2024 KSoLA consensus on secondary dyslipidemia.

Pharmacological lipid-lowering is an essential measure for cardiovascular prevention in modern medicine [ 1 , 2 ]. Elevated blood cholesterol and triglyceride (TG) levels are commonly induced by secondary causes [ 3 ]. If secondary dyslipidemia is suspected, diagnosing and managing the causative factors are critical, as is lipid level monitoring. Therefore, screening for the influence of diet, disease, and drug-induced lipid changes may be an important procedure for clinicians. Furthermore, as many physicians may be insufficiently aware of the side effects of medications that they do not often prescribe [ 4 ], relevant supplemental knowledge can help differentiate secondary dyslipidemia. Many guidelines on lipid-lowering therapy (LLT) address secondary dyslipidemia [ 5 , 6 ]. Although these guidelines describe the causative conditions and the significance of their screening and treatment, these are only briefly described. Nevertheless, dyslipidemia holds a solid position in contemporary clinical medicine [ 7 , 8 ] and has a variety of secondary causes. Therefore, the accumulation and summary of detailed data and a recommended approach for suspected cases are required. Consequently, we reached a consensus regarding secondary dyslipidemia. For practical use by clinicians, hypercholesterolemia and hypertriglyceridemia are presented separately. In addition, three major etiologies— diet, diseases, and drugs—were explained, and recommendations were made. Secondary causes of dyslipidemia are presented in Figure 1 according to their impact on lipoprotein synthesis and clearance. The therapeutic approach for these patients is suggested in Figure 2 .

Among the medical conditions that cause TG elevation, obesity and poorly controlled diabetes are the most common. These conditions frequently result in elevated plasma TG, low HDL-C, variable LDL-C, and increased small density LDL levels. Large VLDL, increased TG in LDL and HDL, glycation of apoproteins, and high susceptibility of LDL to oxidation are qualitative differences in diabetes. Even if the blood LDL concentration is normal, its circulation time is longer in diabetes. VLDL production is increased, and its catabolism is decreased, whereas HDL catabolism is promoted. Postprandial hyperlipidemia is commonly observed [ 59 ]. Greater adipocyte mass and decreased insulin sensitivity of hormone-sensitive lipases result in excessive hepatic VLDL production from the overflow of free FA [ 9 , 30 ]. Furthermore, the increased insulin levels promote hepatic FA synthesis. In addition, insulin resistance reduces LPL activity and decreases the catabolism of chylomicrons and VLDL [ 9 , 30 , 60 ]. Insulin resistance and the subsequent decrease in LPL transcription and increase in LPL inhibitor levels may partly contribute to impaired lipolysis [ 30 ]. Furthermore, low clearance of TG-rich lipoproteins independent of LPL activity has been reported in type 2 diabetes. Moreover, insulin infusion promotes LPL expression in adipocytes [ 9 ]. This condition commonly results in elevated TG levels and low HDL-C levels [ 30 ]. Excess glucocorticoids increase VLDL synthesis and cause hypertriglyceridemia. Hypothyroidism increases TG levels by affecting TG metabolism. Low thyroid hormone levels lead to increased VLDL TG production in the liver. LPL activity is downregulated, reducing the breakdown of TG-rich lipoproteins. In addition, impaired hepatic lipase activity contributes to the accumulation of these lipoproteins. Conversely, thyroid stimulating hormone promotes TG synthesis in adipocytes and hepatocytes [ 48 ]. Lipid metabolism is altered in nephrotic syndrome. In particular, blood cholesterol, TG, and apoB-containing lipoprotein levels are elevated. By downregulating catabolizing enzymes such as LPL, hepatic lipase, and VLDL receptors, this disease can impair the clearance of VLDL and chylomicrons. Hypoalbuminemia increases hepatic protein synthesis, which is one of plausible underlying mechanisms [ 61 ]. This condition is often associated with mildly elevated TG levels. Lipolysis and clearance of remnant lipoproteins are decreased in affected patients. In these patients, the expression and activity of LPL are reduced. Furthermore, insulin resistance induced by parathyroid hormones and other conditions is a contributing factor. The clearance of VLDL particles is compromised in uremia because VLDL receptors are downregulated. Conversely, chronic kidney disease can increase the expression of enzymes involved in TG synthesis [ 62 ]. Hepatitis induced by infection, drugs, or alcohol commonly increases VLDL synthesis and causes mild-to-moderate TG elevation. In contrast, severe hepatic conditions such as liver failure can lead to dramatic decreases in blood cholesterol and TG levels [ 30 ]. Patients with SLE have decreased LPL activity, and some produce anti-LPL antibodies [ 63 ]. Hyperchylomicronemia has also been reported in patients with a variety of other autoimmune diseases, such as polymyositis/dermatomyositis, rheumatoid arthritis, and Sjogren’s syndrome, and these patients were positive for anti-LPL antibodies [ 64 ]. However, some researchers have indicated that measuring anti-LPL antibodies is complicated. On the other hand, some affected patients have anti-GPIHBP1 antibodies [ 65 ]. Improving hypertriglyceridemia with steroid therapy can help to diagnose autoimmunity-associated