- Email: [email protected]
atorvastatin
Journal Pre-proof Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/ atorvastatin
Hanaa S. Sallam, Demidmaa R. Tuvdendorj, Ishwarlal Jialal, Manisha Chandalia, Nicola Abate PII:
S1056-8727(19)31154-7
DOI:
https://doi.org/10.1016/j.jdiacomp.2019.107480
Reference:
JDC 107480
To appear in:
Journal of Diabetes and Its Complications
Received date:
16 October 2019
Revised date:
6 November 2019
Accepted date:
6 November 2019
Please cite this article as: H.S. Sallam, D.R. Tuvdendorj, I. Jialal, et al., Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/atorvastatin, Journal of Diabetes and Its Complications(2019), https://doi.org/10.1016/j.jdiacomp.2019.107480
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
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Sallam et al.
THERAPEUTIC LIFESTYLE CHANGE INTERVENTION IMPROVED METABOLIC SYNDROME CRITERIA AND IS COMPLEMENTARY TO AMLODIPINE/ATORVASTATIN
Hanaa S. Sallam, MD, PhD1,4; Demidmaa R. Tuvdendorj, MD, PhD1; Ishwarlal Jialal, MD, PhD3;
Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX; 2Bay
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1
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Manisha Chandalia, MD2; Nicola Abate, MD1,2
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Area Metabolic Health; and 3California North-State University College of Medicine; Elk Grove, CA
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USA; 4Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
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Nicola Abate, MD
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Corresponding author:
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Running title: TLC in MetS
Department of Internal Medicine Division of Endocrinology
University of Texas Medical Branch Galveston, TX, USA 77555-1060 Phone: 409 772 6314 Fax: 409 772 8709 Email: [email protected]
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ABSTRACT Aims: To examine whether addition of amlodipine (5mg)/atorvastatin (10mg) “A/A” to Therapeutic Lifestyle change intervention (TLC) would beneficially modulate Metabolic Syndrome (MetS) and oxidized low-density lipoprotein cholesterol (Ox-LDL) levels. Methods: Patients with MetS (n=53) were randomized to TLC+placebo or TLC+A/A for 12 months. Anthropometric measurements, blood pressure (BP), lipid profile, plasma Ox-LDL, and
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area under the curve of free fatty acid (AUCFFA) during oral glucose tolerance test, a marker of
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adipose tissue health, were assessed before and after the intervention.
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Results: Twenty-six patients completed the study with an overall improvement of MetS (p=0.02).
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TLC+placebo was beneficial in reversing MetS comparable to TLC+A/A (54% vs. 39%; p=0.08).
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Both treatments decreased systolic BP (p≤0.01). TLC+A/A also decreased diastolic BP and triglyceride levels. The changes in Ox-LDL levels directly correlated with changes in weight in the
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TLC-placebo group (r=0.64; p=0.04). AUCFFA determined the loss of fat mass (r = 0.472, p=0.03).
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Conclusions: 1) Addition of A/A has the advantage of improving the lipid profile and BP; but TLC alone was comparable to TLC+A/A in improving MetS; 2) weight change determines the TLC-
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associated change in Ox-LDL levels; and 3) AT metabolic health is a significant predictor of TLCassociated loss of body fat mass. Keywords: Amlodipine/Atorvastatin, Therapeutic Lifestyle, Ox-LDL, Oxidative Stress, Metabolic Syndrome
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1. INTRODUCTION Metabolic syndrome (MetS)1 is associated with an increased risk for atherosclerotic cardiovascular disease (CVD) due to a clustering of metabolic abnormalities2. The main contributors to CVD in MetS are hypertension and the changes in lipoprotein metabolism characterized by reduced high density lipoprotein cholesterol (HDL-C) and increased triglycerides (TG). Weight loss and therapeutic lifestyle change interventions (TLC) are advocated as first-line
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management in patients with MetS3. Although there is no doubt that diet/exercise and weight loss
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improve MetS criteria4,5, published evidence often utilizes labor-intensive protocols that are
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impractical in a clinical setting. Moreover, the effectiveness of TLC in reducing CVD risk in
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patients with MetS is unclear6. In clinical settings, pharmacological interventions are implemented with anti-hypertensive and hypocholesterolemia agents following recommendations for the
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management of hypertension and hyperlipidemia1,7. Therefore, the primary aim of this study was to
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evaluate whether a real-world clinic-based TLC would result in amelioration of MetS, and compare its effectiveness with that of a combined pharmacological intervention to reduce blood pressure
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(BP) and lipid levels with a single-pill amlodipine (5mg) /atorvastatin (10 mg) (A/A). Since MetS is
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also associated with elevation of both circulating and cellular markers of oxidative stress (OS), which may independently contribute to CVD risk8,9, our second aim was to explore the effect of TLC with or without A/A on OS markers in this patient population. As markers of OS, we measured the plasma levels of oxidized low-density lipoprotein (Ox-LDL). One critical target of TLC is weight loss; however, TLC may induce opposing effects on body fat and lean masses which not necessarily result in weight loss6,10. It would be essential to measure the change in fat mass to accurately evaluate the effect of TLC. The responsiveness of individuals to weight loss interventions may be determined by the degree of adipose tissue (AT)
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responsiveness to lipolytic agents11,12. Although several studies have evaluated the predictors of successful weight loss13,14, none have assessed if AT health determines the effect of TLC on changes of body weight and/or fat mass. We have previously shown that AT lipid kinetics, a marker of AT health, correlates with the area under the curve of free fatty acids (AUC FFA) during oral glucose tolerance test (OGTT)-induced hyperinsulinemia (30-120 min of OGTT)15. Thus, our third
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aim was to determine whether the AUCFFA30-120 can predict the loss in body weight or fat mass. 2. MATERIALS AND METHODS
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2.1. Patients
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Fifty-three volunteers diagnosed with MetS were recruited by public advertisement at the
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outpatient clinics of UT Southwestern Medical Center. Under a randomized placebo-controlled
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study design, patients received either TLC+placebo (n=26) or TLC+A/A (n=27) for one year. Patients were included if they were: 1) men or women aged 40-65 years; 2) diagnosed with MetS
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per NCEP-ATP III revised criteria. A patient is considered with MetS if he/she meets 3 out of the 5
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criteria. While individually, each patient met the criteria for diagnosis, not all patients fulfilled all 5
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criteria. 3) have BP ≥130/85; and 4) pre-menopausal women on a birth control pill. Exclusion criteria were 1) inability to sign a consent form; 2) unwillingness to be available for follow up for up to 12 months; 3) under treatment with anticoagulants or hypercholesterolemia agents; 4) fasting plasma glucose levels >126 mg/dL or currently treated for diabetes; 5) creatinine clearance <50 mL/min; 6) liver function (AST/ALT) three times the upper limit of reference values; 7) pregnant/lactating women; 8) evidence of cholelithiasis, cancer or substance abuse; 9) a cardiovascular event in the last 6 months; and 10) the subject’s physician believes the patient should be started on an antihypertensive regimen (placebo arm is not justified). The research protocol was approved by UT Southwestern Institutional Review Board, and written informed consent was
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obtained from all subjects before study entry. The current study is registered in clinicaltrials.gov (Identifier: NCT03504735). On their first visit, patients were instructed about healthy diet, and exercise. They were also provided with a free access to an exercise facility. Diet and exercise progress were discussed during monthly visits. Additional follow ups were available throughout the study in person, via phone or email. The following measurements were obtained during the first visit (baseline) and after
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2.2. Assessments
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MetS included absence of at least 3 of the 5 MetS criteria.
