Cardiovascular disease (CVD) is the major cause of mortality and morbidity in patients with type 2 diabetes [1]. The increased risk of CVD in subjects with type 2 diabetes consists of multiple factors such as hypertension, smoking, albuminuria and hypercholesterolemia [2]. Among them, hypercholesterolemia is one of the key factors that are amenable to intervention.

A large body of research ranging from molecular to population studies indicates that elevated low density lipoprotein cholesterol (LDL-C) is a major predictor of CVD, including in populations with diabetes [3,4]. Treatments for lowering LDL-C below the target level recommended by several guidelines are emphasized in patients with type 2 diabetes due to the increased risk of CVD [5]. Patients with type 2 diabetes without a history of myocardial infarction are regarded to have the same risk of a coronary event as patients without diabetes who have a history of myocardial infarction [6]. This observation was part of the basis for the recommendation by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) that diabetes should be considered a "coronary heart disease risk equivalent" and the resulting target for aggressive reduction of risk factors [7]. In line with this, recent guidelines from the American Diabetes Association (ADA) recommended the use of statins for primary prevention of CVD in type 2 diabetes patients [8]. Considering the results of previous study mentioned above [6], recent guidelines will provide good evidence on the quantitative relation between achieving target cholesterol concentration and the probability of cardiovascular events in subjects with diabetes [9].

In 2008, the ADA, in consensus with the American College of Cardiology Foundation (ACC), released guidelines [10] following the NCEP 2003 updated recommendations which included an "optional" LDL-C goal <70 mg/dL for patients who are at the "highest risk" for CVD [11]. Highest-risk patients were defined as 1) patients with CVD or 2) patients with diabetes plus one or more additional major CVD risk factors (smoking, hypertension, and family history of premature CVD). High-risk patients was defined as 1) patients who have diabetes but have no major cardiovascular risk factors and 2) patients who do not have diabetes or CVD but have more than two major cardiovascular risk factors. For these patients, the guidelines recommended a target LDL-C less than 100 mg/dL.

Despite available therapies and increased attention to hypercholesterolemia, many patients failed to achieve the LDL-C goals [12]. Data from the third U.S. National Health and Nutrition Examination Survey (NHANES;1988-1994) showed only 42% of patients with diabetes achieved an LDL-C <130 mg/dL [13]. More recent data with the NCEP 2004 updated recommendations demonstrated only 29.4% of very-high-risk patients with both diabetes and CVD reached the LDL-C goal of <70 mg/dL in the United States [14]. There is a need to better understand the reasons why most patients failed to reach these goals despite pharmacological treatment.

Unfortunately, it is uncertain whether target LDL-C level is commonly reached in Korean patients with diabetes. Therefore, we aimed to investigate the lipid target attainment rates according to the ADA and ACC consensus recommendation in Korean patients with diabetes and investigate physician perceptions on lipid target attainment and compared them with actual attainment rates.

In this study, the ADA/ACC recommended LDL-C goal was achieved in approximately 47.4% of Korean patients with diabetes, which was significantly lower than physicians' perceptions (70.6%). Compared to those who did not reach the target LDL-C level, the risk of future coronary heart disease (CHD) was substantially lower among those who did achieve the goal, as shown in the reduction of the Framingham risk score.

This study also demonstrated that there was a large gap between physicians' perceptions and guidelines in categorizing the severity of hypercholesterolemia. Although most physicians answered that they would increase the dosage of lipid-lowering medications if the target LDL-C goal was not reached, only 3.2% prescribed increased titration (Fig. 4A). Although factors affecting physicians' recognition were not analyzed, inferring by the fact that most patients were considered high-risk but not highest-risk to physicians, the updated guidelines might not be fully recognized.

During the treatment period, 65.3% of patients did not have any drug adjustment, including up-titration, add-on, or drug switching (Fig. 4A). Factors such as old age, multi-drug usage, and adverse effects of up-titration or combination therapy might have affected physician decisions. Also, the guidelines used by the physicians may have affected LDL-C level. From the survey, NCEP APT III guidelines [7] (59.8%) were the most frequently used. The 2009/2010 ADA guidelines [8] (27.5%), ADA/ACC consensus statement (4.9%), and Korean Diabetes Association (KDA) guidelines [16] (5.9%) were applied less frequently.

