- Ionut Bebu1⇑,
- Barbara H. Braffett1,
- Trevor J. Orchard2,
- Gayle M. Lorenzi3,
- John M. Lachin1, and
- the DCCT/EDIC Research Group*
OBJECTIVE The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors.
RESEARCH DESIGN AND METHODS In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA1c between models without and with the potential mediator.
RESULTS Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors.
CONCLUSIONS While HbA1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes
Individuals with type 1 diabetes (T1D) are at higher risk of cardiovascular disease (CVD) relative to the general population (1,2). Mechanisms explaining this increased risk are still unclear. While hyperglycemia is a well-established risk factor for microvascular complications in both type 1 (3) and type 2 (4) diabetes, its role in the pathogenesis of macrovascular disease is still under investigation.
In type 2 diabetes (T2D), the association between HbA1c as a marker of long-term glycemia and CVD is weaker than it is for microvascular complications (5), with clinical trials designed to improve glycemic control yielding mixed results (6–8). However, such associations are more apparent with longer follow-up (9) and in meta-analyses (10,11).
In T1D, the HbA1c association with CVD was weak and inconsistent in several early observational studies (12,13), but more recent registry data (2,14) have shown a clearer association. The Diabetes Control and Complications Trial and its follow-up study, Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC), demonstrated that 6.5 years of intensive diabetes therapy (INT) versus conventional therapy (CON) markedly reduced the risk of CVD over a mean follow-up of 17 years (15). This long-term benefit of initial INT was still apparent, although attenuated, after 30 years of follow-up (16). Furthermore, extensive risk factor models have demonstrated that the mean DCCT/EDIC HbA1c was the second strongest risk factor for CVD (i.e., it had the second-lowest P value) after age, even after adjustment for other traditional CVD risk factors (17).
Additional analyses have shown that poor glycemic control is associated with traditional CVD risk factors such as systolic (SBP) and diastolic (DBP) blood pressure, pulse pressure and pulse rate, triglycerides, LDL cholesterol, and HDL cholesterol (18). Therefore, it is important to investigate the potential mediation pathways that might explain the mechanisms relating glycemia and the risk of CVD. More specifically, the goal is to identify risk factors in the causal pathway linking hyperglycemia and the risk of CVD. With >30 years of follow-up and a systematic assessment of potential risk factors for CVD, DCCT/EDIC offers the opportunity to investigate such mediation analyses. Herein, we explore the extent to which the effect of glycemia, as captured by HbA1c, on the risk of CVD is potentially mediated by other traditional CVD risk factors. These analyses build on and expand our recent work, which examined the impact of mediating factors for the effect of glycemia on the risk of subsequent CVD events with increasing diabetes duration (19).
Despite progress in diabetes management, individuals with T1D remain at higher risk of CVD compared with the age-matched general population. A comprehensive assessment of the role of long-term hyperglycemia and of the mechanisms relating hyperglycemia to CVD risk is needed to maximize prevention efforts and reduce excess CVD morbidity and early mortality in T1D (27).
We performed a thorough evaluation of potential mediators of the effect of glycemia, as captured by HbA1c, on the risk of CVD in the DCCT/EDIC cohort. With adjustment for age alone, only a few factors (such as pulse, SBP, total cholesterol, LDL cholesterol, triglycerides, and AER) explained >10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, it is important to note that the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors.
Our analyses confirmed well-known CVD risk factors, such as blood pressure, lipids, and AER. For example, it is well documented that hyperglycemia contributes to kidney disease, as manifested by elevated AER values and impaired eGFR levels (28,29), which in turn are associated with left ventricular hypertrophy and arterial calcification (26,30).