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completion of the one-year intervention. Pre-specified primary outcome measures for resolution of
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2.2.1. Anthropometric and BP Measurements:
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Weight, height and waist circumference were assessed and body mass index (BMI) was calculated. BP was assessed as previously described16. Briefly, three BP measurements
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were taken and averaged using standard outpatient clinic equipment with an oversized
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cuff while the patient was in the sitting position. 2.2.2. Body Composition:
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Body composition was assessed using underwater weighing as previously described17. Briefly, subjects sat in a tub of lukewarm water and were asked to breathe out air and go completely under water for 5-10 seconds to determine the volume displacement. Siri’s equation18 was used to estimate the percentage of body total fat mass. 2.2.3. Blood Chemistry: The Piccolo Lipid Panel Plus Reagent Disc was used to assess fasting plasma TG, HDL-C, total cholesterol (TC), low density lipoprotein (LDL) and glucose according to
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manufacturer instructions. Ox-LDL was assessed in plasma using ELISA (Mercodia, Winston-Salem, NC), as previously described8. 2.2.4. OGTT: Following an overnight fast, blood samples were collected before and after the ingestion of a 75 g glucose drink at 15-30 minute intervals up to 3 hours, as previously described19. The concentrations of plasma insulin and free fatty acids (FFAs) were
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measured using commercially available kits (Human Insulin kit from Mercodia Inc.,
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Salem, NC and Zenbio Inc., Research Park Triangle, NC, respectively). The
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AUCFFA30-120 was calculated using the trapezoid formula as a marker of AT health.
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2.3. Statistical Analysis
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Data were analyzed using IBM SPSS Statistics for Windows, Version 20.0 (Released 2011; IBM Corp. Armonk, NY) and GraphPad Prism version 5.00 for Windows (GraphPad Software, La
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Jolla, CA). Data are presented as median (interquartile range). A two-way repeated-measures analysis of variance with the factors time and intervention with post hoc Bonferroni correction was
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used to assess differences between study arms in having MetS. Non-parametric t-test with
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Wilcoxon matched-pairs signed rank was used to assess the change between study arms in general characteristics and clinical chemistry parameters over a 1-year intervention. Relationship analyses were performed using a linear regression model. The nonparametric data was log transformed for skewed distribution prior to use in the analysis. A p value less than 0.05 was considered statistically significantly. 3. RESULTS 3.1. Effect of interventions on MetS criteria
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Fifty percent of the enrolled subjects (n=26) completed the study; that is 13 patients per group. Patients in the TLC+placebo group were 5 males and 8 females with a mean age of 50 years (range 41-61); while those in the TLC+A/A group were 7 males and 6 females with a mean age of 53 years (range (41-61). The general characteristics of subjects who completed the study are presented in Table A.1. At the beginning of the study, 16 patients had 3 criteria, 6 patients had 4 criteria and 4 patients had 5 criteria of the Mets. There were no differences in age and gender
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distribution between the treatment arms. Reasons for drop out included: job change, relocation, lack
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of time for follow-up (stress, death in the family), inability to be reached, or dissatisfaction with
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weight loss expectations.
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At the end of the study, 3 patients had 3 criteria, 7 patients had 4 criteria and 2 patients had
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5 criteria of the MetS. The number of diagnostic criteria for MetS in all subjects was significantly reduced from 3 (range 3-5) to 2 (range 0-5; p = 0.001). In fact, 54% of those in the TLC+A/A group
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and 46% in the TLC+placebo group no longer had MetS (p = 0.04 each; Figure A.1.). However, there were no significant differences between the two groups (p = 0.3). The median change in body
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weight in all subjects was –1.97 kg (range: -6.4 to +3.6) yet it was not significantly different
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between groups (p = 0.821).
3.2. The additive effect of A/A and TLC on metabolic parameters and OS markers Table A.1. shows the changes in Mets parameters in response to treatment. Both interventions decreased systolic BP (SBP; p = 0.01 vs. baseline), yet only TLC+A/A significantly decreased the diastolic BP (DBP) (p = 0.02 vs. baseline). TLC+A/A decreased TC, non-HDL and LDL (p = 0.004). TLC+placebo also decreased TC and LDL, although less prominently (p = 0.04). Both interventions marginally decreased waist circumference (p 0.07 each). Only TLC+A/A
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marginally decreased TG. Only TLC+placebo significantly decreased HDL-C (p = 0.01 vs. baseline). Both interventions had no statistically different effect on fasting blood glucose. Only TLC+placebo increased plasma Ox-LDL and the Ox-LDL/LDL ratio compared to baseline (p=0.02 and 0.04 for Ox-LDL and Ox-LDL/LDL; respectively- Table A.1.). However, when the subjects in the TLC+placebo group were stratified for weight loss (cutoff level = –1.5 Kg), we found that those who lost more weight had significantly decreased levels of Ox-LDL (p =
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0.04; Figure A.2.a). Changes in Ox-LDL positively correlated to changes in body weight (r = 0.64;
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p = 0.04; Figure A.2.b).
