The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus

An estimated 25.8 million people, or 8.3 % of the US population, were affected by diabetes mellitus in 2010, with 90 %-95 % afflicted with type 2 (T2DM). The American Diabetes Association (ADA) and American Heart Association (AHA) attribute substantial patient morbidity and mortality to T2DM [1]. Furthermore, T2DM is associated with multiple microvascular complications (MVCs) including retinopathy, neuropathy, and nephropathy, all of which contribute to diabetes-associated morbidity and mortality [2, 3]. From 2005–2008, 4.2 million patients with diabetes had diabetic retinopathy, 655,000 of whom developed serious vision loss [4] for a total annual cost of $492.98 million [5]. Diabetic neuropathy affects an estimated 12 %-50 % of those with diabetes, with total annual costs estimated at $10.1 billion. As many as 19 % of T2DM patients have nephropathy and end-stage renal disease, with annual medical costs in the US amounting to about $15 billion [6].

Elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with increased risk for macrovascular events (e.g., myocardial infarction, ischemic stroke, and coronary mortality) among patients with T2DM [3, 7, 8]. However, no consensus exists on possible mechanisms linking these individual lipid subfractions to MVCs. A systematic review of studies assessing associations between lipid subfractions and MVCs noted that dyslipidemia may cause or worsen complications [3]. A European study reported significant associations between elevated levels of total cholesterol (TC) and lower levels of HDL-C with increasing severity of diabetic retinopathy; there was, however, no apparent association between serum TG and retinopathy [9]. Another study found high levels of TC and TG associated with diabetic nephropathy and declining kidney function [10]. The relationship between abnormal lipid subfractions and diabetic neuropathy is relatively unexplored, with only one study showing a small degree of association [11]. Most studies seeking to establish associations between dyslipidemia and microvascular events were of short duration with relatively small sample sizes, rendering them underpowered and with limited generalizability [3]. Nevertheless, available evidence indicates abnormalities among lipid subfractions exacerbate the risk of microvascular events [9].

To date, few studies have investigated the relative magnitude of association between individual lipid subfractions and diabetes-related MVCs. Furthermore, comprehensive literature reviews have not revealed any large-scale real-world studies that assessed the relative associations of standard lipid fractions with diabetic MVCs. In recognition of that gap, this study accessed data from a managed care database to evaluate associations between the levels of lipid subfractions (LDL-C, HDL-C, TG, and non-HDL-C) and the incidence of diabetic retinopathy, peripheral neuropathy, and nephropathy. The impact on risk for MVCs following attainment of ADA targets for specific components of the lipid profile was also quantified [12].

Consistent with the available evidence on diabetic complications [2, 3, 7, 9‐11, 17, 18], 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, 13, 19, 20], 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.

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 mg/dL [23]. 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 [27‐29]. 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.

Claims-based studies are subject to important limitations. The coding of claims is susceptible to lack of specificity, miscoding, improper sequencing, and clerical errors. The study may be hindered by incomplete data in terms of insufficient longitudinal capture of relevant claims (e.g. lack of capture of pre-existing MVCs prior to the start of the patient's health plan eligibility) and/or capture of information that is unobservable in an administrative claims database (e.g. use of over-the-counter medications). Unobservable factors that may influence outcomes are generally omitted when using claims data and in the case of this study, the presence of such unobservable factors are assumed to be occur equally between comparison groups. Important contributory factors of T2DM, such as genetics or alcohol or estrogen use, could not be captured in these data [20]. Because the data used in this study pertain to largely working-age subjects within a managed care population, the findings may not be readily replicable or generalizable to the entire T2DM patient population.

The mean follow-up period in our study was less than 2 years, which may not have been of sufficient duration to determine the onset of MVCs attributable to lipid subfractions. However, because this was an observational claims study, requiring a fixed follow-up period of 4 to 5 years for these patients would have forced survival and subsequently introduced bias. As such, follow-up duration was accounted for as a variable in the survival analysis for risk estimation of MVCs. These inherent study design limitations render the findings hypothesis-generating and need to be confirmed in a prospective, randomized clinical trial.

This study demonstrates significant independent associations among HDL-C, TG and non-HDL-C with risk for microvascular events following the diagnosis of T2DM. Attaining ADA goals for non-HDL-C, HDL-C, and TG levels were significantly associated with a reduced risk of MVCs. There was no clear association, however, between the attainment of the ADA goal for LDL-C and microvascular event risk. These findings suggest that to reduce risk for both macrovascular and microvascular events among patients with T2DM, all components of the lipid profile should be treated to ADA-specified target levels. These findings need to be validated in a prospective, randomized clinical trial.