Dulaglutide and cardiovascular and heart failure outcomes in patients with and without heart failure: a post-hoc analysis from the REWIND randomized trial.

AIMS: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. METHODS AND RESULTS: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31). CONCLUSIONS: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.

A novel kidney disease index reflecting both the albumin-to-creatinine ratio and estimated glomerular filtration rate, predicted cardiovascular and kidney outcomes in type 2 diabetes.

BACKGROUND: The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. METHODS: 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. RESULTS: A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. CONCLUSIONS: The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952.

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.

Dulaglutide and incident atrial fibrillation or flutter in patients with type 2 diabetes: A post hoc analysis from the REWIND randomized trial.

AIM: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. MATERIALS AND METHODS: Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. RESULTS: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. CONCLUSION: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.

Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis.

BACKGROUND: The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. RESULTS: Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028]. CONCLUSIONS: These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).

Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial.

BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company.

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 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.

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.

Circulating chemerin decreases in response to a combined strength and endurance training.

Chemerin is an adipokine that may mediate the link between obesity, inflammation, insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. In this study, we examined the association between chemerin and various cardiometabolic risk factors in cross-sectional setting and tested the hypothesis that a 6-month combined exercise program decreases serum chemerin in overweight or obese, non-diabetic individuals. Serum chemerin concentration was measured in a cross-sectional analysis including 98 individuals with a wide range of age and body mass index (BMI). In addition, chemerin was measured in 79 sedentary, overweight or obese, non-diabetic individuals who completed a 6-month combined endurance and resistance exercise program (CEP, n = 51) or served as controls (C, n = 28). Chemerin was significantly associated with total cholesterol (p = 0.04), triglycerides (p < 0.001), fasting insulin (p < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR, p < 0.001), systolic blood pressure (p = 0.04), highly sensitive C-reactive protein (p = 0.03), leucocytes count (p = 0.047), and leptin (p = 0.008) independently of age and BMI. In multiple regression analysis, chemerin was an independent determinant of HOMA-IR. As a result of the 6-month training program, serum chemerin decreased significantly in CEP group (-13.8 ± 13.2 ng/ml, p < 0.001). A significant association between the changes in chemerin and improved HOMA-IR were found even after adjustment for changes in waist circumference. Among non-diabetic individuals serum chemerin was associated with various cardiometabolic risk factors independently of BMI. In addition, the 6-month combined strength and endurance training program led to a significant reduction in circulating chemerin levels in overweight or obese individuals.

Physical activity is strongly inversely related to post-challenge plasma glucose and glycemic spikes in a risk population for type 2 diabetes.

AIM: To examine the relationship between physical activity (PA) and various cardiometabolic risk factors during an oral glucose tolerance test (OGTT), including glycemic spikes (PGS) in individuals at risk for type 2 diabetes. SUBJECTS AND METHODS: A total of 949 middle-aged subjects from the Risk factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) trial aged 40-70 years were included in the present cross-sectional analysis. Standard 75 g OGTT was performed and blood was collected every 30 min for 2 hours for measurements of plasma glucose (PG) and other cardiometabolic risk factors. PA was assessed using interviewer-administered questionnaire. RESULTS: Post-challenge PGS and maximal PG (PGmax) during OGTT were significantly lower in individuals with high PA vs. individuals with low PA even after body mass index (BMI) adjustment (p = 0.026 and p = 0.035, respectively). In univariate analysis post-challenge PG 30, 60, 90, and 120 minutes, PGS and PGmax during OGTT were significantly inversely correlated to PA. This correlation was attenuated but remained significant after adjustment for BMI. Fasting PG and glycosylated hemoglobin were not correlated to PA. Significantly higher fasting and post-challenge insulin levels were found among subjects with low vs. subjects with medium (p < 0.05) and high PA (p < 0.05). Post-challenge C-peptide and proinsulin levels were significantly lower in participants with high vs. participants with low PA (p < 0.05 for all). The relationship between 2-h PG and PA was observed also in lean subjects and in subjects with normal fasting glucose. In multivariate analysis PA was a significant independent determinant of 2-h PG. CONCLUSION: We found a strong inverse relationship between PA and various post-challenge cardiometabolic parameters during OGTT, including glycemic spikes, in a population at risk for diabetes. This relationship was only partially dependent on BMI.

Effects of supervised vs non-supervised combined aerobic and resistance exercise programme on cardiometabolic risk factors.

