Circulating adiponectin levels are paradoxically associated with mortality rate. A systematic review and meta-analysis (original) (raw)
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PLoS ONE, 2013
Background: This systematic review and meta-analysis of prospective studies evaluates the association between adiponectin concentrations and risk of cardiovascular disease (CVD) in individuals with diabetes mellitus (DM). Methods: PubMed and Embase were searched for prospective studies on the association of adiponectin concentrations and risk of CVD up to June 2013. Random-effect model was selected to pool the relative risk (RR) and 95% CI. Results: Five prospective cohort studies and one nested case-control studies met the included criterion. The estimated summary RR and 95% CI of five prospective cohort studies for type 2 diabetes comparing top vs low tertile of adiponectin concentrations was 0.99 (95% CI: 0.67-1.45), with significant heterogeneity between studies (p = 0.037, I 2 = 60.9%). This heterogeneity was explained by one study conducted in Korean. Conclusions: This study represents the first meta-analysis between adiponectin levels and CVD in diabetic patients and indicated no association was found. This result should be verified further by large sample size, long duration of follow-up, and well-designed prospective clinical trials.
The Adiponectin Paradox for All-Cause and Cardiovascular Mortality
Diabetes
Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role o...
Association of Adiponectin with Coronary Heart Disease and Mortality: The Rancho Bernardo Study
American Journal of Epidemiology, 2006
Hypoadiponectinemia has been implicated in the development of obesity-related conditions, including dyslipidemia and coronary heart disease (CHD). In this study, the authors examined the association of adiponectin with CHD prevalence, incidence, and mortality among 1,513 community-dwelling men and women aged 50-91 years who were followed from 1984-1987 through 2004. In cross-sectional analyses, adiponectin concentrations were positively related to female sex, age, and high density lipoprotein cholesterol level and inversely related to waist girth, triglyceride level, and fasting plasma glucose level (all p's < 0.001). Adiponectin levels in the highest sex-specific quintile, as compared with the lowest, were associated with 44% decreased odds of prevalent CHD (p for trend ¼ 0.03); adjustment for high density lipoprotein cholesterol and/or triglycerides eliminated this association. In 20-year prospective analyses, higher adiponectin concentrations predicted reduced risk of nonfatal myocardial infarction in men only; adiponectin was not associated with fatal incident CHD events or 20-year CHD mortality (n ¼ 215 deaths) in either sex. Adiponectin levels in the highest sex-specific quintile, as compared with lower levels, were associated with almost 40% increased risks of cardiovascular disease death (n ¼ 441) and death from all causes (n ¼ 925), independent of age, sex, waist girth, lipid levels, and glucose level (both p's < 0.001). These results suggest that use of adiponectin for cardiovascular disease risk stratification is premature. adiponectin; cardiovascular diseases; coronary disease; mortality Abbreviations: CHD, coronary heart disease; HDL, high density lipoprotein.
Endocrine, 2017
Purpose: Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD. Methods: A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001-2002) in a sub-sample (n=531; women/men: 222/309; age: 40±11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40±12 years). Results: After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI]: 0.42-0.96; p=0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI: 0.38-0.94; p=0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI: 0.40-0.99; p=0.046). Conclusions: In our study elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine.
Adiponectin: An Emerging Cardiovascular Risk Factor. The REFERENCE Study
Revista Española de Cardiología (English Edition), 2008
Emerging cardiovascular (CV) risk factors such as adiponectin, glycosilated hemoglobin, waist circumference and the high-sensitivity C-reactive protein (hsCRP) level can aid CV risk stratification. It has been shown that classic factors alone are not sufficient to explain CV risk fully. The adiponectin level has been linked to insulin resistance, dyslipidemia and coronary artery disease. This study investigated how the levels of adiponectin and other emerging risk factors are related to CV events in the Spanish population. This cross-sectional study involved 999 patients. They were divided into cases, who had experienced a first CV event in the 3 months prior to the study, and controls. Anthropometric and laboratory parameters recorded both after the event and 3 years before the study started were obtained. Both a low adiponectin level and a high hsCRP level were associated with the occurrence of a CV event. In addition, obesity and a triglyceride level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 150 mg/dL, both observed 3 years before the study, were also associated with the occurrence of an event. There was an inverse relationship between the plasma adiponectin level and waist circumference. Multivariate analysis identified the following significant variables: hsCRP level, a family history of early CV disease and the high-density lipoprotein cholesterol (HDL-C) level 3 years earlier. A low adiponectin level is associated with abdominal obesity. Emergent risk factors do not improve the predictive ability of the Systematic Coronary Risk Evaluation (SCORE) algorithm (which includes total cholesterol, HDL-C, blood pressure and smoking). Further studies evaluating their contribution are needed.
Cardiovascular Diabetology, 2016
Background: Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality. Methods: A Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year). Results: The A allele of rs822354 was associated with both total and HMW adiponectin [β (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23-3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02-1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest. Conclusions: Our data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes.
