Efficacy and Safety of Rapid-Acting Insulin Analogs in Special Populations with Type 1 Diabetes or Gestational Diabetes: Systematic Review and Meta-Analysis.

INTRODUCTION: To assess the efficacy and safety of three available rapid-acting insulin analogs (insulins lispro, aspart and glulisine, respectively) in pregnant women, children/adolescents and people using continuous subcutaneous insulin infusion (CSII) with type 1 diabetes. METHODS: PubMed, EMBASE and Cochrane Reviews were searched electronically, and their bibliographies examined to identify suitable studies for review and inclusion in a meta-analysis. Eligible studies were randomized controlled trials that reported data on relevant clinical outcomes. A different reviewer abstracted data for each of the three subpopulations, and one reviewer abstracted data for all three. Any differences were resolved by consensus or by consulting a fourth reviewer. RESULTS: In people on CSII, rapid-acting insulin analogs lowered postprandial plasma glucose post-breakfast to a greater extent than did regular human insulin (RHI) (mean difference: - 1.63 mmol/L [95% confidence interval - 1.71; - 1.54]), with a comparable risk of hypoglycemia and a trend for lower glycated hemoglobin. In the pediatric population, glycemic control was similar with rapid-acting insulin analogs and RHI, with no safety concerns. Meta-analysis indicated severe hypoglycemic events were comparable for rapid-acting insulin analogs versus RHI (risk difference: 0.00 [95% confidence interval - 0.01; 0.01]). In the pregnancy group, insulin lispro and insulin aspart were safe and effective for both mother and fetus, with glycemic control being at least as good as with RHI. There were no data on insulin glulisine during pregnancy. CONCLUSION: Rapid-acting insulin analogs appear generally safe and effective in these special populations; however, additional trials would be helpful. FUNDING: Novo Nordisk A/S.

The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: The English longitudinal study of ageing.

BACKGROUND: Ferritin constitutes a sensitive iron-storage index and multi-functional protein. Evidence on its association with mortality in general population is scarce and conflicting. We investigated the sex-specific associations of ferritin levels with all-cause and cardiovascular mortality in a population-based cohort. METHODS: Data came from the English Longitudinal Study of Ageing and the national mortality registry. The sample comprised 5,471 participants aged ≥52 years. Blood concentration of ferritin was measured at baseline in 2004-05. Sex-specific Cox proportional hazards models were estimated with adjustment for age, major chronic diseases, marital status, educational attainment, total net household wealth, anemia, inflammatory markers, body mass index, smoking, and physical activity. Stratified analyses by chronic disease status were also performed. RESULTS: We categorized ferritin in sex-specific quartiles. In men, we used, the following categorization: lowest (2-69ng/ml), second lowest (70-118ng/ml), second highest (reference category) (119-193ng/ml) and highest (194-598ng/ml) ferritin quartiles. In women, ferritin was categorized as follows: lowest (2-44ng/ml), second lowest (45-73ng/ml), second highest (reference category) (74-115ng/ml) and highest (116-341ng/ml) ferritin quartiles. 841 deaths of which 262 cardiovascular disease-related were recorded over a mean follow-up time of 7.7 years. Risk for all-cause mortality was found increased in men with hyperferritinemia (194-598ng/ml) and no history of major chronic diseases compared with the reference group [fully-adjusted HR: 1.49 (95%CI 1.03-2.16)]. Among women, those in the lowest ferritin quartile (2-44ng/ml) had increased risk for all-cause mortality [fully-adjusted HR: 1.59 (95%CI 1.18-2.13)] compared with the reference group after adjustment for all covariates. Regarding cardiovascular mortality, we observed a positive association with ferritin levels in men, which was blunted after adjustment for inflammatory markers and lifestyle parameters. Men with no major chronic diseases who were in the highest ferritin quartile had a significantly increased risk of cardiovascular mortality. No association between ferritin levels and cardiovascular mortality was detected in women. CONCLUSION: Circulating ferritin levels showed sex-specific prognostic patterns. High ferritin levels in men with no major chronic disease and low ferritin levels in all women were associated with increased all-cause mortality after adjusting for covariates. High ferritin levels in men with no major chronic diseases were also independently associated with an increased risk of cardiovascular mortality. Future research is needed to clarify the prognostic role of ferritin.

Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis.

