Obesity Paradox and Smoking Gun: A Mystery of Statistical Confounding?

Abstract

The obesity paradox is a term coined for human conditions in which obesity is associated with a lower mortality than being underweight (ie, body below normal or healthy body weight). Smoking is often cited as a key confounder of obesity paradox, but how smoking causes obesity paradox is unknown. Here, we highlight that the obesity paradox can be attributed to insulin resistance (IR) and aberrant lipolysis in cardiovascular diseases (CVD). Obesity is an independent risk factor for the development of diseases associated with increased mortality in the general population, such as CVD, for which obesity increases the risk by ≈2-fold. However, for the elderly population or patients with specific conditions, such as cancer cachexia,1 chronic obstructive lung disease, end-stage renal disease, or advanced chronic kidney disease (who are receiving hemodialysis therapy), a higher body mass index (BMI) is often found to be associated with reduced mortality, whereas lower body mass index is related to higher mortality in these patients. To describe these human conditions, a new term called obesity paradox is coined. The obesity paradox has also been reported in many patients with cardiovascular events; for example, class I obesity (BMI, 30–35 kg/m2) patients who experience heart failure have lower short- and intermediate-term mortality than their leaner counterparts. Similarly, overall in-hospital mortality after acute myocardial infarction is dramatically lower in elderly obese patients (≥70 years) of all classes compared with patients with acute myocardial infarction without obesity. The obesity paradox has also been reported in cardiovascular therapy; for example, elderly patients who are obese or overweight have lower mortality with implantable cardioverter defibrillators than normal BMI patients.2 Because the data to support obesity paradox are exclusively obtained from clinical observations, there are intense debates on whether or not obesity paradox is real or a bias/an artifact derived …