Hypertriglyceridemia in Diabetes Mellitus: Implications for Pediatric Care

Hypertriglyceridemia in Diabetes Mellitus: Implications for Pediatric Care Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). It is estimated that the risk of CVD in diabetes mellitus (DM) is 2 to 10 times higher than in the general population. Much of this increased risk is thought to be related to the development of an atherogenic lipid profile, in which hypertriglyceridemia is an essential component. Recent studies suggest that dyslipidemia may be present in children and adolescents with DM, particularly in T2DM and in association with poor control in T1DM. However, the role of hypertriglyceridemia in the development of future CVD in youth with DM is unclear, as data are scarce. In this review, we will evaluate the pathophysiology of atherogenic hypertriglyceridemia in DM, the evidence regarding an independent role of triglycerides in the development of CVD, and the treatment of hypertriglyceridemia in patients with DM, highlighting the potential relevance to children and the need for more data in children and adolescents to guide clinical practice. diabetes mellitus type 1, diabetes mellitus type 2, hyperlipidemia, triglycerides Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [1–3]. It is estimated that the risk of CVD in diabetes mellitus (DM) is 2 to 10 times higher than in the general population [4–6]. Much of this increased risk is thought to be related to the development of an atherogenic lipid profile, in which hypertriglyceridemia is an essential component [7]. Recent studies suggest that dyslipidemia may be present in children and adolescents with DM, particularly in T2DM and in association with poor control in T1DM [8, 9]. However, the role of hypertriglyceridemia in the development of future CVD in youth with DM is unclear as data are scarce. Current guidelines recommend a primary treatment goal to lower triglyceride levels, only in the prevention and treatment of triglyceride-induced pancreatitis [10–13]. Studies in childhood DM highlight the importance of understanding the relationship of triglycerides to CVD risk [4, 9]. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial, dyslipidemia worsened over the nearly 4 years of the study, including in those who were started on metformin; increasing hemoglobin A1c was associated with worsening dyslipidemia [9]. In the SEARCH for Diabetes in Youth Case-Control Study, patients with T1DM and T2DM who had excellent glucose control had lower triglyceride levels and higher high-density lipoprotein cholesterol (HDL-C) compared with those with poor control [14]. In this review, we will evaluate the pathophysiology of atherogenic hypertriglyceridemia in DM, the evidence regarding an independent role of triglycerides in the development of CVD, and the treatment of hypertriglyceridemia in patients with DM, highlighting the potential relevance to children and the need for more data in children and adolescents to guide clinical practice. Although this paper is not a systematic review, relevant literature was found by searching MEDLINE, Google Scholar, the Cochrane Library, and Web of Science for references published up to December 2017. In addition, we searched the references listed in the relevant publications. There were no language restrictions. The search terms were kept general and included hypertriglyceridemia, cardiovascular disease, diabetes mellitus, insulin resistance, diet, hyperglycemia, physical activity, statins, fibrates, omega-3 fatty acids, and combinations of these search terms. 1. Pathophysiology Dyslipidemia is not an obligatory component of DM. In fact, in well-controlled T1DM, the lipid profile is often normal [14, 15]. However, in poorly controlled T1DM and T2DM, or in obese patients who develop T2DM, an atherogenic triad of lipid abnormalities consisting of elevated triglycerides, low levels of HDL-C, and an increased prevalence of small, dense low-density lipoprotein particles is often found [7, 16]. The link among these various components of dyslipidemia is likely secondary to the increase in circulating very low-density lipoprotein (VLDL) remnant particles and chylomicron remnants, which is often clinically estimated by measuring apolipoprotein B levels or by non-HDL-C [17]. Increased VLDL levels can be the result of increased VLDL production in the liver, reduced catabolism, or both [12, 18]. The mechanisms relating to this process are complex, but can be reduced to three pathways. First, in patients with insulin resistance, lipolysis of triglycerides in adipocytes and myocytes is unchecked, leading to a flood of fatty acids returning to the liver [19–21]. The increase in fatty acids returning to the liver stimulates increased VLDL production by the liver [15, 22]. Second, insulin resistance indirectly leads to an overproduction of both apolipoprotein B and VLDL, by failing to initiate degradation of apolipoprotein B in the liver [21, 23]. Thirdly, there is evidence that increased expression of apolipoprotein CIII in the setting of insulin resistance contributes to the overproduction of VLDL [24]. Higher insulin levels contribute to the decreased uptake up of VLDL particles, leading to prolonged circulation of these atherogenic particles [15, 17]. As VLDL and chylomicron remnants are cleared by the same mechanisms, the persistence of VLDL remnants prevents efficient clearance of chylomicron remnants, leading to the characteristic postprandial hyperlipidemia seen in patients with DM [17, 24]. Another mechanism of reduced catabolism of triglycerides is through the reduced function of lipoprotein lipase in muscle and adipose, leading to decreased uptake of free fatty acids by these cells and thus increased free fatty acids contributing to the cycle of VLDL overproduction [24]. 