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3.3. AT health and the effect of interventions on body weight and fat mass
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Because the addition of A/A to TLC showed no effect on changes in body weight or % fat
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mass when compared to TLC+placebo, the linear regression analyses to determine the effect of AT health (i.e., AUCFFA30-120) on changes in body weight and % fat mass were conducted in a
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combined group of all subjects regardless of their treatment. Linear regression analyses
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demonstrated that AUCFFA30-120 during the OGTT predicted 22% (r = 0.472, p = 0.036) of the
weight (p = 0.5).
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variability in the delta change of % body fat mass (Figure A.3.) but not the delta change in body
4. DISCUSSION
This study showed that in patients with MetS 1) A/A in addition to TLC improves the lipid profile and BP, two criteria of MetS; however, TLC alone reduced the metabolic parameters defining MetS comparable to TLC+A/A; 2) weight loss is the key to obtain TLC-associated reduction in Ox-LDL levels, while A/A prevents the increase in Ox-LDL that was observed in individuals who did not lose, or even gained, weight; and 3) AT metabolic health, expressed as
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AUCFFA30-120 during OGTT-induced hyperinsulinemia, is a significant predictor of loss of body fat mass, but not body weight. MetS has become increasingly prevalent in the US population, affecting almost 25% of adults20. Patients with MetS are at a higher risk of developing various comorbidities, including CVD complications, and resulting in 1.5-fold higher rates of all-cause mortality21. The benefit of
favorably to TLC
13,14,24,25
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TLC in preventing CVDs has been well documented22-24. However, not all subjects respond . Villareal et al. demonstrated that only 59% of participants showed an
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improvement in metabolic health24. According to our expectations, adding A/A improved both the
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lipid profile and BP (both systolic and diastolic). Yet, TLC+placebo also beneficially affected some
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metabolic parameters, in accord with previously reported data26,27. As a result, both interventions
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comparably reduced the number of patients with MetS. Our data support the previous reports that weight loss per se improves MetS criteria; however, it needs to be emphasized that only continued
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exercise maintains this improvement, even with weight regain28.
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We observed an overall improvement of MetS criteria in the TLC group compared to the
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AA group. SBP was significantly reduced in both arms. Though we expected greater reduction in SBP in the AA group, SBP was comparably reduced in TLC. DBP was only reduced in the AA group, which is reasonable, as amlodipine has been reported to exert greater reduction in DBP during exercise compared to placebo29. HDL-C showed significant reduction only in the TLC group. This observed reduction in HDL-C was after 1 year of intervention, suggesting that it was not due to a rapid weight loss. Other Mets parameters showed insignificant or no change in response to either interventions.
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Oxidation of LDL infiltrating the arterial wall is known to promote leukocyte phagocytic action, and differentiation of macrophages and foam cells, resulting in atheroma plaque formation. Excessive reactive OS species initiate immune cell infiltration, further worsening endothelial dysfunction30. Since MetS is considered a chronic inflammatory state that is linked to OS, the reduction of the oxidation of the LDL molecule is a predictor of the reduction of atherogenic risk among these patients. Oh et al. reported that a 6-month TLC decreased the levels of chemokines
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related to stress and inflammation in patients with MetS31. A small-scale pilot study confirmed the
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salutary effect of a 24-week TLC (supervised aerobic exercise/Mediterranean diet), reducing
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protein-bound oxidized phenylalanine and tyrosine moieties OS markers32. Atorvastatin, a component of the A/A pill, is an anti-lipidemic agent shown to reduce not only metabolic
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parameters but OS markers in patients with diabetes33,34. We have previously shown that A/A
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treatment for 12 weeks dose-dependently decreased Ox-LDL9. However, no long-term studies on
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the effect of A/A on Ox-LDL in combination with TLC have yet been reported. Interestingly, in our study the Ox-LDL levels were increased in the TLC+placebo group. However, this change in Ox-
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LDL levels depended on the change in body weight as the Ox-LDL levels were significantly
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decreased in individuals who had lost more than 1.5 kg of their body weight. Our data suggest that weight loss is essential to achieve TLC-associated reduction in Ox-LDL. TLC may not always decrease body weight6. Proposed predictors of successful weight loss include age, behavior and psychological motivation. We hypothesized that AT metabolic health is another predictor of successful weight loss. It is now well accepted that the impaired AT health associates with reduced blood flow in AT, resulting in AT unresponsiveness to lipolytic agents12,35. This condition may explain why metabolically unhealthy people may be less responsive to weight loss interventions11,12. We have previously shown a direct correlation between AT lipid kinetics, the
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marker of AT metabolic health, and AUCFFA30-120 during OGTT-induced hyperinsulinemia15. Moreover, we reported an inverse correlation between that AUCFFA30-120 and the subcutaneous AT ability to accumulate excess calories, a marker of AT health. In the current study, we report that AUCFFA30-120 during OGTT was a significant predictor of loss of body fat mass but not body weight. Our current data suggest that AT metabolic health may beneficially affect the outcome of TLC, i.e., body fat loss. It is possible that TLC decreased fat mass yet increased lean body mass,
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thus resulting in unchanged body weight10. Further studies are warranted to explore the effects of
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modulation of AT metabolic health to enhance the effect of TLC on body fat mass and weight loss,
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subsequently on metabolic health.
