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. Author manuscript; available in PMC: 2015 Dec 9.
Published in final edited form as: Circulation. 2014 Nov 5;130(24):2143–2151. doi: 10.1161/CIRCULATIONAHA.114.009098

Body Mass Index and the Risk of All-Cause Mortality Among Patients with Type 2 Diabetes

Wenhui Zhao 1,2, Peter T Katzmarzyk 1, Ronald Horswell 1, Yujie Wang 1,3, Weiqin Li, Jolene Johnson 1,4, Steven B Heymsfield 1, William T Cefalu 1, Donna H Ryan 1, Gang Hu 1
PMCID: PMC4302029  NIHMSID: NIHMS634035  PMID: 25378546

Abstract

Background

Several prospective studies have evaluated the association between body mass index (BMI) and death risk among patients with diabetes; however, the results have been inconsistent.

Methods and Results

We performed a prospective cohort study of 19,478 African American and 15,354 white patients with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of different levels of BMI stratification with all-cause mortality. During a mean follow up of 8.7 years, 4,042 deaths were identified. The multivariable-adjusted (age, sex, smoking, income and type of insurance) hazard ratios (HRs) 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 (1.46–2.07), 1.23 (1.08–1.41), 1.00, 1.19 (1.03–1.39), and 1.23 (1.05–1.43) for African Americans, and 1.70 (1.42–2.04), 1.51 (1.27–1.80), 1.07 (0.94–1.21), 1.00, 1.07 (0.93–1.23), and 1.20 (1.05–1.38) for whites, respectively. When stratified by age, smoking status, patient types or use of anti-diabetic drugs, 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.

Conclusions

The current study indicated a U-shaped association of BMI with all-cause mortality risk among African American and white patients with type 2 diabetes. A significantly increased risk of all-cause mortality was observed among African Americans with BMI<30 kg/m2 and BMI ≥35 kg/m2, and among whites with BMI<25 kg/m2 and BMI ≥40 kg/m2 compared with patients with BMI 30–34.9 kg/m2.

Keywords: all-cause death, body mass index, cohort study, type 2 diabetes

Diabetes is considered “the epidemic of the 21st century”, affecting approximately 26 million individuals in the US alone, or nearly 12% of the US population.1 Obesity is associated with the development of type 2 diabetes,2 and approximately 45–65 % patients with type 2 diabetes are obese in the US.3 However, the relationship between body mass index (BMI) and mortality among patients with established diabetes is unclear. Some studies provide supportive information of inverse associations,3–7 other studies have reported positive associations,8,9 U-shaped associations,10–12 or no association13 between BMI and mortality among patients with diabetes. The reasons for the difference in associations across studies are not clear; however, the study samples differed at baseline by mean BMI, health status, ethnicity, and duration of diabetes. Moreover, many previous studies had small samples, and thus lacked adequate statistical power when the analysis was focused on those who are extremely obese (BMI ≥40 kg/m2). In addition, most epidemiological studies only use a single measurement of BMI at baseline to predict risk of all-cause mortality, which may produce potential bias. The aim of the present study is to examine the race-specific association between different levels of BMI at baseline and during follow-up with the risk of all-cause mortality among patients with type 2 diabetes in the Louisiana State University Hospital-Based Longitudinal Study (LSUHLS).

Methods

Study Population

Between 1997 and 2012, LSU Health Care Services Division (LSUHCSD) operated seven public hospitals and affiliated clinics in Louisiana, which provided quality medical care to the residents of Louisiana regardless of their income or insurance coverage.14–24 Overall, LSUHCSD facilities have served about 1.6 million patients (35% of the Louisiana population) since 1997. Administrative, anthropometric, laboratory (test code, test collection date, test result values, and abnormal flag), clinical diagnosis, and medication data collected at these facilities are available in electronic form for both inpatients and outpatients from 1997. Using these data, we have established the LSUHLS.14 A cohort of patients with diabetes was established by using the ICD-9 (code 250) through the LSUHLS database between January 1, 1999, and December 31, 2009. Both inpatients and outpatients were included and all patients were under primary care. LSUHCSD’s internal diabetes disease management guidelines call for physician confirmation of diabetes diagnoses by applying the American Diabetes Association criteria: a fasting plasma glucose level ≥126 mg/dl; 2-hour glucose level ≥200 mg/dl after a 75-g 2-hour oral glucose tolerance test (OGTT); one or more classic symptoms plus a random plasma glucose level ≥200 mg/dl.25 The first record of diabetes diagnosis was used to establish the baseline for each patient in the present analyses due to the design of the cohort study. Before diagnosis with diabetes, these patients have used our system for an average of 5.0 years. We have validated the diabetes diagnosis in LSUHCSD hospitals. The agreement of diabetes diagnosis was 97%: 20,919 of a sample of 21,566 hospital discharge diagnoses based on ICD codes also had physician-confirmed diabetes using the ADA diabetes diagnosis criteria.25