2. Role of Triglycerides in CVD, Adult Studies Hypertriglyceridemia is generally defined by fasting levels (Table 1). According to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [11], a normal fasting triglyceride level is less than 150 mg/dL, but an optimal level is considered to be less than 100 mg/dL. Triglyceride levels from 150 to 199 mg/dL are defined as borderline, whereas levels from 200 to 499 mg/dL are defined as high, and levels greater than 500 mg/dL are considered very high [15]. Table 1. Categories of Triglyceride Levels Under Fasting Conditions NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL Fasting is defined as having a sample drawn after a patient has fasted for 8 to 12 hours. Abbreviations: NCEP-ATP, Third Report of the National Cholesterol Education Program-Adult Treatment Panel; NHLBI, National Heart Lung and Blood Institute. View Large Table 1. Categories of Triglyceride Levels Under Fasting Conditions NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL Fasting is defined as having a sample drawn after a patient has fasted for 8 to 12 hours. Abbreviations: NCEP-ATP, Third Report of the National Cholesterol Education Program-Adult Treatment Panel; NHLBI, National Heart Lung and Blood Institute. View Large In most studies assessing the role of triglycerides in the development of CVD in patients with DM, triglyceride levels are obtained following an 8- to 12-hour fast. A possibly more convenient measurement is to obtain a nonfasting triglyceride level. Nonfasting lipid profiles, on average, result in an increase in triglycerides of 26 mg/dL above fasting levels, increased total cholesterol of 8 mg/dL, and a decrease of 8 mg/dL for both low-density lipoprotein cholesterol (LDL-C) and HDL-C [25]. Evidence suggests that postprandial (nonfasting) triglyceride levels may have a stronger association with CVD than fasting levels [26]. For instance, in the Women’s Health Study, nonfasting triglyceride levels were found to be independently associated with CVD events, but fasting triglycerides were not [27]. This finding is especially relevant to those with DM as deranged postprandial lipid metabolism is more common in those with insulin resistance [28]. Although there is concern that nonfasting levels may misclassify some patients, updated LDL-C modeling using nonfasting samples may actually perform better in predicting future CVD events and have been the standard in Denmark since 2009 [6, 29, 30]. Although an atherogenic triad composed of hypertriglyceridemia, low HDL-C, and increased prevalence of small, dense low-density lipoprotein particles is associated with an increased risk of CVD [31], the independent role of hypertriglyceridemia in CVD has been controversial. The independent association between triglycerides and CVD often is muted once models control for HDL-C and LDL-C [5, 15, 26, 32]. For example, for patients being treated with statins, triglyceride level was not associated with CVD risk in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [33] nor were they predictive of CVD events in the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) [34]. In addition, the risk of CVD does not appear to be elevated in patients with inherited forms of severe hypertriglyceridemia, unless the inherited form is associated with increased apolipoprotein production or associated with an increase in triglyceride-rich remnant particles [6, 15]. In fact, the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults does not suggest targeting triglycerides with the goal to reduce CVD risk, only to reduce the risk of triglyceride-induced pancreatitis [10]. However, there is also increasing evidence of an independent role of hypertriglyceridemia in the development of CVD [26, 32, 35–39]. For instance, in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID), each 89 mg/dL decrease in triglycerides reduced the risk of CVD by 11% in those taking pravastatin [40]. Similarly, a 2016 study that controlled for body mass index demonstrated that an elevated triglyceride level was associated with increased coronary plaque development in patients whose LDL-C was well controlled with lipid-lowering therapy [41]. Further, there is evidence that triglycerides are independent markers of risk of recurrent disease after myocardial infarctions, even in those with well-controlled LDL-C and controlling for body mass index [42, 43]. In a large Mendelian randomization study, a