More than one in five (22.5%) Look AHEAD participants had an abnormal GXT despite a prescreening process that excluded anyone who reported CVD symptoms during the previous 3 months or those with any history of several CVD abnormalities. Other studies have sought to determine the prevalence of CVD in individuals with diabetes, using various markers for CVD. In the Milan Study on Atherosclerosis in Diabetes (MiSAD) (4
), all participants had diabetes and were aged 40–65 years at study entry, and only ST segment changes constituted an abnormal GXT. In MiSAD, 13.2% of the 735 participants had abnormal tests. Although this overall abnormal rate is lower than what we observed, MiSAD had a higher rate of ST segment changes than our population did (7.6%). The Detection of Ischemia in Asymptomatic Diabetics (DIAD) (13
) study, which evaluated 522 individuals with type 2 diabetes, who were aged 50–75 years and had no history of CVD, found that 113 (22%) had abnormal adenosine perfusion stress tests. To the extent that these markers approximate true CVD, the prevalence of CVD in middle-aged asymptomatic diabetic adults is likely between 13 and 22%. Our overall rates are consistent with this observation.
Age was the only predictor that showed a consistent association with abnormal tests. Although this is the first description of such a large group of diabetic participants to undergo stress testing, in nondiabetic populations, the association of greater age with GXT abnormalities has been known for several decades (14
Impaired exercise capacity
Of the participants, 12% were not able to attain a workload of at least 5 METs, with 58% of the abnormal tests due to impaired exercise capacity. Of those who did not achieve at least 5 METs, 73.6% reported a Borg score of at least 19, compared with 83.6% of those who did reach at least 5 METs (P < 0.001). Therefore, motivation may have been a factor in poor exercise capacity for some participants.
Ribisl et al. (15
) found that among the 5,145 randomized Look AHEAD participants, greater age, higher BMI, and higher A1C predicted lower exercise capacity. The present analysis, which includes participants not randomized and thus may represent a broader and potentially more generalizable cross-section of the diabetic population, also adds analysis of ECG and blood pressure variables. In contrast to the report of Ribisl et al., the association between A1C and impaired exercise capacity is not present in this larger sample.
Myers et al. (2
) showed that in 6,213 men referred for a clinical exercise test, 25.5% failed to achieved a maximal exercise capacity of 5 METs, and those with diabetes had an age-adjusted relative mortality risk from any cause of ~2.3 (95% CI 1.5–3.5) compared with those who achieved >8 METs. In our study, the lower prevalence (12%) of impaired exercise capacity may be explained in part by population differences. Participants in the study of Myers et al. underwent exercise testing for clinical reasons, which included symptomatic CVD or other conditions for which potential participants in Look AHEAD were excluded before stress testing.
This analysis showed divergent directions of association between SBP and DBP and impaired exercise capacity. These bivariate associations persist in regression models in which SBP and DBP are controlled for each other. Elevated SBP is a well-recognized risk factor for CVD and has been associated with decreased exercise endurance (16
). Sufficiently elevated DBP is also a diagnostic criterion for hypertension and is associated with adverse CVD events (17
) and ischemia (4
). However, in older populations, lower DBP is associated with CVD (18
) and is believed to result from decreased compliance of the aorta and its large branches due to atherosclerotic disease (19
). Wider pulse pressure has been shown to be a strong predictor of CVD events in older individuals with type 2 diabetes (20
). Some younger Look AHEAD participants may be expected to have less central atherosclerotic burden and, hence, better arterial compliance, on the basis of age alone. However, all participants had type 2 diabetes. The clear association of lower DBP with abnormal GXTs in this population suggests that decreased arterial compliance may originate at an earlier age in individuals with diabetes.
ST segment depression of at least 1.0 mm is a recognized threshold for an abnormal ECG response to exercise. This definition provides a sensitivity of 45% and a specificity of 85% for coronary artery disease diagnosed by angiography (21
). Factors associated with an increased risk of ST segment depression and ventricular arrhythmia included greater age and lower BMI. Greater age is a known CVD risk factor. The association of lower BMI with ECG changes may be explained by the increased rate of impaired exercise capacity with higher BMI. Those with a lower BMI exercised to a higher level (), creating a greater cardiac stress, which increased the chance of detecting ST segment changes or arrhythmias.