After excluding patients with incomplete data of BMI measurement (N=19,201), smoking information (N=12,309), treatment information (N=12,219), and other required variables for analysis (all variables listed in Table 1) (N=1488), and the patients with only one BMI measurement (N=84), the present study included 34,832 patients with type 2 diabetes (15,354 white and 19,478 African American) who were 30 to 94 years of age with complete repeated data on all risk factor variables. Patients were excluded if they were underweight (BMI <18.5) because these patients may have other comorbidities. In these 34,832 patients with diabetes, about 77.3% of patients qualify for free care (by virtue of being low income and uninsured – any individual or family unit whose income is at or below 200% of Federal Poverty Level), about 4.9% of patients are self-pay (uninsured, but incomes not low enough to qualify for free care), about 5.2% of patients are covered by Medicaid, about 10.4% of patients have Medicare, and about 2.2% of patients are covered by commercial insurance. Compared with patients with diabetes excluded in the present study (45,301) due to missing data on any required variables or having only one BMI measurement, the patients with type 2 diabetes included in the present study were younger (52.3 vs. 54.4 years old), had less African Americans (56.0% vs. 59.2%), and less males (37.8% vs. 42.0%). The study and analysis plan were approved by Pennington Biomedical Research Center and LSU Health Sciences Center Institutional Review Boards, LSU System. We did not obtain informed consent from participants involved in our study because we used anonymized data compiled from electronic medical records.

Table 1.

Baseline characteristics according to body mass index categories among African American and white patients with type 2 diabetes

Body mass index (kg/m2)
18.5–22.9 23–24.9 25–29.9 30–34.9 35–39.9 ≥40 P value
African American
No. of participants 1,150 1,168 4,599 4,944 3,576 4,041
Male, % 52.4 48.9 43.3 37.2 28.4 20.8 <0.001
Age, mean (SD), yr 52.9 (11.0) 53.1 (11.0) 53.0 (10.3) 51.8 (9.9) 50.4 (9.6) 47.7 (9.4) <0.001
Income, mean (SD), $/family 18,102 (31,424) 18,132 (29,809) 18,099 (28,181) 19,122 (27,822) 18,976 (26957) 18,984 (25,970) 0.42
Systolic BP, mean (SD), mm Hg 140 (27) 142 (25) 145 (24) 147 (24) 148 (25) 150 (25) <0.001
HbA1c, mean (SD), % 8.26 (3.1) 8.22 (3.0) 8.12 (2.8) 7.99 (2.6) 7.98 (2.5) 7.68 (2.4) <0.001
LDL cholesterol, mean (SD), mg/dL 109 (44) 111 (40) 114 (42) 116 (41) 115 (39) 113 (37) <0.001
Glomerular filtration rate (mL/min/1.73 m2), % <0.001
  ≥90 57.5 58.0 54.3 51.7 51.9 54.7
  60–89 30.3 30.5 33.5 37.2 37.6 36.1
  30–59 9.9 9.2 10.0 9.7 9.2 8.1
  15–29 1.4 1.0 1.4 1.1 1.0 0.8
  <15 0.9 1.3 0.8 0.5 0.3 0.3
Smoking status, % <0.001
  Never smoking 43.7 54.9 63.3 68.9 72.8 78.3
  Past smoking 8.4 7.5 7.4 6.5 6.9 6.6
  Current smoking 47.9 37.7 29.3 24.6 20.3 15.1
Type of insurance, % <0.001
  Free 71.2 74.2 76.1 78.3 79.8 82.6
  Self-pay 8.5 7.2 6.4 6.1 5.1 4.3
  Medicaid 8.5 7.5 6.0 5.2 5.7 6.1
  Medicare 10.4 10.0 9.8 8.8 7.2 5.1
  Commercial 1.3 1.0 1.6 1.6 2.0 1.9
Patients types <0.001
  Outpatients only 35.2 39.6 47.7 50.1 51.0 48.0
  Outpatients and inpatients 64.8 60.4 52.3 49.9 49.0 52.0
Uses of medications, N %
  Glucose-lowering medication 56.1 60.2 64.4 67.5 69.2 69.4 <0.001
    Oral hypoglycemic agents 23.2 27.1 33.4 34.5 34.5 36.7
    Insulin* 32.9 33.1 31.0 33.0 34.7 32.7
  Lipid-lowering medication 41.3 49.3 54.6 58.4 58.5 55.2 <0.001
  Antihypertensive medication 65.6 70.0 73.1 76.8 78.4 78.7 <0.001
White
No. of participants 688 824 3,375 3,919 2,951 3,597
Male, % 44.6 48.1 48.3 44.2 38.3 29.9 <0.001
Age, mean (SD), yr 55.1 (12.9) 56.7 (11.9) 56.1 (10.8) 54.6 (9.9) 52.9 (9.5) 50.2 (9.2) <0.001
Income, mean (SD), $/family 19,799 (30,131) 21,264 (30,145) 20,678 (28,521) 19,496 (25,136) 19,955 (24,698) 19,596 (22,661) 0.252
Systolic BP, mean (SD), mm Hg 134 (24) 136 (22) 139 (23) 141 (22) 142 (22) 145 (22) <0.001
HbA1c, mean (SD), % 7.39 (2.5) 7.39 (2.4) 7.33 (2.1) 7.33 (2.1) 7.29 (2.0) 7.16 (1.9) 0.002
LDL cholesterol, mean (SD), mg/dL 107 (39) 113 (45) 112 (43) 110 (42) 109 (39) 108 (37) <0.001
Glomerular filtration rate (mL/min/1.73 m2), % <0.001
  ≥90 41.3 39.8 34.2 33.9 35.7 37.8
  60–89 40.5 42.1 47.5 47.8 48.0 47.4
  30–59 15.4 16.7 16.6 17.1 14.8 13.5
  15–29 1.9 1.0 1.2 1.1 1.2 1.0
  <15 0.9 0.4 0.6 0.2 0.3 0.3
Smoking status, % <0.001
  Never smoking 43.8 52.0 59.6 63.6 67.5 69.0
  Past smoking 8.9 6.9 6.9 7.6 7.6 8.4
  Current smoking 47.3 41.1 33.5 28.8 24.9 22.7
Type of insurance, % <0.001
  Free 66.8 68.2 72.0 75.3 78.7 82.7
  Self-pay 4.2 4.5 4.1 3.8 3.6 3.2
  Medicaid 5.4 4.3 3.5 3.5 4.3 4.4
  Medicare 20.4 20.2 17.3 14.1 10.6 7.3
  Commercial 3.2 2.9 3.1 3.4 2.8 2.4
Patients types <0.001
  Outpatients only 40.4 44.4 48.2 47.8 46.0 46.0
  Outpatients and inpatients 59.6 55.6 51.8 52.2 54.0 54.0
Uses of medications, N %
  Glucose-lowering medication 47.0 51.3 57.7 61.5 65.0 66.0 <0.001
    Oral hypoglycemic agents 21.4 28.2 34.6 35.7 35.1 37.5
    Insulin 25.6 23.1 23.1 25.8 29.9 28.5
  Lipid-lowering medication 42.7 51.9 56.5 61.9 61.4 58.0 <0.001
  Antihypertensive medication 55.1 60.8 67.1 71.1 72.0 73.2 <0.001
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Data are mean (standard deviation) or percentage; all continuous variables are adjusted for age and sex, except for age (adjusted for sex only).

