Chronic exposure to high glucose-containing peritoneal dialysis solution and consequent abdominal obesity are potential sources of insulin resistance in patients requiring prevalent peritoneal dialysis. The aim of this study was to elucidate the prognostic values of insulin resistance on new-onset cardiovascular events in nondiabetic patients undergoing prevalent peritoneal dialysis.
A total of 201 nondiabetic patients undergoing prevalent peritoneal dialysis were recruited. Insulin resistance was assessed by homeostatic model assessment of insulin resistance (HOMA-IR). The primary outcome was new-onset cardiovascular events during the follow-up period. Cox proportional hazard analysis was performed to ascertain the independent prognostic value of HOMA-IR for the primary outcome.
The mean age was 53.1 years and male was 49.3% (
Insulin resistance measured by HOMA-IR was an independent risk factor for new-onset cardiovascular events in nondiabetic patients undergoing prevalent peritoneal dialysis.
Cardiovascular disease (CVD) is the most important and leading cause of death in those with end-stage renal disease (ESRD)
In patients with ESRD, many factors including uremia, chronic inflammation, and abnormal adipokines are involved in the development of insulin resistance. Previous studies revealed that insulin resistance was prevalent and was an independent predictor of cardiovascular mortality in nondiabetic patients with ESRD and on hemodialysis (HD)
The study was carried out in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Yonsei University Health System (YUHS) Clinical Trial Center, Seoul, Korea. We obtained informed written consent from all participants involved in the current study.
All consecutive nondiabetic patients with ESRD older than 18 years of age who underwent PD for>3 months at YUHS were initially screened for enrollment between January 2009 and December 2009 in this prospective observational study. Patients were considered eligible if they had no history of malignancy or chronic inflammatory disease such as systemic lupus erythematosus or rheumatoid arthritis, and had no overt infection during the 3 months prior to study entry. We also excluded patients with a history of kidney transplantation, a history of HD for>3 months prior to PD, or a history of CVD within 3 months prior to study entry (
Demographic and clinical data recorded at study entry included: age, sex, PD duration, primary renal disease, smoking status, and medication use. Body mass index (BMI) and biochemical data were measured at study enrollment. Patients were weighed in light clothing, and height was measured with shoes off. BMI was calculated as weight/height (kg/m2). Diabetes mellitus was defined as previously described
In addition, high-sensitivity C-reactive protein (hs-CRP) concentrations were determined by a latex-enhanced immunonephelometric method using a BNII analyzer (Dade Behring, Newark, DE, USA). Kt/V urea was determined from the total loss of urea nitrogen in spent dialysate using PD Adequest 2.0 for Windows software (Baxter Healthcare, Deerfield, IL, USA).
Patients were followed up at 3-month intervals through January 1, 2014. All deaths and hospitalizations were noted in a serious adverse event database. All events were retrieved from the database and carefully reviewed to determine incident CVD. Primary outcomes were major cardiovascular events, which were defined as death or hospitalization from an acute coronary syndrome and stable angina requiring coronary revascularization or coronary artery bypass surgery. Cerebrovascular events were defined as transient ischemic attack, stroke, or carotid endarterectomy and peripheral vascular disease defined as ischemic limb loss and/or ulceration or peripheral revascularization procedure that also included major cardiovascular events. When a patient died within 60 days after transfer to HD, the death was regarded as a mortality event. Loss to follow-up, kidney transplantation, and transfer to HD were censored in the final analysis.
Continuous variables were expressed as mean±standard deviation, or median (interquartile range), whereas categorical variables were expressed as a number (percentage). Normality of distribution was ascertained by the Kolmogorov-Smirnov test. Patients were divided into three groups according to the tertile value of their HOMA-IR. To compare the baseline characteristics, analysis of variance or Kruskal-Wallis test and Chi-square tests were used for continuous variables and categorical variables, respectively. Univariate and multivariate linear regression analyses were performed to determine significant factors associated with HOMA-IR. Comparisons for major cardiovascular events were performed by the Kaplan-Meier analysis and a log-rank test. The independent predictive value of HOMA-IR for primary outcome was confirmed by Cox proportional hazards regression models, which included significant variables in univariate analysis. Statistical analysis was performed with SPSS for Windows version 18.0 (SPSS Inc., Chicago, IL, USA). A
Baseline demographic and laboratory characteristics of patients are detailed in
In univariate analysis, HOMA-IR was positively associated with BMI, previous history of CVD, TG, and serum calcium level, but it was negatively associated with HDL-C (
During a mean follow-up duration of 36.8±16.2 months, the primary outcome was observed in 36 patients (17.9%), and 12 patients (6.0%) died from a new-onset cardiovascular event. The patients with cardiovascular events were significantly older and had a much more prevalent history of previous CVD. The log hs-CRP and HOMA-IR were significantly higher, whereas % lean body mass (%LBM) was significantly lower in patients with new-onset cardiovascular events (
In this observational study, we demonstrated that HOMA-IR was closely correlated with the parameters of metabolic syndrome such as BMI, impaired fasting glucose, and serum TG level. In addition, increased HOMA-IR was significantly associated with new-onset cardiovascular events as well as history of previous CVD. The current study showed that insulin resistance, as assessed by HOMA-IR, might be a risk factor for CVD in nondiabetic patients with prevalent PD.