technique that can help inform decisions on causality, nonfasting triglycerides were associated with an increased risk of CVD of 2.8 times for each 1 mmol/L (89 mg/dL) increase in triglyceride levels [44, 45]. The ratio of triglycerides to HDL-C has been associated with an increased risk of CVD [46]. Various cutoff points have been used, varying from 2.5 for men and 2 for women [15] to 3.5 for both sexes [46]. A ratio as low as 2:1 has been used in children to identify risk factors for metabolic syndrome, with studies in children and adolescents indicating that a higher ratio is associated with increased number of markers of CVD [47, 48]. African Americans, both adolescents and adults, tend to have a higher HDL-C and lower triglycerides than whites, but a higher rate of CVD. It appears that the ratio in which an atherogenic dyslipidemia develops is lower in African Americans and closer to 2:1. After controlling for the triglyceride-to-HDL-C ratio, adolescents and adults have similar levels of obesity and inflammatory markers, suggesting a similar atherogenic substrate related to high triglycerides at a much younger age [49, 50]. The Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial [51] and the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) [52] suggest the association between HDL-C and CVD is much less than previously thought and strengthens the argument that hypertriglyceridemia has a causal role in atherosclerosis [6, 52]. Similarly, only one trial investigating cholesteryl ester transfer protein inhibitors has demonstrated reduction in CVD risk, even with meaningful elevations in HDL-C [53–55]. Non-HDL-C appears to improve risk prediction and progression of atherosclerosis than LDL-C. Non-HDL-C measures all lipoproteins containing apolipoprotein B, including the triglyceride-rich lipoproteins. In a study of adults on statins, non-HDL-C had a stronger association with plaque progression than LDL-C [41]. This is further supported by the Mendelian randomization studies on triglycerides that help control for the very high day-to-day variability of triglycerides in the general population, a factor that can confound traditional epidemiologic analysis [45, 56]. Another factor increasing the relevance of hypertriglyceridemia in DM is a better understanding of the role of triglycerides in the development of atherosclerosis. Although triglycerides are absent in atherosclerotic plaques, remnant particles, which are triglyceride rich, likely contribute to the inflammatory component of atherosclerosis and do enter developing plaques similar to LDL-C [45]. For example, in patients with genetically high LDL-C, this inflammation is absent, suggesting the inflammation is not primarily a result of LDL-C [57]. To summarize, the role of triglycerides in the development of CVD remains unresolved, but recent evidence using more sophisticated methods suggests that triglycerides may have a more important role in the development of CVD in patients with DM. 3. Treatment Recommendations for Adults Treatment of hypertriglyceridemia in T1DM and T2DM depends on the degree of elevation of triglycerides. For those with less than very high hypertriglyceridemia (<500 mg/dL) [15], the focus of treatment has been on reducing CVD risk, rather than the triglyceride level. However, for those with significantly higher levels, triglyceride-induced pancreatitis is a potentially serious complication. Although it can occur at lower levels, patients with triglyceride levels greater than 800 mg/dL are thought to be at the highest risk. In one study, 15% of patients with a triglyceride level >20 mmol/L (1770 mg/dL) had triglyceride-induced pancreatitis, whereas the prevalence dropped to 3% when the triglyceride level ranged from 10 to 20 mmol/L (885 to 1770 mg/dL) [58]. For patients with triglycerides levels in this range, the goal of treatment should be to lower the triglyceride level quickly. In the prevention and treatment of triglyceride-induced pancreatitis, fat should be eliminated or severely restricted. For those with symptoms of pancreatitis, patients should fast until they improve. After improvement, a nonfat diet should be implemented slowly. For many patients with DM, poor glucose control will be the primary driver of hypertriglyceridemia and may actually be a presenting symptom at diagnosis of DM [59]. In these patients, insulin can rapidly lower triglyceride levels in concert with stabilizing blood glucose levels, particularly in patients presenting concurrently with triglyceride-induced pancreatitis and diabetic ketoacidosis (DKA) [60, 61]. In one of the largest studies of triglyceride-induced pancreatitis in patients with DKA, at least 11% of patients with DKA had evidence of pancreatitis, with the risk of pancreatitis being associated with the severity of acidosis and hyperglycemia [62]. Once patients are able to tolerate oral intake, fibrates and/or omega-3 fatty acid supplements can be useful in reducing triglyceride levels in the long term (Table 2). The American Heart Association states it is reasonable to start triglyceride-lowering medications once triglyceride