BACKGROUND: Vitamin B-12 and folate are micronutrients essential for normal embryogenesis. Vitamin B-12 insufficiency in pregnancy is high in certain parts of the world, such as India, and although this has been linked to low birth weight (LBW) in these populations, the relation between vitamin B-12 and birth weight (BW) elsewhere is unknown. OBJECTIVES: We performed a systematic review to assess 1) the worldwide prevalence of vitamin B-12 insufficiency in pregnancy and 2) its association with BW. DESIGN: A search of 5 electronic databases was performed to identify eligible articles. Random-effects meta-analysis was conducted according to geographic regions and pregnancy trimesters for the prevalence subreview and by categorical measures of BW. RESULTS: A total of 57 and 23 articles were included for the prevalence and BW subreviews, respectively. The pooled estimates of vitamin B-12 insufficiency were 21%, 19%, and 29% in the first, second, and third trimesters, respectively, with high rates for the Indian subcontinent and the Eastern Mediterranean. The large heterogeneity between studies was partially addressed by creating a standardized score for each study (mean vitamin B-12 insufficiency ÷ cutoff value), which internally corrected for geographic region, trimester, and assay type. Twelve of the 13 longitudinal studies included showed a decrease in mean or median vitamin B-12 across trimesters. Pooled analysis showed nonsignificantly lower maternal vitamin B-12 concentrations in LBW than in normal-BW infants and higher odds of LBW with lower vitamin B-12 values (adjusted OR: 1.70; 95% CI: 1.16, 2.50), but studies from India largely contributed to the latter. CONCLUSIONS: Our review indicates that vitamin B-12 insufficiency during pregnancy is common even in nonvegetarian populations and that concentrations of vitamin B-12 decrease from the first to the third trimester. There is no consistent association between vitamin B-12 insufficiency and LBW. However, given the long-term risks of LBW, this observation warrants further cohort studies and randomized controlled trials.

Sizable variations in circulatory disease mortality by region and country of birth in six European countries.

BACKGROUND: Circulatory disease mortality inequalities by country of birth (COB) have been demonstrated for some EU countries but pan-European analyses are lacking. We examine inequalities in circulatory mortality by geographical region/COB for six EU countries. METHODS: We obtained national death and population data from Denmark, England and Wales, France, the Netherlands, Scotland and Sweden. Mortality rate ratios (MRRs) were constructed to examine differences in circulatory, ischaemic heart disease (IHD) and cerebrovascular disease mortality by geographical region/COB in 35-74 years old men and women. RESULTS: South Asians in Denmark, England and Wales and France experienced excess circulatory disease mortality (MRRs 1.37-1.91). Similar results were seen for Eastern Europeans in these countries as well as in Sweden (MRRs 1.05-1.51), for those of Middle Eastern origin in Denmark (MRR = 1.49) and France (MRR = 1.15), and for East and West sub-Saharan Africans in England and Wales (MRRs 1.28 and 1.39) and France (MRRs 1.24 and 1.22). Low ratios were observed for East Asians in France, Scotland and Sweden (MRRs 0.64-0.50). Sex-specific analyses showed results of similar direction but different effect sizes. The pattern for IHD mortality was similar to that for circulatory disease mortality. Two- to three-fold excess cerebrovascular disease mortality was found for several foreign-born groups compared with the local-born populations in some countries. CONCLUSIONS: Circulatory disease mortality varies by geographical region/COB within six EU countries. Excess mortality was observed for some migrant populations, less for others. Reliable pan-European data are needed for monitoring and understanding mortality inequalities in Europe's multiethnic populations.

Mortality from circulatory diseases by specific country of birth across six European countries: test of concept.

BACKGROUND: Important differences in cardiovascular disease (CVD) mortality by country of birth have been shown within European countries. We now focus on CVD mortality by specific country of birth across European countries. METHODS: For Denmark, England and Wales, France, The Netherlands, Scotland and Sweden mortality information on circulatory disease, and the subcategories of ischaemic heart disease, and cerebrovascular disease, was analysed by country of birth. Information on population was obtained from census data or population registers. Directly age-standardized rates per 100 000 were estimated by sex for each country of birth group using the WHO World Standard population 2000-25 structure. For differences in the results, at least one of the two 95% confidence intervals did not overlap. RESULTS: Circulatory mortality was similar across countries for men born in India (355.7 in England and Wales, 372.8 in Scotland and 244.5 in Sweden). For other country of birth groups-China, Pakistan, Poland, Turkey and Yugoslavia-there were substantial between-country differences. For example, men born in Poland had a rate of 630.0 in Denmark and 499.3 in England and Wales and 153.5 in France; and men born in Turkey had a rate of 439.4 in Denmark and 231.4 in The Netherlands. A similar pattern was seen in women, e.g. Poland born women had a rate of 264.9 in Denmark, 126.4 in England and Wales and 54.4 in France. The patterns were similar for ischaemic heart disease mortality and cerebrovascular disease mortality. CONCLUSION: Cross-country comparisons are feasible and the resulting findings are interesting. They merit public health consideration.

Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies.

PURPOSE: To assess the prior hypothesis that low blood vitamin B12, partly through hyperhomocysteinemia and partly through direct effects, increases the risk of cardiovascular diseases and diabetes. As background, we also extracted all-cause mortality from the studies that met our criteria. METHODS: A systematic review of prospective cohort studies identified through searching six electronic databases, screening of reference lists, and citation search. Included studies reported data on the association between vitamin B12 blood levels, or other appropriate surrogate biological markers e.g. holotranscobalamin or serum/urine methylmalonic acid, and fatal or non-fatal incident diabetes and cardiovascular events. RESULTS: Seven studies were included. Studies differed regarding the population studied, length of follow-up, study outcomes, and data analysis--a narrative synthesis approach was performed to examine the results. Most studies met few of the quality assessment criteria which were adapted from the Scottish Intercollegiate Guidelines Network (SIGN). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia (RR = 1.76; 95% CI = 1.16-2.68). After controlling for homocysteine, the association persisted although weakened (RR = 1.57; 95% CI = 1.02-2.43), suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality (RR = 1.00; 95% CI = 1.00-1.00 and HR = 1.15; 95% CI = 1.08-1.22, respectively) and combined fatal and non-fatal coronary events (RR = 1.00; 95% CI = 1.00-1.00). No association between study outcomes and vitamin B12 levels was found in four other studies. CONCLUSIONS: Surprisingly, there is only very limited evidence that vitamin B12 deficiency predisposes to the risk of mortality and morbidity from either cardiovascular diseases or diabetes in adults. Current data do not support vitamin B12 supplementation to reduce the risk of cardiovascular diseases or diabetes.

Ankle--brachial index predicts level of, but not change in, cognitive function: the Edinburgh Artery Study at the 15-year follow-up.

The ankle-brachial index (ABI), a marker of generalized atherosclerosis, is related to cognitive impairment in older adults. We investigated whether ABI is associated specifically with age-related cognitive decline. We measured ABI at recruitment and 5 and 12 years later in a sample of individuals aged 55-74 years. Cognition was measured in 717 of these participants 10 years after recruitment and 5 years later. It was found that ABI was associated with the level of cognitive function, even after adjustment for estimated premorbid function and concurrently measured anxiety and depression (standardized coefficient of 0.07), but this was attenuated by anxiety and depression. ABI was not associated with change in cognitive function. In conclusion, over long time periods, low ABI may be associated with reduced cognitive function in older adults, at least partly because the associated poor health creates anxiety and depression.

Genetic variants associated with altered plasma levels of C-reactive protein are not associated with late-life cognitive ability in four Scottish samples.

It is unknown whether the relationship between raised inflammatory biomarker levels and late-life cognitive ability is causal. We explored this issue by testing the association between genetic regulators of plasma C-reactive protein (CRP) and cognition. Data were analysed from four cohorts based in central Scotland (Total N = 4,782). Associations were tested between variants in the CRP gene and both plasma CRP levels and a battery of neuropsychological tests, including a vocabulary-based estimate of peak prior cognitive ability and a general (summary) cognitive factor score, or 'g'. CRP levels were associated with a number of variants in the CRP gene (SNPs), including rs1205, rs1130864, rs1800947, and rs1417938 (P range 4.2e-06 to 0.041). Higher CRP levels were also associated with vocabulary-adjusted cognitive ability, used here to estimate lifetime cognitive change (P range 1.7e-04 to 0.038). After correction for multiple testing and adjustment for age and sex, no statistically significant associations were found between the SNPs and cognition. CRP is unlikely to be a causal determinant of late-life cognitive ability.

Age-associated cognitive decline.

INTRODUCTION: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. AREAS OF AGREEMENT AND CONTROVERSY: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age. EMERGING AREAS FOR DEVELOPING RESEARCH: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.

