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1.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
2.  Health Factors and Risk of All-Cause, Cardiovascular, and Coronary Heart Disease Mortality: Findings from the MONICA and HAPIEE Studies in Lithuania 
PLoS ONE  2014;9(12):e114283.
Aims
This study investigated the trends and levels of the prevalence of health factors, and the association of all-cause and cardiovascular (CVD) mortality with healthy levels of combined risk factors among Lithuanian urban population.
Methods
Data from five general population surveys in Kaunas, Lithuania, conducted between 1983 and 2008 were used. Healthy factors measured at baseline include non-smoking, normal weight, normal arterial blood pressure, normal level of total serum cholesterol, normal physical activity and normal level of fasting glucose. Among 9,209 men and women aged 45–64 (7,648 were free from coronary heart disease (CHD) and stroke at baseline), 1,219 death cases from any cause, 589 deaths from CVD, and 342 deaths from CHD occurred during follow up. Cox proportional hazards regression was used to estimate the association between health factors and mortality from all causes, CVD and CHD.
Results
Between 1983 and 2008, the proportion of subjects with 6 healthy levels of risk factors was higher in 2006–2008 than in 1983–1984 (0.6% vs. 0.2%; p = 0.09), although there was a significant increase in fasting glucose and a decline in intermediate physical activity. Men and women with normal or intermediate levels of risk factors had significantly lower all-cause, CVD and CHD mortality risk than persons with high levels of risk factors. Subjects with 5–6 healthy factors had hazard ratio (HR) of CVD mortality 0.35 (95% confidence interval (CI) 0.15–0.83) compared to average risk in the whole population. The hazard ratio for CVD mortality risk was significant in men (HR 0.34, 95% CI 0.12–0.97) but not in women (HR 0.38, 95% CI 0.09–1.67).
Conclusions
An inverse association of most healthy levels of cardiovascular risk factors with risk of all-cause and CVD mortality was observed in this urban population-based cohort. A greater number of cardiovascular health factors were related with significantly lower risk of CVD mortality, particularly among men.
doi:10.1371/journal.pone.0114283
PMCID: PMC4257606  PMID: 25479610
3.  Trends in Prevalence of Dyslipidaemias and the Risk of Mortality in Lithuanian Urban Population Aged 45–64 in Relation to the Presence of the Dyslipidaemias and the Other Cardiovascular Risk Factors 
PLoS ONE  2014;9(6):e100158.
The aim of this study was to provide reliable information on dyslipidaemias, to estimate the trend of the prevalence of dyslipidaemias and other selected cardiovascular disease (CVD) risk factors at population level, and to evaluate the risk of all-cause and CVD mortality in relation to presence of mixed dyslipidaemias and other CVD risk factors.
Methods
Data from the five surveys (1983–2008) are presented. A random sample of 9,209 subjects aged 45–64 was selected for statistical analysis. During follow-up there were 1653 death cases from any cause, 864 deaths from CVD. Estimates of hazard ratios (HR) and 95% confidence intervals (CI) were based on the multivariate Cox proportional hazards regression for all-cause mortality and CVD mortality.
Results
During 25 year period the prevalence of normal total cholesterol level (<5.2 mmol/L) significantly increased only in women; triglycerides and high density lipoprotein (HDL) cholesterol did not change in men and women. Findings in our longitudinal study showed that in men and women mixed dyslipidaemias (HDL cholesterol <1.03 mmol/L plus triglycerides ≥1.70 mmol/L) significantly increased the risk for all-cause and CVD mortality (respectively in men HR = 1.30; HR = 1.15, in women HR = 1.83; HR = 2.13). These mixed dyslipidaemia combinations combination with the other risk factors such as arterial hypertension, high fasting glucose level increased all-cause and CVD mortality risk in men and women; while, these mixed dyslipidaemias plus smoking increased all-cause and CVD mortality risk only in men compared to never smokers without these dyslipidaemias (respectively HR = 1.89; HR = 1.92); and these dyslipidaemias plus obesity increased all-cause and CVD mortality risk in women (respectively HR = 2.25; HR = 2.39) and CVD mortality risk in men (HR = 1.72), as compared to responders without obesity and these dyslipidaemias.
Conclusion
Mixed dyslipidaemias (reduced HDL cholesterol plus elevated triglycerides) significantly increased the risk for all-cause and CVD mortality in this Lithuanian population aged 45–64 years.
doi:10.1371/journal.pone.0100158
PMCID: PMC4067295  PMID: 24955583
4.  Accessibility and use of urban green spaces, and cardiovascular health: findings from a Kaunas cohort study 
Environmental Health  2014;13:20.
Background
The aims of this study were to explore associations of the distance and use of urban green spaces with the prevalence of cardiovascular diseases (CVD) and its risk factors, and to evaluate the impact of the accessibility and use of green spaces on the incidence of CVD among the population of Kaunas city (Lithuania).
Methods
We present the results from a Kaunas cohort study on the access to and use of green spaces, the association with cardiovascular risk factors and other health-related variables, and the risk of cardiovascular mortality and morbidity. A random sample of 5,112 individuals aged 45-72 years was screened in 2006-2008. During the mean 4.41 years follow-up, there were 83 deaths from CVD and 364 non-fatal cases of CVD among persons free from CHD and stroke at the baseline survey. Multivariate Cox proportional hazards regression models were used for data analysis.