A few studies have evaluated the attainability of the more aggressive LDL-C treatment goal recommended by the NCEP ATPIII or ADA guidelines [14,17]. Kennedy et al. [14] reported that it would be extremely difficult to reach an LDL-C goal of <70 mg/dL in patients with diabetes and CVD in the United States. They estimated that 25% of patients would require more than two lipid-lowering drugs at maximal doses to attain this goal [14]. In a recent survey of 4,888 patients treated with statins, only 38% reached the recommended LDL-C level according to the NCEP guidelines [12]. Although our study was conducted ten years later and used the ADA/ACC guidelines, our findings were consistent with the results of above studies.

It has been suggested that if LDL-C goals are not met, it is necessary to take patient opinions about their illness into account. A prospective survey in Australia using prescription renewals as a surrogate for drug discontinuation found that 60% of patients stopped their medication after 1 year, and half of them discontinued within 3 months of therapy initiation. A major reason for discontinuation was lack of self-perception regarding the need for further treatment [18]. However, when patients were compliant, there were many possible pitfalls underlying patient non-achievement with current treatment goals such as inappropriate drug or dose selection, limited drug efficacy. Failure to achieve target LDL-C level was in large part due to inadequate doses or titration by physicians. Most patients who began treatment with a statin remained at the initial dose [19,20].

In other studies [19,21], patients with diabetes had the lowest success rate in the treatment with lipid lowering drugs. However, subjects with diabetes are known to be at a substantially higher risk for stroke [22], CHD, and death [5]. Moreover, diabetics with [23] or without [24] established CHD benefit from statin treatment in a manner equal to or greater than that of nondiabetic subjects [20,21]. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study which compared structured care and usual care in clinical practice in Greece [23] found that diabetic patients showed early reductions of more than 50% in total mortality, coronary mortality, coronary morbidity, and stroke in the structured care arm. The Collaborative Atorvastatin Diabetes Study (CARDS) showed that, over a 3-year period, a daily 10 mg dose of atorvastatin reduced the risk of a major cardiovascular event in patients with type 2 diabetes mellitus without incident CHD by 37% and that of stroke by almost half (48%) [24]. In our study population, 10.8% of subjects had previous CVD, and a majority (61.9%) was classified as at highest-risk. Although the current treatment gap in LDL-C targets is comparable with published international data, this gap is unacceptable, and undoubtedly leads to an excess number of cardiovascular deaths, infarcts, strokes and need for revascularization. To improve the management of hypercholesterolemia, physicians should be aware of and focus on patients with diabetes. A recent randomized controlled trial demonstrated the incremental impact of team-based care approach to cholesterol management in patients with diabetes [25]. Although primary study outcome was set as achieving LDL-C level of 100 mg/dL regardless of CVD risk, it showed that physician-paramedical staff approach can be considered to improve LDL-C goal attainment.

A major strength of this study was the large sample size; nearly 2,600 patients were included in the main analysis. Another advantage is the inclusion of a survey concerning physician perceptions in the diagnosis of hypercholesteroelemia and treatment strategy. However, this study had several limitations. The diagnosis of CVD used to classify patients into high-risk and highest-risk categories was based on a chart review. Thus, misclassification of LDL-C severity and outcome may have occurred. Also, we did not have detailed dietary information for the patients and therefore could not estimate the effects of dietary intervention on LDL-C level [26]. Another limitation was that the study population did not reflect patients with diabetes who were receiving primary care. Finally, the sex-specific Framingham CHD predictions have not been validated in Koreans. The Framingham prediction was first demonstrated in Caucasians and was later applied to Japanese-Americans and other ethnic groups after recalibration for differing prevalence of risk factors [27]. However, no validation or recalibration has been carried out in Koreans. Furthermore, our study was able to measure the effect of statins over only a short-term period. In many instances, statin treatment had been ongoing for a long period of time. Additionally, patient compliance with the lipid-modifying drugs was not monitored.

In conclusion, this study showed that actual LDL-C target attainment rates according to the ADA/ACC consensus statement were low in Korean patients with diabetes. However, more than 70% of physicians perceived their patients to have achieved these goals. Thus, our results suggested that changes in clinical practices and physician perceptions might be needed to reach cholesterol target goals recommended by updated guidelines.