The impact of diabetes on the relationship of coronary artery disease and outcome: a study using multimodality imaging

Patients with type 2 diabetes have increased risk of developing coronary artery disease (CAD) [1]. Prediabetes, i.e. a state of impaired glycaemia not fulfilling the criteria for diabetes, is also associated with increased risk of developing cardiovascular disease [2]. Furthermore, type 2 diabetes and prediabetes are associated with impaired survival compared with nondiabetic patients [3, 4].

Coronary computed tomography angiography (CTA) allows non-invasive detection of non-obstructive or obstructive CAD and provides prognostic information. However, coronary CTA is limited in assessing the hemodynamic significance of a coronary stenosis, often requiring further functional evaluation for myocardial ischemia, such as myocardial perfusion imaging (MPI) [5]. Positron emission tomography (PET) enables quantitative MPI to assess the hemodynamic significance of epicardial coronary stenosis as well as coronary microvascular dysfunction, and its use has been rapidly increasing in recent years [6]. Furthermore, combining data from different imaging modalities, such as coronary CTA and PET, may provide incremental diagnostic and prognostic information [7].

Previously, quantitative ⁸²Rb PET MPI showed that patients with type 2 diabetes and reduced myocardial flow reserve (MFR) had high annual adverse event rate, whereas diabetic patients with preserved MFR had similar outcome as nondiabetic patients with reduced MFR [8]. Furthermore, Murthy et al. found an extremely low rate of cardiac mortality in diabetic patients with preserved CFR as quantified by ⁸²Rb PET [9]. Combination of anatomical and functional information may provide complementary prognostic information [10, 11] but the value of combined coronary CTA and myocardial perfusion imaging in diabetic patients remains uncertain.

In our hospital, selective hybrid CTA/PET imaging is provided as routine clinical service in symptomatic patients with suspected CAD [12]. The hemodynamic significance of suspected obstructive stenosis detected by coronary CTA is routinely evaluated by ¹⁵O-water PET MPI. We sought to compare imaging phenotypes of CAD and their association with long-term outcomes in patients with no diabetes, prediabetes, or type 2 diabetes.

Among 1743 patients, 1214 had no diabetes (69.7%), 259 had prediabetes (14.9%), and 270 had type 2 diabetes (15.5%). Patient characteristics are shown in Table 1.

Patients with type 2 diabetes were older, more frequently male and had less often family history of premature CAD than non-diabetic patients. Non-diabetic patients had lower body mass index and were less often hypertensive, dyslipidemic or smoking as compared with patients having prediabetes or type 2 diabetes. There was no difference in the rate of angina pectoris among the 3 groups, but patients with type 2 diabetes had less frequently ischemia on exercise ECG. Patients with prediabetes or type 2 diabetes were more often using anti-ischemic medication, lipid-lowering medication, antithrombotic medication, and angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), compared with non-diabetic patients.

Selective combined imaging strategy with initial coronary CTA and downstream PET MPI identifies patients at increased risk for future adverse events among those referred for evaluation of chest pain or equivalent symptoms [12]. The current study demonstrates that advanced anatomical and functional coronary imaging provides comparable prognostic information in symptomatic patients with no diabetes, prediabetes, or type 2 diabetes. The prevalence of obstructive CAD and myocardial ischemia are higher in diabetic patients as expected, and in addition, the risk of death, MI or UAP are higher in these patients. However, there was no significant interaction between the presence of prediabetes/type 2 diabetes and the prognostic value of CTA/PET imaging findings.

The highest annual adverse event rate (up to 4.7%) was found in patients with type 2 diabetes and hemodynamically significant CAD, i.e., obstructive coronary stenosis on CTA and abnormal myocardial stress perfusion on PET. This is in line with previous studies demonstrating high mortality in patients with concomitant diabetes and CAD [15]. Interestingly, previous evidence indicated that the prognosis is comparable for non-diabetic patients with abnormal myocardial flow reserve and diabetic patients with preserved myocardial flow reserve [8, 16]. Moreover, Murthy et al. reported a very low annual rate of cardiac mortality in diabetic patients with preserved CFR whereas diabetics with reduced CFR had annual cardiac mortality rate comparable to patients with prior CAD [9].

In our study, type 2 diabetes was associated with worse outcome (unadjusted HR 1.76, p = 0.003) but was not an independent predictor in multivariable models adjusted for either CTA/PET imaging findings or coronary calcium score, separately. Furthermore, the findings were consistent in sub-analyses restricted to patients not undergoing early revascularization. This may be partly explained by generally low rate of adverse events in the contemporary population such as in our study. However, this is in line with a large cohort study showing that the presence of diabetes was not a predictor of future MI in patients without CAD on coronary angiography, although being associated with all-cause mortality [17]. The absence of significant interaction between diabetes status and the prognostic value of CTA/PET imaging findings suggests that the prognostic performance of CTA/PET imaging was consistent in diabetics, prediabetics, as well as non-diabetic patients.