Plasma Adiponectin for Prediction of Cardiovascular Events and Mortality in High-Risk Patients
The Journal of Clinical Endocrinology & Metabolism, 2008
The prognostic value of plasma levels of adiponectin, an adipocytokine with antiatherogenic, antiinflammatory, and insulin-sensitizing effects, is contentious. Objective: The objective of the study was to investigate whether plasma adiponectin levels predict cardiovascular (CV) events and mortality in high-risk coronary artery disease (CAD) patients. Design, Setting, Participants, and Main Outcome Measure: We measured plasma adiponectin and examined its impact on the incidence of CV deaths and events at follow-up in the context of all potentially relevant background covariates in 712 high-risk patients of the Genetic and ENvironmental factors in Coronary Atherosclerosis study who underwent coronary angiography for suspected CAD. Based on the population plasma adiponectin median (6.38 g/ml, interquartile range 4.2-10.2), we split the patients in a high-and a low-plasma adiponectin subgroup. After a median follow-up of 3.8 years (interquartile range 3.3-4.3 yr), outcome data were obtained in 100% of the patients and 45 CV deaths (6.4%) were recorded. Kaplan-Meier analysis unexpectedly showed a higher CV death rate in high-plasma adiponectin than low-plasma adiponectin patients. By contrast, multivariate Cox regression analysis, in which potential confounders, including ongoing medical treatment, were considered, showed no impact of plasma adiponectin on CV death. Similar negative results were obtained using the propensity score that considered all relevant covariables and medical treatment rate, which differed between the high-and low-plasma adiponectin group. Conclusions: In high-risk CAD patients, plasma adiponectin above the median (6.38 g/ml) implies a paradoxical higher risk of CV death. However, when relevant covariates that differ between highand low-plasma adiponectin groups are considered, this association wanes, indicating that the clustering of plasma adiponectin with other covariates can abolish its impact on CV prognosis.
Association between adiponectin and heart failure risk in the Physicians’ Health Study
2012
Limited data are available on the association between adiponectin and incident heart failure. In the current ancillary study to the Physicians' Health Study, we used a prospective nested-case control design to examine whether plasma adiponectin concentration was related to the risk of heart failure. We selected 787 incident heart failure cases and 787 matched controls for the current analysis. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Adiponectin was measured using ELISA. Heart failure occurrence was self-reported in annual follow-up questionnaire. Validation of self-reported heart failure in this cohort has been published. The mean age was 58.7 years. In a conditional logistic regression adjusting for age, race, time of blood collection, year of birth, hypertension, atrial fibrillation, smoking, alcohol intake, and exercise, estimates of the relative risk (95% confidence interval) were 1.0 (ref), 0.74 (0.53-1.04), 0.67 (0.48-0.94), 0.70 (0.50-0.99), and 0.92 (0.65-1.30) from the lowest to the highest quintile of adiponectin, respectively, p for quadratic trend 0.004. Additional adjustment for potential mediating factors including diabetes, C-reactive protein, and body mass index led to the attenuation of the estimate of effect [1.0 (ref), 0.81 (0.57-1.15), 0.75 (0.53-1.06), 0.83 (0.58-1.18), and 1.26 (0.87-1.81) across consecutive quintiles of adiponectin]. Our data are consistent with a J-shaped association between total adiponectin and the risk of heart failure among US male physicians.
Adiponectin and Mortality in Patients Undergoing Coronary Angiography
The Journal of Clinical Endocrinology & Metabolism, 2006
Context: The adipokine adiponectin has been suggested to protect from coronary artery disease (CAD). However, studies addressing the association between adiponectin and mortality are sparse. Objective: To elucidate the relationship between adiponectin and mortality. Design, Setting and Participants: Adiponectin was determined in 2473 persons with and 673 persons without angiographic CAD. During a mean follow-up period of 5.45 years, 427 persons with CAD and 55 persons without CAD died. Main Outcome Measure: Hazard ratios for mortality according to adiponectin levels. Results: Adiponectin was positively related to female gender, age, LDL cholesterol, HDL cholesterol, homocysteine, and N-terminal pro-B-type natriuretic peptide. It was inversely related to glomerular filtration rate, body mass index and triglycerides and was low in diabetes mellitus and CAD. An increase of one standard deviation in adiponectin was associated with unadjusted and fully adjusted hazard ratios for death from any cause of 1.31 (95% confidence interval [CI] 1.20-1.42) and 1.22 (95% CI 1.12-1.34), and for death from cardiovascular causes of 1.32 (95% CI 1.19-1.45) and 1.23 (95% CI 1.11-1.37), respectively. In angiographic CAD, stable CAD and unstable CAD, the predictive value of adiponectin was similar to that in the entire cohort, but it did not attain statistical significance in persons without angiographic CAD. Adiponectin was also positively related to the risk of death from noncardiovascular causes. Conclusions: Despite the common view about adiponectin as a protective molecule in cardiovascular disease high adiponectin independently predicts all-cause, cardiovascular and non-cardiovascular mortality in individuals with CAD.