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The drawback of this study is the small sample size, and many dropouts (50% at the end of
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1-year intervention). However, this dropout rate is comparable to that of other studies reporting a 54% drop out for a 1-year period36. One of the reasons for dropping out of the study was the
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subjects’ disappointment that they did not lose more weight. This is understandable, as they had heavy baseline weights which made them more susceptible to having unrealistic expectations for
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weight loss37. Yet the strengths of this study lie in the utilization of state-of-the-art investigations
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(i.e. underwater weighing for precise body fat calculation; AUCFFA30-120 during OGTT for evaluation of AT metabolism). We also utilized interventions (i.e. TLC) with minimal resources in a clinical setting; this is similar to real-life scenario which makes the study and results easily reproducible. 5. CONCLUSIONS Our study demonstrated that although both TLC alone or in combination with A/A may be beneficial in improving the metabolic health of patients with MetS, addition of A/A may prevent weight-gain-associated increase in Ox-LDL; and weight loss is the key to observe TLC-associated
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decrease in Ox-LDL. Regardless of intervention, AT health is a significant predictor of successful loss of fat mass; therefore, selection of patients who would favorably respond to TLC and improve their metabolic health may be determined based on their estimated AT health. 6. ACKNOWLEDGEMENTS The authors would like to express their gratitude to the study participants for their
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dedication and time; and to Dr. Peter Snell help with underwater weighing; and Dr. Magdalene
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Szuszkiewicz-Garcia and Dr. Thanalakshmi Seenivasan, PhD for their assistance in patient
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recruitment.
This study was funded by Pfizer Inc., and conducted with the support of the Institute for
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Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical
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and Translational Science Award (UL1 TR001439) and Mentored Career Development (KL2)
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Award (KL2TR001441) from the National Center for Advancing Translational Sciences, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily
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represent the official views of the National Institutes of Health.
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7. Declaration of Interest
All authors have no competing interests to declare. 8. REFERENCES 1.
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Res Clin Pract. 2014;106(3):511-521.
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maintenance among overweight and obese adults--a two-year retrospective study. Diabetes
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9. Appendices Table A.1. Baseline General Characteristics and Clinical Chemistry Parameters for Subjects who completed the Study. TLC + Placebo (n=13)
TLC + AA (n=13) Paired t-test p value
Nonparametric t-test p value for deltas
0.1
105(83-123)
102(84-116)
0.2
0.6
33(31-37)
0.1
36(31-39)
35(30-38)
0.3
0.5
42(33-44)
41(32-44)
0.9
41(36-48)
40(34-45)
0.07
0.1
Hip (cm)
130(113-135)
117(109-119)
0.3
131(124-135)
120(112-125)
0.3
0.5
Waist (cm)
109(97-116)
108(94-114)
0.08
122(105-127)
112(103-126)
0.07
1
0.89(0.78-0.99)
0.95(0.86-1.06)
0.5
0.92(0.75-1.07)
0.9
0.7
FBG (mg/dl)
94(93-101)
104(100-115)
0.07
102(98-108)
102(91-107)
0.5
0.01
SBP (mm Hg)
140(135-145)
127(124-135)
0.01
143(135-151)
131(124-140)
0.002
0.8
DBP (mm Hg)
85(81-87)
85(80-88)
0.3
87(80-93)
84(72-86)
0.02
0.2
TC (mg/dL)
233(194-257)
204(172-220)
0.04
213(183-248)
158(139-185)
0.002
0.2
TG (mg/dL)
140(122-188)
160(136-213)
0.1
145(119-173)
90(68-136)
0.07
0.08
47(37-56)
39(34-45)
0.01
51(37-56)
42(38-56)
0.5
0.7
165(140-187)
0.09
162(133-182)
120(88-140)
0.002
0.1
127(82-143)
0.03
134(108-144)
100(75-113)
0.004
0.3
175(140-189)
0.02
125(90-144)
114(98-152)
0.9
0.4
1.3(1.1-1.8)
0.04
1.1(0.6-1.3)
1.3(0.9-1.3)
0.3
0.4
Weight (Kg)
90(80-106)
97(77-106)
BMI
35(31-37)
Body Fat (%)
HDL-c (mg/dL)
186(159-192)
LDL (mg/dL)
148(117-177)
OxLDL (u/mL)
135(97-162)
OxLDL/LDL
0.9(0.7-1.2)
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Non-HDL (mg/dL)
0.98(0.72-1.03)
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Waist/hip ratio
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Variables
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Baseline (BsL)
Paired t-test p value
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Baseline (BsL)
PostIntervention (1 year)
PostIntervention (1 year)
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Data are presented as median (interquartile range). Comparisons between lifestyle modifications
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(TLC) and Amlodipine/Atorvastatin (A/A) or Placebo groups were performed by paired t-test for each intervention arm. Non-parametric t-test with Wilcoxon matched-pairs signed rank was used to assess the delta change over 1-year intervention between study arms. p<0.05 was considered statistically significant. BMI, body mass index; DBP, diastolic blood pressure; FBG, fasting blood glucose; HDL-C, high density lipoprotein-cholesterol; LDL-C, low-density lipoprotein cholesterol; Ox-LDL, oxidized LDL; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.
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10. FIGURE LEGENDS Figure A.1.: Effect of Interventions on Metabolic Syndrome (MetS). All patients had the metabolic syndrome at baseline. TLC+placebo was nearly as effective as TLC+A/A in improving patients with MetS (p=0.01 and p=0.04 for TLC+A/A and TLC+placebo; respectively). Figure A.2.: Effect of Weight Loss on Plasma Oxidized Low Density Lipoprotein (Ox-LDL)
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Levels. a. Change in Ox-LDL within groups shows that only in the TLC+placebo group, patients who lost weight had significantly decreased Ox-LDL (p = 0.04 for weight loss vs. no weight loss).
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Weight loss cutoff level = –1.5 Kg (dotted vertical line). b. Change in Ox-LDL significantly
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correlated with weight change in the TLC + Placebo Group only (r = 0.64; p = 0.04).
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Figure A.3.: Linear Regression Analyses. Adipose tissue health, expressed as AUCFFA30-120
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during oral glucose tolerance test, was significantly and directly correlated with change in body fat
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prior to use in the analysis.
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mass loss (r = 0.485, p = 0.036). The AUCFFA30-120 was log transformed for skewed distribution
Highlights
Can Amlodipine/atorvastatin + Therapeutic Lifestyle change improve Metabolic Syndrome?
This is a placebo-controlled study including 2 arms of intervention for 12 months.
Both interventions comparably reversed the Metabolic Syndrome.