Insulin resistance is a physiological circumstance in which cells are not able to react with normal responses to the hormonal effects of insulin. In the general population, several factors including obesity, increased TG level, sedentary lifestyle, and high-fat diet can induce insulin resistance
The connection between CVD and insulin resistance is well known, as they have been shown to be closely interrelated
Chronic inflammation and protein-energy wasting play an important role in the development of CVD in patients with ESRD. Inflammation and malnutrition complex are closely associated with atherosclerosis and poor clinical outcomes in dialysis patients
Malnutrition-inflammation complex syndrome is a nontraditional risk factor for CVD in ESRD. Serum albumin and %LMB is a classic marker for malnutrition and is a strong risk factor of mortality in dialysis patients
There are several limitations to this study. First, the study patients were all Korean and undergoing prevalent PD at a single center, and the duration of PD in the study population was relatively diverse. Thus, selection bias is possible and there could be some limitation in the euglycemic clamp for practical reasons. Even though the accuracy of the euglycemic clamp is superior to other methods, its invasiveness may cause it to be difficult to use for a large study population. The HOMA-IR method is easy to use and results from HOMA-IR are usually consistent with results acquired by the euglycemic clamp technique
The authors declare no conflict of interest.
Baseline characteristics of patients according to the homeostatic model assessment of insulin resistance tertiles
Variables | All ( | 1st tertile ( | 2nd tertile ( | 3rd tertile ( | |
---|---|---|---|---|---|
Age (y) | 53.1±8.3 | 52.2±8.8 | 52.3±8.0 | 54.6±7.9 | 0.16 |
Male | 99 (49.3) | 34 (50.8) | 35 (52.2) | 30 (44.8) | 0.67 |
BMI (kg/m2) | 23.4±3.0 | 22.6±2.3 | 23.3±3.0 | 24.4±3.5 | 0.002 |
% Lean body mass | 72.5±10.3 | 73.1±10.7 | 72.6±10.3 | 71.7±9.9 | 0.74 |
PD duration (mo) | 83±54.3 | 96.3±54.5 | 71.2±48.3 | 81.5±57.6 | 0.027 |
Kt/V | 2.0±0.4 | 2.0±0.5 | 2.0±0.4 | 2.0±0.3 | 0.93 |
Icodextrin use | 90 (44.8) | 31 (46.3) | 30 (44.8) | 29 (43.3) | 0.94 |
Previous CVD | 34 (16.9) | 8 (4.0) | 12 (6.0) | 14 (7.0) | 0.37 |
IFG | 32 (15.9) | 4 (6.0) | 9 (13.4) | 19 (28.4) | 0.001 |
New-onset DM | 12 (6.0) | 3 (1.5) | 3 (1.5) | 6 (3.0) | 0.28 |
Smoker | 49 (24.4) | 16 (8.0) | 20 (10.0) | 13 (6.5) | 0.37 |
Hemoglobin (g/dL) | 10.5±1.5 | 10.3±1.6 | 10.8±1.6 | 10.6±1.3 | 0.12 |
BUN (mg/dL) | 60.7±19.0 | 61.6±19.0 | 62.4±19.4 | 58.2±18.5 | 0.39 |
Creatinine (mg/dL) | 11.9±3.4 | 12.4±3.7 | 11.6±3.4 | 11.7±3.2 | 0.35 |
Albumin (g/dL) | 3.6±0.4 | 3.5±0.4 | 3.7±0.4 | 3.7±0.5 | 0.017 |
Total cholesterol (mg/dL) | 182.1±36.1 | 176.8±36.9 | 183.8±37.2 | 185.8±34.1 | 0.32 |
