BMI and the Risk of All-Cause Mortality Among Patients with Type 2 Diabetes Mellitus

Cardiology Review® Online, February 2015, Volume 31, Issue 1

Studies have identified lower-than-normal BMIs to be associated with higher mortality in comparison with normal body weight and overweight individuals in patients with coronary artery disease. This has given rise to the term "obesity paradox" in which being overweight/obese confers a survival advantage in individuals that have been diagnosed with a medical condition. Against this backdrop, this study attempted to evaluate whether there is an association between BMI and death risk among patients with type 2 diabetes mellitus.

Saurav Chatterjee, MD

Review

Zhao W, Katzmarzyk PT, Horswell R, et al. Body mass index and the risk of all-cause mortality among patients with type 2 diabetes mellitus. Circulation. 2014;130:2143-2151.

A recent large systematic review identified a lower association of mortality with normal body weight (body mass index [BMI] of 18.5 to <25), overweight (BMI of 25 to <30), and grade 1 obesity (BMI of 30 to <35) compared with both grade 2 obesity (BMI of 35 to <40); and grade 3 obesity (a BMI of ≥40) in the general population.1 Other studies2 have identified lower-than-normal BMIs to be associated with higher mortality in comparison with normal body weight and overweight individuals in patients with coronary artery disease. This has given rise to the term “obesity paradox” in which being overweight/obese confers a survival advantage in individuals that have been diagnosed with a medical condition. Against this backdrop, Zhao et al have attempted to evaluate whether there is an association between BMI and death risk among patients with diabetes mellitus.3

Study Details

In the current study,3 a population of 19,478 black and 15,354 white patients with type 2 diabetes mellitus (all residents of Louisiana, and participants of the Louisiana State University Hospital-Based Longitudinal Study [LSUHLS]) were included in a prospective analysis. Cox proportional hazard regression models were used to estimate the association of different levels of BMI stratification with all-cause mortality. There are several unique features of the present study,3 including the use of administrative data, which included multiple measures of BMI captured over time, large samples of both blacks and whites, and adults with a range of health behaviors.

During a mean follow-up of 8.7 years, 4042 deaths were identified. The multivariable-adjusted (age, sex, smoking, income, and type of insurance) hazard ratios for all-cause mortality associated with BMI levels (18.5-22.9, 23-24.9, 25-29.9, 30-34.9 [reference group], 35-39.9, and ≥40 kg/m2) at baseline were 2.12 (95% confidence interval [CI], 1.80-2.49), 1.74 (95% CI, 1.46-2.07), 1.23 (95% CI, 1.08-1.41), 1.00, 1.19 (95% CI, 1.03-1.39), and 1.23 (95% CI, 1.05-1.43) for blacks, and 1.70 (95% CI, 1.42-2.04), 1.51 (95% CI, 1.27-1.80), 1.07 (95% CI, 0.94-1.21), 1.00, 1.07 (95% CI, 0.93-1.23), and 1.20 (95% CI, 1.05-1.38) for whites, respectively. When adjusted for smoking, income, type of insurance, and other cardiovascular disease risk factors (A1C, low-density lipoprotein cholesterol, systolic blood pressure, estimated glomerular filtration rate, use of antihypertensive drugs, glucose-lowering agents, and cholesterol-lowering agents) a U-shaped association was still present. When BMI was included in the Cox model as a time-dependent variable, the U-shaped association of BMI with all-cause mortality risk did not change. This U-shaped association did not change among white and black patients with diabetes mellitus. The risk nadir of the U-shaped association of BMI with all-cause mortality was observed at a BMI of 30 to 35 kg/m2.

In summary, the study by Zhao et al revealed a U-shaped association between BMI and all-cause mortality risk among black and white patients with type 2 diabetes mellitus. A significantly increased risk of all-cause mortality was observed among blacks with BMI <30 kg/m2 and ≥35 kg/m2, and among whites with BMI <25 kg/m2 and ≥40 kg/m2, compared with patients with BMI of 30 to 34.9 kg/m2.

COMMENTARY

How should we counsel patients with diabetes about body weight?

This is an important study that used administrative data from the Louisiana State University Health Care Services Division, which covers approximately 35% of the population of the state of Louisiana. The study reveals a U-shaped all-cause mortality curve among patients with diabetes mellitus, with a risk nadir at approximately 30 to 35 kg/m2 for blacks and approximately 25 to 40 kg/m2 for whites. Although weight reduction should be of benefit in reducing all-cause mortality among obese patients with diabetes, this study, and others like it, raises the question of how to counsel, with respect to body weight, patients with diabetes.