levels are over 500 mg/dL [15]. If the pancreatitis or hypertriglyceridemia persist, despite medical management, plasmapheresis is one potential option. Plasmapheresis is preferred over more selective forms of apheresis because filtering of triglycerides often leads to clogging of apheresis filters. Of note, intravenous heparin was once used in the treatment of very high triglyceride levels but should now be avoided. Although heparin is able to release lipoprotein lipase from the endothelium and therefore increases triglyceride hydrolysis, this effect is temporary and increases the risk of rebound hypertriglyceridemia [63, 64]. Table 2. Triglyceride-Lowering Effects of Common Lipid-Lowering Medications [15] Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% a In children, 4 g per day lowers triglycerides by approximately 50 mg/dL [84, 85] and by 15% to 30% in adults [86–88]. View Large Table 2. Triglyceride-Lowering Effects of Common Lipid-Lowering Medications [15] Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% a In children, 4 g per day lowers triglycerides by approximately 50 mg/dL [84, 85] and by 15% to 30% in adults [86–88]. View Large 4. Moderately Increased Triglycerides A. Role of Glucose Control Poor glucose control is central to many of the consequences of T1DM and T2DM. However, tightly controlling glucose will likely be insufficient to reduce all CVD risk and may actually increase risk, as was demonstrated in Action to Control Cardiovascular Risk in Diabetes (ACCORD) [4, 65, 66]. One potential explanation for this counterintuitive finding is that tight glucose control is most important in the early stages of T1DM and T2DM and that the increased possibility of hypoglycemia with tight glucose regulation in older adults is associated with excessive risk. Only in the Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, in which tight glucose control was started early in the course of the illness, did a reduction in CVD risk occur [4, 67, 68]. Glucose control appears to be of most importance in the prevention and treatment of triglyceride-induced pancreatitis, rather than in reducing CVD risk factors [65]. B. Role of Diet and Physical Activity A healthy diet, sufficient physical activity, smoking cessation, and moderation in the use of alcohol remain first-line treatments for hypertriglyceridemia, particularly for patients with DM (Table 3)[2, 4, 12, 69]. In adult trials, a modest reduction in weight by 5% to 10% can lead to a decrease of triglyceride levels by approximately 20% [70]. For patients with DM and hypertriglyceridemia, reducing carbohydrates may be the most effective strategy to reduce triglycerides and improve the atherogenic triad [26]. Substantial reduction in calories from carbohydrates, especially those from foods and beverages with added sugar, can lead to a 10% to 20% reduction in triglyceride levels [4]. In the large Primary Prevention of Cardiovascular Disease With a Mediterranean Diet (PREDIMED), a diet high in nuts and polyunsaturated fatty acids reduced hypertriglyceridemia and the risk of CVD in adults [71]. A subgroup analysis of patients with DM also showed an improvement in hypertriglyceridemia [71]. However, in comprehensive review of diets with different macronutrient compositions, the primary driver for improved triglyceride levels was caloric restriction, rather than the macronutrient content [72]. In adults, aerobic exercise also can reduce triglycerides by 20% if a low-calorie diet is followed [70]. Taken together, reductions of 50% or more in triglyceride levels could potentially be attained through intensive therapeutic lifestyle change [15, 73]. Table 3. Treatment of Hypertriglyceridemia in Adults With DM [11, 12] TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction Abbreviation: TG, triglyceride. View Large Table 3. Treatment of Hypertriglyceridemia in Adults With DM [11, 12] TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction Abbreviation: TG, triglyceride. View Large However, the role of lifestyle interventions in patients with DM is not conclusive. Findings from the 2013 Look Action for HEAlth in Diabetes (Look AHEAD) did not find that moderate weight loss in obese patients with T2DM led to a reduction in CVD risk factors [74]. Similarly, an intensive lifestyle intervention in patients with DM did not result in reduced risk of CVD and was stopped prematurely, with average follow-up of over 8 years [75]. A systematic review by Nield et al. [76] did not find evidence of a benefit of nutrition interventions in adults with DM, although the lack of high-quality studies was noted. In the absence of long-term results, it is difficult to determine the impact of lifestyle interventions if they are started at young age. C. Statins Statins are the most effective of the lipid-lowering medications in reducing the risk of CVD in patients with DM and hypertriglyceridemia [15]. Statins generally reduce triglycerides by 10% to 15%, depending on baseline triglyceride level, specific statin, and its dose [12, 70]. In LIPID, each 89 mg/dL decrease in triglycerides reduced the risk of CVD by 11% in those