Obesity is bad regardless of the obesity paradox for hypertension and heart disease

Obesity has risen significantly worldwide and has become a major health and societal problem.1, 2 Obesity does not imply good health since obesity is associated with several major cardiovascular risk factors, which include the metabolic syndrome, hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia, which lead to increased cardiovascular and all-cause mortality in obese people.3, 4 Despite these adverse cardiovascular effects of obesity, some studies indicate better cardiovascular outcomes in obese individuals with the so called "obesity paradox,"5-10 in contrast to other studies that show adverse cardiovascular outcomes of obesity.11-16 The obesity paradox has been demonstrated in patients with preexisting coronary artery disease (CAD)5-10 as well as in patients with heart failure (HF)17, 18 and hypertension19-23 and is giving the wrong signal in obese people and in our efforts to stem the tide of obesity in the United States and elsewhere.24, 25 Since obesity begets CAD, hypertension, and HF, it is therefore better to prevent these complications by preventing obesity instead of inviting them and then trying to treat them. In this respect, a new large study in 3.5 million people has demonstrated that obesity even in metabolically healthy persons is associated with higher cardiovascular and all-cause mortality compared with nonobese healthy individuals.15 This commentary is based on the findings of this study together with other recent study findings. Obesity is associated with several cardiometabolic abnormalities1, 4 and is a major risk factor for increased cardiovascular and all-cause mortality14-16, 26 and accounts for one in five deaths worldwide.27 In a major study of 3.5 million men and women, Caleyachetty and colleagues15 demonstrated that after 5.4 years of follow-up, even metabolically healthy obese (MHO) individuals had a higher risk for coronary heart disease, cerebrovascular disease, and HF than normal weight (NW) metabolically healthy (NWMH) individuals. This large study clearly demonstrated that obesity is a major cardiovascular risk factor, even when not associated with cardiometabolic risk factors. The question is how many obese individuals remain metabolically healthy. In this respect, Bell and coworkers28 investigated the incidence of T2DM in a review of 1770 MHO patients 18 years and older. The pooled adjusted relative risk (RR) for incident T2DM was 4.03 for MHO adults and 8.93 for metabolically unhealthy obese adults. Thus, MHO adults are at an increased risk for developing T2DM than NWMH adults. In another study, Kaur and colleagues29 investigated whether metabolic health persists in overweight and obese individuals long term. They studied 1099 NW, overweight, or obese male individuals (mean age 46.4 years) for 20 years. Metabolic health was based on the absence of abnormal low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, blood pressure, fasting glucose, and other cardiovascular risk factors. Insulin resistance increased in MHO overweight or MHO individuals (median homeostatic model assessment of insulin resistance, 2.63; 95% confidence interval, 1.79–3.65 [P < .001]) compared with NWMH individuals (homeostatic model assessment of insulin resistance, 1.67; 95% confidence interval, 1.08–2.67 [P < .001]) from baseline. The proportions of initially MHO overweight and MHO individuals who remained metabolically healthy at visits two, three, and four were 54%, 48%, and 39%, respectively, compared with the proportions of initially NWMH individuals (68%, 51%, and 41%) who remained metabolically healthy at visits two, three, and four, respectively. The visits occurred every 2 to 3 years after the first visit. This study shows that there is a drift towards unhealthy status for NW, overweight, and obese individuals, thus further increasing their cardiovascular risk. Several studies5-10 have demonstrated an obesity paradox in patients with existing CAD after percutaneous coronary intervention (PCI) or coronary artery bypass grafting. These data are summarized in Table 1. In an analysis of 23 182 patients with CAD, Park and colleagues5 reported a higher incidence of major adverse cardiovascular events (MACE) in patients with body mass index (BMI, kg/m2) <18.5, 18.5–19.9, and 20.0–22.4 and lower in those with BMIs 25.0–27.4, 27.5–29.9, and ≥30.0. Herrmann and colleagues6 similarly reported an increased incidence of MACE among 3579 patients with acute myocardial infarction (MI) according to their BMI 4.2%, 2.6%, 2.3%, and 1.7% for BMIs <24.5, 24.5 to <27.1, 27.1–30.1, and >30.1, respectively (P = .01). Niedziela and coworkers7 reported from a meta-analysis of 218 532 patients with acute coronary syndrome a higher mortality in those with low BMI (RR 1.47) than in those with NW, obesity, and severe obesity (RR 0.70, RR 0.60, and RR 0.70, respectively). Holroyd and colleagues8 examined the association of in-hospital and 30-day post-PCI MACE and mortality of different BMIs in 345 192 patients with CAD. The odds ratios for 30-day mortality were lowest for the patients with higher BMIs (0.86 for BMI 25–30 and 0.90 for BMI > 30). Similar results were found for the 1- and 5-year post-PCI analysis. Azhari and associates9 examined the effects of obesity on cardiovascular outcomes in 28 742 patients with CAD. The 1-year post-PCI incidence of MACE and death was lower in overweight and obese than the underweight and NW patients (HR 0.71 [P = .005] and 0.78 [P = .056], respectively). Faggioni and colleagues10 examined the effects of obesity on cardiovascular mortality, all-cause mortality, and MACE in 11 557 women aged 63 to 70 years with CAD. The patients were classified according to BMI as underweight (BMI < 18.5), NW (BMI 18.5–24.9), overweight (BMI 25–29.9), obese (BMI 30–34.9), or morbidly obese (BMI ≥ 35). After 3 years of post-PCI follow-up, the incidence of MACE and all-cause death were higher only in underweight patients (HR 1.35 and HR 2.20), but not different between NW, overweight, obese, and severely obese patients. In contrast to these studies, other studies have not shown an obesity paradox,11-16 and their data are summarized