Figure 1
Figure 2
Figure 3
Hanaa S. Sallam, Demidmaa R. Tuvdendorj, Ishwarlal Jialal, Manisha Chandalia, Nicola Abate PII:
S1056-8727(19)31154-7
DOI:
https://doi.org/10.1016/j.jdiacomp.2019.107480
Reference:
JDC 107480
To appear in:
Journal of Diabetes and Its Complications
Received date:
16 October 2019
Revised date:
6 November 2019
Accepted date:
6 November 2019
Please cite this article as: H.S. Sallam, D.R. Tuvdendorj, I. Jialal, et al., Therapeutic lifestyle change intervention improved metabolic syndrome criteria and is complementary to amlodipine/atorvastatin, Journal of Diabetes and Its Complications(2019), https://doi.org/10.1016/j.jdiacomp.2019.107480
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
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THERAPEUTIC LIFESTYLE CHANGE INTERVENTION IMPROVED METABOLIC SYNDROME CRITERIA AND IS COMPLEMENTARY TO AMLODIPINE/ATORVASTATIN
Hanaa S. Sallam, MD, PhD1,4; Demidmaa R. Tuvdendorj, MD, PhD1; Ishwarlal Jialal, MD, PhD3;
Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX; 2Bay
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1
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Manisha Chandalia, MD2; Nicola Abate, MD1,2
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Area Metabolic Health; and 3California North-State University College of Medicine; Elk Grove, CA
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USA; 4Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
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Nicola Abate, MD
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Corresponding author:
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Running title: TLC in MetS
Department of Internal Medicine Division of Endocrinology
University of Texas Medical Branch Galveston, TX, USA 77555-1060 Phone: 409 772 6314 Fax: 409 772 8709 Email: [email protected]
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ABSTRACT Aims: To examine whether addition of amlodipine (5mg)/atorvastatin (10mg) “A/A” to Therapeutic Lifestyle change intervention (TLC) would beneficially modulate Metabolic Syndrome (MetS) and oxidized low-density lipoprotein cholesterol (Ox-LDL) levels. Methods: Patients with MetS (n=53) were randomized to TLC+placebo or TLC+A/A for 12 months. Anthropometric measurements, blood pressure (BP), lipid profile, plasma Ox-LDL, and
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area under the curve of free fatty acid (AUCFFA) during oral glucose tolerance test, a marker of
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adipose tissue health, were assessed before and after the intervention.
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Results: Twenty-six patients completed the study with an overall improvement of MetS (p=0.02).
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TLC+placebo was beneficial in reversing MetS comparable to TLC+A/A (54% vs. 39%; p=0.08).
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Both treatments decreased systolic BP (p≤0.01). TLC+A/A also decreased diastolic BP and triglyceride levels. The changes in Ox-LDL levels directly correlated with changes in weight in the
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TLC-placebo group (r=0.64; p=0.04). AUCFFA determined the loss of fat mass (r = 0.472, p=0.03).
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Conclusions: 1) Addition of A/A has the advantage of improving the lipid profile and BP; but TLC alone was comparable to TLC+A/A in improving MetS; 2) weight change determines the TLC-
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associated change in Ox-LDL levels; and 3) AT metabolic health is a significant predictor of TLCassociated loss of body fat mass. Keywords: Amlodipine/Atorvastatin, Therapeutic Lifestyle, Ox-LDL, Oxidative Stress, Metabolic Syndrome
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1. INTRODUCTION Metabolic syndrome (MetS)1 is associated with an increased risk for atherosclerotic cardiovascular disease (CVD) due to a clustering of metabolic abnormalities2. The main contributors to CVD in MetS are hypertension and the changes in lipoprotein metabolism characterized by reduced high density lipoprotein cholesterol (HDL-C) and increased triglycerides (TG). Weight loss and therapeutic lifestyle change interventions (TLC) are advocated as first-line
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management in patients with MetS3. Although there is no doubt that diet/exercise and weight loss
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improve MetS criteria4,5, published evidence often utilizes labor-intensive protocols that are
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impractical in a clinical setting. Moreover, the effectiveness of TLC in reducing CVD risk in
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patients with MetS is unclear6. In clinical settings, pharmacological interventions are implemented with anti-hypertensive and hypocholesterolemia agents following recommendations for the
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management of hypertension and hyperlipidemia1,7. Therefore, the primary aim of this study was to
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evaluate whether a real-world clinic-based TLC would result in amelioration of MetS, and compare its effectiveness with that of a combined pharmacological intervention to reduce blood pressure
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(BP) and lipid levels with a single-pill amlodipine (5mg) /atorvastatin (10 mg) (A/A). Since MetS is
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also associated with elevation of both circulating and cellular markers of oxidative stress (OS), which may independently contribute to CVD risk8,9, our second aim was to explore the effect of TLC with or without A/A on OS markers in this patient population. As markers of OS, we measured the plasma levels of oxidized low-density lipoprotein (Ox-LDL). One critical target of TLC is weight loss; however, TLC may induce opposing effects on body fat and lean masses which not necessarily result in weight loss6,10. It would be essential to measure the change in fat mass to accurately evaluate the effect of TLC. The responsiveness of individuals to weight loss interventions may be determined by the degree of adipose tissue (AT)
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responsiveness to lipolytic agents11,12. Although several studies have evaluated the predictors of successful weight loss13,14, none have assessed if AT health determines the effect of TLC on changes of body weight and/or fat mass. We have previously shown that AT lipid kinetics, a marker of AT health, correlates with the area under the curve of free fatty acids (AUC FFA) during oral glucose tolerance test (OGTT)-induced hyperinsulinemia (30-120 min of OGTT)15. Thus, our third
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aim was to determine whether the AUCFFA30-120 can predict the loss in body weight or fat mass. 2. MATERIALS AND METHODS
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2.1. Patients
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Fifty-three volunteers diagnosed with MetS were recruited by public advertisement at the
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outpatient clinics of UT Southwestern Medical Center. Under a randomized placebo-controlled
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study design, patients received either TLC+placebo (n=26) or TLC+A/A (n=27) for one year. Patients were included if they were: 1) men or women aged 40-65 years; 2) diagnosed with MetS
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per NCEP-ATP III revised criteria. A patient is considered with MetS if he/she meets 3 out of the 5
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criteria. While individually, each patient met the criteria for diagnosis, not all patients fulfilled all 5
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criteria. 3) have BP ≥130/85; and 4) pre-menopausal women on a birth control pill. Exclusion criteria were 1) inability to sign a consent form; 2) unwillingness to be available for follow up for up to 12 months; 3) under treatment with anticoagulants or hypercholesterolemia agents; 4) fasting plasma glucose levels >126 mg/dL or currently treated for diabetes; 5) creatinine clearance <50 mL/min; 6) liver function (AST/ALT) three times the upper limit of reference values; 7) pregnant/lactating women; 8) evidence of cholelithiasis, cancer or substance abuse; 9) a cardiovascular event in the last 6 months; and 10) the subject’s physician believes the patient should be started on an antihypertensive regimen (placebo arm is not justified). The research protocol was approved by UT Southwestern Institutional Review Board, and written informed consent was
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obtained from all subjects before study entry. The current study is registered in clinicaltrials.gov (Identifier: NCT03504735). On their first visit, patients were instructed about healthy diet, and exercise. They were also provided with a free access to an exercise facility. Diet and exercise progress were discussed during monthly visits. Additional follow ups were available throughout the study in person, via phone or email. The following measurements were obtained during the first visit (baseline) and after
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2.2. Assessments
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MetS included absence of at least 3 of the 5 MetS criteria.