hypertriglyceridemia. TG levels increase, whereas HDL-C and LDL-C levels decrease in these patients. Free FA levels increase, indicating enhanced tissue lipolysis, which is more prominent in patients in septic shock [ 66 ]. Blood TG levels can increase up to 4-fold in the third trimester. However, they frequently remain <250 mg/dL, and are well-tolerated. An increase in estrogen and human placental lactogen levels during this period contributes to insulin resistance and TG elevation. Estrogen increases VLDL synthesis and impairs lipolysis; human placental lactogens also inhibit lipolysis [ 67 ]. The aim of TG lowering is to prevent acute pancreatitis and atherosclerotic cardiovascular disease. While chylomicron particles increase the risk of the former, smaller remnant particles may increase the risk of the latter [ 9 ]. Correcting secondary factors of hypertriglyceridemia is crucial before implementing other TG-lowering measures. For example, weight reduction through caloric restriction can reduce TG levels by approximately 10% [ 9 ]. Physical activity and exercise are known to reduce TG levels up to 30%. However, when managing individuals with secondary dyslipidemia, it is essential to personally target greatest contributor among secondary etiologies [ 46 ]. Anti-LPL antibodies may lead to elevated TG levels in patients with autoimmune diseases. However, measuring anti-LPL antibody levels is impossible in most clinical settings. This antibody is usually assayed by immunoblotting or enzyme-linked immunosorbent assay using purified LPL from post-heparin plasma. However, these methods have some technical limitations [ 63 ]. If TG levels are > 225 mg/dL during pregnancy, regular monitoring and lifestyle modifications are required. If TG levels are > 500 mg/dL despite implementing non-pharmacological measures, omega-3 FAs may be initiated [ 67 ].

A lifestyle that accelerates obesity, including excessive calorie intake and low physical activity, commonly worsens hypertriglyceridemia [ 9 ]. Obesity, especially abdominal obesity, is a major cause of secondary dyslipidemia. Therefore, an appropriate energy intake is important. The timing of daily energy intake also affects total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. A Taiwanese study found that shifting consumption of 100 kcal from nighttime to breakfast or lunch could reduce LDL-C by 1.5 mg/dL [ 10 ]. Cholesterol synthesis in humans increases in the evening and night, possibly due to the peak activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. Saturated FAs are a key factor in elevating LDL-C levels. Saturated FAs are associated with dyslipidemia in individuals whose diet includes saturated FAs at ≥ 10% of the total energy intake [ 11 ]. Specifically, saturated FAs with 12–16 carbon atoms tend to increase LDL-C levels [ 12 ]. Palm oil, including palmitic acid, elevates LDL-C levels by 9 mg/dL compared with other vegetable oils [ 13 ]. The most plausible underlying mechanism is the effect of saturated FAs on LDL receptor (LDLR) activity [ 14 ]. Polyunsaturated FAs can upregulate the mRNA and protein expression of LDLR and downregulate FA synthase. Conversely, monounsaturated FAs decrease apoC3 and apoB100 synthesis, which are the underlying mechanisms for lipid lowering by unsaturated FAs [ 15 ]. Trans FA consumption increases blood LDL-C and TG levels to a greater extent than isocaloric intake of saturated FAs [ 16 ]. In human cells, elaidic acid, the most common trans FA, increases the expression of enzymes involved in cholesterol and FA biosynthesis compared with oleic acid [ 17 ]. A diet high in carbohydrates raises blood TG levels and decreases high-density lipoprotein-cholesterol (HDL-C) levels. Increased insulin concentrations resulting from a high-carbohydrate diet stimulate fat synthesis by elevating malonyl-CoA, which contributes to the conversion of FAs from oxidative to TG synthesis [ 18 ]. A low-carbohydrate diet leads to an improvement in blood TG and HDL-C levels compared with a low-fat diet [ 19 ]. A low-carbohydrate diet decreases TG levels to a greater extent than a moderate-carbohydrate diet, whereas it increases LDL-C [ 20 ]. LDL-C levels increase as carbohydrate intake decreases [ 21 ]. These results indicate the potential risks and benefits of a low-carbohydrate diet and underscore carbohydrate replacement over carbohydrate restriction. Adding fructose to the diet to boost energy intake increases blood TG levels. Associations between fructose and simple sugars, increased lipogenesis, and very low-density lipoprotein (VLDL) production have also been highlighted. Consuming ≥ 100 g of fructose per day or added sugars ≥ 10% of the total energy intake is known to elevate blood TG levels [ 9 ]. Fructose has been shown to increase (postprandial) TG concentrations only in hypercaloric trials [ 22 ]. Excessive consumption of red meat, a major source of saturated FAs, is associated with the risk of dyslipidemia. In a Korean cohort study, a one serving (60 g) increase in red meat intake was associated with a higher risk of hypercholesterolemia in both men and women [ 23 ]. According to data from the National Health and Nutrition Examination Survey in the United States, as the percentage calorie intake from added sugar increased, the risk of hypertriglyceridemia increased [ 24 ]. An analysis of the Framingham Offspring study showed that more than one serving of