*

Insulin group included patients who used insulin only and used both insulin and oral hypoglycemic agents.

Baseline and follow-up measurements

The patient’s characteristics, including age of diabetes diagnosis, sex, race/ethnicity, family income, smoking status, types of health insurance, body weight, height, body mass index (BMI), blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, HbA1c, estimated glomerular filtration rate (eGFR), and medication (antihypertensive drug, cholesterol lowering drug and anti-diabetic drug) within a half year before or after the diabetes diagnosis (baseline), and during follow-up after the diabetes diagnosis (follow-up) were extracted from the computerized hospitalization records. Using a set of questions about smoking status at each clinical visit, the patients were classified into three groups: current smokers, past smokers (stopping smoking at least 6 months), and never smokers.

At all 7 public hospitals and affiliated clinics, specially trained nurses measured height, weight, and blood pressure. Height was measured without shoes and weight was measured with light clothing. BMI was calculated by dividing weight in kilograms by the square of height in meters. For the present analysis, we chose the BMI measures within a half year before the diagnosis of diabetes as baseline measurement. The mean values of BMI and other measurements (HbA1c, LDL cholesterol, blood pressure and eGFR) were calculated for each participant for each year of follow up. For example, at year one the mean is the average of one year values and at three year it is the average of three year values. In the case of a death event during follow-up, the last year for estimating mean values was the year before the death occurred. The last value of BMI was the last measurement of BMI before death occurred, or before the end of follow-up (June 30, 2013). The average number of BMI measurements during the follow-up period was 15.0 (median 11; interquartile range 5–21).

Prospective follow-up

Follow-up information was obtained from the LSUHLS inpatient and outpatient database by using the unique number assigned to every patient who visits the LSUHCSD hospitals. The diagnosis of all-cause death was the primary endpoint of interest of the study. Mortality outcomes were assessed by linkage with the State Center for Health Statistics at Louisiana’s Office of Public Health (the Louisiana Office of Public Health Vital Records Registry). Follow-up of each cohort member continued until the date of the death, or June 30, 2013.