Results
We found that the distance from people’s residence to green spaces was not related to the prevalence of health-related variables. However, the prevalence of cardiovascular risk factors and the prevalence of diabetes mellitus were significantly lower among park users than among non-users. During the follow up, an increased risk of non-fatal and fatal CVD combined was observed for those who lived ≥629.61 m from green spaces (3rd tertile of distance to green space) (hazard ratio (HR) = 1.36), and the risk for non-fatal CVD–for those who lived ≥347.81 m (2nd and 3rd tertile) and were not park users (HR = 1.66) as compared to men and women who lived 347.8 m or less (1st tertile) from green space. Men living further away from parks (3rd tertile) had a higher risk of non-fatal and fatal CVD combined, compared to those living nearby (1st tertile) (HR = 1.51). Compared to park users living nearby (1st tertile), a statistically significantly increased risk of non-fatal CVD was observed for women who were not park users and living farther away from parks (2nd and 3rd tertile) (HR = 2.78).
Conclusion
Our analysis suggests public health policies aimed at promoting healthy lifestyles in urban settings could produce cardiovascular benefits.
doi:10.1186/1476-069X-13-20
PMCID: PMC4000006  PMID: 24645935
Green spaces; Cardiovascular diseases; Risk factors
5.  Health, Alcohol and Psychosocial factors In Eastern Europe (HAPIEE) study: dietary patterns and their association with socio-demographic factors in Lithuanian urban population of Kaunas city 
Objectives
The purpose of this study was to identify the main dietary patterns in Lithuanian urban population and to determine their association with socio-demographic factors.
Methods
Data from the survey performed in the framework of the HAPIEE (Health, Alcohol, Psychosocial factors in Eastern Europe) study were presented. A random sample of 7087 individuals aged 45-72 years was screened in 2006-2008.
Results
Factor analysis of the main dietary patterns revealed five-factor solution which accounted 47.8 % of the variance: “fresh vegetables and fruit” “sweets” “porridge and cereals” “potatoes, meat, boiled vegetables and eggs” “chicken and fish”. “Fresh vegetables and fruits” factor and “sweets” factor were inversely associated with age both in men and women: older people consumed less frequent than average of particular food groups. Dietary patterns of people with good self-rated health and university education were healthier than among people with lower education and poorer health.
Conclusion
Nutrition education efforts should focus on improving food diversity, with particular targeting of lower educated, single, and older people.
doi:10.1007/s00038-010-0170-3
PMCID: PMC3947489  PMID: 20703510
dietary patterns; socio-demographic factors; education; self-rated health
6.  Comparison of four definitions of the metabolic syndrome and odds of ischemic heart disease in the Lithuanian urban population 
Objectives
The purpose of this study was to compare the prevalence of metabolic syndrome diagnosed using four different definitions in the Lithuanian urban population and to determine their association with ischemic heart disease.
Methods
Data from the survey performed in the framework of the HAPIEE (Health, Alcohol, and Psychosocial factors In Eastern Europe) study were presented. A random sample of 7087 individuals aged 45-72 years was screened in 2006-2008.
Results
In Lithuanian urban population of Kaunas city aged 45-72 years, the highest prevalence of metabolic syndrome was determined according to the new Joint Interim Societies (JIS) definition (44.1% of men and 48.7% of women). After adjusting for age, education, smoking habits the metabolic syndrome (irrespective of definition) was associated with a significantly higher risk of ischemic heart disease.
Conclusion
All four metabolic syndrome definitions were associated with ischemic heart disease risk; however odds of this disease were higher in people with metabolic syndrome defined by American Heart Association National Heart Lung Blood Institute definition and National Cholesterol Education program Adult Treatment Panel III definition, than by the new JIS definition.
doi:10.1007/s00038-011-0244-x
PMCID: PMC3947490  PMID: 21384223
metabolic syndrome; odds of ischemic heart disease
7.  Correlates of depressive symptoms in urban middle-aged and elderly Lithuanians 
Purpose
The study aimed to examine the prevalence of depressive symptoms and their correlates in urban middle-aged and elderly Lithuanian adults.
Methods
Data from the survey was collected within the framework of the international project HAPIEE (Health, Alcohol and Psychosocial Factors in Eastern Europe). A random sample of 7,115 individuals aged 45–72 years was screened in 2006–2008.