taking pravastatin [40]. However, much of the risk reduction in CVD is related to statin’s ability to lower LDL-C and the triglyceride-lowering effect remains modest. As a result, the 2013 ACC/AHA guidelines on reducing CVD and the Endocrine Society guidelines on hypertriglyceridemia in DM do not suggest the use of statins to reduce triglycerides and only recommend statins for reducing CVD [10, 12]. There is a growing body of literature suggesting statins should be first line to reduce CVD in patients with hypertriglyceridemia, especially if the apolipoprotein B level is high [15]. Unfortunately, patients with hypertriglyceridemia are typically excluded from statin trials; in addition, no clinical trial has evaluated the use of non-HDL-C or apolipoprotein b as primary risk factors for CVD, and the evidence to use these markers as therapy targets is limited to secondary analysis [6, 45]. D. Fibrates Fibrates are the most potent of the lipid-lowering therapies with regard to triglycerides. They reduce triglycerides by decreasing VLDL production and increase the activity of lipoprotein lipase [12]. Studies suggest fibrates decrease triglyceride levels by 30% to 50% and lead to small increases in HDL-C, but generally have no effect on LDL-C [12]. Fibrates have been demonstrated to reduce microvascular complications of DM, such as retinopathy, nephropathy, and amputations [77]. The efficacy of fibrates in reducing CVD in patients with DM has been disappointing, and fibrates likely do not lower all-cause mortality [12, 78]. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, there was no effect of fenofibrate on CVD events [79]. Similar results were reported by the ACCORD trial, which added a fenofibrate to statin therapy [65]. However, in ACCORD, fibrates reduced CVD events in the subgroup with triglyceride levels greater than 204 mg/dL and HDL-C less than 35 mg/dL [80, 81]. In summary, there is scant evidence that fibrates used in patients with DM have worse outcomes compared with statins [82]. E. Omega-3 Fatty Acids Omega-3 fatty acids lower triglycerides primarily through reducing triglyceride synthesis in the liver, inhibiting VLDL production, and increasing clearance of triglycerides [83]. Omega-3 fatty acid supplements are well tolerated, but only have a modest effect on triglyceride levels. Triglycerides are usually lowered between 15% to 30%, and LDL-C usually remains unchanged, or even slightly increases [84–88]. In a systematic review, omega-3 fatty acids decreased triglycerides in patients with DM and had no effect on glucose control [89, 90]. The effect of reducing atherosclerotic events, though, is mixed. In JELIS, a study of the effectiveness of omega-3 fatty acids in Japanese adults who were already prescribed a statin, the risk of major cardiac events was reduced by 19% [91]. However, these results were not replicated in the Outcome Reduction With Initial Glargine Intervention trial, Age-Related Eye Disease Study 2, or in the Risk Prevention Study of Omega-3 Fatty Acids [92–94]. The variability of results may depend on several factors, including dose and formulation of supplement, baseline triglyceride level, and baseline omega-3 fatty acid level in the subject of interest. Based on the available evidence, a 2017 statement from the American Heart Association found no evidence that omega-3 fatty acid supplementations reduce CVD in patients with DM [95]. Supplemental omega-3 fatty acids are available as either over-the-counter formulations or in a prescription formulation. Omega-3 fatty acid preparations typically include docosahexaenoic acid and eicosapentaenoic acid (EPA), either alone or in combination. Lovaza, Epanova, and Omtryg, which include both DHA and EPA, are approved by the Federal Drug Administration. Vascepa, a formulation of EPA only, is also approved by the Federal Drug Administration. Omega-3 fatty acids also can be obtained from the diet, such as from fish and vegetables [96]. F. Niacin Niacin was the first drug to be approved to treat dyslipidemia. Depending on dose and formulation, Niacin typically leads to a 15% to 30% reduction in triglycerides in patients with and without DM [90, 97–99]. The reduction in triglycerides is a result of inhibition of lipolysis in adipose tissue, which reduces the return of free fatty acids to the liver [70]. Despite the decrease in triglycerides, niacin does not appear to reduce the risk of CVD as was demonstrated in AIM-HIGH [50]. In fact, in some populations, it may also increase the risk of stroke and worsen glucose control in patients with DM [100–103]. 