in Table 2. Coutinho and coworkers11 investigated the association of central obesity expressed by waist circumference and waist to hip ratio compared with BMI on mortality in a review involving 15 923 patients with CAD. Central obesity (waist circumference > 102 cm for men or >88 cm in women, and waist to hip ratio ≥ 0.90 for men and ≥0.85 for women) was associated with increased mortality (HR 1.70), whereas BMI was inversely associated with mortality (HR 0.64). In addition, central obesity was associated with higher mortality in patients with normal and high BMI (HR 1.70 for normal BMI and HR 1.93 for BMI ≥ 30). Akin and colleagues12 investigated the effects of obesity in 5806 patients with CAD after PCI, of whom 2839 were overweight, 1531 were obese, and 1436 were NW. The in-hospital and 1-year incidence of MACE and all-cause mortality was similar between the NW, overweight, and obese patients (7.1%, 5.6%, and 5.5%, respectively) for MACE, and (3.3%, 2.4%, and 2.4%, respectively) for all-cause mortality. Hallberg and colleagues13 studied the effects of obesity on long-term survival in 922 patients with CAD undergoing coronary artery bypass grafting. The 10-year survival was better in the obese (BMI ≥ 30) than the overweight (BMI 25–29.9) and NW (BMI 18.5–24.9) patients. However, the 20-year survival was not different between the groups (HR 0.67, 0.82, and 0.68) for obese, overweight, and NW patients, respectively. In a major review of 299 059 patients, Fan and colleagues14 demonstrated that MHO overweight and MHO patients had a higher incidence of cardiovascular events after a follow-up of ≥15 years (RR 1.47 and 2.00, respectively). Also, NWMU adults had a higher incidence of cardiovascular death (RR 1.55) and all-cause death (RR 1.27). Flegal and colleagues16 analyzed the effects of obesity on all-cause mortality in 2.88 million patients from 97 studies. The summary HRs were 0.94 for overweight patients and 1.18 for all grades of obesity. Similarly, Caleyachetty and colleagues15 analyzed the effects of obesity on the incidence of coronary heart disease, cerebrovascular disease, and HF in 3.5 million individuals free of cardiovascular disease at baseline. They classified them according to BMI as underweight (BMI < 18.5), NW (BMI 18 to <25), overweight (BMI 25 to <30), and obese (BMI ≥ 30), and health status as MHO and MHNW patients if they did not have diabetes mellitus, hypertension, or hyperlipidemia. After a mean follow-up of 5.4 years and multiple adjustments, the HR for MHO for coronary heart disease was 1.49, for cerebrovascular disease was 1.07, and for HF was 1.96 compared with MHNW individuals. The obesity paradox has been reported in patients with hypertension (Table 3). Barrett-Connor and associates19 reported the obesity paradox in 1985 in 1727 patients with systolic hypertension (50–79 years). Obese patients with systolic blood pressure ≥160 mm Hg had lower cardiovascular and ischemic heart disease mortality than nonobese patients with hypertension. Subsequently, other investigators reported similar observations. Uretsky and coworkers20 reported that patients with hypertension with CAD who participated in the INVEST (International Verapamil-Trandolapril Study) had a lower incidence of nonfatal myocardial infarction, nonfatal stroke, or death, if they were overweight (P < .001), class 1 obese, (P < .001), or class 2 or 3 obese (P < .001) compared with NW patients. In a recent review, Esler and colleagues21 explained the obesity paradox on the activity of the sympathetic nervous system by stating that: (1) sympathetic nervous system activity is normal or low in obese persons compared with NW persons, (2) norepinephrine reuptake is normal in obese persons but reduced in NW persons, and (3) there is no sympathetic nerve epinephrine co-release in obese persons compared with sympathetic nerve epinephrine co-release in NW persons. In a recent major review involving 489 222 patients with hypertension, Jayedi and Shab-Bidar22 found a reverse J-shaped association between BMI and risk of all-cause mortality with a nadir for BMI of 27.5 to 30 (RR 0.92), but not for cardiovascular mortality. Because of heterogeneity of the studies, these results should be taken with caution. In a subanalysis by Shah and colleagues23 of 5423 patients from the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) without T2DM or cardiovascular disease at baseline, those who had impaired fasting glucose had higher cardiovascular and all-cause mortality (HR 1.23), whereas obese patients had lower all-cause mortality (HR 0.76). After excluding underweight (BMI < 22 kg/m2) patients and smokers, neither impaired fasting glucose nor obesity were associated with increased all-cause mortality. The obesity paradox has created a major debate regarding the role of obesity as a major risk factor for cardiovascular disease, hypertension, T2DM, and the metabolic syndrome and cardiovascular and all-cause mortality. The major problem with the obesity paradox is the notion that it considers obesity as a benign condition, by using BMI as a measure of total body fat, but not fat distribution.3 An obese athlete by BMI standards is not the same as a similar BMI in an obese sedentary person, and Coutinho and colleauges11 demonstrated that obesity by BMI standards was not associated with higher mortality compared with central obesity. Similarly, previous studies have also shown that central obesity is a better discriminator of cardiovascular risk than BMI.30-33 Also, the evidence from the presented data is weak and several studies have compared obese with underweight persons who are older and have several comorbidities, which could account for their higher mortality. Thus, based on the recent evidence,15, 16 the obesity paradox is a misnomer and could convey the wrong message to the general public that obesity is not bad and it may negate the efforts of national and international committees to stem the tide of obesity,24, 25 so much so that some authors incensed with this problem recommend that journals no longer accept articles about the "obesity paradox.34 The author declares no conflict of interest and that no funds were received for the preparation of this article.