ENRGISE – a RCT of anti-inflammatory therapy in older persons Marco Pahor, MD University of Florida Institute on Aging www.aging.ufl.edu
Inflammation & cytokinemia are associated with: • Disability, impaired • Alzheimer’s Disease physical function • Anemia • Frailty • Atherosclerosis • Gastrointestinal dis. • Autoimmune Dis. • Infection • Cancer • Obesity, adiposity • Cerebrovascular Dis. • Osteoarthritis • Coronary Heart Dis. • Osteoporosis • Congestive Heart Fail. • Periodontal disease • COPD • Renal disease • Dementias • Sarcopenia • Depression • Sedentary lifestyle • Diabetes • Smoking
Distribution of 3 Inflammatory Markers l Mean: 3.00 mg/L C R P Median: 1.68 2 0 4 0 6 0 8 0 IQR: 0.99 – 3.14 C R P Mean: 2.40 pg/ml I L 6 Median: 1.83 5 1 0 1 5 IQR: 1.27 – 2.77 I L 6 Mean: 3.48 pg/ml T N F Median: 3.16 5 1 0 1 5 2 0 2 5 IQR: 2.44 – 4.11 T N F
HABC - Spearman Correlations Among Markers (N=3037) Y1,Y2 CRP IL-6 TNF Chol Glucose (n=411) CRP 0.66 0.46 0.12 0.03 0.10 IL-6 0.63 0.27 -0.12 0.15 TNF 0.41 -0.03 0.11 Chol 0.72 0.01 Gluc 0.74
Event-Free Survival According to Baseline Quintiles of hs-CRP and LDL Cholesterol Quintiles of hsCRP Quintiles of LDL 1.00 1.00 CVD Event-Free Survival Probability 0.99 0.99 1 1 2 2 0.98 0.98 3 3 4 4 0.97 0.97 5 5 0.96 0.96 0 2 4 6 8 0 2 4 6 8 Years of Follow-Up Years of Follow-Up Ridker et al N Engl J Med. 2002;347:1157-1165.
CHD Events (n= 188; RR, 95%CI) IL-6 in highest tertile 1.71 (1.27-2.29) CRP in highest tertile 1.33 (0.98-1.80) TNF- α in highest tertile 1.67 (1.23-2.26) Current smoking 1.32 (0.98-1.77) Total cholesterol > 240 mg/dl 1.13 (0.76-1.70) LDL cholesterol ≥ 130 mg/dl 1.07 (0.80-1.44) HDL cholesterol ≤ 40 mg/dl 1.19 (0.84-1.70) Hypertension 1.28 (0.95-1.22) Diabetes 1.90 (1.33-2.70) BMI> 30 kg/m 2 1.51 (1.10-2.07) Adjusted for age, gender and race Cesari et al Circulation 2003; 108:2317
HABC – Inflammation and CVD events Number of 5 markers in p = 0.12 p = 0.02 p < 0.001 the upper 4 4 tertile 3 3 RR 0 1 2 2 2 3 1 1 0.5 Stroke CHF CHD (n=60) (n=92) (n=188) Cesari et al Circulation 2003; 108:2317
HABC - Inflammatory markers and cognition Yaffe et al. Neurology 61:76-80, 2003
Sarcopenia in the context of the International Classification of Function (ICF) model ↑ Healthcare cost Body (physiological) Sarcopenia Biology functions Muscle atrophy & neural transmission, hormones, & intramuscular adipose proteolysis, autophagy, ↑ Caretaker Stress apoptosis, satellite cells, Body structure inflammation, oxidative stress, energy production, blood flow Dynapenia ↓ Independence Loss of muscle strength Disease metabolic, pulmonary, Participation Activity limitations Aging vascular, immune, In life situations organ-specific Difficulties in executing tasks Environmental Personal factors Buford et al. Ageing Research Reviews 2010
Buford et al. Ageing Research Reviews 2010
Inflammation and Prevalence of Frailty in Older Women Enrolled in WHAS Leng et al. JAGS 55:864–871, 2007
EPESE - IL-6 and 4 year incident mobility disability 95% CI 1 Probability Adjusted 0.8 probability 2.5 pg/ml 0.6 0.4 95% CI 0.2 0 -0.5 0 0.5 1 1.5 2 2.5 3 n=633 Ln (IL-6) Ferrucci et al JAGS 1999;47:639
HABC - Inflammation markers by mobility disability CRP (mg/L) IL-6 (pg/mL) 9 7 p<.001 p<.001 8 6 7 5 6 4 5 4 3 3 2 2 1 1 0 0 no yes no yes incident disability incident disability Penninx et al JAGS 2004;52:1105
HABC - Inflammation markers by mobility disability TNF- α (pg/mL) 8 p<.001 7 6 5 4 3 2 1 0 no yes incident disability Penninx et al JAGS 2004;52:1105
HABC - Inflammation & incidence of mobility disability tertile incidence RR* 95% CI I 22.2% 1 CRP II 26.9% 1.05 0.88-1.26 III 41.4% 1.40 1.18-1.68 I 19.8% 1 IL-6 II 30.6% 1.34 1.11-1.62 III 40.2% 1.65 1.37-1.98 I 25.0% 1 TNF- α II 28.7% 1.09 0.91-1.30 III 36.1% 1.18 0.99-1.41 *adjusted for age, gender, race, education, fat mass, smoking, CVD, COPD, diabetes, cancer, arthritis, NSAIDs, corticosteroids albumin, creatinine, EPESE perf. Penninx et al JAGS 2004;52:1105
HABC - Composite measure of inflammation and RR of mobility disability 3 RR P-trend <.001 2 1 0 0 1 2 3 number of high inflammatory markers (upper tertile) Penninx et al JAGS 2004;52:1105