Statistical analyses

The association between BMI and all-cause mortality was analyzed by using Cox proportional hazards models. BMI was evaluated in the following 2 ways: (1) as 6 categories (BMI <23, 23–24.9, 25–29.9, 30–34.9 [reference group], 35–39.9, and ≥40 kg/m2), and (2) as a continuous variable. Different categories of BMI were included in the models as dummy and categorical variables. A time-dependent Cox model was used to handle the multiple observations of BMI for each subject with the counting process style of input.26 The proportional hazards assumption in the Cox model was assessed with graphical methods, and with models including time-by-covariate interactions.27 In general, all proportionality assumptions were appropriate. All analyses were adjusted for age and sex, and further for smoking, income, and type of insurance. We stratified the samples by race because there was a significant interaction between race and BMI on all-cause mortality. To avoid the potential bias due to occult disease at baseline, additional analyses were carried out excluding the subjects who died during the first two years of follow-up. We used the restricted cubic spline nested in time-dependent Cox models to test whether there is a dose-response or non-linear association of BMI as a continuous variable with all-cause mortality risk.28 Statistical significance was considered to be P<0.05. All statistical analyses were performed with PASW for Windows, version 20.0 (IBM SPSS Inc, Chicago, III) and SAS for Windows, version 9.3 (SAS Institute, Cary, NC).

Results

General characteristics of the study population are presented by race in Table 1 and by smoking status in Online table 1–3. During a mean follow-up period of 8.7 years, 4,042 subjects (1,946 African American and 2,096 White) died. All-cause mortality among African Americans (11.5/1000 person-years) was lower than white (16.4/1000 person-years). There was a significantly increased risk of all-cause mortality observed among African Americans with baseline BMI<30 kg/m2 and BMI ≥35 kg/m2, and among whites with BMI<25 kg/m2 and BMI ≥40 kg/m2 compared with patients with baseline BMI 30–34.9 kg/m2 (Table 2). After further adjustment for smoking, income, type of insurance, and other CVD risk factors (HbA1c, LDL cholesterol, systolic blood pressure, eGFR, use of antihypertensive drugs, glucose-lowering agents, and cholesterol-lowering agents), this U-shaped association did not change among white and African American patients with diabetes. When BMI was considered as a continuous variable by using restricted cubic splines, a nadir of the U-shaped association of BMI with all-cause mortality was observed at BMI of 30–35 kg/m2 (Table 2 and Figure 1).

Table 2.

Hazard ratio of all-cause mortality according to different levels of BMI at baseline and during follow-up among African American and white patients with type 2 diabetes

Body mass index (kg/m2)
18.5–22.9 23–24.9 25–29.9 30–34.9 35–39.9 ≥40
Baseline
African American 1,150 1,168 4,599 4,944 3,576 4,041
  No. of deaths 232 187 521 408 298 300
  Person-years 4,599 10,320 41,747 45,060 31,775 36,069
  Age- and sex-adjusted mortality rate/10,000 person-years* 252 169 149 111 117 126
  Age and sex adjusted HR (95% CI) 2.36 (2.01–2.78) 1.81 (1.52–2.15) 1.28 (1.12–1.45) 1.00 1.20 (1.03–1.40) 1.26 (1.08–1.46)
  Multivariable adjusted HR (95% CI)† 2.12 (1.80–2.49) 1.74 (1.46–2.07) 1.23 (1.08–1.41) 1.00 1.19 (1.03–1.39) 1.23 (1.05–1.43)
  Multivariable adjusted HR (95% CI)‡ 1.95 (1.64–2.32) 1.70 (1.42–2.04) 1.23 (1.07–1.41) 1.00 1.20 (1.02–1.40) 1.22 (1.04–1.43)
White 688 824 3,375 3,919 2,951 3,597
  No. of deaths 162 173 520 494 351 396
  Person-years 5,321 6,590 27,760 32,726 24,969 30,219
  Age- and sex-adjusted mortality rate/10,000 person-years* 304 249 203 177 160 211
  Age and sex adjusted HR (95% CI) 1.97 (1.65–2.35) 1.53 (1.29–1.82) 1.09 (0.97–1.24) 1.00 1.07 (0.93–1.23) 1.22 (1.06–1.39)
  Multivariable adjusted HR (95% CI)† 1.70 (1.42–2.04) 1.51 (1.27–1.80) 1.07 (0.94–1.21) 1.00 1.07 (0.93–1.23) 1.20 (1.05–1.38)
  Multivariable adjusted HR (95% CI)‡ 1.57 (1.30–1.90) 1.46 (1.22–1.75) 1.01 (0.89–1.14) 1.00 1.05 (0.91–1.21) 1.18 (1.03–1.36)
Follow-up using time-dependent models
African American
  Age and sex adjusted HR (95% CI) 2.64 (2.25–3.10) 2.08 (1.75–2.46) 1.38 (1.22–1.58) 1.00 1.15 (0.99–1.35) 1.38 (1.19–1.61)
  Multivariable adjusted HR (95% CI)† 2.37 (2.01–2.78) 1.95 (1.65–2.32) 1.34 (1.18–1.53) 1.00 1.14 (0.97–1.33) 1.35 (1.15–1.57)
  Multivariable adjusted HR (95% CI)‡ 2.18 (1.84–2.59) 2.02 (1.69–2.41) 1.35 (1.18–1.55) 1.00 1.17 (0.99–1.37) 1.35 (1.15–1.58)
White
  Age and sex adjusted HR (95% CI) 2.14 (1.80–2.55) 1.47 (1.23–1.76) 1.14 (1.01–1.29) 1.00 1.05 (0.91–1.20) 1.17 (1.02–1.34)
  Multivariable adjusted HR (95% CI)† 1.88 (1.58–2.24) 1.37 (1.15–1.63) 1.12 (0.99–1.27) 1.00 1.04 (0.91–1.20) 1.15 (1.01–1.32)
  Multivariable adjusted HR (95% CI)‡ 1.77 (1.47–2.14) 1.31 (1.09–1.58) 1.10 (0.97–1.24) 1.00 1.01 (0.88–1.17) 1.19 (1.03–1.37)
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Abbreviations: HR, hazard ratio; CI, confidence interval.

