In this study, we explored the association and the time-varying effects of BMI on mortality in patients with hypertension in a large retrospective cohort. Being underweight was associated with a higher risk of all-cause mortality, but the adverse effects of underweight gradually diminished over time. Meanwhile, overweight and class 1 obesity had a protective effect on death in both sexes, but its beneficial effects were also only observed in the first 5 years after registration. However，in the elderly, overweight, class I obesity and class II obesity had continuous protective effects on mortality. To the best of our knowledge, this is the first study to evaluate the time-varying effects of BMI on all-cause mortality in people with hypertension within a long-term follow-up period. Our findings provide useful data for guiding the long-term management of hypertension patients.
Hypertension is a major public health concern worldwide, and thus the risk factors for all-cause mortality in patients with hypertension have become the subject of many studies. Our findings are consistent with those of previous studies that explored the relationship between BMI and all-cause mortality in hypertension patients and found that underweight is a risk factor for all-cause mortality, whereas overweight and obesity have protective effects on survival.[16, 21, 22] Xu et al. found a higher risk of mortality among patients who were underweight (<18.5 kg/m2) than their normal weight counterparts (18.5-24.9 kg/m2) (HR=1.75, 95% CI: 1.63-1.87). Several prospective studies conducted in Japan and other Asian countries have also reached similar conclusions.[23, 24]These findings could be because chronic disease, prior to the diagnosis of hypertension, may lead to weight loss and an increased risk of death. However, the time-varying changes in the HRs of BMI have not been evaluated.
Based on previous studies, this study explored the effects of different BMI categories on the long-term survival of hypertension patients using a time-dependent Cox regression model in a relatively large sample and long-term follow-up cohort. At 1 year after registration, the risk of death for underweight patients was higher than that at 5 and 10 years after registration. This may be because hypertension patients nearing death have poor physical condition and thus seek more aggressive medical management. Thus, more patients were identified and received treatment. Underweight patients who survived medical management may consciously gain weight in search of a higher survival rate, which may explain the weakening of the role of underweight on mortality over time. In addition, at different follow-up time points, even 10 years after registration, the risk of all-cause mortality in underweight patients with hypertension was higher than that of normal weight patients. This ruled out the possible causal inversion of weight loss when impending death in studies of underweight patients with high mortality.
Evidence of the obesity paradox has been found in many cardiovascular disease studies——that is, compared with patients of normal weight, measured by all-cause mortality，overweight and obese patients have improved short-term and long-term survival——including coronary heart disease, myocardial infarction, atrial fibrillation, heart failure as well as hypertension. Most of these studies were conducted in patient cohorts recruited from elderly subjects.[22, 26-30]In 1985, Barrett-Connor and Khaw conducted an index study on 1,727 male patients with hypertension between the ages of 50 and 79, and for the first time proposed that overweight and obesity reduced all-cause mortality.Yang et al. evaluated 20694 hypertension patients aged 45-75 years in China and found that compared with those with normal weight (BMI, 18.5-23.9 kg/m2), the risk for mortality was lower in those who were overweight (BMI, 24.0-27.9 kg/m2) (HR=0.78) and obese (BMI ≥28 kg/m2) (HR=0.64). Jayedi et al. conducted a meta-analysis of a prospective and retrospective cohort study to investigate the relationship between BMI and all-cause mortality in hypertension patients and found the lowest mortality rate in those with a BMI of 27.5-30 kg/m2.Consistent findings were found in the current study that overweight and obesity had protective effects on mortality especially in elderly patients. One of the physiological explanations emphasized that patients who are defined as obese according to the BMI cut-off point may have healthy metabolic characteristics. Compared with non-obese individuals with many risk factors (such as dyslipidemia), obese individuals with healthy metabolic characteristics may have a lower risk of mortality.[34, 35]In addition, a prospective study that measured sympathetic nerve activity in heart failure using the cardiac norepinephrine spillover method found higher activity in normal weight hypertension patients than their obese counterparts. This supports that obese hypertension patients do not experience the toxic effects of sympathetic nerve activation.[30, 36, 37]
