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Journal of Endocrinology & Metabolism

Original Article

Volume 5, Number 3, June 2015, pages 215-219

Cardiorespiratory Fitness Impact on All-Cause Mortality in Prediabetic Veterans

The CDC estimates that 79 million Americans (approximately one in three) have prediabetes, a condition associated with developing type 2 diabetes (DM2) which is a major cause of cardiovascular disease (CVD) and strokes, and is the seventh leading cause of death in the United States [1, 2]. The US Diabetes Prevention Program, which compared active lifestyle intervention or metformin to standard lifestyle in overweight Americans with impaired glucose tolerance (IGT), demonstrated that active lifestyle reduced the incidence of DM2 by 58% [3]. Follow-up of this cohort showed that diabetes risk was 56% lower in patients who returned to normal glucose tolerance [4]. A number of different studies have given support to the notion that physical exercise and weight loss significantly impact prevention or delay of DM2 in patients with IGT [5-10]. Though lifestyle intervention has become a routine recommendation for patients with prediabetes, there is a paucity of data regarding mortality outcome [8]. Recently, the Da Qing study showed a significant decrease in cardiovascular and all-cause mortality [11] and cardiorespiratory fitness (CRF) was a strong modulator of survival in a large relatively healthy prediabetic cohort [12].

The Veterans Health Administration utilizes an electronic health information database of patients given equal access to high quality health care independent of financial status. The objective of this study was to evaluate the role of CRF on all-cause mortality in veterans with prediabetes.

Between January 1995 and December 2010, a total of 1,118 prediabetic veterans underwent symptom-limited exercise tolerance testing (predominantly Bruce and Modified Bruce Protocols) in Washington, DC, and Palo Alto, California, for routine testing or to assess for exercise-induced ischemia as previously described in detail [13, 14]. All demographic, clinical information and vital signs were obtained from the patient’s records within 3 months of the exercise tolerance test. BMI was calculated as weight in kilograms divided by the square of height in meters. Demographic data are included in Table 1. Based on their calculated peak metabolic equivalents (METs), four CRF categories were established as follows: least-fit (< 5.8 METs; lowest 25th percentile), low-fit (5.8 - 7 METs), moderate-fit (7.1 - 8.4 METs) and high-fit (≥ 8.5 METs; > 75th percentile).

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Table 1. Population Demographics

The date of death was verified from the Veterans Affairs Beneficiary Identification and Record Locator System File. Cox proportional hazard analyses were applied to assess the risk among the fitness categories. The analyses were adjusted for age, BMI, history of CVD, cardiovascular medications (ACE inhibitors, beta blockers, calcium channel blockers, diuretics and statins) as well as risk factors (hypertension, dyslipidemia and smoking).

The least-fit category was used as the reference group. All hypotheses were two-sided and P-values < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software (Version 15.0; SPSS, Chicago, IL).

In a mean follow-up period of 7.7 years (8,610 person-years), there were a total of 251 deaths, averaging 29.1 events per 1,000 person-years. The composition of the quartiles was similar in terms of gender, race, incidence of dyslipidemia, as well as cholesterol values (Table 1). Higher CRF category patients were noted to have a mean age which was generally younger than the least-fit patients, although there did appear to be an overlap regarding age stratification. It was noted that for every 1 year difference, there was a 1.9% increased risk in mortality or a 10-year mortality risk of 21%. Additionally, the presence of CVD (ranging from a history of NSTEMI to four vessel bypass) essentially doubled the risk of mortality (Table 2). As such, age and CVD are adjusted for in the final analysis. BMI, smoking status, usage of cardiovascular medications and presence of hypertension on the other hand were not statistically significant in correlation with overall mortality (Table 3).

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Table 2. Variables in the Equation

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Table 3. Variables Not in the Equation

An inverse and graded association between CRF and mortality risk was observed (P = 0.002 for trend). For every 1-MET increase in CRF, the adjusted all-cause mortality was lowered by 13% (hazard ratios (HR) = 0.87; CI: 0.81 - 0.94, P < 0.001). Compared to the least-fit individuals, all-cause mortality risk was reduced by 32% in low-fit individuals (HR = 0.68; CI: 0.50 - 0.94, P = 0.002), by 40% in moderate-fit individuals (HR = 0.60; CI: 0.41 - 0.87, P = 0.007) and by 54% in high-fit individuals (HR = 0.46; CI: 0.30 - 0.70, P < 0.001). A summary of these results is illustrated in Figure 1.

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Figure 1. Relative risk for all-cause mortality according to fitness group.

We observed a strong inverse and graded association between CRF and mortality risk with a 13% decrease for every 1-MET increase in fitness. All-cause mortality risk was markedly reduced by 32% when comparing the low-fit and least-fit individuals and by approximately 50% when comparing high-fit and least-fit individuals. Notably, BMI and CVD factors such as cardiovascular medications, smoking status and hypertension did not appear to be significant factors in the correlation between CRF and mortality risk. These results conform to our prior studies in several chronic illnesses [14-16].

