Consistent with the available evidence on diabetic complications [2
], this study found significant independent associations between HDL-C, LDL-C, TG, and non-HDL-C and risks for MVC among patients with T2DM in a real-world managed care population. Although management of LDL-C is the primary goal of therapy, our findings suggest further benefit may be obtained by expanding treatment goals to include modification of other lipid subfractions in addition to LDL-C. These associations persisted after controlling for numerous covariates, including comorbidities and concomitant medications.
A 1 mg/dL increase in HDL-C levels was associated with a significant decrease (0.5
%) in the risk of MVCs. Furthermore, patients who achieved HDL-C goals during follow-up also reduced their risk for experiencing MVCs by 10.5
%. These findings suggest that targeting HDL-C in addition to LDL-C as recommended by NCEP ATP III may have benefits beyond CHD risk reduction [12
]. In the case of TGs, a significant increase in risk (0.1
%) for a MVC event was observed for a 1
mg/dL increase in the serum levels of TG. Further underscoring the risks associated with suboptimal TG goals [2
], the study found TG goal attainment lowered the risk of MVC by 15.1
%. The relationship of elevated TG and/or reduced HDL-C levels with MVCs was recently demonstrated by Zoppini et al., who showed a high TG/HDL-C ratio approximately doubled the risk for MVC over a 5-year period in 979 Caucasian patients with T2DM [21
]. In a prospective observational study of 6,499 patients with diabetes and dyslipidemia, Teramoto et al. confirmed the importance of controlling TG and HDL-C in conjunction with HbA1C levels in patients with T2DM [22
]. Taken together, these studies highlight the importance of targeting atherogenic dyslipidemia as a means to reduce MVCs in patients with T2DM. Our results further extend these findings by emphasizing the need to treat HDL-C and triglycerides to ADA defined targets in order to beneficially impact risk for both macrovascular and microvascular events.
Continuous LDL-C levels and achievement of LDL-C goals were positively and negatively associated with MVC event risk, respectively in our study. However, the KM curves between those achieving versus those not achieving LDL-C goals were not statistically different (P
.3513), indicating a lack of proportionality of MVC event risk over time. LDL-C reduction does not appear to mitigate risk for MVCs in diabetic patients.
Guidelines recommend non-HDL-C as a secondary target for therapy after risk-stratified LDL-C levels have been reached in patients with baseline TG >200
]. One of the key results in this study was the 17.3
% reduction in the risk of MVCs for those attaining non-HDL-C goals compared to those not reaching the goals. Non-HDL-C, defined as TC minus HDL-C, is a sensitive surrogate measure of total atherogenic lipoprotein burden in serum and is a useful index for predicting the risk of CVD, especially among patients with diabetes since it circumvents the reliability issues associated with using LDL-C in a diabetic population [24
]. These findings hint at a potential role for non-HDL-C in predicting risk for microangiopathy in T2DM patients since it singularly combines the impact of total cholesterol and its various atherogenic lipoproteins in place of LDL-C. Furthermore, evidence exists that after achieving LDL-C goal levels, non-attainment of non-HDL-C target goals among T2DM patients is markedly associated with residual risk and dyslipidemia [25
Overall, the current study highlights the possible benefits of treating any or all components of the lipid beyond LDL-C alone, in order to most optimally reduce morbidity and mortality in diabetic patients. The sensitivity analyses further confirmed the hypothesis that independently achieving HDL-C, TG, HDL-C and TG and non-HDL-C goals can lead to significant reductions in MVC risk irrespective of LDL-C goal attainment. This suggests that attainment of lipid goals other than LDL-C can translate into incremental reductions in risk of MVCs. Furthermore, this study lays the groundwork for conducting additional research to identify the best predictive models for estimating MVC risk (e.g., correlating Log (TG)/HDL-C with risk for MVC) [26
]. More importantly, these study findings suggest that a gap exists between the current practice recommendations and the appropriate management of MVC risk among T2DM patients.
Post hoc analyses of multiple clinical trials suggest that fenofibrate therapy impacts risk for MVC. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found that patients receiving fenofibrate treatment had a reduced risk of a first and follow-up laser intervention for proliferative retinopathy, lower extremity amputation, and progression to albuminaria and nephropathy versus those on placebo [27
]. Similarly, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) group of studies evaluating the effect of intensive glycemic control and combination therapy for dyslipidemia found significantly reduced progression rates of diabetic retinopathy for patients who received fenofibrate versus those who received placebo [30
]. The Diabetes Atherosclerosis Intervention Study (DAIS) reported reduced progression of albumin excretion for fenofibrate treatment versus placebo [31
]. While the confounding effect arising out of fenofibrate usage was controlled for in the present analysis, our results underscore the relative importance of the other components of the standard lipid profile besides LDL-C to microangiopathy risk. They also emphasize the importance of appropriately managing HDL-C, TG, and, non-HDL-C levels through therapeutic lifestyle changes and appropriate pharmacotherapy.
With the increasing prevalence of T2DM adding to the clinical and overall healthcare burdens of patients and society, there is an urgent need for optimal and timely disease management. In the absence of guidelines for the management of lipid subfraction levels to reduce the risk of diabetic microangiopathy, the control of these modifiable risk factors may lead to reducing or delaying the incidence of T2DM-related MVCs [29
]. These findings suggest that there may be a need to simultaneously target improvements in multiple lipid subfractions beyond LDL-C, and that pursuing overall lipid subfraction improvements may lead to benefits beyond macrovascular risk reduction for patients with T2DM.