OBJECTIVE: We examined the effect of a 6-month combined aerobic and resistance training programme on cardiometabolic risk factors in nondiabetic subjects and compared its effectiveness when executed under strict professional supervision or without direct supervision. METHODS: Eighty-five sedentary, non-diabetic subjects (27 men and 58 women), mean age 47.5 +/- 0.6 years, mean body mass index (BMI, 33.8 +/- 0.6 kg/m2) participated in a combined exercise programme assigned to supervised (S, n = 31), non-supervised (NS, n = 24) or control group (C, n = 30). Cardiometabolic risk parameters were assessed at baseline and after the 6-month training. RESULTS: In both the S and NS group there was a significant decrease in BMI (-1.6 +/- 0.3, p < 0.001 and -1.0 +/- 0.3 kg/m2, p = 0.004), waist circumference (-10.1 +/- 1.1 cm, p < 0.001 and -7.8 +/- 0.8 cm, p < 0.001), fat mass (-1.8 +/- 0.4%, p < 0.001 and -2.1 +/- 0.6%, p = 0.003), and a significant increase in fat-free mass (+1.7 +/- 0.4%, p < 0.001 and +2.0 +/- 0.7%, p = 0.008), and aerobic capacity (+6.9 +/- 1.1, p < 0.001 and +6.9 +/- 0.8 ml/kg per min, p = 0.008). Fasting glucose did not change in S and NS, but increased in C (p = 0.048). In the S group a significant decrease in fasting insulin (p < 0.001), homeostasis model assessment of insulin resistance (p < 0.001), highly sensitive C-reactive protein (p = 0.004), leucocytes count (p = 0.04), systolic high (p < 0.001) and diastolic (p = 0.009) blood pressure was found. Comparable significant decreases in total and low-density lipoprotein cholesterol were observed in all study groups. CONCLUSIONS: A 6-month combined exercise programme led to substantial improvement of various cardiometabolic risk factors. This programme was effective even when executed without direct supervision, although the effects were more pronounced in the supervised group. Our findings suggest that non-supervised exercise programmes may be a valuable, cost-effective tool to translate the current physical activity guidelines in a real-life setting.

Association of physical activity with insulin resistance, subclinical inflammation, coagulation, and fibrinolytic biomarkers among population at high risk for type 2 diabetes.

OBJECTIVE: TO investigate the association of physical activity with insulin resistance and biomarkers of inflammation, coagulation, and fibrinolysis in a population at high risk for type 2 diabetes. PATIENTS AND METHODS: A total of 778 subjects from the Risk factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) study aged 40-70 years were included in the present cross-sectional analysis. RESULTS: Participants classified as having low physical activity (PA) were more insulin resistant in comparison to participants with medium (P = 0.042) and high PA (P = 0.015). Individuals with high physical activity had a significantly lower leucocytes count than individuals with low PA (P = 0.027) and significantly lower hs-CRP and fibrinogen concentrations than individuals with medium (P = 0.011 and P = 0.021) and low physical activity (P = 0.04 and P = 0.007). Although a trend towards a decrease in plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) levels with increasing physical activity was present, significant differences were observed only between subjects with high and medium physical activity (P = 0.045 and P = 0.033). In multivariate regression analyses physical activity was an independent determinant of insulin resistance, leucocytes count, hs-CRP, and fibrinogen concentrations. CONCLUSIONS: Physical activity was independently associated with insulin resistance and biomarkers of inflammation, whereas only a tendency towards decreased concentrations of coagulation and fibrinolytic biomarkers with increasing physical activity was observed.

Relationship of physical activity and eating behaviour with obesity and type 2 diabetes mellitus: Sofia Lifestyle (SLS) study.

OBJECTIVE: Physical inactivity and excessive food consumption play a major role in the etiology of obesity and type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the relationship of physical activity (PA) and eating behaviour with obesity and T2DM in citizens of Sofia, Bulgaria. PATIENTS AND METHODS: A total of 511 randomly chosen participants completed a validated questionnaire concerning age, body height and weight, medical history, and motivation for a lifestyle change. The Baecke PA questionnaire and the Three Factor Eating Questionnaire were also completed. RESULTS: Body mass index (BMI) was significantly higher among subjects in the lowest compared with the middle (P = 0.002) and with the highest tertile of leisure time PA (P < 0.001), also between the lowest and the highest tertile group of sport PA (P = 0.001). BMI differed significantly in the highest vs. the middle (P = 0.04), as well as vs. the lowest (P= 0.017) tertile of uncontrolled eating behaviour. The prevalence of T2DM was significantly greater in the lowest vs. the middle (P = 0.027) and the highest (P = 0.02) tertile of leisure time PA. In a multiple regression analysis both leisure time PA and uncontrolled eating were independently associated with BMI (beta = -0.13, 95% CI -1.83 to -0.11, P = 0.03 and beta = 0.32, 95% CI 0.23 to 0.44, P < 0.001). CONCLUSIONS: We found a strong inverse relationship between the level of PA during leisure time (including sport), BMI, and the prevalence of T2DM. Uncontrolled eating behaviour was also found to have a significant effect on BMI.

The metabolic syndrome in Bulgaria.