Potential methodological limitations remain in the assessment of the associations between obesity and health outcomes. The most serious concern is an apparent spurious “reverse causation” associated with total mortality.4 People with a history of chronic comorbidities including cardiovascular diseases or cancer frequently lose weight; thus, people with a lower weight might increase the estimated risk of death. The authors accounted for this by excluding patients with a history of coronary heart disease and cancer (which could minimize the influence of reverse causation). U-shaped associations did not change. Additionally, the authors performed another sensitivity analysis by excluding the subjects who died during the first 2 years of follow-up, and the U-shaped association was still present. Another major concern is the adequate control for confounding factors and potential overadjustment for the physiological effects of excess fatness such as hypertension, diabetes mellitus, and dyslipidemia, which were controlled for statistically in multivariable analyses, thus artificially removing some of the effects of being overweight. Furthermore, when the authors restricted the analysis to subjects who had never smoked, the results did not change.

This study represents the largest sample of blacks included in a study testing the hypothesis of the obesity paradox. Although other studies have tested whether the relationship between BMI and mortality varied by race,5 no studies in the past have described a different nadir of mortality for blacks compared with whites. In the LSUHLS, the lowest risk for mortality was observed in the BMI range of 30 to 35 kg/m2 in blacks, but at a lower level (25 to 30 kg/m2) in whites. The finding assumes greater significance given that blacks are more likely to be obese than their white counterparts.6 An editorial7 recommends that these findings should be used to justify adherence to recommendations for cardiovascular disease risk factor control in patients who may be at lower risk because of the absence of obesity.

The results of the study should be interpreted in light of the following limitations, as acknowledged largely by the authors themselves.3 One limitation of the study is that the analysis was not performed on a representative sample of the population, which limits the generalizability of this study. More than 45,000 patients with diabetes mellitus were excluded in the present study because of missing data on the required variables, and these patients were younger, were less often black, and were less often male compared with the patients with type 2 diabetes mellitus included in the study. Excluding these patients might have introduced a potential selection bias. Third, the authors did not have information on specific causes of death for all patients and could not assess cardiovascular and cancer morality as a separate end point. Fourth, although specially trained nurses measured body weight at each clinical visit, clinically measured BMI might not be as accurate as BMI measured in carefully conducted laboratory studies. Fifth, even though the analyses adjusted for an extensive set of confounding factors, residual confounding resulting from measurement error in the assessment of confounding factors, unmeasured factors such as physical activity, education, and dietary factors, could not be excluded.

While this current study elucidates certain aspects of the obesity paradox, there still remains a need to reevaluate the long-term effects of weight loss on mortality risk among patients with type 2 diabetes. The meessage7 from the current report should be that all persons with diabetes mellitus, regardless of weight status, should be treated aggressively to mitigate health risks.

References

1. Flegal KM, Kit BK, Oprana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2012;309(1):71-82.

2. Sharma A, Chatterjee S, Wu W, Lichstein E. Risk of cardiac mortality and myocardial infarctions in BMI<20 kg/m2: can rates of myocardial infarctions explain the higher cardiac mortality? J Am Coll Cardiol. 2013;61(10_S). doi:10.1016/S0735-1097(13)61533-8.

3. Zhao W, Katzmarzyk PT, Horswell R, et al. Body mass index and the risk of all-cause mortality among patients with type 2 diabetes. Circulation. 2014;130:2143-2151.

4. Hu G, Heymsfield SB. Is mortality risk reduced in overweight or obese diabetics? J Gen Intern Med. 2014;29:3-4.

5. Carnethon MR, De Chavez PJ, Biggs ML, et al. Association of weight status with mortality in adults with incident diabetes. JAMA. 2012;308:581-590.

6. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295:1549-1555.

7. Carnethon MR. Diabetes in the absence of obesity: a risky condition. Circulation. 2014;130:2031-2032.

About the Author

Saurav Chatterjee, MD, is Clinical and Research Fellow in Cardiology at Mount Sinai St Luke’s Hospital in New York City. He graduated from Calcutta National Medical College with honors and was a Resident in cardiology in Mercy Hospital, Kolkata, India, as well as trial coordinator of the CRESCENDO trial in Kolkata, India. He recently completed his residency in Internal Medicine from Maimonides Medical Center in Brooklyn, NY, and was Clinical and Research Fellow in Preventive Cardiology and Outcomes Research at Brown University and Providence VAMC in Providence, RI. Dr Chatterjee is the recipient of the 2012 Young Investigator Award for Health Outcomes and Population Genetics at the Annual Scientific Sessions of the American College of Cardiology 2012 in Chicago, and also the 2011 American Association of Cardiologists of Indian Origin (AACIO) Young Investigator Award for Interventional Cardiology and Electrophysiology.