*

Adjusted for age and sex by the direct method to the year 2010 US Census population.

†

Adjusted for age, sex, type of insurance, income, and smoking.

‡

Adjusted for age, sex, type of insurance, income, smoking, HbA1c, low-density lipoprotein cholesterol, systolic blood pressure, glomerular filtration rate, use of antihypertensive drugs, glucose-lowering agents, and cholesterol-lowering agents.

Figure 1.

Figure 1

Figure 1

Figure 1

Figure 1

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Hazard ratios for all-cause mortality based on different levels of BMI at baseline and during follow-up among African American and white patients with type 2 diabetes. Adjusted for age, sex, type of insurance, income, and smoking.

A total of 84 patients were excluded in the present study due to only one BMI measurement, and these patients might die shortly after their first BMI measurement. To avoid this potential bias, we did an analysis on all diabetic patients with at least one BMI measurement. The multivariable-adjusted (age, sex, smoking, income and type of insurance) hazard ratios (HRs) of 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] 1.80–2.50), 1.74 (1.46–2.07), 1.23 (1.08–1.40), 1.00, 1.19 (1.02–1.38), and 1.22 (1.05–1.42) for African Americans, and 1.69 (1.41–2.02), 1.50 (1.26–1.79), 1.06 (0.94–1.20), 1.00, 1.06 (0.93–1.22), and 1.19 (1.04–1.36) for whites, respectively.

The U-shaped association BMI with all-cause mortality was confirmed among African American and white patients with diabetes who were never smokers (Tables 3 and 4). When stratified by age, sex, use of antidiabetic drugs, and patient types (outpatients and inpatients), this U-shaped association was still present in some of the subgroups (Tables 3 and 4).

Table 3.

Hazard ratio of all-cause mortality according to different levels of BMI at baseline and during follow-up among African American patients with diabetes of various subpopulations