Large-scale epidemiological data on cardiovascular diseases and diabetes in migrant and ethnic minority groups in Europe.

BACKGROUND: Data on differences by ethnicity in cardiovascular diseases (CVDs) and diabetes, reflecting the influence of diverse cultural, social and religious factors, are important to providing clues to disease aetiology and directing public health interventions and health care resources. METHODS: Through a network of European public health researchers and searches of bibliographic databases and internet sites, we determined the availability and characteristics of ethnically relevant data on mortality and morbidity from coronary heart disease (CHD), stroke and diabetes, in current European Union countries; data from the four countries comprising the UK were assessed separately. RESULTS: In total, 25 countries had one or more relevant data sets (72 in total); however, two-thirds (n = 47) of the data sources came from only eight Nordic and Western European countries. For several countries, no data could be identified. Ethnically relevant, national death registers were available in 24 countries. Country of birth was the most common indicator of ethnicity. Data on CHD, stroke and diabetes morbidity among migrant and ethnic minority populations are currently scarce; both between and within countries, there are important differences in how ethnicity as well as disease outcomes are defined and measured which limits data comparability. CONCLUSION: Reliable routine data are key to evidence-based public health policies at both national and EU level. EU countries have a relatively weak base for assessing needs and planning health care interventions for its migrant and ethnic minority populations. The lack of ethnically relevant data on CVD and diabetes across the EU needs to be addressed urgently.

Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations?

BACKGROUND: South Asians are susceptible to cardiovascular disease (CVD), especially after migration to affluent countries. Contributing factors include high prevalence of diabetes, and possibly insulin resistance. Excess adiposity centrally may underlie such metabolic disturbances. The thrifty genotype, thrifty phenotype, adipose tissue compartment and variable disease selection hypotheses are among the explanations posed. METHODS: Data from individual studies and review articles known to the authors were examined. A Medline bibliographic database search was also performed. Reference lists were reviewed to identify additional relevant data sources. Key references were examined by both authors. RESULTS: We propose, and evaluate, the evidence for a 'mitochondrial efficiency hypothesis' i.e. that ancestral changes in mitochondrial coupling efficiency enhanced the successful adaptation of South Asians to environmental stressors by maximizing the conversion of energy to adenosine triphosphate (ATP) rather than heat. This adaptation may be disadvantageous when South Asians are physically inactive and consume high-caloric diets. There is evidence that common mitochondrial mutations vary geographically. Mutations, including those affecting the function of mitochondrial uncoupling proteins (UCPs), may influence the balance of energy and heat production. These may influence basal metabolic rate (BMR), energy efficiency, the tendency to gain weight and hence metabolic disease. UCP gene polymorphisms are related to differences in BMR between African-Americans and Europeans. Similar data for South Asians are lacking but the few studies comparing BMR indicate that South Asians have a lower BMR, which is explained by a lower lean body mass, and higher fat mass. Once adjusted for body composition, BMR is similar. A high fat mass, per se, is a strategy for reducing energy use while conserving body size. Indians in the USA had higher oxidative phosphorylation capacity than Northern European Americans. CONCLUSION: The evidence justifies full exploration of this mitochondrial efficiency hypothesis in South Asians, which may also be relevant to other warm-climate adapted populations.

Peripheral arterial disease and cognitive function.

As a marker of generalized atherosclerosis, peripheral arterial disease (PAD) has implications not only for the affected lower extremity but also to overall cardiovascular health. It confers an increased risk of non-fatal and fatal vascular events which increases with the severity of the disease. Patient-based studies have shown that individuals with advanced PAD tend to perform poorly on cognitive tests compared to controls. In population studies, PAD is associated with an increased cognitive decline independently of previous cerebrovascular disease and cardiovascular risk factors. A low ankle-brachial index (ABI) may be an early predictor of cognitive decline and of potential value in identifying individuals at increased risk of cognitive impairment. In patients with PAD, secondary preventive measures directed at decreasing the long-term systemic vascular complications may also be important to the preservation of cognitive health. However, evidence suggests that PAD patients may be undertreated with regard to atherosclerotic risk factors, as demonstrated by an undue emphasis on symptom relief rather than essential risk factor reduction. More research needs to be carried out to determine the predictors of cognitive function in PAD patients, whether subtle cognitive disturbances are related to activities of daily living, including medical treatment compliance, and whether neuroprotective strategies and atherosclerotic risk factor control positively influence cognitive function in these high-risk patients.