The recent acknowledgment that diabetes imparts risk of CVD events equivalent to a known history of CVD (22
) makes our observed rate of angina seem low (1.1%) for a cohort of individuals with diabetes aged >45 years. However, before the GXT, we excluded potential participants who reported recent angina. The expected rate of angina in this population is unknown. Nevertheless, our data show that even in asymptomatic overweight or obese adults with diabetes who have been carefully screened for cardiovascular symptoms, angina still occurs with maximal stress testing, albeit at a rate of 1.1%.
Abnormal heart rate recovery occurred in 5.0% of participants undergoing stress testing. Many of the predictors of abnormal heart rate recovery we found are known risk factors for CVD (22
). Abnormal heart rate recovery was associated with higher BMI. As discussed, those with lower BMI exercised to higher MET levels than those with higher BMI. However, those with higher BMI routinely demonstrate higher workloads for more routine tasks. This higher inherent workload leads to a higher catecholamine state, which causes less difference between baseline and peak exercise heart rate and a slower heart rate recovery after exercise. In fact, our data confirm out this conclusion. Higher BMI was associated with a higher resting and first-stage exercise heart rate and a smaller increase in heart rate from resting to peak exercise (P
< 0.001 in each case, data not shown).
Others have proposed that either an exaggerated (23
) or a low (7
) SBP response may reflect underlying cardiovascular abnormalities. The cross-sectional data presented here do not settle the question of whether a larger or smaller SBP response to exercise increases CVD risk. However, because greater age was associated with every category of established abnormality that we examined and greater age was associated with lower SBP response, it is conceivable that a lower SBP response is associated with higher risk of adverse CVD outcomes.
Implications of results on future Look AHEAD study outcomes
Look AHEAD GXT eligibility criteria were adopted for participant safety, given that unsupervised exercise training was part of the study intervention. These tests eliminated 638 potential participants: 11.1% of those reaching the final stage of screening and 49% of those who had abnormal GXT results. These criteria may reduce the rate of the trial's primary end point and the generalizability of the findings.
For the first year of testing, data forms included text fields for “significant ST segment changes” and angina; however, these responses were not required. This approach was changed thereafter to require physicians to indicate the degree of ST depression. Independent reviews by an experienced exercise physiologist and a clinician experienced in GXT were conducted for all tests that included at least 1.0 mm of ST depression and the 405 instances when physicians noted ST depression but did not quantify it. The 180 instances for which these two reviewers disagreed were resolved by a cardiologist independent of Look AHEAD, whose decision was final. We did not have sufficient data to comment on ST segment slope. Full data were not available for the 638 participants who were deemed ineligible for randomization into Look AHEAD by physicians who supervised their GXTs, but whose results are included in this analysis, which may have led to an underestimation of abnormality rates.
Because the present analysis is concerned with baseline data in Look AHEAD, follow-up outcome data on the participants are not available for this report. Those with clinically significant abnormalities were referred to their physicians.
Some clinicians may argue that our definition of abnormal GXT results may more accurately be termed predictors of CVD events or CVD mortality. Whether heart rate recovery and maximal achieved workload should be used to define abnormality or simply be included among a list of risk criteria is certainly open for debate; however, for simplicity, we included these factors in what we termed abnormal.
Among a large cohort of overweight and obese individuals with type 2 diabetes, 22.5% had abnormal stress tests by ECG, angina, heart rate recovery, or exercise capacity criteria despite thorough pretest screening. Diminished exercise capacity is the most common abnormality in this cohort, occurring at nearly twice the rate of any other abnormality. The most consistent risk factor for any type of abnormality is older age, which is even a more consistent risk factor than duration of diabetes or history of CVD. These results support heightened vigilance for CVD in older patients with diabetes. Continued follow-up in these individuals as part of the Look AHEAD study will determine whether any of these abnormalities during exercise testing are accurate predictors of subsequent cardiovascular events.