Body mass index (kg/m2)
18.5–22.9 23–24.9 25–29.9 30–34.9 35–39.9 ≥40
Baseline
Sex
  Male 2.04 (1.63–2.55) 1.77 (1.41–2.24) 1.12 (0.93–1.35) 1.00 1.37 (1.10–1.72) 1.11 (0.85–1.44)
  Female 2.19 (1.71–2.79) 1.65 (1.27–2.16) 1.38 (1.15–1.65) 1.00 1.10 (0.90–1.34) 1.28 (1.06–1.55)
Age groups, yr
  <50 2.42 (1.80–3.24) 2.22 (1.65–2.98) 1.16 (0.90–1.48) 1.00 1.21 (0.93–1.57) 1.07 (0.83–1.39)
  50–59 1.76 (1.32–2.34) 1.76 (1.31–2.36) 1.20 (0.97–1.49) 1.00 1.02 (0.79–1.31) 1.19 (0.93–1.52)
  60–94 2.43 (1.85–3.20) 1.52 (1.11–2.10) 1.40 (1.13–1.74) 1.00 1.36 (1.04–1.76) 1.30 (0.97–1.75)
Smoking status
    Never 2.55 (1.93–3.37) 1.95 (1.48–2.58) 1.39 (1.14–1.70) 1.00 1.26 (1.01–1.58) 1.61 (1.30–2.00)
    Ever 1.74 (0.82–3.66) 0.79 (0.23–2.69) 1.08 (0.59–1.97) 1.00 1.27 (0.63–2.54) 1.06 (0.51–2.20)
    Current 1.70 (1.21–2.37) 1.44 (1.00–2.08) 1.05 (0.77–1.42) 1.00 1.28 (0.90–1.83) 0.99 (0.64–1.52)
Using glucose-lowering agents
  No 1.86 (1.50–2.31) 1.71 (1.37–2.14) 1.27 (1.07–1.50) 1.00 1.21 (0.99–1.47) 1.17 (0.96–1.43)
  Oral hypoglycemic agents 2.00 (1.29–3.09) 1.60 (1.00–2.57) 1.11 (0.80–1.55) 1.00 0.94 (0.62–1.41) 1.26 (0.85–1.86)
  Insulin 2.45 (1.79–3.35) 1.72 (1.21–2.44) 1.25 (0.97–1.61) 1.00 1.29 (0.98–1.71) 1.35 (1.02–1.80)
Patient types
  Outpatients only 2.29 (1.56–3.36) 2.07 (1.39–3.09) 1.40 (1.05–1.87) 1.00 1.45 (1.05–2.00) 1.53 (1.10–2.13)
  Inpatients and outpatients 1.86 (1.55–2.23) 1.52 (1.25–1.84) 1.16 (1.01–1.35) 1.00 1.14 (0.96–1.34) 1.10 (0.93–1.31)
Follow-up using time-dependent models
Sex
  Male 2.62 (2.09–3.28) 2.12 (1.67–2.69) 1.43 (1.18–1.73) 1.00 1.46 (1.15–1.85) 1.46 (1.12–1.9)
  Female 2.16 (1.69–2.75) 1.80 (1.40–2.31) 1.29 (1.08–1.55) 1.00 0.95 (0.78–1.17) 1.25 (1.04–1.51)
Age groups, yr
  <50 2.60 (1.94–3.47) 2.28 (1.69–3.07) 1.20 (0.94–1.54) 1.00 1.11 (0.85–1.45) 1.13 (0.87–1.46)
  50–59 2.18 (1.64–2.89) 2.09 (1.56–2.79) 1.32 (1.06–1.64) 1.00 1.12 (0.86–1.45) 1.36 (1.06–1.75)
  60–94 2.52 (1.93–3.31) 1.79 (1.33–2.42) 1.54 (1.24–1.91) 1.00 1.13 (0.85–1.51) 1.43 (1.07–1.92)
Smoking status
    Never 2.87 (2.19–3.75) 1.99 (1.51–2.63) 1.50 (1.23–1.82) 1.00 1.17 (0.93–1.48) 1.67 (1.34–2.07)
    Ever 1.58 (0.63–3.91) 2.91 (1.26–6.68) 1.60 (0.84–3.05) 1.00 2.03 (0.99–4.19) 1.33 (0.60–2.96)
    Current 2.24 (1.59–3.15) 1.79 (1.23–2.61) 1.37 (1.00–1.88) 1.00 1.33 (0.91–1.96) 1.27 (0.81–1.99)
Using glucose-lowering agents
  No 1.97 (1.60–2.43) 1.82 (1.46–2.28) 1.28 (1.08–1.52) 1.00 1.06 (0.86–1.30) 1.26 (1.03–1.53)
  Oral hypoglycemic agents 2.51 (1.63–3.89) 2.20 (1.41–3.44) 1.45 (1.04–2.04) 1.00 1.04 (0.67–1.61) 1.58 (1.05–2.38)
  Insulin 2.91 (2.11–3.99) 1.97 (1.40–2.78) 1.40 (1.08–1.81) 1.00 1.32 (0.99–1.76) 1.39 (1.04–1.86)
Patient types
  Outpatients only 2.42 (1.68–3.48) 2.17 (1.49–3.15) 1.21 (0.91–1.60) 1.00 1.16 (0.83–1.61) 1.52 (1.10–2.10)
  Inpatients and outpatients 2.08 (1.74–2.50) 1.71 (1.41–2.08) 1.32 (1.14–1.53) 1.00 1.11 (0.93–1.32) 1.23 (1.03–1.46)
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Adjusted for age, sex, race, type of insurance, income, and smoking at baseline (in the baseline analyses), during follow-up (in the follow-up analyses) and at last visit (in the last visit analyses), other than the variable for stratification.

Table 4.

Hazard ratio of all-cause mortality according to different levels of BMI at baseline and during follow-up among white patients with diabetes of various subpopulations