Triglyceride (mg/dL) | 140.6±106.8 | 100.3±52.1 | 137.2±80.1 | 184.2±147.9 | < 0.001 |
HDL-C (mg/dL) | 46.8±13.5 | 47.9±13.0 | 49.0±14.1 | 43.5±12.9 | 0.041 |
LDL-C (mg/dL) | 108.5±31.9 | 103.8±29.2 | 111.5±34.5 | 110.1±31.7 | 0.34 |
Calcium (mg/dL) | 9.0±0.8 | 8.9±0.7 | 9.0±0.7 | 9.1±1.0 | 0.41 |
Phosphate (mg/dL) | 4.8±1.1 | 4.8±1.2 | 4.8±1.2 | 5.0±1.0 | 0.85 |
iPTH (pg/mL) (IQR) | 262.5 (71.5–322.8) | 254 (80.6–343.0) | 281.3 (71.0–212.7) | 252 (41.0–313.0) | 0.91 |
log hs-CRP (mg/L) | 0.2±0.8 | 0.2±0.8 | 0.2±0.7 | 0.3±0.8 | 0.67 |
Fasting glucose (mg/dL) | 91.7±15.3 | 86.8±10.2 | 91.1±9.1 | 97.1±21.6 | < 0.001 |
Fasting insulin (µU/mL) | 11.1±8.5 | 4.4±1.2 | 9.2±2.0 | 19.7±9.4 | < 0.001 |
HOMA-IR | 2.6±2.1 | 0.9±0.3 | 2.1±0.4 | 4.7±2.2 | < 0.001 |
Medication | |||||
ACEi or ARB | 178 (88.6) | 62 (92.5) | 58 (86.6) | 58 (86.6) | 0.46 |
Ca-based P-binder | 163 (81.1) | 56 (83.6) | 53 (79.1) | 53 (79.1) | 0.42 |
Non Ca-based P-binder | 40 (19.9) | 13 (19.4) | 12 (17.9) | 15 (22.4) | 0.34 |
Statin | 25 (12.4) | 7 (10.5) | 7 (10.5) | 11 (16.4) | 0.48 |
Data are presented as
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BUN, blood urea nitrogen; Ca, calcium; CVD, cardiovascular disease; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hs-CRP, high-sensitivity c-reactive protein; IFG, impaired fasting glucose; iPTH, intact parathyroid hormone; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; P, phosphorus; PD, peritoneal dialysis; SD, standard deviation.
Cerebrovascular disease, coronary artery disease, peripheral artery disease.
Univariate linear regression analysis for the association of homeostasis model assessment-insulin resistance with clinical and biochemical variables (
Variables | β | |
---|---|---|
Age | 0.133 | 0.06 |
Female | 0.041 | 0.57 |
Body mass index | 0.222 | 0.002 |
% Lean body mass | −0.068 | 0.34 |
Peritoneal dialysis duration | 0.029 | 0.68 |
Kt/V | −0.079 | 0.27 |
Previous cardiovascular disease | 0.151 | 0.032 |
Smoker | −0.059 | 0.41 |
Hemoglobin | 0.034 | 0.63 |
BUN | −0.96 | 0.18 |
Creatinine | −0.009 | 0.90 |
Albumin | 0.138 | 0.051 |
Total cholesterol | 0.051 | 0.47 |
Triglyceride | 0.421 | < 0.001 |
HDL-C | −0.16 | 0.023 |
LDL-C | −0.002 | 0.98 |
Calcium | 0.179 | 0.011 |
Phosphate | −0.037 | 0.6 |
Intact parathyroid hormone | −0.07 | 0.32 |
log hs-CRP | 0.058 | 0.41 |
BUN, blood urea nitrogen; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol.
Multivariate linear regression analysis for the association of homeostasis model assessment-insulin resistance with clinical and biochemical variables (
Variables | β | |
---|---|---|
Age | 0.055 | 0.41 |
Female | −0.037 | 0.58 |
Body mass index | 0.169 | 0.011 |
Previous cardiovascular disease | 0.137 | 0.029 |
Triglyceride | 0.331 | < 0.001 |
HDL-C | 0.017 | 0.81 |
Calcium | 0.121 | 0.07 |
HDL-C, high-density lipoprotein cholesterol.