SSB per day caused a 1.52 times higher risk of TG elevation than less than one serving per day [ 25 ]. High sugar intake enhances fructose metabolism, which mostly occurs in the liver. Excessive fructose accumulation increases de novo lipogenesis and inhibits FA oxidation, which in turn increases lipid supply in the liver. Elevated lipid levels promote VLDL secretion [ 26 ]. Furthermore, although non-nutritive sweeteners are often used as alternatives to sugar, the World Health Organization (WHO) has announced that the long-term consumption of non-nutritive sweeteners may be associated with the risk of non-communicable diseases [ 27 ]. Consuming ultra-processed foods, which mainly contain free sugars, trans FAs, and saturated FAs, is a risk factor for dyslipidemia. A study that analyzed the intake of ultra-processed foods according to the NOVA classification identified the followings. Individuals in the highest tertile had a 2.7 times higher risk of hypertriglyceridemia than those in the lowest tertile [ 28 ]. In a Korean cohort study, the increased consumption of processed meat was associated with a higher risk of hypercholesterolemia and hypertriglyceridemia [ 23 ]. Every 1 oz of alcohol intake in non-drinkers increases blood TG levels by 5–10% [ 29 ]. Excessive alcohol intake suppresses hepatic FA oxidation, thereby promoting hepatic TG synthesis and VLDL secretion [ 9 , 30 ]. In particular, TG elevation can be more severe in individuals with underlying hypertriglyceridemia [ 9 ]. Dietary habits characterized by an excessive intake of refined grains, saturated fats, and sodium have a negative impact on lipid metabolism. In 2023, the American Heart Association highlighted issues with the Northeast Asian diet, including the Korean diet, that increase cardiovascular risk: the absence of dietary fiber in refined grains, such as white rice, high saturated fat and dietary cholesterol from animal protein and organ meats, and high sodium intake [ 31 ]. According to cancer screening data from the Korean National Cancer Center, Western dietary patterns, characterized by a higher intake of bread, snacks, noodles, meat, pizza, hamburgers, sugar, oil, and fat, were associated with a higher risk of total cholesterol and LDL-C levels [ 32 ]. Appropriate energy intake to maintain healthy weight is required. Energy needs vary according to individual’s age, sex, size, and activity [ 33 ]. Weight loss reduces cholesterol and TG levels [ 34 ]. In excessive adiposity, a 5% decrease in body weight reduces LDL-C by 3–5% [ 35 ]. Any diet that results in weight reduction, regardless of nutrient composition, can decrease blood TG levels. A study comparing four diets with different nutritional contents found that all four reduced TG levels and weight to similar extents [ 36 ]. For overweight individuals with hypertriglyceridemia, a 5–10% weight reduction is reasonable and is expected to lower TG levels by 20% [ 9 ]. Nonnutritive sweeteners are not recommended for weight control or risk reduction of these diseases. The 2020 Dietary Reference Intakes for Koreans recommends an intake of saturated FA < 7% and trans FA < 1% of total energy [ 37 ]. A greater intake of monounsaturated FAs (nuts, olive oil, etc.) and marine omega-3 polyunsaturated FAs is recommended [ 9 ]. Replacing saturated fat with unsaturated fat lowers lipid levels and cardiovascular risk [ 38 , 39 ], and substituting with unsaturated FAs and carbohydrates lowers LDL-C levels by 3 mg/dL [ 40 ]. In addition, substituting red meat with high-quality plant protein sources such as legumes leads to a reduction in total cholesterol and LDL-C [ 41 ]. A meta-analysis revealed that high dietary fiber intake reduces total cholesterol compared with low fiber intake, with 25–29 g/day showing health benefits [ 42 ]. Dietary fiber, especially water-soluble fiber, reduced intestinal fat absorption and increased hepatic LDLR with lower VLDL secretion, thereby lowering blood cholesterol levels in animals [ 43 ]. The WHO recommends consuming at least 400 g of fruits and vegetables per day to increase dietary fiber intake [ 44 ]. Similarly, the 2020 Dietary Reference Intakes for Koreans recommends dietary fiber ≥ 30 g/day and ≥ 20 g/day for adult men and women, respectively [ 37 ]. The WHO emphasizes the consumption of whole grains, fruits and vegetables, legumes, and nuts to prevent noncommunicable diseases [ 44 ]. These foods are also recommended by international guidelines for LDL-C management and cardiovascular health [ 45 ]. The benefits of carbohydrate replacement have been emphasized over those of carbohydrate restriction. To improve dietary principles and personalized nutritional recommendations for secondary dyslipidemia, referral to a dietitian nutritionist is recommended [ 46 ]. The optimal diet for those with elevated TG levels is fiber-rich and includes < 50–60% carbohydrates, mostly consisting of whole grains, fruits, and vegetables [ 9 ]. The European Society of Cardiology recommends reducing alcohol consumption to lower TG levels [ 5 ]. The dietary guidelines for Americans limit alcohol consumption to two cups per day for men and one cup per day for women [ 47 ]. Furthermore, they recommended that people who do not consume alcohol refrain from starting to drink [ 33 ], as alcohol can exacerbate TG elevation in individuals with baseline hypertriglyceridemia; complete abstinence is recommended for these individuals.

