In this study, we evaluated the long-term clinical outcomes according to the glycemic control status in diabetes patients with established cardiovascular disease who underwent PCI. Although diabetes patients with established CAD are at a high risk for future cardiovascular events, almost 60% of the patients were categorized in the UC group. The major study findings were, as follows: (1) the incidence of MACCEs was lower in the AC group (HbA1c level < 6.5%) than in the MC and UC groups; (2) the difference in the MACCE incidence was driven by stroke; and (3) AC was an independent predictor of reduced rates of MACCEs and stroke.
The association between glycemic control and clinical outcomes after PCI in patients with diabetes has been evaluated. Several studies have suggested that the effect of dysglycemia at the time of admission or before PCI can be related to poor prognosis after PCI in diabetes patients with acute coronary syndrome [13–16]. However, the glycemic status before PCI cannot reflect the long-term effects of glycemic control because catecholamine surge induced in response to acute coronary events may be associated with dysglycemia. Therefore, we categorized the study population based on the mean observed HbA1c level during the follow-up period, which reflects the glycemic control status after PCI.
With respect to PCI performed before the DES implantation era, prospective registry data suggested that optimal glycemic control (HbA1c level ≤ 7%) was associated with a lower rate of TVR . However, in the era of first-generation DES implantation, the PCI registry data showed that the preprocedural HbA1c level was not associated with future adverse outcomes, as noted by the absence of a benefit of strict glycemic control in preventing macrovascular complications . Other studies on the HbA1c level and PCI outcomes in patients with diabetes showed that glycemic control status was not associated with the incidence of major adverse cardiovascular events, defined as death, MI, and target vessel failure [9, 19]. Our study also reported that the incidence of cardiac death, nonfatal MI, TVR, and all-cause mortality was similar among the three groups. However, our study defined the primary endpoint as the incidence of MACCEs, which included stroke events, and the AC group showed a significantly reduced rate of MACCEs, compared with the MC and UC groups, driven by stroke events. Our median follow-up duration was > 6 years; therefore, the long-term effect of the glycemic control status is reflected more effectively in our study than in the previous studies. The data on the glycemic control status after PCI in diabetes patients from another registry showed that HbA1c levels ≤ 7% measured at 2 years after PCI were associated with a reduced rate of MACCEs, mostly driven by target lesion revascularization . However, the HbA1c level measured at 2 years after PCI cannot accurately reflect the glycemic control status. To reflect the accurate glycemic control status after the index procedure, we evaluated the mean observed HbA1c level during the follow-up period. Furthermore, a strength of our study is that the clinical effect of aggressive glycemic control (HbA1c level < 6.5%) was investigated, and an association between aggressive glycemic control and reduced rates of MACCEs and stroke was noted.
The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial investigated the effects of intensive glucose control on the vascular outcomes and found that the rate of the combined outcome of major macrovascular and microvascular events decreased . However, the reduced rate of the primary outcome was mainly owing to the reduced rates of microvascular events and not of macrovascular events. Another large-scale randomized trial, the ACCORD study, reported that despite a nonsignificant decrease in the rate of ischemic events in patients with intensive glycemic control, higher rates of all-cause mortality were observed . The Veterans Affairs Diabetes Trial on the effects of intensive and standard glucose control on cardiovascular events also reported that intensive glucose control had no significant effect on the incidence of major cardiovascular events . Previous randomized trials have shown that intensive glycemic control is associated with an increased rate of hypoglycemic events. Hypoglycemia may be a major contributor towards adverse cardiovascular events in patients with a high cardiovascular risk . Our study showed that a mean observed HbA1c level of < 6.5% was significantly associated with a reduced rate of MACCEs, mainly driven by stroke. Recently, many effective oral hypoglycemic agents, such as dipeptidyl peptidase 4 inhibitors or sodium glucose co-transporter 2 (SGLT2) inhibitors, associated with a low risk for hypoglycemia, have been administered in patients with cardiovascular disease. Large-scale randomized trials on intensive glycemic control with such drugs are needed.
The data from the U.K. Prospective Diabetes Study showed that a higher HbA1c level was associated with an increased rate of nonfatal MI and stroke . The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study evaluated the clinical effect of glycemic control in patients with T2DM and a history of macrovascular disease . In this trial, an HbA1c level ≥ 7.5% was a strong positive predictor of a stroke event, and aggressive glycemic control with pioglitazone was associated with a reduced rate of stroke . Traditionally, stroke is associated with macrovascular complications in patients with T2DM. However, in patients with T2DM, stroke due to cerebral small-vessel disease from fibrinoid necrosis, usually lacunar stroke, is more commonly encountered . Our study also showed that a mean observed HbA1c level of < 6.5% was associated with a lower incidence of stroke, similar to that reported previously. However, the other components of the primary endpoint showed similar incidences among the three groups. It is possible that intensive glycemic control in patients with T2DM is mainly driven by reduced microvascular complications, including stroke due to small-vessel disease. Although the patients in the AC group were older than those in the UC group, the incidence of stroke was lower in the AC group than in the UC group (HR 0.373, 95% CI 0.157–0.886, p = 0.025). Therefore, in diabetes patients with established coronary heart disease, the glycemic control status is an important factor for predicting future adverse events, especially stroke.
There are several limitations of this study. First, our study was based on single-center PCI registry data, and the intrinsic limitations related to the retrospective study design cannot be disregarded. Therefore, aggressive control of the HbA1c levels does not indicate aggressive glycemic management. To evaluate the clinical outcomes of strict glycemic control in diabetes patients with CAD, large-scale prospective randomized studies should be required. However, our study aimed to evaluate the long-term outcomes according to the mean observed HbA1c level in a relatively large real-world population of diabetes patients with CAD. Future prospective studies on the long-term clinical outcomes according to glycemic control with current oral hypoglycemic agents should be conducted, on the basis of our study results. Second, as our data were based on the patients’ electronic medical records, it was difficult to acquire data regarding the hypoglycemic events. However, to the best of our knowledge, serious hypoglycemic events leading to lethal arrhythmias, cardiovascular events, and mortality did not occur. Third, SGLT2 inhibitors were not prescribed during the study period. Recently, several large-scale randomized trials have reported that SGLT2 inhibitors reduce the rates of adverse cardiovascular outcomes [25, 26]. Our study findings strongly suggest that further large-scale randomized studies should be conducted for evaluating strict glycemic control with SGLT2 inhibitors in diabetes patients with CAD.