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completion of the one-year intervention. Pre-specified primary outcome measures for resolution of
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2.2.1. Anthropometric and BP Measurements:
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Weight, height and waist circumference were assessed and body mass index (BMI) was calculated. BP was assessed as previously described16. Briefly, three BP measurements
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were taken and averaged using standard outpatient clinic equipment with an oversized
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cuff while the patient was in the sitting position. 2.2.2. Body Composition:
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Body composition was assessed using underwater weighing as previously described17. Briefly, subjects sat in a tub of lukewarm water and were asked to breathe out air and go completely under water for 5-10 seconds to determine the volume displacement. Siri’s equation18 was used to estimate the percentage of body total fat mass. 2.2.3. Blood Chemistry: The Piccolo Lipid Panel Plus Reagent Disc was used to assess fasting plasma TG, HDL-C, total cholesterol (TC), low density lipoprotein (LDL) and glucose according to
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manufacturer instructions. Ox-LDL was assessed in plasma using ELISA (Mercodia, Winston-Salem, NC), as previously described8. 2.2.4. OGTT: Following an overnight fast, blood samples were collected before and after the ingestion of a 75 g glucose drink at 15-30 minute intervals up to 3 hours, as previously described19. The concentrations of plasma insulin and free fatty acids (FFAs) were
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measured using commercially available kits (Human Insulin kit from Mercodia Inc.,
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Salem, NC and Zenbio Inc., Research Park Triangle, NC, respectively). The
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AUCFFA30-120 was calculated using the trapezoid formula as a marker of AT health.
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2.3. Statistical Analysis
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Data were analyzed using IBM SPSS Statistics for Windows, Version 20.0 (Released 2011; IBM Corp. Armonk, NY) and GraphPad Prism version 5.00 for Windows (GraphPad Software, La
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Jolla, CA). Data are presented as median (interquartile range). A two-way repeated-measures analysis of variance with the factors time and intervention with post hoc Bonferroni correction was
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used to assess differences between study arms in having MetS. Non-parametric t-test with
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Wilcoxon matched-pairs signed rank was used to assess the change between study arms in general characteristics and clinical chemistry parameters over a 1-year intervention. Relationship analyses were performed using a linear regression model. The nonparametric data was log transformed for skewed distribution prior to use in the analysis. A p value less than 0.05 was considered statistically significantly. 3. RESULTS 3.1. Effect of interventions on MetS criteria
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Fifty percent of the enrolled subjects (n=26) completed the study; that is 13 patients per group. Patients in the TLC+placebo group were 5 males and 8 females with a mean age of 50 years (range 41-61); while those in the TLC+A/A group were 7 males and 6 females with a mean age of 53 years (range (41-61). The general characteristics of subjects who completed the study are presented in Table A.1. At the beginning of the study, 16 patients had 3 criteria, 6 patients had 4 criteria and 4 patients had 5 criteria of the Mets. There were no differences in age and gender
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distribution between the treatment arms. Reasons for drop out included: job change, relocation, lack
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of time for follow-up (stress, death in the family), inability to be reached, or dissatisfaction with
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weight loss expectations.
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At the end of the study, 3 patients had 3 criteria, 7 patients had 4 criteria and 2 patients had
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5 criteria of the MetS. The number of diagnostic criteria for MetS in all subjects was significantly reduced from 3 (range 3-5) to 2 (range 0-5; p = 0.001). In fact, 54% of those in the TLC+A/A group
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and 46% in the TLC+placebo group no longer had MetS (p = 0.04 each; Figure A.1.). However, there were no significant differences between the two groups (p = 0.3). The median change in body
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weight in all subjects was –1.97 kg (range: -6.4 to +3.6) yet it was not significantly different
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between groups (p = 0.821).
3.2. The additive effect of A/A and TLC on metabolic parameters and OS markers Table A.1. shows the changes in Mets parameters in response to treatment. Both interventions decreased systolic BP (SBP; p = 0.01 vs. baseline), yet only TLC+A/A significantly decreased the diastolic BP (DBP) (p = 0.02 vs. baseline). TLC+A/A decreased TC, non-HDL and LDL (p = 0.004). TLC+placebo also decreased TC and LDL, although less prominently (p = 0.04). Both interventions marginally decreased waist circumference (p 0.07 each). Only TLC+A/A
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marginally decreased TG. Only TLC+placebo significantly decreased HDL-C (p = 0.01 vs. baseline). Both interventions had no statistically different effect on fasting blood glucose. Only TLC+placebo increased plasma Ox-LDL and the Ox-LDL/LDL ratio compared to baseline (p=0.02 and 0.04 for Ox-LDL and Ox-LDL/LDL; respectively- Table A.1.). However, when the subjects in the TLC+placebo group were stratified for weight loss (cutoff level = –1.5 Kg), we found that those who lost more weight had significantly decreased levels of Ox-LDL (p =
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0.04; Figure A.2.a). Changes in Ox-LDL positively correlated to changes in body weight (r = 0.64;
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p = 0.04; Figure A.2.b).