Various causes including diet, diseases, and drugs can contribute to secondary elevation of blood cholesterol and TG. Screening and identification of potential causes are primary steps for secondary dyslipidemia. Managing secondary factors, especially focusing on the greatest contributor, needs to be preceded before additional treatment.

Some drugs cause mild changes in blood TG levels, whereas others cause severe changes ( Table 2 ) [ 46 ]. Mild-to-moderate TG elevation occurs after the administration of b-blockers, particularly nonselective ones (atenolol, propranolol, and metoprolol). In addition, thiazide and loop diuretics cause mild increases in TG levels [ 9 , 52 ]. Although the underlying mechanisms are unclear, b-blockers and diuretics without intrinsic sympathomimetic activity increase reflex a-adrenergic activity, which can inhibit LPL and increase TG levels. Diuretics have been associated with worsening insulin resistance that may contribute to lipid changes [ 53 ]. Unopposed estrogens used as oral hormone replacements may increase TG levels by 30–40% in a dose-dependent manner and are associated with increased VLDL production [ 9 , 52 , 53 ]. In contrast, the influence of transdermal estrogens without a first-pass effect is minimal. The effects of combined estrogen/progestogen therapy on TG levels are inconsistent. Oral contraceptives with second generation progestogens, including levonorgestrel, and third generation progestogens, such as desogestrel, increase TG levels by up to 50–75%. Although tamoxifen, a selective estrogen receptor modulator, can increase TG levels by 0–30%, severe elevations are uncommon [ 9 , 52 ]. The effects of tamoxifen appear to be related to lipase inhibition [ 53 ]. Post-transplant, prednisone increases TG levels, but not in a dose-dependent manner. In healthy individuals and patients with lupus, TG levels increase by up to 40% with glucocorticoid use [ 53 ]. This effect arises from increased VLDL production and the concomitant hyperinsulinemia [ 54 ]. Variable degrees of TG elevation (35–144%) have been reported after the use of isotretinoin, a retinoid derivative. This results from the inhibition of FA oxidation and an increase in apoC3 [ 9 ]. Acitretin, used for severe psoriasis, can increase TG levels by up to 60% [ 52 ]. These agents are commonly used after transplantation and may increase TG levels by 0–70% [ 52 ]. In general, the effect of cyclosporine on TG levels is less consistent than its effect on LDL-C levels. Ritonavir can elevate TG levels by 200–300%, whereas indinavir and nelfinavir cause an increase of 0–55% [ 52 ]. L-asparaginase infrequently induces severe hypertriglyceridemia and is associated with LPL inhibition [ 9 ]. Second-generation antipsychotics are associated with mild-to-severe hypertriglyceridemia. Among these, clozapine and olanzapine are associated with a high risk of elevated TG levels [ 9 ]. Haloperidol causes a TG elevation of approximately 50%, although this effect is only seen in women [ 52 ]. Before administering drugs known to considerably increase TG levels, these should be measured both before initiating therapy and weeks later, which can be helpful for monitoring the effects of the causative agent. When very severe hypertriglyceridemia occurs, discontinuation and avoidance of the causative agents are required to prevent pancreatitis. In addition, hypertriglyceridemia is a contraindication for some drugs, including isotretinoin [ 52 , 68 ]. When treating patients with post-transplant hypertriglyceridemia, drug interactions between fibrate and cyclosporine must be considered [ 5 ].