Results
Depressive symptoms were differently associated with independent variables by sex. In men, deprivation (OR 1.85, 95 % CI 1.54–2.17), being divorced (OR 2.34, 95 % CI 1.61–3.39) or widowed (OR 3.64, 95 % CI 2.40–5.52), physical inactivity (OR 1.30, 95 % CI 1.02–1.65), having a history of spine and joint disease (OR 1.72, 95 % CI 1.36–2.17), average perceived health (OR 2.14, 95 % CI 1.55–2.95), poor perceived health (OR 5.13, 95 % CI 3.39–7.76), average quality of life (OR 2.0, 95 % CI 1.55–2.95), or poor quality of life (OR 8.86, 95 % CI 5.19–15.13) were significantly associated with depressive symptoms. In women, deprivation (OR 1.28, 95 % CI 1.15–1.43), being widowed (OR 1.52, 95 % CI 1.23–1.88), mean dose of alcohol per occasion 40–79.9 g (OR 1.65, 95 % CI 1.18–2.30) and more than 80 g (OR 2.09, 95 % CI 1.14–3.82), physical inactivity in leisure time (OR 1.27, 95 % CI 1.04–1.57), having a history of spine and joint disease (OR 1.26, 95 % CI 1.06–1.51), average perceived health (OR 2.56, 95 % CI 1.89–2.72), poor perceived health (OR 5.07, 95 % CI 3.62–7.11), average quality of life (OR 2.27, 95 % CI 1.89–2.72), or poor quality of life (OR 7.21, 95 % CI 4.73–11.00) were significantly associated with depressive symptoms.
Conclusions
Health status and lifestyle factors are associated with depressive symptoms. Associations between depressive symptoms and long-term health problems are partially mediated by self-rated quality of life and self-rated health.
doi:10.1007/s00127-014-0833-0
PMCID: PMC4108842  PMID: 24570202
Depressive symptoms; Health status; Life-style factors; Middle-aged and elderly Lithuanian adults
8.  Cardiovascular risk factors and cognitive function in middle aged and elderly Lithuanian urban population: results from the HAPIEE study 
BMC Neurology  2012;12:149.
Background
The purpose of this study was to examine associations between cardiovascular risk factors and cognitive ability in middle aged and elderly Lithuanian urban population.
Methods
Data from the survey performed in the framework of the HAPIEE (Health, Alcohol, Psychosocial Factors in Eastern Europe) study were presented. A random sample of 7,087 individuals aged 45–72 years was screened in 2006–2008.
Results
The scores of immediate recall and delayed verbal recall, cognitive speed and attention were significantly lower in men than in women; yet numerical ability scores were higher in men. Significant associations between lowered cognitive functions and previous stroke (in male OR = 2.52; 95% CI = 1.75-3.64; in female OR = 2.45; 95% CI = 1.75, 3.64) as well as ischemic heart disease history (among male OR = 1.28; 95% CI = 1.03-1.60) have been determined. Higher level of physical activity in leisure time (among female OR = 1.32; 95% CI = 1.03-1.69), poor self-rated health (among male OR = 1.57; 95% CI = 1.15-2.14) and poor quality of life (in male OR = 1.67; 95% CI = 1.07-2.61; in female OR = 2.81; 95% CI = 1.92-4.11) were related to lowered cognitive function.
Conclusions
The findings of the study suggest that associations between cardiovascular risk factors and lowered cognitive function among healthy middle-aged and elderly adults strongly depend on gender.
doi:10.1186/1471-2377-12-149
PMCID: PMC3517768  PMID: 23199035
9.  Trends in prevalence, awareness, treatment, and control of hypertension, and the risk of mortality among middle-aged Lithuanian urban population in 1983–2009 
Background
Arterial hypertension (AH) is a main risk factor for the risk from cardiovascular (CVD) and stroke mortality. Only few data was published on prevalence, awareness and management of AH in Lithuania. Development of objective approaches to the treatment and control of AH reduces the risk of mortality. The aim of this study was to evaluate time trends, the prevalence, awareness, treatment and control of AH and risk of mortality among Lithuanian urban population aged 45–64 years during the period of 1983–2009.
Methods
Time trends of AH and risk of mortality were examined in three MONICA health surveys in 1983, 1986, 1992, and in one health survey according to MONICA protocol in 2002 included randomly recruited of 2,218 men and 2,491 women. AH was defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP of ≥90 mmHg or current use of antihypertensive medication. The main outcome measures were all-cause mortality, mortality from CVD, coronary heart disease (CHD) and stroke. The mean duration of follow-up was 11.8 ± 9.2 years. All survey periods were age standardized to the year 2006 of Kaunas population. The estimates of hazard ratio and 95% confidence interval were based on the multivariate Cox proportional hazards regression.
Results
In men during 1983–2002 period hypertension prevalence was 52.1–58.7% and did not significantly change whereas in women decreased from 61.0 to 51.0%. There was a significant increase in hypertension awareness among hypertensive men and women (45.0 to 64.4% and 47.7 to 72.3%, respectively) and in treated hypertensives (55.4 to 68.3% in men and 65.6 to 86.2% in women). Adjusted Cox proportional hazard regression analyses revealed a strong dose–response association between blood-pressure level and all-cause, CVD, CHD and stroke-mortality risk in both men and women groups.
Conclusion
In Lithuanian urban population the prevalence of hypertension remains high. Despite positive changes in hypertension awareness and treatment, hypertension control remains poor. A strong dose–response association between the level of BP and all-cause, CVD, CHD and stroke mortality risk was indicated.
doi:10.1186/1471-2261-12-68
PMCID: PMC3480954  PMID: 22937997
Hypertension; Awareness; Treatment; Control; Risk of mortality

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