In addition to such well-known CVD risk factors, our analyses also identified pulse rate and pulse pressure as potential mediators of the effect of glycemia on the risk of CVD. Higher pulse rate and higher pulse pressure were previously shown to be associated with poor glycemic control in T1D (18) and with higher risk of CVD, both in the general population (31,32) and in individuals with T1D (17). This study cannot provide the mechanisms underlying these relationships, and the exact pathways by which glycemia affects the risk of CVD remain unclear. However, it may be hypothesized that chronic hyperglycemia might induce extensive glycation of vascular mesenchymal tissues leading to arterial stiffness (33), with pulse pressure then acting as a marker of arterial and aortic stiffness and vascular aging as previously suggested in individuals with T1D (34,35). Likewise, chronic hyperglycemia might cause an imbalance between parasympathetic (cholinergic) and sympathetic (adrenergic) components of the autonomic nervous system leading to increased heart rate (cardiac autonomic neuropathy), which in turn may lead to myocardial ischemia resulting from an imbalance between myocardial oxygen demand and supply and possible ventricular arrhythmias (31).
Estimated glucose disposal rate (eGDR) is a measure of insulin sensitivity and defined based on the waist-to-hip ratio, hypertension (yes/no), and HbA1c (36). Since glycemia (as captured by HbA1c) is a complete mediator of the effect of the original DCCT treatment group on CVD, and HbA1c is a component of eGDR, it is not surprising that eGDR is a mediator of the effect of the original DCCT treatment group on CVD. That HbA1c is a component of eGDR likely also explains why eGDR was not a mediator of the effect of glycemia, as captured by HbA1c, on CVD risk. Also note that hypertension, another component of eGDR, was among the DCCT baseline exclusion criteria.
The analyses herein assessed whether the association of HbA1c or the DCCT treatment group assignment with CVD risk can be explained by the association of HbA1c or treatment group with other potential mediating factors in this cohort. While none of the risk factors considered completely mediated the effect of hyperglycemia on the risk of CVD, this does not mean that other factors do not play a role.
Indeed, we recently developed multivariate regression models (17), which showed that traditional risk factors such as SBP, triglycerides, LDL cholesterol, and pulse, among others, had significant associations with risk of any-CVD and MACE in addition to the associations noted with age and mean HbA1c. We then conducted a detailed assessment of the changes in the mediation patterns for four traditional risk factors (SBP, triglycerides, LDL cholesterol, and pulse) with HbA1c over successive 10-year intervals such as 10–20, 11–21, etc., years of EDIC (19). While the association of HbA1c with CVD outcomes was stable over time, the association of these traditional risk factors increased with time, and the proportion of the effect of glycemia that was mediated by these factors increased with time. For example, the association of HbA1c with CVD risk over 10–20 years of follow-up was minimally mediated by SBP (2.7%), whereas over 20–30 years, 26% of the HbA1c association was mediated by SBP. Similar results were observed for the other three risk factors.
The previous and current analyses demonstrate that over time, the association of mean HbA1cwith CVD risk is increasingly mediated by its association with other risk factors. These results emphasize the importance of effective CVD and diabetes-related risk factor management to reduce the occurrence of CVD outcomes in T1D.
While the DCCT was a randomized trial, the follow-up EDIC is an observational study. As with any observational study, one cannot exclude the possibility of unmeasured confounding, and, therefore, the results should be interpreted with care. However, given the large number and the standardized assessment of the risk factors collected in the DCCT/EDIC cohort, and the nearly complete follow-up (with 94% of the surviving cohort still actively participating), we feel confident in our findings.
In conclusion, traditional CVD risk factors (such as SBP, triglycerides, LDL cholesterol, and pulse, among others) and diabetes-related renal risk factors (such as AER and eGFR) are strongly associated with the risk of any-CVD and MACE and are strongly associated with mean HbA1c and the DCCT treatment group assignment. However, these other factors explain only a part of the effect of glycemia on the risk of any-CVD and MACE, no more than 30% individually or 50% in combination, and the association of HbA1c with CVD risk remains significant. Thus, while HbA1c is associated with many of these other risk factors, its association with one or a collection of these factors alone cannot fully explain its effects on risk of CVD, and controlling the levels of these nonglycemic risk factors may only reduce the effect of glycemia on the risk of CVD by ∼50%. These findings suggest that aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.
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