InChianti – Inflammation and physical performance in older persons Adjusted Physical Performance Score 3 p=<0.01 * * p=<0.05 p=<0.05 2.5 * * 2 1.5 0.86-1.46 1.46-2.28 <0.59 <0.86 0.59 0.60 >2.28 >0.60 CRP (mg/dl) IL-6 (pg/dl) Cesari et al J Gerontol 2004; 59A:242
Changes in physical function measures per 1 SD increment in log(CRP) and log(IL-6) Brinkley et al. J Gerontol; 2008;64A:455
ADAPT – Diet, exercise and IL-6 Control (n=70) 0.1 Exercise (n=74) 0.05 Diet (n=74) 0 ∆ log IL-6 Diet+Exe. (n=71) -0.05 -0.1 -0.15 -0.2 -0.25 Baseline 6 mo 18 mo treatment effect for weight loss (P=0.009) adjusted for age, race, gender, BMI, baseline IL-6 Nicklas et al Am J Clin Nutr 2004;79:544
LIFE-P – Physical activity and IL-6 Nicklas et al. JAGS; 2008;56:2045
LIFE-P – Physical activity and IL-6 According to SPPB at baseline Nicklas et al. JAGS; 2008;56:2045
LIFE-P – Physical activity and IL-6 According to IL-6 at baseline Nicklas et al. JAGS; 2008;56:2045
ENabling Reduction of low- Grade Inflammation in Seniors - Pilot Study Funding: NIA U01AG050499 Abbott grant for study drug – the company has no other involvement with the study 23
- Double-blinded, 2x2 factorial randomized pilot trial - 5 field centers - Coordinating Center: University of Florida - Data Management Quality Control: Wake Forest University - n=300 – follow-up duration 12 months Tufts Northwestern Pittsburgh Wake Forest Florida ClinicalsTrials.gov NCT02676466
Specific Aims 1 Conduct a pilot RCT in 300 older persons at risk of mobility decline to assess: – Compared with placebo, the effects of losartan, ω -3, and losartan+ω -3 on IL-6 and walking speed; – The recruitment yields, the target population, adherence, retention, tolerability of the interventions – The primary outcome, sample-size, design, and cost for the main trial; – The intra-subject variability of IL-6, – The dosage and safety of the interventions 25
Specific Aims 2 Measure novel and established inflammatory markers • Characterize the effect of losartan and ω -3 on these biomarkers and determine: – Are these cytokines/pathways impacted by the interventions? – Are the changes in these markers pre- vs. post-intervention less than, equivalent to, or greater than that of IL-6? • Assess if these biomarkers yield independent information from IL-6 with respect to change in walking speed and/or provide benefit for screening participants for the main trial 26
Background Figure 5.1. The relation of inflammation to loss of physical function. The three main sources of inflammation in the elderly (genetic and epigenetic factors, exogenous factors and endogenous factors) combine to cause molecular and biochemical changes with important consequences, which in turn lead to physiological consequences, and ultimately to mobility limitation and mortality. These changes are complex with thousands of genes and other macromolecules involved; some examples of important pathways are listed. The potential impact of the chosen interventions are shown. MOLECULAR AND BIOCHEMICAL SOURCES PHYSIOLOGICAL CONSEQUENCES CONSEQUENCES Genetic & Epigenetic Factors Directly related : NF-kB activation & cytokine production* & , loss Directly related : Exogenous Factors MOBILITY of mitochondrial function*, myocyte Loss of muscle Smoking, Air pollution, Alcohol, apoptosis* & , loss of muscle regeneration*, LIMITATION mass/function: sarcopenia* Infectious burden, diet* proinflammatory lipid signaling*, etc. and ultimately Major Mobility Endogenous Factors Indirectly related : Indirectly related : Disability Chronic diseases* & such as Adiposity , Subclinical disease Monocyte & platelet activation burden*, Oxidative stress status*, atherosclerosis Loss of insulin signaling* cardiovascular disease, Innate and adaptive immune diabetes Increased osteoclast bone resorption * Potential effect of ω -3 diabetes, osteoporosis, etc response capacity, hypertension osteoporosis, etc. & Potential effect of ARB 27
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