Body mass index (kg/m2)
18.5–22.9 23–24.9 25–29.9 30–34.9 35–39.9 ≥40
Baseline
Sex
  Male 1.69 (1.32–2.18) 1.67 (1.33–2.10) 1.12 (0.95–1.32) 1.00 1.09 (0.89–1.32) 1.12 (0.92–1.38)
  Female 1.67 (1.29–2.16) 1.33 (1.02–1.74) 1.00 (0.83–1.21) 1.00 1.05 (0.87–1.28) 1.25 (1.04–1.50)
Age groups, yr
  <50 1.60 (1.09–2.36) 1.45 (0.95–2.20) 1.15 (0.86–1.54) 1.00 0.95 (0.70–1.29) 0.96 (0.73–1.26)
  50–59 1.62 (1.13–2.33) 1.41 (1.01–1.98) 1.09 (0.87–1.36) 1.00 1.17 (0.93–1.47) 1.30 (1.04–1.61)
  60–94 1.90 (1.48–2.43) 1.75 (1.38–2.21) 1.12 (0.94–1.33) 1.00 0.99 (0.80–1.22) 1.13 (0.90–1.42)
Smoking status
    Never 1.71 (1.25–2.35) 1.28 (0.97–1.70) 0.99 (0.82–1.20) 1.00 0.99 (0.80–1.21) 1.28 (1.05–1.56)
    Ever 1.53 (0.70–3.37) 0.62 (0.17–2.29) 0.67 (0.37–1.23) 1.00 0.70 (0.36–1.36) 1.28 (0.72–2.29)
    Current 1.73 (1.21–2.46) 1.61 (1.14–2.28) 1.09 (0.84–1.42) 1.00 1.14 (0.84–1.57) 1.31 (0.95–1.79)
Using glucose-lowering agents
  No 1.73 (1.40–2.14) 1.44 (1.15–1.79) 1.09 (0.93–1.28) 1.00 1.19 (0.99–1.41) 1.17 (0.98–1.40)
  Oral hypoglycemic agents 1.42 (0.81–2.48) 1.82 (1.21–2.75) 1.20 (0.89–1.61) 1.00 1.04 (0.73–1.48) 1.82 (1.31–2.53)
  Insulin 1.23 (0.78–1.93) 1.29 (0.86–1.94) 0.88 (0.66–1.16) 1.00 0.87 (0.66–1.15) 0.96 (0.73–1.25)
Patient types
  Outpatients only 1.84 (1.30–2.61) 1.10 (0.75–1.62) 0.90 (0.71–1.16) 1.00 1.01 (0.77–1.34) 1.29 (0.98–1.70)
  Inpatients and outpatients 1.52 (1.23–1.87) 1.58 (1.30–1.92) 1.13 (0.98–1.31) 1.00 1.06 (0.90–1.24) 1.12 (0.96–1.31)
Follow-up using time-dependent models
Sex
  Male 2.15 (1.69–2.73) 1.44 (1.14–1.82) 1.21 (1.03–1.42) 1.00 1.07 (0.88–1.30) 1.09 (0.88–1.35)
  Female 1.59 (1.23–2.06) 1.29 (0.98–1.68) 1.00 (0.83–1.21) 1.00 1.00 (0.82–1.21) 1.18 (0.98–1.41)
Age groups, yr
  <50 2.02 (1.38–2.97) 1.42 (0.93–2.17) 1.29 (0.97–1.73) 1.00 1.04 (0.77–1.41) 0.95 (0.72–1.26)
  50–59 1.79 (1.27–2.53) 1.35 (0.96–1.89) 1.06 (0.85–1.32) 1.00 1.05 (0.84–1.32) 1.26 (1.02–1.57)
  60–94 2.05 (1.61–2.61) 1.55 (1.22–1.97) 1.19 (1.01–1.41) 1.00 0.98 (0.8–1.22) 1.02 (0.8–1.29)
Smoking status
    Never 1.92 (1.42–2.61) 1.34 (1.01–1.79) 1.02 (0.84–1.23) 1.00 0.99 (0.80–1.22) 1.22 (1.00–1.5)
    Ever 1.53 (0.66–3.55) 1.28 (0.43–3.79) 0.80 (0.43–1.46) 1.00 0.99 (0.52–1.88) 1.63 (0.89–2.98)
    Current 1.88 (1.35–2.61) 1.18 (0.82–1.68) 1.06 (0.82–1.37) 1.00 0.94 (0.68–1.29) 1.17 (0.85–1.62)
Using glucose-lowering agents
  No 1.78 (1.44–2.20) 1.34 (1.08–1.66) 1.16 (0.99–1.35) 1.00 1.13 (0.95–1.35) 1.11 (0.93–1.33)
  Oral hypoglycemic agents 1.99 (1.23–3.22) 1.65 (1.09–2.48) 1.15 (0.86–1.54) 1.00 0.97 (0.67–1.40) 1.79 (1.28–2.50)
  Insulin 1.66 (1.08–2.54) 1.09 (0.68–1.76) 0.96 (0.73–1.25) 1.00 0.87 (0.66–1.15) 0.92 (0.69–1.21)
Patient types
  Outpatients only 1.68 (1.18–2.39) 1.17 (0.81–1.68) 0.84 (0.65–1.07) 1.00 1.00 (0.76–1.32) 1.31 (0.99–1.72)
  Inpatients and outpatients 1.81 (1.48–2.21) 1.36 (1.11–1.67) 1.23 (1.07–1.42) 1.00 1.02 (0.87–1.20) 1.06 (0.90–1.24)
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Adjusted for age, sex, race, type of insurance, income, and smoking at baseline (in the baseline analyses), during follow-up (in the follow-up analyses) and at last visit (in the last visit analyses), other than the variable for stratification.

When BMI was included in the Cox model as a time-dependent variable, we found the same U-shaped association between BMI and all-cause mortality risk (Tables 2, 3, and 4). When we excluded patients with a history of coronary heart disease and cancer (n=5,540), the U-shaped association between BMI and all-cause mortality did not change (Online table 4). After excluding the subjects who died during the first two years of follow-up (n=415), the multivariable-adjusted U-shaped association between BMI and all-cause mortality did not change (Online table 4).