Compared with the young and middle-aged patients, relatively stable protective effects of overweight and obesity were shown in the elderly over time. One possible reason is that aging is related to fat redistribution. Although there is evidence that there is a biological advantage in excess fat storage during disease. Body fat may play a role in reducing oxidative stress and inflammation, lowering the level of B-type natriuretic peptide, and improving the secretion of amino acids and adipokines, which may improve the survival rate of obese individuals.[38-40]But with age, body composition will change as fat mass increases and muscle mass decreases. In other words, even if the weight and BMI are the same, the elderly may have more fat mass than the young and middle-aged.Adipose tissue can also produce soluble TNF-α receptor to neutralize the adverse effects of TNF-α, which is related to the worse prognosis of these patients.[42, 43] In addition, aging is related to a significant decrease in energy expenditure and fat oxidation, a decrease in skeletal muscle mass, and an increase in visceral fat accumulation. Therefore, the protective effect of nutritional status in overweight and obese elderly may be the reason for this phenomenon.Besides, it is worth noting that in our study, with the exclusion of the elderly, overweight and class I obesity no longer had significant protective effects compared with normal weight at 10 years after registration. Although overweight still had a protective effect in men at 10 years after registration, the time-varying effects of BMI for both sexes were similar, and the HRs that changed with time increased linearly. Sensitivity analysis also yielded similar results. A possible reason is that the good survival of overweight patients may be related to the high prevalence of relatively benign comorbidities (e.g., well-controlled hypertension). As the follow-up time is extended, the condition deteriorates, and overweight patients no longer have survival advantages. Given that previous studies explaining the obesity paradox did not reveal the time-varying effects of overweight and class I obesity on all-cause mortality in hypertension patients over time, whether overweight and obesity can achieve long-term survival advantages in young and middle-aged patients needs further verification. It is necessary to treat obesity as a time-varying exposure and take into account changes in weight status to understand the relationship between true obesity and mortality.
The primary strength of this study was that a large sample population was followed up for 8 years. The electronic health records of residents in Minhang District provide comprehensive and accurate retrospective cohort data, including demographic information and physiological indicators. Because this is a long-term follow-up study, the Cox PH model with time-varying coefficients may be more suitable for data analysis than the Cox model. The use of RCS to assess time-by-covariate interactions also allowed us to evaluate the PH assumption and evaluate whether the factor’s HR changes linearly or non-linearly with time, which violated the assumption, and then graphically display the correlation between the risk factor and the research outcomes. Furthermore, we adopted the standard BMI classification for Asians, which differs greatly from the Western population in body composition. At a given BMI, the proportion of body fat in the Asian population tends to be higher, thus making them susceptible to cardiovascular disease.Therefore, the results of studies may vary under different populations, races, or BMI classification standards. The BMI classification standard adopted in this study is more suitable for this research population to obtain more accurate conclusions. In addition, we conducted a stratified analysis based on sex and age to eliminate potential confounding effects and further revealed the association between BMI and outcomes in hypertension patients of different sexes and ages.
However, this study also has some limitations. First, the BMI index alone cannot distinguish central obesity from abdominal obesity. Robustness and obesity may also lead to the same BMI, and thus the interpretation of the results may be biased. Second, the number of patients who were underweight or overweight was relatively small, especially after stratified analysis of age. This reduced the statistical power of BMI in different age groups on the time-varying effect of all-cause mortality. Third,the possibility of a selection bias, which may have influenced the results, could not be ruled. Obese patients are more likely to seek treatment and disease management and thus may achieve a higher survival rate. In the future, when further studying the relationship between BMI and mortality in patients with hypertension, we should consider the changes in dynamic BMI or include the body fat percentage in the analysis.