Clinical characteristics of subjects according to new-onset cardiovascular event
Variables | New-onset CV event | Without CV event | |
---|---|---|---|
( | ( | ||
Age (y) | 57.9±7.5 | 52.0±8.1 | < 0.001 |
Male | 16 (44.4) | 83 (50.3) | 0.52 |
Body mass index (kg/m2) | 24±3.4 | 23.3±3.0 | 0.29 |
% Lean body mass | 67.8±10.1 | 73.5±10.1 | 0.003 |
Peritoneal dialysis duration (mo) | 87.7±52.1 | 81.9±54.9 | 0.56 |
Kt/V | 2.0±0.3 | 2.0±0.4 | 0.83 |
Previous CVD | 11 (30.6) | 23 (13.9) | 0.016 |
New-onset DM | 2 (1.0) | 10 (5.0) | 0.63 |
Smoker | 6 (16.7) | 43 (26.1) | 0.23 |
Hemoglobin (g/dL) | 10.4±1.5 | 10.6±1.5 | 0.42 |
BUN (mg/dL) | 56.4±17.0 | 61.7±19.3 | 0.13 |
Creatinine (mg/dL) | 11.3±3.3 | 12.0±3.4 | 0.27 |
Albumin (g/dL) | 3.5±0.4 | 3.6±0.5 | 0.31 |
Total cholesterol (mg/dL) | 181.0±36.1 | 182.4±36.2 | 0.84 |
Triglyceride (mg/dL) | 136.4±78.7 | 141.5±112.2 | 0.8 |
HDL-C (mg/dL) | 44.4±12.5 | 47.3±13.6 | 0.25 |
LDL-C (mg/dL) | 113.6±28.5 | 107.3±32.6 | 0.29 |
Calcium (mg/dL) | 9.0±1.0 | 9.0±0.8 | 0.91 |
Phosphate (mg/dL) | 4.7±1.2 | 4.9±1.1 | 0.31 |
iPTH (pg/mL) | 173.9 (71.5–32.9) | 153.5 (53.4–454.1) | 0.57 |
log hs-CRP (mg/L) | 0.6±1.0 | 0.1±0.7 | 0.012 |
HOMA-IR | 3.3±2.4 | 2.4±1.9 | 0.044 |
Data are presented as
BUN, blood urea nitrogen; CVD, cardiovascular disease; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hs-CRP, high-sensitivity c-reactive protein; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation.
Cerebrovascular disease, coronary artery disease, peripheral artery disease.
Univariate Cox regression analysis for the association of new-onset cardiovascular events with clinical and biochemical variables (
Variables | Hazard ratio (95% CI) | |
---|---|---|
Age (per 1 y) | 1.107 (1.059–1.158) | < 0.001 |
Female | 0.963 (0.497–1.867) | 0.91 |
Body mass index (per 1 kg/m2) | 1.094 (0.981–1.221) | 0.11 |
% Lean body mass (per 1%) | 0.953 (0.920–0.987) | 0.008 |
Peritoneal dialysis duration (per 1 mo) | 1.003 (0.997–1.009) | 0.32 |
Kt/V (per 1) | 0.867 (0.332–2.261) | 0.77 |
Previous CVD | 2.118 (1.042–4.308) | 0.038 |
Smoker | 0.656 (0.272–1.580) | 0.35 |
Hemoglobin (per 1 g/dL) | 0.875 (0.695–1.102) | 0.26 |
BUN (per 1 mg/dL) | 0.989 (0.969–1.009) | 0.27 |
Creatinine (per 1 mg/dL) | 0.964 (0.865–1.075) | 0.51 |
Albumin (per 1 g/dL) | 0.603 (0.275–1.326) | 0.21 |
Total cholesterol (per 1 mg/dL) | 0.998 (0.989–1.007) | 0.65 |
Triglyceride (per 1 mg/dL) | 0.999 (0.996–1.003) | 0.66 |
HDL-C (per 1 mg/dL) | 0.979 (0.953–1.006) | 0.13 |
LDL-C (per 1 mg/dL) | 1.002 (0.993–1.012) | 0.62 |
Calcium (per 1 mg/dL) | 1.005 (0.667–1.514) | 0.98 |
Phosphate (per 1 mg/dL) | 0.885 (0.675–1.161) | 0.38 |
iPTH (per 1 pg/mL) | 1.000 (0.999–1.001) | 0.54 |
log hs-CRP (per 1 mg/L) | 1.850 (1.320–2.593) | < 0.001 |
HOMA-IR (per 1) | 1.180 (1.045–1.332) | 0.008 |
BUN, blood urea nitrogen; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hs-CRP, high-sensitivity c-reactive protein; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol.
Multivariate Cox regression analysis for the association of new-onset cardiovascular events with clinical and biochemical variables (
Variables | Hazard ratio (95% CI) | |
---|---|---|
Age (per 1 y) | 1.092 (1.035–1.152) | 0.001 |
Female | 0.685 (0.310–1.511) | 0.35 |
% Lean body mass (per 1%) | 0.978 (0.931–1.027) | 0.37 |
Previous CVD | 1.534 (0.690–3.410) | 0.29 |
log hs-CRP (per 1 mg/L) | 2.286 (0.907–2.127) | 0.13 |
HOMA-IR (per 1) | 1.180 (1.034–1.348) | 0.014 |
CI, confidence interval; CVD, cardiovascular disease; HOMA-IR, homeostasis model assessment-insulin resistance; hs-CRP, high-sensitivity c-reactive protein.
Cerebrovascular disease, coronary artery disease, peripheral artery disease.