Zafrir et al1 reported that among patients who underwent cardiac catheterization, overweight and moderately obese individuals showed lower long-term mortality rate than normal-weight counterparts. This study confirms a paradoxical effect of adiposity excess on mortality rate in patients with coronary artery disease2 as well as in other high-risk conditions, including type 2 diabetes3 and end-stage renal disease.4 The intrinsic nature of the obesity paradox in these frail individuals is unknown. Drugs, which improve adipocytokine profiles (angiotensin-converting-enzyme inhibitors/sartans, statins, metformin, and pioglitazone) and which are frequently used in high-risk patients, might switch the adipose tissue effect on chronic low-grade inflammation toward a positive direction, thus favoring obese individuals. Conversely, among high-risk patients, a normal-weight status could be a marker of pre-existing diseases causing both weight loss and increasing mortality rate.5 In addition, data from the CRUSCADE registry showed that body mass index (BMI) is inversely related to age at myocardial infarction in high-risk individuals.6 If this occurs also with age at death, it could account for some of the obesity paradox through a survival bias affecting obese patients entering prospective studies on mortality risk. Finally, one should also keep in mind that BMI is questioned for reliably measuring adiposity7 thus adding further uncertainty. This elusive scenario needs to be addressed. Randomized controlled trials (RCTs) are gold standard to address causality. A recent meta-analysis of RCTs on the effect of diet-induced weight-loss reported a beneficial effect on all-cause but, surprisingly, not on cardiovascular mortality and on incident cardiovascular events.8 Unfortunately, average weight loss in the above mentioned RCTs was modest and possibly not sufficient to exert clearly detectable beneficial effects. In addition, high-risk subjects were not specifically investigated,8 thus leaving unaddressed the role of weight-loss in these patients. When RCTs are lacking, Mendelian randomization (MR) studies may help indirectly address causality. By this approach, a cause-effect relationship underlying an observed association is suggested if genetic variants known to robustly affect the exposure (i.e., adiposity, in our case) turn out to be also associated with the outcome (i.e., mortality rate, in our case).9 Some recent MR studies speak against a true obesity paradox reporting that BMI-increasing genetic variants associate neither with mortality rate in type 2 diabetes10 nor with coronary artery disease,11 the leading cause of death worldwide. Unfortunately, because of intrinsic limitations regarding sample size paucity10 and the outcome addressed which is only a proxy of mortality risk,11 neither study can say a definitive word on this subject. In all, the possibility of an obesity paradox in modulating the risk of death in high-risk patients may distract clinicians from the importance of weight management. MR studies conducted in well-powered samples of frail patients are timely needed. However, when designing these studies, information on environmental factors, including eating and/or exercise habits that the MR approach cannot intrinsically control, are preferable. Results from such efforts will help decide whether or not it is worthwhile embarking in expensive and time-consuming RCTs on the effect of weight-loss on mortality risk in frail patients. In the meanwhile, given the deleterious role adiposity excess exerts since childhood on both all-cause and cardiovascular mortality,12, 13 preventing obesity must be our primary goal.

Is There Really a Paradoxical Effect of Obesity on Mortality Rate in High-Risk Patients? It Is Time for Large Mendelian Randomization Studies / Trischitta, Vincenzo; Di Paola, Rosa. - In: THE AMERICAN JOURNAL OF CARDIOLOGY. - ISSN 0002-9149. - 122:5(2018), pp. 910-910. [10.1016/j.amjcard.2018.04.063]

Is There Really a Paradoxical Effect of Obesity on Mortality Rate in High-Risk Patients? It Is Time for Large Mendelian Randomization Studies

Vincenzo Trischitta;
2018

Abstract

Zafrir et al1 reported that among patients who underwent cardiac catheterization, overweight and moderately obese individuals showed lower long-term mortality rate than normal-weight counterparts. This study confirms a paradoxical effect of adiposity excess on mortality rate in patients with coronary artery disease2 as well as in other high-risk conditions, including type 2 diabetes3 and end-stage renal disease.4 The intrinsic nature of the obesity paradox in these frail individuals is unknown. Drugs, which improve adipocytokine profiles (angiotensin-converting-enzyme inhibitors/sartans, statins, metformin, and pioglitazone) and which are frequently used in high-risk patients, might switch the adipose tissue effect on chronic low-grade inflammation toward a positive direction, thus favoring obese individuals. Conversely, among high-risk patients, a normal-weight status could be a marker of pre-existing diseases causing both weight loss and increasing mortality rate.5 In addition, data from the CRUSCADE registry showed that body mass index (BMI) is inversely related to age at myocardial infarction in high-risk individuals.6 If this occurs also with age at death, it could account for some of the obesity paradox through a survival bias affecting obese patients entering prospective studies on mortality risk. Finally, one should also keep in mind that BMI is questioned for reliably measuring adiposity7 thus adding further uncertainty. This elusive scenario needs to be addressed. Randomized controlled trials (RCTs) are gold standard to address causality. A recent meta-analysis of RCTs on the effect of diet-induced weight-loss reported a beneficial effect on all-cause but, surprisingly, not on cardiovascular mortality and on incident cardiovascular events.8 Unfortunately, average weight loss in the above mentioned RCTs was modest and possibly not sufficient to exert clearly detectable beneficial effects. In addition, high-risk subjects were not specifically investigated,8 thus leaving unaddressed the role of weight-loss in these patients. When RCTs are lacking, Mendelian randomization (MR) studies may help indirectly address causality. By this approach, a cause-effect relationship underlying an observed association is suggested if genetic variants known to robustly affect the exposure (i.e., adiposity, in our case) turn out to be also associated with the outcome (i.e., mortality rate, in our case).9 Some recent MR studies speak against a true obesity paradox reporting that BMI-increasing genetic variants associate neither with mortality rate in type 2 diabetes10 nor with coronary artery disease,11 the leading cause of death worldwide. Unfortunately, because of intrinsic limitations regarding sample size paucity10 and the outcome addressed which is only a proxy of mortality risk,11 neither study can say a definitive word on this subject. In all, the possibility of an obesity paradox in modulating the risk of death in high-risk patients may distract clinicians from the importance of weight management. MR studies conducted in well-powered samples of frail patients are timely needed. However, when designing these studies, information on environmental factors, including eating and/or exercise habits that the MR approach cannot intrinsically control, are preferable. Results from such efforts will help decide whether or not it is worthwhile embarking in expensive and time-consuming RCTs on the effect of weight-loss on mortality risk in frail patients. In the meanwhile, given the deleterious role adiposity excess exerts since childhood on both all-cause and cardiovascular mortality,12, 13 preventing obesity must be our primary goal.
2018
obesity; all-cause mortality; cardiovascular mortality
01 Pubblicazione su rivista::01f Lettera, Nota
Is There Really a Paradoxical Effect of Obesity on Mortality Rate in High-Risk Patients? It Is Time for Large Mendelian Randomization Studies / Trischitta, Vincenzo; Di Paola, Rosa. - In: THE AMERICAN JOURNAL OF CARDIOLOGY. - ISSN 0002-9149. - 122:5(2018), pp. 910-910. [10.1016/j.amjcard.2018.04.063]
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