Migrant and ethnic health research: report on the European Public Health Association Conference 2007.

Europe largely shifted from being a region of net emigration to one of net immigration during the second half of the 20th Century. Multi-ethnic societies in Europe are faced with a multiplicity of challenges, including meeting the diverse health and healthcare needs of ethnic-minority groups. A major issue facing Europe is filling the current gap in the availability of high-quality data on health determinants, health status and health service use among migrant populations throughout the region. As evidence-based decision making in public health and healthcare greatly depends on the availability of relevant health information, improving the collection of valid and comparable ethnic-minority health data should be regarded as a high priority. Migration, ethnicity and health researchers across Europe have been building alliances, particularly through the migrant health section of the European Public Health Association (EUPHA). The 2007 EUPHA Conference in Helsinki highlighted the public health challenges and opportunities facing an ever-growing and increasingly diversified European region, and provided public health professionals and researchers a platform to share their work, concerns and visions for the future. As the ethnic diversification of Europe continues, the challenges to the unification of its many populations become even more unpredictable. Such diversity may ease unification or could exacerbate existing political and economic tensions. It behooves us to take the actions now that will make Europe a more cohesive and successful place in the years to come.

Cardiovascular diseases and decline in cognitive function in an elderly community population: the Edinburgh Artery Study.

OBJECTIVE: To investigate cognitive performance and 4-year change in cognitive function in relation to different clinical manifestations of atherosclerotic disease in an elderly community population. METHODS: The Edinburgh Artery Study is a population cohort study of men and women who were recruited to a baseline survey in 1987 and 1988. From the time of study entry, the participants have been invited to two follow-up clinical examinations and continuously monitored for major fatal and nonfatal vascular events. All alive and eligible subjects were invited for cognitive testing in two study years when the mean age of the sample was 73.1 (standard deviation = 5.0) years. A follow-up cognitive assessment was performed in 2002 and 2003 on 452 survivors. RESULTS: In multivariate analyses controlling for demographic characteristics, depression, and major atherosclerotic risk factors, stroke was associated with a significantly worse performance on tests of verbal memory (p = .02) and letter fluency (p = .002). In addition, stroke was related to a significantly steeper 4-year decline in verbal memory performance (p = .04). Among the subjects who had not had an overt stroke, those with symptomatic peripheral arterial disease experienced a significantly greater 4-year decline in verbal memory functioning (p = .04). CONCLUSIONS: In older people, stroke is associated with both worse performance on cognitive tests and progressive verbal memory decline. Elderly individuals with vascular diseases other than stroke may also be vulnerable to a greater decline in verbal memory function. A relationship between vascular diseases and verbal memory decline may exist independently of depressed mood and major atherosclerotic risk factors.

Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study.

OBJECTIVES: To determine whether circulating markers of activated inflammation and hemostasis are associated with cognitive decline in older people. DESIGN: Prospective cohort study (Edinburgh Artery Study). SETTING: Eleven general practices in Edinburgh, Scotland. PARTICIPANTS: A sample of 452 men and women followed for 16 years. MEASUREMENTS: Biomarker data were collected in 1987/88, and cognitive assessment was first conducted in 1998/99, when the mean age of the sample +/- standard deviation was 73.1+/-5.0), and subsequently in 2002/03. Information was obtained on verbal declarative memory (Wechsler Logical Memory Test (LMT)), nonverbal reasoning (Raven's Standard Progressive Matrices), verbal fluency (Verbal Fluency Test), information processing speed (Wechsler Digit Symbol Test), and a general cognitive factor representing the variance common to the individual test scores. RESULTS: In age-adjusted analyses, plasma fibrinogen, interleukin-6 (IL-6), and intercellular adhesion molecule 1 (ICAM-1) were negatively associated with performance on all cognitive measures in 2002/03 except the LMT (correlation coefficients from -0.10 to -0.24). In multivariate analyses controlling for demographic characteristics, depression, and cardiovascular morbidity and risk factors, fibrinogen independently predicted 4-year decline in nonverbal reasoning (P<.05). Also, when cognitive change was estimated from peak prior level, IL-6 turned out to be inversely related to decline in information processing speed (P<.05). Similarly, ICAM-1 was associated with a greater decline in general cognitive ability (P<.05) and nonverbal ability (P<.05). CONCLUSION: Systemic markers of inflammation and hemostasis are associated with a progressive decline in general and specific cognitive abilities in older people, independent of major vascular comorbidity.