The American Diabetes Association currently recommends that DM2 persons undertake at least 150 min per week of moderate-to-vigorous aerobic exercise spread out at least 3 days during the week with no more than 2 consecutive days between bouts of physical activity, and that persons with DM2 should undertake moderate-to-vigorous resistance training at least 2 - 3 days per week [17]. More recently, the Australian Exercise and Sport Science promotes 210 min of moderate-intensity exercise or 125 min of more intense exercise per week that should also include resistance training [18]. Using these exercise parameters has been shown to be efficacious in several diabetes prevention programs. The Diabetes Prevention Program (DPP) included 3,819 prediabetics who were randomly assigned to an intensive lifestyle intervention group comprising of 7% weight loss and at least 150 min of physical activity per week, metformin with standard lifestyle advice and a control group. A 58% reduction in the incidence of DM2 was seen in the intensive lifestyle intervention group compared with the control group, and it was further noted that exercise was also more effective than metformin in preventing progression to diabetes (NNT 6.9 vs. 13.9) [3, 4]. In the Swedish 6-year Malmo feasibility study, 415 men of ages 47 - 49 years participated in a large population-based screening program. Persons with diabetes, prediabetes or normal glucose tolerance were non-randomly assigned to lifestyle intervention or usual care groups. After 6 years, the 10.6% of the prediabetic patients in the lifestyle intervention group developed diabetes compared to 28.6% in the usual care group [5]. In the Chinese Da Qing Impaired Glucose Tolerance and Diabetes Study, 557 prediabetic patients were randomly assigned to a control group or one of three intervention groups involving diet, exercise, or diet and exercise. After 6 years, the incidence of diabetes in the control group was 67.7% compared with 43.8% in the diet group, 41.1% in the exercise group, and 46% in the combination diet and exercise group [6]. Fourteen years after the end of this trial, the lifestyle group showed a significant reduction in severe diabetic retinopathy [19], with subsequent decrease in all-cause and cardiovascular deaths 3 years later [11]. The Finnish Diabetes Prevention Study included 522 overweight prediabetic patients allocated to lifestyle intervention or usual care groups. After 3 years, the incidence of diabetes in the intervention group was 58% lower than the control group [7]. One study examined the risk of all-cause or cardiovascular mortality associated with metabolic syndrome, obesity and CRF in a sample of 19,173 men stratified by BMI, of which 3,745 had metabolic syndrome at baseline. The presence of obesity and metabolic syndrome was associated with an increased risk of all-cause as well as cardiovascular-related mortality as compared to healthy patients. The authors did note, however, that inclusion of CRF as a covariate resulted in the disappearance of differences in relative risk of all-cause mortality and attenuation in the relative risk estimates of CVD to non-significance [20].

In another study, the role of CRF as a predictor of cancer mortality among men with prediabetes and diabetes finding that overall, higher levels of CRF were associated with a lower risk of cancer mortality as compared to those with lower levels of fitness in both prediabetic patients as well as diabetic patients. Additionally, similar trends with all-cause mortality were seen in both prediabetes patients as well as diabetes patients [21].

Mechanistically, enhanced fitness in prediabetics has been shown to have salutary impact on a multitude of cardiovascular risk parameters and provides the best opportunity for a durable therapeutic impact [22]. Our study is unique in that it associates exercise capacity with mortality risk in a veteran population, a cohort with high co-morbidity, high medication utilization and inactivity [23]. It is further strengthened by the utilization of the Veterans Health Information Database along with a patient population who receives high quality care without regard for socioeconomic status. This equal access to care irrespective of financial status [24] permits epidemiologic evaluations while minimizing the influence of medical care disparities [25]. Nevertheless, there are a number of limitations including the retrospective design, the observational aspect and the possibility that some patients were lost to follow-up. We looked at baseline BMI and CRF level at the time of the routine exercise stress test, but did not account for any weight changes or fitness level changes over time. Additionally, the actual physical activity patients engaged in and changes in glycemic control were not accounted for over time as well. Additionally, our study did not note mortality specifically due to CVD, although it was noted that the presence of CVD does not necessarily translate into mortality due to cardiovascular etiology. Future studies could be done to validate the predicted fitness mortality risk determined by this study with the 10-year Framingham Risk Score to determine the clinical utility of CRF at baseline.

In summary, this study demonstrates that a significant mortality benefit is associated with baseline fitness levels with the most substantial relative reduction in mortality occurring with comparison of low-fit to least-fit individuals. With increasing incidence of diabetes, prediabetic patients are considered a novel group to target with a preventative approach through exercise. This study underscores the importance of enhanced CRF in individuals with prediabetes.

Conflict of Interest

The authors have no conflicts of interest to disclose.

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Journal of Endocrinology and Metabolism is published by Elmer Press Inc.