Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes mellitus, although cardiovascular complications and death from CVD have recently been decreasing [1]. Dyslipidemia in patients with diabetes is an important treatment target because mortality from CVD is two to four times higher in patients with diabetes than in those without [2,3]. In the UK Prospective Diabetes Study (UKPDS), low-density lipoprotein cholesterol (LDL-C) was the strongest predictor of coronary heart disease in patients with type 2 diabetes mellitus (T2DM) among several risk factors for CVD, and each 39 mg/dL increase in LDL-C increased the coronary heart disease risk by about 60% [4]. Lowering the LDL-C level is the primary target for CVD prevention, but the actual goals differ among various guidelines. In this report, we present the experts’ opinions on lipid management in Koreans with T2DM from a thorough review of previous randomized controlled trials, worldwide guidelines, and Korean data. The Korean Diabetes Association (KDA) and Korean Society of Lipid and Atherosclerosis (KSoLA) have reached a consensus for lipid management in patients with T2DM.

The treatment goal of LDL-C in patients with diabetes was derived from randomized controlled trials on primary and secondary prevention of CVD using drug interventions, meta-analyses, and systematic reviews of those studies [5-10]. The benefits of statin treatment for CVD have been consistently demonstrated in studies of patients with T2DM and subgroup analyses of patients with diabetes in several clinical studies of statins. The Collaborative Atorvastatin Diabetes Study (CARDS) is a representative primary prevention study of statins in patients with T2DM [11]. Atorvastatin (10 mg) was administered to patients with T2DM aged 40 to 75 years with one or more cardiovascular risk factors; the mean LDL-C concentration was 72 mg/dL, which was reduced by 39% compared to baseline, and the risk of major cardiovascular events was reduced by 37% [11]. Representative studies that demonstrated the secondary prevention effect of statin therapy in patients with T2DM with prior CVD are the Treating to New Targets (TNT) [6] and Pravastatin or Atorvastatin Evaluation and Infection Trial (PROVE-IT) [12]. In these studies, when LDL-C concentration was maintained at 57 to 77 mg/dL by administering 80 mg of atorvastatin, the incidence of CVD was significantly reduced compared to the group for which LDL-C concentration was maintained at 81 to 99 mg/dL with atorvastatin 10 mg or pravastatin 40 mg [6,12]. In a meta-analysis of 14 randomized clinical trials, when LDL-C was reduced by 1 mmol/L with statin therapy, there was a 23% reduction in major cardiovascular events over 5 years, regardless of baseline LDL-C concentration or other underlying characteristics, and the benefits of statin treatment were similar between type 1 diabetes mellitus (T1DM) and T2DM [7]. Because patients with T2DM benefited from a relative risk reduction comparable to that of non-diabetic patients in this meta-analysis by the Cholesterol Treatment Trialists’ Collaboration [7], the benefit of absolute reduction in LDL-C by statin therapy can be greater in patients with diabetes, considering the higher absolute risk, than in patients without diabetes. Recent trials evaluating the effects of the combination of statins and ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with atherosclerotic CVD, such as the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) [13], Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) [14], and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trial [15], showed that even when LDL-C was lowered to less than 70 mg/dL, further reduction of LDL-C lowered the risk of major cardiovascular events.

The IMPROVE-IT study included 18,144 patients who were hospitalized for acute coronary syndrome within 10 days of the study. In the statin and ezetimibe combination treatment group, LDL-C was 15.8 mg/dL lower than that in the statin monotherapy group (53.7 mg/dL vs. 69.5 mg/dL as the median time-weighted average LDL-C level), and the relative risk of CVD significantly decreased by 6.4% at 7 years of follow-up [13]. In the subgroup analysis, the relative risk of CVD was reduced by 14% in patients with diabetes, indicating that the preventive effect of CVD was greater among such patients [16].

In the FOURIER study including 27,564 patients with CVD, the LDL-C levels reduced by 59% (from 92 to 30 mg/dL) in the group in which evolocumab was added to statin. The relative risk of CVD was reduced by 15% over a median of 2.2 years [14]. A subgroup analysis of 11,031 patients with diabetes in this study showed similar results [17]. In the ODYSSEY OUTCOMES trial including 18,924 patients with recent acute coronary syndrome, the risk of CVD was significantly reduced by 15% over a median of 2.8 years in the group in which alirocumab was added to statins, with an LDL-C level of 53.3 mg/dL at 48 months [15]. A subgroup analysis of patients with diabetes showed similar results [18].

Not all patients with diabetes have the same CVD risk. Long duration of diabetes (for T2DM ≥10 years and for T1DM ≥20 years), albuminuria (≥30 mg/g of urine albumin/creatinine ratio), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², retinopathy, neuropathy, and ankle-brachial index <0.9 are well-known risk factors that increase cardiovascular risk in patients with diabetes [19]. In the 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines [20], diabetic patients with (1) target organ damage defined as albuminuria, chronic kidney disease (CKD) with an eGFR of <30 mL/min/1.73 m², retinopathy, or neuropathy; (2) three or more major risk factors including age, hypertension, dyslipidemia, smoking, and obesity; and (3) early onset T1DM with a long duration of >20 years were classified as a very high-risk group with a 10-year cardiovascular mortality risk exceeding 10%. In these patient groups, the LDL-C target is recommended to be a reduction of 50% or more from the baseline and <1.4 mmol/L (<55 mg/dL) [20].

In a 9.3-year follow-up study of 248,000 Korean patients with T2DM aged 30 to 90 years using the Korean National Health Insurance Service (NHIS) database, among diabetic patients without prior CVD, the incidence of myocardial infarction and stroke was increased when accompanied by CKD (eGFR <60 mL/min/1.73 m²), hypertension, long duration of diabetes, and three or more cardiovascular risk factors [21]. In particular, the incidence rate of CVD was similar to or higher in patients with three or more major risk factors (14.1/1,000-person years) or CKD (18.3/1,000-person years) than in patients with prior CVD (14.1/1,000-person years) [21].

According to the Diabetes Fact Sheet 2021 of the KDA, 76.5% of Korean adults with diabetes had hyper-LDL-cholesterolemia, and only 38.3% of adults achieved the target level of LDL-C (<100 mg/dL) [22]. In a recent retrospective observational study using electronic medical record data of 2,000 T2DM patients at 15 hospitals, LDL-C goal achievement remained suboptimal according to several current guidelines for dyslipidemia management [23]: 34.9% to 55.2% in very high-risk patients according to the KDA guidelines [24], 15.7% to 26.6% according to the ESC and EAS guidelines [20], and only 15.5% according to the American Diabetes Association guidelines [25]. In a study using the Korean NHIS database including approximately 153,000 patients with diabetes, LDL-C goal attainment rates were 32.6% in patients without a high risk of CVD (<100 mg/dL) and 12.2% in patients with a high risk of CVD (<70 mg/dL) [26]. When assessing the gap between real-world practice and clinical guidelines, investigators’ assessment of risk was underestimated by 71.6% compared to that by clinical guidelines [27]. Physicians’ perceptions of the target achievement rate of LDL-C were higher than the actual achievement rate (70.6% vs. 47.4%) [28], and physician satisfaction with patients’ LDL-C levels was the primary reason for the non-intensification of statin therapy [27].

The primary treatment goal for dyslipidemia in diabetic patients is the control of LDL-C. Non-high-density lipoprotein cholesterol (HDL-C) or apolipoprotein B can be used as a target when LDL-C has reached the target level but hypertriglyceridemia persists, or when the blood sample is drawn in a non-fasting state [29]. The target goal of non-HDL-C is to add 30 mg/dL to the existing target LDL-C level (Table 1).

Efforts have been made to suggest appropriate lipid management targets for Koreans using retrospective data [21,55-58]. However, there is a lack of independent studies to establish lipid management goals in Korean with diabetes or to evaluate whether achieving the treatment goals based on evidence from other ethnic groups is effective in preventing CVD in Korean patients with diabetes. Therefore, well-designed randomized clinical trials targeting Koreans are needed in the future to strengthen the evidence of this statement.

1. The primary treatment goal for dyslipidemia in patients with diabetes is to control their LDL-C levels.

2. To determine the LDL-C treatment goal for each patient with T2DM, the patient’s comorbidities, including CVD and target organ damage (albuminuria, CKD, retinopathy, neuropathy, and left ventricular hypertrophy), major cardiovascular risk factors (age, family history of premature atherosclerotic CVD, hypertension, smoking, and low HDL-C), and duration of diabetes must be identified first.

3. In patients with T2DM and CVD, an LDL-C goal of <55 mg/dL and a reduction in LDL-C level by 50% or more from the baseline is recommended.

4. For the primary prevention of CVD in patients with T2DM who have a duration of diabetes ≥10 years or who have major cardiovascular risk factors or target organ damage, an LDL-C goal of <70 mg/dL is recommended.

5. For the primary prevention of CVD in patients with T2DM who have any target organ damage or more than three major cardiovascular risk factors, an LDL-C goal of <55 mg/dL is considered an option.

6. For the primary prevention of CVD in patients with T2DM who have a duration of diabetes <10 years and no major cardiovascular risk factors, an LDL-C goal of <100 mg/dL is recommended.

7. Statin is the first-line treatment for patients with diabetes and dyslipidemia.

8. The addition of ezetimibe or PCSK9 inhibitors should be considered for patients with diabetes and CVD if the target LDL-C goal is not met by a maximum tolerable dose of statin.