Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes

Abstract

BackgroundCardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney.MethodsWe studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay.ResultsThe cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04–1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23–2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts.ConclusionsPlasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0753-5) contains supplementary material, which is available to authorized users.

Distinguishing Low and High Water Consumers—A Paradigm of Disease Risk

“…Then, when physiologists discovered that both LOW and HIGH exhibited a normal P OSM and body weight (i.e., suggesting euhydration) but that LOW had higher plasma AVP compared to HIGH, they began to ask, "What are the possible mechanisms of long-term negative health effects that result from habitually consuming a small volume of water?". This prompted human epidemiological studies which eventually revealed statistically significant links between elevation of plasma AVP or copeptin (i.e., released in equimolar quantities with AVP) and increased risk of developing diabetes [29][30][31], hyperglycemia [32], insulin resistance, metabolic syndrome [33,34], abdominal obesity [35], stroke, cardiovascular disease, cardiovascular events, cardiovascular death [7,[36][37][38], hypertension [34] and kidney disease [38][39][40]. In some of these studies, the data of thousands of adults were involved in the analysis, providing robust statistical power.…”

Elevated copeptin, arterial stiffness, and elevated albumin excretion in adolescents with type 1 diabetes

“…Furthermore, their participants were younger than ours, and age and pubertal status are well-known factors affecting copeptin concentrations. 21 In adults, several studies have demonstrated that copeptin concentrations are elevated in people with T1D, 10 T2D, 11 and DKD and CVD. 22 A growing body of epidemiological research also indicates that high copeptin concentrations predict future CVD and all-cause mortality in adults with diabetes, yet the data are less consistent in the non-diabetes population.…”

“…In contrast to AVP, copeptin is stable for days, easily measured and mimics fluctuations in AVP concentration . Several studies have demonstrated relationships between increased copeptin and the development or worsening of CVD and DKD in cohorts of adults with diabetes . In addition to water reabsorption in the collecting ducts via vasopressin‐2 (V2) receptor activity, AVP stimulates V1a receptor at arterial smooth muscles and the liver as well as V1b receptor at hypothalamus, resulting in vasoconstriction, hepatic glucose production and cortisol secretion, thereby hastening cardiorenal complications in diabetes .…”

“…A growing body of epidemiological research has demonstrated that arginine vasopressin (AVP) concentrations are increased in adults with T1D and T2D, and may represent a biomarker of cardiorenal risk. [9][10][11] AVP is cosecreted with copeptin, the c-terminal part of AVP precursor, into the blood in an equimolar ratio. 12 In contrast to AVP, copeptin is stable for days, easily measured and mimics fluctuations in AVP concentration.…”

“…12 Several studies have demonstrated relationships between increased copeptin and the development or worsening of CVD and DKD in cohorts of adults with diabetes. 10,11,13 In addition to water reabsorption in the collecting ducts via vasopressin-2 (V2) receptor activity, AVP stimulates V1a receptor at arterial smooth muscles and the liver as well as V1b receptor at hypothalamus, resulting in vasoconstriction, hepatic glucose production and cortisol secretion, thereby hastening cardiorenal complications in diabetes. 13 Increased AVP also stimulates the renin-angiotensin-aldosterone system, attenuates natriuresis and thereby increases renal oxygen consumption in experimental animal and human models.…”