The prevalence of the metabolic syndrome (MetS), a cluster of central obesity, hyper/dyslipiemia, hyperglycemia, and hypertension is constantly increasing worldwide. Although, the exact mechanisms underlying the development of the MetS are not completely understood, modern lifestyle of physical inactivity and unhealthy nutrition, obesity, and their interaction with genetic factors are considered largely responsible. It has been convincingly demonstrated that the metabolic syndrome is associated with substantially increased risk for the development of type 2 diabetes mellitus, as well as, with increased cardiovascular disease (CVD) morbidity and mortality. The prevalence of obesity and type 2 diabetes in Bulgaria has dramatically increased in the last decades. For the same period CVD mortality in the country have also gradually increased and Bulgaria is nowadays among the countries with the highest macrovascular disease death rates in Europe. A number of epidemiological studies have demonstrated that the prevalence of the MetS and of its individual components has also increased during the last decades and is nowadays relatively high among the general population in Bulgarian and extremely high among high-risk individuals. Surprisingly, the prevalence of the MetS is also high among the low risk population in the country and most of its components that are independent predictors of CVD mortality are largely undiagnosed. Furthermore, the presence of the MetS is associated with history of myocardial infarction in the country. Although objective data is somewhat scarce, several studies have reported association of the low physical activity level and the unhealthy nutritional habits with the prevalence of cardiometabolic diseases among the Bulgarian population. Taking into account these observations it may be suggested that indeed the high metabolic syndrome prevalence that results as a consequence of unhealthy lifestyle is responsible for the extremely high CVD mortality rates in Bulgaria. Therefore, large-scale screening programmes should be undertaken within this population in combination with health prevention strategies promoting regular physical activity and improvement of nutritional habits.

Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies.

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated. RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored. RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference. CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

Prevalence and type of dyslipidaemia in a population at risk for cardiovascular death in Bulgaria.

UNLABELLED: Hypercholesterolaemia, hypertriglyceridaemia and low high-density lipoprotein (HDL) cholesterol are established risk factors of macrovascular disease, which leads to stroke and myocardial infarction and is the leading cause of death in Bulgaria. The AIM of our study was to examine the prevalence and type of hyper/dyslipidaemia in patients with myocardial infarction, hypertension and type 2 diabetes mellitus in Bulgaria. MATERIAL AND METHODS: A total of 1230 subjects were examined who had positive own and family history of acute myocardial infarction (AMI) (n=365), hypertension (n=250), type 2 diabetes mellitus (n=250), or neither of the diseases, healthy controls (n=365). All participants filled a questionnaire on medical history, current medication, lifestyle and family history. They underwent standardised measurements of anthropometric parameters and blood pressure. Venous blood was drawn after an overnight fast to test for atherosclerosis risk factors such as lipids, glucose, etc. RESULTS: Although younger than the controls the patients with history of AMI, hypertension and type 2 diabetes had a significantly higher body mass index and waist circumference, as well as significantly higher blood pressure. Seventy percent of the AMI patients received lipid lowering treatment. Total cholesterol level was higher in all patients groups than that in controls, the difference being statistically significant for the AMI patients. Triglycerides were significantly higher in the AMI and the diabetic group in comparison with the controls. HDL cholesterol was lower in all patients groups than that in the controls, the difference being significant between the controls and patients with history ofAMI and diabetes. Hypercholesterolemia was observed in 69.6% of the AMI patients, 51% of the hypertensive patients, 56% of the diabetics and 36% of the controls; triglycerides level above 1.7 mmol/l was found in 85% of the AMI subjects, 28% of the hypertensive patients, 36% of the diabetic patients and 14% of the controls; and low HDL cholesterol--in 61% of the AMI patients, 21% of the hypertensive patients, 28% of the diabetics and 16% of the controls. CONCLUSIONS: Our study demonstrates that hypercholesterolemia, hypertriglyceridemia and low HDL cholesterol are very common in patients with history of myocardial infarction, hypertension and type 2 diabetes in Bulgaria and that treatment of the main cardiovascular risk factors seems to be insufficient in these patients.

Pulse pressure is a strong predictor of cardiovascular risk: Data of the risk factors in impaired glucose tolerance for atherosclerosis and diabetes and the Sofia Metabolic Syndrome studies.

UNLABELLED: The aim of the present study was to examine the relationship between pulse pressure (PP), cardiovascular risk factors and intima-media thickness (IMT) in a population at risk for type 2 diabetes and atherosclerosis in Saxony, and to assess the association between PP and history of myocardial infarction in the general population of Bulgaria. MATERIAL AND METHODS: The Risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study included 1139 subjects, aged 40-70 years, with a family history of type 2 diabetes, obesity and/or hyper/dyslipoproteinemia. The SMS study included 1018 subjects (> 14 years of age) from the general population of Bulgaria. RESULTS: In RIAD study, PP was significantly correlated with age, plasma glucose, body mass index, microalbuminuria, triglycerides, waist-to-hip ratio, plasminogen activator inhibitor, total cholesterol, free fatty acids, leucocytes count and HDL-cholesterol (inversely). PP was also significantly correlated with carotid IMT. In multivariate analysis PP was an independent determinant of IMT. In the Sofia Metabolic Syndrome (SMS) study PP was significantly correlated with age, body mass index, waist circumference and fasting glucose and was an independent significant determinant of history of myocardial infarction. CONCLUSIONS: PP was an important cardiovascular risk factor both in a risk population for type 2 diabetes and atherosclerosis in Saxony and in the general population of Bulgaria.

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.