Getting Off the Chronic Disease Merry-Go-Round: What s the Weight of the Research?

Transcription

1 Getting Off the Chronic Disease Merry-Go-Round: What s the Weight of the Research? Jody Dushay, MD MMSc Beth Israel Deaconess Medical Center Boston, MA Session 445 No disclosures Disclosure Jody Dushay, MD MMSc Clinical Case (CVD), type 2 diabetes (T2DM), CVD, T2DM, 58 yo postmenopausal female 5 5, 200 lbs, BMI 33 kg/m 2 Waist 110cm BP 130/80 Fasting labs: HDL 35, TG 180, LDL 95, ALT 52, glucose 110 Medications: HCTZ, simvastatin Family history: + T2DM in sister and mother; + breast cancer in mother; + CVD in father (heart attack age 60) Exam: No clinical stigmata to suggest secondary causes of obesity Cortisol excess: moon facies, supraclavicular fullness, cervicodorsal fat pad, wide red/purple striae Thyroid: no goiter Clinical Case Postmenopausal female BMI 33 Increased CV risk Central obesity Impaired fasting glucose No secondary causes Obesity increases our patient s risk of developing cardiovascular disease, type 2 diabetes, 1

2 Obesity is an inflammatory state Several proinflammatory factors are increased in the setting of excess adiposity: Obesity is an inflammatory state Adipocyte derived: Interleukin 6 () Plasminogen activator inhibitor-1 () Retinol-binding protein 4 (RBP4) Normal adipose tissue Adipose tissue in obesity Macrophages Free fatty acids Hepatocyte derived C-reactive protein () fibrinogen INSULIN RESISTANCE RBP4 INFLAMMATION Inflammation contributes to the development of CVD and T2DM Obesity is a lipotoxic state Elevated basal and postprandial levels of free fatty acids (FFA) and triglycerides (TG) cause lipotoxicity Elevated circulating FFA block glucose transport activity contributes insulin resistance Elevated circulating TG are stored in tissues where they prevent normal function pancreas, muscle, liver, heart Luc F. et al., Nature 2006; 444: Obesity is an insulin resistant state Location, location: distribution of body fat affects risk of metabolic sequelae Ongoing controversy regarding which comes first, insulin resistance or hyperinsulinemia Insulin resistance beta cell compensation euglycemia beta cell dysfunction reduced insulin secretion/insulin deficiency hyperglycemia T2DM 2

3 Distribution of body fat affects metabolic risk Visceral fat is biochemically different from subcutaneous fat Khandekar et al Nature Reviews 2011: Garaulet et al., Am J Clin Nutr 2001: Saturated fatty acids Monounsaturated Polyunsaturated (CVD), type 2 diabetes (T2DM), CVD, T2DM, Several very large, observational, prospective studies confirm that obesity is an independent risk factor for clinical cardiovascular disease Framingham Heart Study 3 decades of follow up Manitoba Study of Health and Aging Nurses Health study Willett et al., NEJM, 1999 Hubert et al, Circulation 1983:

4 How does obesity affect the heart? To meet increased metabolic needs (i.e., metabolic demands of excess adipose tissue), circulating blood volume increases cardiac output increases How does obesity affect the heart? Increase in blood volume increases venous return to the right and the left ventricles Leads to dilation and increased wall tension Dilation and increased wall tension hypertrophy of the left ventricle (LVH) accompanied by a decrease in diastolic chamber compliance (decreased compliance during relaxation/filling) eventually leads to an increase in LV filling pressure and LV enlargement If LVH cannot keep up with LV dilation systolic dysfunction (pump problem) Aurigemma et al., Circulation 2013 Obesity is a risk factor for cancer Type of Cancer Relative Risk (BMI > 30 vs < 27) Proposed Mechanism Endometrial 3.40 Elevated estrogen levels (increased aromatase activity with excess fat) Esophageal 1.92 GERD tissue damage Pancreas 1.72 Growth factors, inflammation Kidney 1.70 Growth factors, inflammation Gallbladder 1.66 Gallstones tissue damage Breast (postmenopausal) 1.26 Elevated estrogen levels Colorectal 1.22 Growth factors, inflammation Adapted from Byers and Sedjo, Diabetes Obesity and Metabolism 2011: Obesity is a risk factor for cancer Mechanisms: Primary and secondary effects of obesity Primary: Body habitus itself can increase risk Abdominal adiposity GERD esophageal cancer Adipokines play a role in the development of cancer TNF α: promotes angiogenesis and metastasis Leptin Hormonal changes associated with obesity Hyperinsulinemia Increased IGF-1 levels Increased estrogen levels (more fat, more aromatase) Obesity increases risk of cancer Normal adipose tissue leptin Adipose tissue in obesity Insulin Estrogen Free fatty acids Macrophages TUMORIGENESIS (CVD), type 2 diabetes (T2DM), CVD, T2DM, 4

5 developing type 2 diabetes Diabetes Prevention Program Lifestyle intervention: 7kg weight loss at year 1, 4kg weight loss at year 4 58% reduction in the development of T2DM Significantly greater reduction than treatement with metformin or troglitazone Finnish Diabetes Prevention Study 4.2 kg weight loss year 1, 3.5kg weight loss year 2 58% reduction in the development of T2DM with intensive lifestyle vs standard treatment developing CVD < 4.5kg > 4.5kg Eilat-Adar et al, Am J Epidemiol 2005: developing some kinds of cancer Type of Study Type of Cancer Population Studied Cohort Breast Postmenopausal women Bariatric Surgery Dietary Randomized Control Trial Weight loss Cancer risk reduction 5-16% 11-64% All types Men and women 19-32% 24-78% Breast Women % difference between groups 4-24% (recurrance in some studies) PRACTICE APPLICATIONS Epidemiological studies demonstrate convincingly that obesity is associated with increased risk for developing cardiovascular disease, type 2 diabetes, and some types of cancer Inflammation, insulin resistance, lipotoxicity and the sequelae of all of these contribute to increased risk Weight loss can significantly reduce the risk of developing CVD, T2DM Adapted from Byers and Sedjo, Diabetes Obesity and Metabolism 2011: