Patients with type 2 diabetes (T2DM), or with poorly controlled type 1 diabetes (T1DM), typically present with a mixed dyslipidemia, including fasting or postprandial hypertriglyceridemia accompanied by reduced HDL-C levels and increased small dense low-density lipoprotein (sdLDL) levels. Even in T1DM patients with good glycemic control, sdLDL remains higher than in the general population. Among the cardiovascular risks brought by dyslipidemia in diabetes, LDL-C is recognized as the primary risk factor, while sdLDL, because it circulates longer in the blood and more readily enters and is retained beneath the arterial intima, is more atherogenic than LDL. Non-HDL-C represents the cholesterol contained in all atherogenic lipoprotein particles, and an abnormal elevation of this indicator can serve as an important factor for predicting ASCVD risk. 

Based on disease duration, the presence or absence of ASCVD, and the status of major target organ damage, patients with diabetes are categorized as ultra-high risk, very high risk or high risk (Table 1), so as to facilitate ASCVD risk assessment and to define lipid intervention targets and recommended target values according to risk stratum (Table 2). LDL-C and non-HDL-C serve as the primary lipid-lowering targets, and ApoB as the secondary target for ASCVD risk intervention. Abnormalities of TG, Lp(a) and HDL-C are all associated with increased ASCVD risk, but strong evidence that pharmacological intervention on these lipid measures reduces ASCVD risk is still lacking; they are therefore listed as potential lipid-modifying targets for ASCVD risk control in patients with diabetes and still require clinical attention.

Strategies for achieving lipid targets in patients with diabetes include lifestyle intervention and pharmacotherapy (Table 3).

Whatever the type of dyslipidemia, a healthy and balanced diet should run through the whole course of lifestyle intervention.In terms of diet, intake of total fat, saturated fatty acids, cholesterol and trans fatty acids should be limited, while intake of unsaturated fatty acids (vegetable oils) should be moderately increased, particularly foods rich in ω-3 polyunsaturated fatty acids. Intake of vegetables, fruits and high-fiber foods should be increased, and patients with hypertriglyceridemia should also reduce refined carbohydrates and favor low-sugar diets rich in fiber (such as whole grains). For physical activity, at least 150 min of moderate-intensity exercise per week is recommended, and those aiming to lose weight should further increase weekly exercise intensity and duration. Patients in whom exercise is inappropriate because of large glycemic fluctuations or other target organ damage should resume activity gradually once their condition has stabilized. Through control of total caloric intake and increased physical activity, body mass index should be maintained below 24 kg/m2. To raise HDL-C, smoking cessation (including e-cigarettes) is required; to lower TG, alcohol should be avoided or limited (alcohol intake <25 g/d for men and <15 g/d for women), and those with hypertriglyceridemia need to restrict alcohol intake even more strictly.

For those in whom lifestyle intervention alone is unlikely to reach lipid targets, it is recommended to initiate pharmacotherapy alongside lifestyle intervention, so as to reach lipid targets more quickly and reduce ASCVD events. The strategy and flowchart of cholesterol-lowering treatment in patients with diabetes are shown in Figure 1.

By mechanism, cholesterol-lowering drugs fall into three major categories, namely statins, cholesterol absorption inhibitors and PCSK9 inhibitors(Table 4). Statins, as the foundation of cholesterol-lowering therapy, promote hepatocyte uptake and clearance of LDL particles from the blood and significantly reduce serum TC, LDL-C and ApoB levels. Multiple studies have confirmed that statins significantly reduce ASCVD events in patients with diabetes. Because Chinese populations tolerate high-dose statins poorly, high-intensity statins are not recommended; moderate-intensity statins are recommended as the initial lipid-lowering regimen. Cholesterol absorption inhibitors include ezetimibe and hybutimibe, which inhibit intestinal absorption of dietary and biliary cholesterol. Ezetimibe combined with a statin brings greater benefit to patients with diabetes who have acute coronary syndrome, with significant reductions in the risk of myocardial infarction, ischemic stroke and primary endpoint events. PCSK9 inhibitors increase the clearance of serum LDL and thereby lower LDL-C levels, and also improve TG, ApoB and Lp(a). PCSK9 monoclonal antibodies help most T2DM patients at high or very high ASCVD risk reach lipid targets rapidly, with good safety and tolerability and without affecting glycemic levels. In addition, other cholesterol-lowering agents are available in clinical practice, such as Xuezhikang, bile acid sequestrants, probucol, Zhibitai and policosanol.

The TG management strategy for patients with diabetes is shown in Table 5.

No drug targeting Lp(a) has yet entered clinical use, and control of Lp(a) still relies mainly on cholesterol lowering. PCSK9 inhibitorscan reduce Lp(a) levels in patients with diabetes by approximately 20%-30% and significantly reduce the occurrence of MACE, and can therefore be considered a clinical treatment option.

The mechanisms by which lipid-lowering drugs affect blood glucose are not yet fully understood. Studies show that statins and niacin are unfavorable for glycemic control and carry a risk of increasing new-onset diabetes. However, given that the cardiovascular protective effect of statins far outweighs their adverse effects, and that different types and doses differ in their impact on glycemic levels, it is not recommended that patients with diabetes discontinue statins because of poor glycemic control. Once lipid control has reached target, moderate-intensity statins that are relatively neutral in their effect on blood glucose and offer a favorable clinical cost-effectiveness ratio should be preferred, and monitoring of blood glucose or HbA1c should be strengthened before and during treatment.If lipid control has not reached target, combination with other agents may be considered rather than increasing the statin dose. Cholesterol absorption inhibitors, PCSK9 inhibitors, probucol, bempedoic acid, fibrates and high-purity ω-3 fatty acids are neutral with respect to glucose regulation, and some studies further suggest that these agents may improve glucose metabolism, reduce insulin resistance and alleviate fatty liver to a certain extent. Although bile acid sequestrants can improve both glucose and lipid metabolism, their lipid-lowering effect is weak and gastrointestinal adverse reactions are relatively prominent, so they are rarely used in clinical practice in China. Clinical studies of new Lp(a)-lowering drugs are still ongoing, and the effect of their long-term use on blood glucose remains unclear.

For patients taking lipid-lowering drugs for the first time, lipid levels, liver enzymes, creatine kinase and other indicators should be rechecked at 4 to 6 weeks of treatment. If lipid targets are met and no adverse drug reactions occur, the interval can gradually be extended to once every 3 to 6 months. If lipid targets are still not met after 4 to 6 weeks of treatment, the dose or type of lipid-lowering drug should be adjusted promptly, or lipid-lowering drugs with different mechanisms of action should be used in combination. Whenever the type or dose of a lipid-lowering drug is adjusted, rechecking at 4 to 6 weeks of treatment is required. In addition, because long-term statin use may cause abnormal glucose metabolism, monitoring of blood glucose and/or HbA1c should be strengthened at the same time.

For children and adolescents diagnosed with diabetes, it is recommended that those aged 10 years and above undergo lipid testing and assessment once blood glucose is under control or after 3 months of glucose-lowering drug therapy.Ideal lipid levels in children and adolescents with diabetes are LDL‑C<2.6 mmol/L, HDL‑C>0.9 mmol/L, TG<1.7 mmol/L and non-HDL‑C<3.4 mmol/L. Those with persistent dyslipidemia should receive intervention to bring lipids into the ideal range. Interventions are based on healthy lifestyle measures such as a low-fat, high-fiber diet, regular exercise, maintenance of ideal body weight and adequate sleep, together with optimized glycemic control. Those with familial hypercholesterolemia may consider starting lipid-lowering therapy, using agents including statins, ezetimibe, bile acid sequestrants and PCSK9 inhibitors, although evidence on the long-term safety of these drugs in children and adolescents is limited.

All patients with diabetes aged 75 years or older are at very high ASCVD risk, and active lipid-lowering therapy is recommended.Studies confirm that such patients also benefit from LDL-C-lowering treatment, but the consensus does not make an explicit recommendation for the LDL‑C target value. In very elderly patients, a moderate-intensity statin combined with a non-statin agent (ezetimibe, PCSK9 inhibitors, etc.) may be considered as a means of intensive lipid-lowering therapy. During treatment, monitoring for adverse reactions such as impaired liver and kidney function and muscle injury should be strengthened.

Patients with diabetes and comorbid CKD have a significantly increased risk of cardiovascular death and are directly classified into the very high ASCVD risk group. In non-dialysis patients with mild to moderate renal insufficiency, statin therapy can significantly reduce the risk of all-cause death, and combination with a cholesterol absorption inhibitor or a PCSK9 inhibitor can also bring cardiovascular benefit.Statins, however, have not been shown to significantly reduce the risk of cardiovascular disease in hemodialysis patients. High-dose statins should be avoided in patients with CKD, and dose adjustment schemes for statins across CKD stages are shown in Table 6. Cholesterol absorption inhibitors and PCSK9 inhibitors are safe in patients with impaired renal function and do not require dose adjustment.

MAFLD is defined by evidence of hepatic steatosis based on pathology or imaging together with one of three conditions: overweight/obesity, T2DM, or metabolic dysfunction. It is an independent risk factor for ASCVD, and patients with diabetes and comorbid MAFLD have an even higher ASCVD risk. Patients with MAFLD and normal liver function may use moderate-intensity statins.Those with serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation within 3 times the upper limit of normal and normal total bilirubin levels may be observed at the original or a reduced dose; if ALT or AST rises to ≥3 times the upper limit of normal, statins should be discontinued; patients with mild hepatic impairment (Child‑Pugh score 5-6) may be switched to a cholesterol absorption inhibitor or a PCSK9 inhibitor.Decompensated cirrhosis and acute liver failure are contraindications to statins, and evidence for the use of other types of lipid-lowering drugs in these patients is lacking.

Pregnancy can cause a physiological rise in blood cholesterol, with LDL‑C levels increasing by up to 50%; abnormally elevated cholesterol during pregnancy increases the risk of preterm birth and fetal atherosclerosis. Lipid management in pregnancy focuses on screening together with lifestyle changes such as dietary management, appropriate exercise, and abstinence from tobacco and alcohol, as well as maintaining blood glucose in an appropriate range; the choice of lipid-lowering drugs is very limited.

China has the largest number of people with diabetes in the world, and effective management of dyslipidemia in patients with diabetes, together with reduction of cardiovascular event risk, is of profound significance for the Healthy China initiative. Performing ASCVD risk stratification in patients with diabetes and defining lipid target values and lipid-lowering treatment regimens according to each risk stratum are the keys to lipid management in diabetes. Several issues in lipid management for patients with diabetes remain to be resolved, including lipid-lowering treatment targets, randomized controlled trials of new lipid-lowering drugs, and lipid-lowering regimens for special populations. More large-scale, multicenter clinical studies involving both T1DM and T2DM patients are needed in the future to provide higher-quality evidence for lipid management in patients with diabetes.