Discussion

Our study found a U-shaped association of BMI with all-cause mortality risk among African American and white patients with type 2 diabetes. A significantly increased risk of all-cause mortality was observed among African Americans with BMI<30 kg/m2 and BMI ≥35 kg/m2, and among whites with BMI<25 kg/m2 and BMI ≥40 kg/m2 compared with patients with BMI 30–34.9 kg/m2.

Only a few prospective studies have evaluated the association between BMI and total mortality among patients with diabetes, and the results are controversial. Some studies provide supportive information of an “obesity paradox” which describes the inverse association between excess adiposity as defined by BMI and mortality,3–7 other studies have reported positive associations,8,9 U-shaped associations,10–12 or no association13 between BMI and mortality among patients with diabetes. The recently published results from the Look AHEAD (Action for Health in Diabetes)29 have shown that an intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. In the present study, our data showed a significantly increased risk of all-cause mortality among both African American and white patients with type 2 diabetes in the high BMI group and the low BMI group as well. The most benefit for all-cause mortality risk associated with BMI was among African Americans with BMI 30–34.9 kg/m2 and among whites with BMI 25–39.9 kg/m2. We found this U-shaped association of all-cause mortality risk by BMI at baseline as well as during follow-up. In addition, this U-shaped association was present in different age, sex, antidiabetic medication and smoking groups.

Potential methodological concerns should be considered when assessing the associations between obesity and health outcomes.30 The most serious concern is reverse causation associated with total mortality. People with a history of CVD or cancer frequently lose weight and thus people with a lower weight might increase the estimated risk death. When we excluded patients with a history of coronary heart disease and cancer which can minimize the influence of reverse causation, the U-shaped association did not change. Moreover, we performed another sensitivity analysis by excluding the subjects who died during the first two years of follow-up, and the U-shaped association was still present. Another major concern is the adequate control for confounding factors and potentially over-adjusting for the physiologic effects of excess fatness, such as hypertension, diabetes, and dyslipidemia, which were controlled statistically, thus artificially removing some of the effects of being overweight. All three of these concerns were statistically controlled for in our study. Further when we restrict the analysis to subjects who have never smoked, the results did not change. Our result is different from a recent published paper which showed a direct linear relationship between BMI and mortality among those who had never smoked.12

Potential explanations of this U-shaped association among patients with diabetes are unclear. For the negative part of the curve, the increased risk of death associated with a low BMI, some investigators have suggested that patients with low-normal weight are associated with a clinical sign of insufficient insulin secretion which could potentially lead to faster progression of nephropathy and subsequently, increased mortality.10 For the positive part of the curve, the increased risk of death associated with a high BMI, many previous studies among patients with diabetes failed to show it because of the small sample size which limited the statistical power when the analysis was focused on those who are extreme obese, like BMI ≥40 kg/m2. There is substantial evidence supporting the biologic plausibility of a U-shaped association between adiposity and the risk of death in the general population, and a recently published meta-analysis showed the same U-shaped association as our study.31 Obesity is a well-established risk factor for numerous chronic diseases32 and adipose tissue can release a large number of cytokines and bioactive mediators which play important roles in the pathogenesis of many obesity related cardiovascular diseases.33

There are several strengths in our study, including the large sample size, long follow-up time, and the use of administrative databases to avoid differential recall bias. We have used baseline BMI levels or BMI values as time-dependent variables in Cox models, which can avoid potential bias from a single baseline measurement. In addition, participants in this study use the same public health care system which minimizes the influence from the accessibility to health care. The reliance on direct assessments of BMI rather than self-reported values are also marked strengths of this study. One limitation of our study is that our analysis was not performed on a representative sample of the population which limits the generalizability of this study; however, LSUHCSD hospitals are public hospitals and cover over 1.6 million patients most of whom are low income persons in Louisiana. The results of the present study will have wide applicability for the population with low income and without health insurance in the US. Second, more than 45,000 patients with diabetes were excluded in the present study due to missing data on one or more of the required variables, and these patients were younger, had less African Americans, and less males compared with the patients with type 2 diabetes included in the present study. Excluding these patients might have a possible selection bias. Third, we did not have information on cause-specific death reasons 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.34 Fifth, even though our analyses adjusted for an extensive set of confounding factors, residual confounding due to the measurement error in the assessment of confounding factors, unmeasured factors such as physical activity, education, and dietary factors, cannot be excluded.

Our study demonstrates a U-shaped association of BMI with all-cause mortality risk among African American and white patients with type 2 diabetes. A significantly increased risk of all-cause mortality was observed among African Americans with BMI<30 kg/m2 and BMI ≥35 kg/m2, and among whites with BMI<25 kg/m2 and BMI ≥40 kg/m2 compared with patients with BMI 30–34.9 kg/m2.

Supplementary Material

Clinical Perspective
Supplemental Material

Acknowledgments

Funding Sources: This work was supported by Louisiana State University’s Improving Clinical Outcomes Network (LSU ICON), the Louisiana Clinical Data Research Network (LACDRN), and 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health which funds the Louisiana Clinical and Translational Science (LA CaTS) Center.

Footnotes

Disclosures: None.

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