glargine or omega-3 fatty * acid on cognitive function over time, the annualised change in test scores, and the development of probable cognitive impairment were measured. All analyses were restricted to those participants who had a cognitive measurement at both baseline and at least one follow-up visit. The ORIGIN trial is registered with ClinicalTrials.gov, NCT00069784. FINDINGS: Participants were randomly assigned between Sept 1, 2003, and Dec 15, 2005. MMSE and DSS were assessed in 11,685 and 3392 ORIGIN participants (mean age 63.4 years [SD 7.7]), who were followed up for a median of 6.2 years (IQR 5.8-6.7). There was no difference in the rate of change of cognitive test scores between the insulin glargine and standard care groups (for the MMSE 0.0046, 95% CI -0.0132 to 0.0224, p=0.39; and for the DSS -0.0362, -0.2180 to 0.1455, p=0.34) or between the omega-3 fatty acid and placebo groups (for the MMSE 0.0013, 95% CI -0.0165 to 0.0191, p=0.21; and for the DSS -0.0605, -0.2422 to 0.1212, p=0.72). Similarly, the incidence of probable cognitive impairment did not differ between the insulin glargine and standard care groups (p=0.065) or the omega-3 fatty acid and placebo groups (p=0.070). In a subgroup analysis, allocation to insulin glargine versus standard care seemed to reduce the decline in the MMSE (but not the DSS) in participants with dysglycaemia but without evidence of diabetes (pinteraction=0.024). INTERPRETATION: In this relatively young cohort of people with dysglycaemia, insulin mediated normoglycaemia and omega-3 fatty acid for over 6 years had a neutral effect on the rate of cognitive decline and on incident cognitive impairment. Future studies should assess the effect of these interventions in an older cohort or the effect of other glucometabolic interventions on cognitive decline. FUNDING: Sanofi.

Fenofibrate improves endothelial function and plasma myeloperoxidase in patients with type 2 diabetes mellitus: an open-label interventional study.

BACKGROUND: Fenofibrate offers a number of benefits on the cardiovascular system and it is plausible that its anti-inflammatory, anti-oxidant and anti-fibrotic effects and enhancement of cardiac metabolic performances may account for its direct cardioprotective effects.In this study we aimed to investigate the effect of fenofibrate on endothelial function assesed by vascular studies and levels of soluble E-selectin (sE-selectin) as well as the effect on plasma myeloperoxidase (MPO) in patients with type 2 diabetes mellitus (T2DM) without previous use of lipid-lowering medication. METHODS: 27 patients (14 men and 13 women) with T2DM and good glycemic control (HbA1c: min 5.9%, max: 7.1%) treated with metformin monotherapy, without previous use of lipid-lowering medication were enrolled in this study. Vascular studies included measures of brachial artery diameter before and after release of a suprasystolic ischemia. FMD was calculated as the percent (%) change in arterial diameter following reactive hyperemia. Student's paired t test and Wilcoxon Signed Ranks Test were used to compare values before and after fenofibrate therapy. RESULTS: Fenofibrate therapy significantly increased post ischemia mean brachial artery diameter at 60 s (from 4.7 [4.4; 5.0] mm to 4.9 [4.6; 5.2] mm, p = 0.01) and at 90 s (from 4.7 [4.4; 5.0] mm to 4.9 [4.6; 5.1], p = 0.02). FMD response to hyperaemia at 60 s increased with 4.5 ± 13.7% (median value pre- treatment: 22.2%, median value post- treatment 25.0%, z = -2.9, p = 0.004). After 8 weeks of fenofibrate therapy, plasma MPO levels decreased to 49.5 [30.3; 71.5] ng/ml (% change from baseline = 4.6%, z = -2.2, p = 0.03) and mean plasma sE-selectin levels decreased to 67.1 [54.4; 79.8] ng/ml, (% change from baseline = 2.6%, p = 0.03). CONCLUSION: In patients with T2DM without previous treatment for dyslipidemia, short-term treatment with fenofibrate improved vascular endothelial function as demonstrated by increased post ischemia mean brachial artery diameter, increased FMD and decreased plasma sE-selectin and favorably affected plasma MPO levels. Therefore, fenofibrate may be considered a protective cardiovascular drug in this group of patients. TRIAL REGISTRATION: (Australian New Zealand Clinical Trials Registry ANZCTR12612000734864).

Relationship of endothelial cell selective adhesion molecule to markers of oxidative stress in type 2 diabetes.

BACKGROUND: Endothelial dysfunction is an important contributor to micro and macrovascular complications of type 2 diabetes (T2D) and is reflected by increased systemic oxidative stress. Endothelial cell selective adhesion molecule (ESAM) influences endothelial function. We aimed to assess, for the first time to our knowledge, the relationship of soluble ESAM to markers of systemic oxidative stress. MATERIALS AND METHODS: ESAM, malondialdehyde (MDA) level and catalase activity were determined in 54 T2D patients and 43 controls. RESULTS: T2D patients had significantly higher ESAM when compared to controls (16.07 ± 5.77 µg/L versus 8.57 ± 5.28 µg/L, p < 0.0001), they also had higher MDA level (3.88 ± 1.50 µmol/L vs. 1.58 ± 0.72 µmol/L, p < 0.0001) and lower catalase activity (3.07 (2.63-3.44) U/mg vs. 8.72 (4.55-10.46) U/mg, p < 0.0001). In T2D patients ESAM was inversely related to catalase activity (r = -0.27, p = 0.04), relationship to MDA level was direct but not significant (r = 0.16, p = 0.24). MDA concentration correlated inversely to catalase activity (r = -0.28, p = 0.04). In multiple regression catalase activity remained significantly correlated to ESAM (p = 0.02) and MDA level was significantly related to glycated hemoglobin (p = 0.01); there was trend towards a positive correlation of MDA level to ESAM (p = 0.08). When patients were divided according to oxidative stress, those with increased oxidative stress (defined as MDA concentration > 2.98 µmol/L and catalase activity < 3.38 U/mg) had higher ESAM than the rest of the patients (17.99 ± 5.02 µg/L vs. 14.29 ± 5.94 µg/L p = 0.01). CONCLUSION: ESAM is higher in T2D than in controls and parallels oxidative stress: ESAM is inversely related to catalase activity and higher ESAM is found in T2D patients with increased oxidative stress.