The current European guidelines recommend the use of coronary CTA especially in symptomatic patients with relatively low pre-test likelihood of CAD and highlight its high negative predictive value both regarding diagnosis and prognosis [5]. In our study cohort the prevalence of hemodynamically significant CAD was almost two-fold (26.7% vs. 14.5%) in type 2 diabetes patients compared with non-diabetic patients, which is in line with previous literature regarding diabetes-related risk of CAD [1]. Importantly, obstructive CAD could be still excluded by coronary CTA alone in about half the diabetic patients in our study cohort, including 19% with normal coronary arteries and 33% with anatomically non-obstructive CAD, and this was associated with low adverse event risk despite the presence of diabetes. The good prognosis of patients without CAD in our study is in line with previous studies evaluating diabetics with the use of coronary CTA [18]. This suggests that coronary CTA can be used as a first-line diagnostic test for suspected CAD in diabetic similarly to non-diabetic patients, and the need for downstream testing for myocardial ischemia remains reasonable.

Both microvascular and macrovascular involvement is well documented in diabetic CAD patients, and worse outcome may in part be attributable to coronary microvascular dysfunction [9, 19, 20]. The treatment options for coronary microvascular dysfunction are limited, further emphasizing the need for strict glycaemic control and other preventive strategies in diabetic patients [21]. Per our institutional protocol, myocardial perfusion imaging is triggered by a suspected obstructive stenosis on coronary CTA, and therefore, “pure” coronary microvascular dysfunction without CAD may be missed. On the other hand, in patients undergone PET perfusion imaging, quantification of stress myocardial blood flow integrates the effects of both epicardial and microvascular coronary circulation.

In our study cohort, the outcome of prediabetic patients was quite similar to nondiabetic patients. However, prediabetic patients with obstructive CAD on CTA but normal myocardial perfusion had unexpectedly low rate of adverse events. We acknowledge that this may reflect statistical noise due to the relatively small number of prediabetic patients and generally favourable outcome of our study cohort (i.e., a low number of adverse events). It is to be noted, that whereas prediabetic patients are at increased risk of developing cardiovascular disease, we can assume that screening and proper management might contribute to prevention of cardiovascular disease in prediabetics [4]. For example, we found a slightly higher rate of statin therapy in prediabetic than in nondiabetic patients of our study cohort. Furthermore, in our study cohort type 2 diabetes with hemodynamically significant CAD was associated with considerably worse outcome than in prediabetic patients. This makes a case for early intervention in prediabetic patients in order to prevent development of full-blown type 2 diabetes, especially in CAD patients.

Recently, the extent of coronary atherosclerosis measured as the number of segments with plaque on CTA (segment involvement score) was found to provide incremental prognostic information over stenosis severity and presence of perfusion defect in diabetic patients undergoing hybrid coronary CTA and single photon emission computerized tomography MPI [11]. Our results are generally in line with that study regarding the complementary prognostic role of anatomic and functional imaging findings in CAD; nevertheless, we did not assess the extent of coronary atherosclerosis. According to the guidelines, the selection of non-invasive tests in suspected CAD depends on, e.g., local expertise and availability, and we acknowledge that the availability of hybrid PET-CT imaging is variable [5]. The additional radiation dose from downstream PET perfusion imaging was low in our cohort, but there are also alternative methods such as CTA-based estimation of fractional flow reserve that allow non-invasive hemodynamic assessment of coronary stenosis without any additional radiation [22]. However, these were not assessed in the current study cohort, preventing direct comparison of their feasibility and prognostic value.

Notably, almost all (97%) early revascularizations in our study cohort were performed in patients with obstructive CAD associated with abnormal perfusion. Therefore, we did not include early revascularization in the multivariable models as there was a very low number of early revascularizations in other patient groups compared to those with abnormal perfusion. However, we performed sub-analyses restricted to patients not undergoing early revascularization.

Although the cohort was reasonably sized and the median follow-up time was 6.43 years, the number of adverse events remained moderately low, limiting the statistical power in subgroup analyses. Furthermore, this study was retrospective, and some information was not available. Therefore, patients with unknown diabetes status were excluded from the analysis. The registries in Finland are reliable and complete, and any detected adverse events were manually confirmed using electronic medical records [23]. All-cause mortality rather than cardiovascular mortality was used to avoid verification bias. In addition, data are missing about whether imaging triggered other secondary prevention measures than revascularizations, and regarding the control of blood glucose in patients with diabetes.

Coronary CTA followed by selective downstream use of PET MPI predicts outcome in patients with suspected CAD equally in presence or absence of type 2 diabetes. In about half of the diabetic patients, obstructive CAD could be excluded by coronary CTA alone, and this was associated with favourable outcome. The prevalence of hemodynamically significant CAD was almost two-fold in type 2 diabetes compared with non-diabetic patients. The combination of hemodynamically significant CAD and type 2 diabetes was associated with the highest adverse event rate during long-term follow-up; however, there was no significant interaction between the presence of prediabetes or type 2 diabetes and the prognostic value of CTA/PET imaging findings.