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3.3. AT health and the effect of interventions on body weight and fat mass
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Because the addition of A/A to TLC showed no effect on changes in body weight or % fat
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mass when compared to TLC+placebo, the linear regression analyses to determine the effect of AT health (i.e., AUCFFA30-120) on changes in body weight and % fat mass were conducted in a
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combined group of all subjects regardless of their treatment. Linear regression analyses
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demonstrated that AUCFFA30-120 during the OGTT predicted 22% (r = 0.472, p = 0.036) of the
weight (p = 0.5).
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variability in the delta change of % body fat mass (Figure A.3.) but not the delta change in body
4. DISCUSSION
This study showed that in patients with MetS 1) A/A in addition to TLC improves the lipid profile and BP, two criteria of MetS; however, TLC alone reduced the metabolic parameters defining MetS comparable to TLC+A/A; 2) weight loss is the key to obtain TLC-associated reduction in Ox-LDL levels, while A/A prevents the increase in Ox-LDL that was observed in individuals who did not lose, or even gained, weight; and 3) AT metabolic health, expressed as
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AUCFFA30-120 during OGTT-induced hyperinsulinemia, is a significant predictor of loss of body fat mass, but not body weight. MetS has become increasingly prevalent in the US population, affecting almost 25% of adults20. Patients with MetS are at a higher risk of developing various comorbidities, including CVD complications, and resulting in 1.5-fold higher rates of all-cause mortality21. The benefit of
favorably to TLC
13,14,24,25
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TLC in preventing CVDs has been well documented22-24. However, not all subjects respond . Villareal et al. demonstrated that only 59% of participants showed an
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improvement in metabolic health24. According to our expectations, adding A/A improved both the
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lipid profile and BP (both systolic and diastolic). Yet, TLC+placebo also beneficially affected some
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metabolic parameters, in accord with previously reported data26,27. As a result, both interventions
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comparably reduced the number of patients with MetS. Our data support the previous reports that weight loss per se improves MetS criteria; however, it needs to be emphasized that only continued
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exercise maintains this improvement, even with weight regain28.
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We observed an overall improvement of MetS criteria in the TLC group compared to the
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AA group. SBP was significantly reduced in both arms. Though we expected greater reduction in SBP in the AA group, SBP was comparably reduced in TLC. DBP was only reduced in the AA group, which is reasonable, as amlodipine has been reported to exert greater reduction in DBP during exercise compared to placebo29. HDL-C showed significant reduction only in the TLC group. This observed reduction in HDL-C was after 1 year of intervention, suggesting that it was not due to a rapid weight loss. Other Mets parameters showed insignificant or no change in response to either interventions.
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Oxidation of LDL infiltrating the arterial wall is known to promote leukocyte phagocytic action, and differentiation of macrophages and foam cells, resulting in atheroma plaque formation. Excessive reactive OS species initiate immune cell infiltration, further worsening endothelial dysfunction30. Since MetS is considered a chronic inflammatory state that is linked to OS, the reduction of the oxidation of the LDL molecule is a predictor of the reduction of atherogenic risk among these patients. Oh et al. reported that a 6-month TLC decreased the levels of chemokines
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related to stress and inflammation in patients with MetS31. A small-scale pilot study confirmed the
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salutary effect of a 24-week TLC (supervised aerobic exercise/Mediterranean diet), reducing
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protein-bound oxidized phenylalanine and tyrosine moieties OS markers32. Atorvastatin, a component of the A/A pill, is an anti-lipidemic agent shown to reduce not only metabolic
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parameters but OS markers in patients with diabetes33,34. We have previously shown that A/A
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treatment for 12 weeks dose-dependently decreased Ox-LDL9. However, no long-term studies on
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the effect of A/A on Ox-LDL in combination with TLC have yet been reported. Interestingly, in our study the Ox-LDL levels were increased in the TLC+placebo group. However, this change in Ox-
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LDL levels depended on the change in body weight as the Ox-LDL levels were significantly
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decreased in individuals who had lost more than 1.5 kg of their body weight. Our data suggest that weight loss is essential to achieve TLC-associated reduction in Ox-LDL. TLC may not always decrease body weight6. Proposed predictors of successful weight loss include age, behavior and psychological motivation. We hypothesized that AT metabolic health is another predictor of successful weight loss. It is now well accepted that the impaired AT health associates with reduced blood flow in AT, resulting in AT unresponsiveness to lipolytic agents12,35. This condition may explain why metabolically unhealthy people may be less responsive to weight loss interventions11,12. We have previously shown a direct correlation between AT lipid kinetics, the
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marker of AT metabolic health, and AUCFFA30-120 during OGTT-induced hyperinsulinemia15. Moreover, we reported an inverse correlation between that AUCFFA30-120 and the subcutaneous AT ability to accumulate excess calories, a marker of AT health. In the current study, we report that AUCFFA30-120 during OGTT was a significant predictor of loss of body fat mass but not body weight. Our current data suggest that AT metabolic health may beneficially affect the outcome of TLC, i.e., body fat loss. It is possible that TLC decreased fat mass yet increased lean body mass,
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thus resulting in unchanged body weight10. Further studies are warranted to explore the effects of
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modulation of AT metabolic health to enhance the effect of TLC on body fat mass and weight loss,
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subsequently on metabolic health.
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The drawback of this study is the small sample size, and many dropouts (50% at the end of
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1-year intervention). However, this dropout rate is comparable to that of other studies reporting a 54% drop out for a 1-year period36. One of the reasons for dropping out of the study was the
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subjects’ disappointment that they did not lose more weight. This is understandable, as they had heavy baseline weights which made them more susceptible to having unrealistic expectations for
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weight loss37. Yet the strengths of this study lie in the utilization of state-of-the-art investigations
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(i.e. underwater weighing for precise body fat calculation; AUCFFA30-120 during OGTT for evaluation of AT metabolism). We also utilized interventions (i.e. TLC) with minimal resources in a clinical setting; this is similar to real-life scenario which makes the study and results easily reproducible. 5. CONCLUSIONS Our study demonstrated that although both TLC alone or in combination with A/A may be beneficial in improving the metabolic health of patients with MetS, addition of A/A may prevent weight-gain-associated increase in Ox-LDL; and weight loss is the key to observe TLC-associated
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decrease in Ox-LDL. Regardless of intervention, AT health is a significant predictor of successful loss of fat mass; therefore, selection of patients who would favorably respond to TLC and improve their metabolic health may be determined based on their estimated AT health. 6. ACKNOWLEDGEMENTS The authors would like to express their gratitude to the study participants for their
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dedication and time; and to Dr. Peter Snell help with underwater weighing; and Dr. Magdalene
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Szuszkiewicz-Garcia and Dr. Thanalakshmi Seenivasan, PhD for their assistance in patient
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recruitment.
This study was funded by Pfizer Inc., and conducted with the support of the Institute for
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Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical
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and Translational Science Award (UL1 TR001439) and Mentored Career Development (KL2)
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Award (KL2TR001441) from the National Center for Advancing Translational Sciences, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily
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represent the official views of the National Institutes of Health.
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7. Declaration of Interest
All authors have no competing interests to declare. 8. REFERENCES 1.
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de Glisezinski I, Moro C, Pillard F, et al. Aerobic training improves exercise-induced lipolysis in SCAT and lipid utilization in overweight men. Am J Physiol Endocrinol Metab. 2003;285(5):E984-990.
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Hickner RC, Kemeny G, Clark PD, et al. In vivo nitric oxide suppression of lipolysis in subcutaneous abdominal adipose tissue is greater in obese than lean women. Obesity (Silver
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9. Appendices Table A.1. Baseline General Characteristics and Clinical Chemistry Parameters for Subjects who completed the Study. TLC + Placebo (n=13)
TLC + AA (n=13) Paired t-test p value
Nonparametric t-test p value for deltas
0.1
105(83-123)
102(84-116)
0.2
0.6
33(31-37)
0.1
36(31-39)
35(30-38)
0.3
0.5
42(33-44)
41(32-44)
0.9
41(36-48)
40(34-45)
0.07
0.1
Hip (cm)
130(113-135)
117(109-119)
0.3
131(124-135)
120(112-125)
0.3
0.5
Waist (cm)
109(97-116)
108(94-114)
0.08
122(105-127)
112(103-126)
0.07
1
0.89(0.78-0.99)
0.95(0.86-1.06)
0.5
0.92(0.75-1.07)
0.9
0.7
FBG (mg/dl)
94(93-101)
104(100-115)
0.07
102(98-108)
102(91-107)
0.5
0.01
SBP (mm Hg)
140(135-145)
127(124-135)
0.01
143(135-151)
131(124-140)
0.002
0.8
DBP (mm Hg)
85(81-87)
85(80-88)
0.3
87(80-93)
84(72-86)
0.02
0.2
TC (mg/dL)
233(194-257)
204(172-220)
0.04
213(183-248)
158(139-185)
0.002
0.2
TG (mg/dL)
140(122-188)
160(136-213)
0.1
145(119-173)
90(68-136)
0.07
0.08
47(37-56)
39(34-45)
0.01
51(37-56)
42(38-56)
0.5
0.7
165(140-187)
0.09
162(133-182)
120(88-140)
0.002
0.1
127(82-143)
0.03
134(108-144)
100(75-113)
0.004
0.3
175(140-189)
0.02
125(90-144)
114(98-152)
0.9
0.4
1.3(1.1-1.8)
0.04
1.1(0.6-1.3)
1.3(0.9-1.3)
0.3
0.4
Weight (Kg)
90(80-106)
97(77-106)
BMI
35(31-37)
Body Fat (%)
HDL-c (mg/dL)
186(159-192)
LDL (mg/dL)
148(117-177)
OxLDL (u/mL)
135(97-162)
OxLDL/LDL
0.9(0.7-1.2)
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Non-HDL (mg/dL)
0.98(0.72-1.03)
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Waist/hip ratio
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Variables
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Baseline (BsL)
Paired t-test p value
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Baseline (BsL)
PostIntervention (1 year)
PostIntervention (1 year)
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Data are presented as median (interquartile range). Comparisons between lifestyle modifications
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(TLC) and Amlodipine/Atorvastatin (A/A) or Placebo groups were performed by paired t-test for each intervention arm. Non-parametric t-test with Wilcoxon matched-pairs signed rank was used to assess the delta change over 1-year intervention between study arms. p<0.05 was considered statistically significant. BMI, body mass index; DBP, diastolic blood pressure; FBG, fasting blood glucose; HDL-C, high density lipoprotein-cholesterol; LDL-C, low-density lipoprotein cholesterol; Ox-LDL, oxidized LDL; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.
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10. FIGURE LEGENDS Figure A.1.: Effect of Interventions on Metabolic Syndrome (MetS). All patients had the metabolic syndrome at baseline. TLC+placebo was nearly as effective as TLC+A/A in improving patients with MetS (p=0.01 and p=0.04 for TLC+A/A and TLC+placebo; respectively). Figure A.2.: Effect of Weight Loss on Plasma Oxidized Low Density Lipoprotein (Ox-LDL)
of
Levels. a. Change in Ox-LDL within groups shows that only in the TLC+placebo group, patients who lost weight had significantly decreased Ox-LDL (p = 0.04 for weight loss vs. no weight loss).
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Weight loss cutoff level = –1.5 Kg (dotted vertical line). b. Change in Ox-LDL significantly
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correlated with weight change in the TLC + Placebo Group only (r = 0.64; p = 0.04).
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Figure A.3.: Linear Regression Analyses. Adipose tissue health, expressed as AUCFFA30-120
lP
during oral glucose tolerance test, was significantly and directly correlated with change in body fat
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prior to use in the analysis.
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mass loss (r = 0.485, p = 0.036). The AUCFFA30-120 was log transformed for skewed distribution
Highlights
Can Amlodipine/atorvastatin + Therapeutic Lifestyle change improve Metabolic Syndrome?
This is a placebo-controlled study including 2 arms of intervention for 12 months.
Both interventions comparably reversed the Metabolic Syndrome.
Figure 1
Figure 2
Figure 3