5. Treatment Recommendations for Children Data in children and adolescents is much less robust than it is in adults with DM. Current pediatric guidelines focus on treating hypertriglyceridemia as the primary treatment goal only in regards to prevention and treatment of triglyceride-induced pancreatitis (Table 4) [13]. It should be noted, though, that non-HDL-C is recommended as a secondary target for those with elevated triglycerides despite reaching LDL-C goals. For all degrees of hypertriglyceridemia, treatment in children and adolescents is based on small studies and/or extrapolated from trials in adults. The 2011 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (2011 Expert Panel) has different thresholds for hypertriglyceridemia for those <10 years old and for those ≥10 years old (Table 1) [13]. To ensure an accurate diagnosis, classification of hypertriglyceridemia should be based on at least two fasting lipid panels, unless the initial value is >1000 mg/dL [13]. Table 4. Treatment Recommendations for Hypertriglyceridemia in Children and Adolescents [13] TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 Abbreviations: omega-3, omega-3 fatty acid supplement; TG, triglyceride level. a 10 to 19 years old. b <10 years old. View Large Table 4. Treatment Recommendations for Hypertriglyceridemia in Children and Adolescents [13] TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 Abbreviations: omega-3, omega-3 fatty acid supplement; TG, triglyceride level. a 10 to 19 years old. b <10 years old. View Large Except in patients at risk for triglyceride-induced pancreatitis, the initial treatment of patients with DM and hypertriglyceridemia is a 6-month trial of lifestyle modifications. The 2011 Expert Panel [13] suggests using the Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) if the triglyceride level is ≥100 mg/dL for children less than 10 years old or ≥130 mg/dL for those ≥10 years old [13]. In contrast, the American Diabetes Association Standards of Medical Care in Diabetes-2018 recommends the Step 2 American Heart Association diet [104]. Both the CHILD-1 and Step 2 American Heart Association diets recommend that total fat intake be <30% of total calories, trans fatty acids be eliminated, and saturated fat limited to 8% to 10% of total calories. If the CHILD-1 diet is insufficient, or the initial triglyceride level is ≥500 mg/dL, the more restrictive CHILD-2 diet is recommended. Although the CHILD-1 and CHILD-2 diets are very similar, the CHILD-2 diet restricts saturated fat to <7% of total calories and specifically recommends that 10% of total calories are from monounsaturated fat [13]. Per the 2011 Expert Panel, sufficient physical activity is defined as having at least 1 hour each day of moderate-to-vigorous activity and at least 3 days per week with 1 hour of vigorous-intensity physical activity [13]. In one study, a reduction in sugar-sweetened beverages coupled with increased physical activity levels was associated with lower triglyceride levels and reduced insulin resistance in boys, but not girls [105]. For most children and adolescents, weight loss, increased physical activity, and following the CHILD-1 or CHILD-2 diets should be effective in improving triglyceride levels. However, dietary intervention trials have failed to find that diet alone is adequate [106, 107]. In those in whom it fails, guidelines recommend medication referral to a lipid specialist, intensifying glucose control, and consideration of lipid-lowering therapy. In children and adolescents with DM, poor glucose control is associated with a more atherogenic lipid profile [8, 108]. Although adequate glucose control is of the utmost importance in DM, it often is insufficient to normalize the lipid profile [108]. Until the LDL-C is normalized, statins are recommended as the initial medication in patients with DM and dyslipidemia [13]. As opposed to adult guidelines that focus on reducing risk profiles, guidelines in pediatrics continue to use level-driven goals. As DM is considered a high-risk condition, statins are recommended if the LDL-C is ≥130 mg/dL and goal LDL-C levels are <100 mg/dL. Unfortunately, data on the long-term efficacy and safety of statins in reducing CVD risk in children and adolescents with DM is limited. However, studies of children and adolescents with familial hypercholesterolemia provide evidence that statins are safe and can effectively improve the lipid profile and markers of CVD risk [109–112]. Studies of the use of statins in children and adolescents with DM have found similar results, including benefits beyond LDL-C lowering [113–115]. Although there are concerns of worsening insulin sensitivity with the use of statins in adults, in a randomized control trial in adolescents with T1DM and elevated LDL-C, atorvastatin was not found to increase insulin resistance. Further, this pilot study found atorvastatin was associated with lower levels of LDL-C, apolipoprotein B, and atherogenic lipoprotein subparticles [106]. In the most recent guidelines, the use of fish oil supplements, fibrates, or niacin can be considered if triglycerides or non-HDL-C remains elevated. However, the guidelines do not provide specific recommendations in regards to treatment thresholds or doses [13]. As mentioned, fibrates are recommended in adults only to prevent triglyceride-induced pancreatitis. In children and adolescents, the safety and efficacy of fibrates is limited to a single study in youth with familial hypercholesterolemia, which demonstrated similar safety and efficacy for reducing CVD risk as in adults [116]. There also is limited data on omega-3 supplements. In two small studies, omega-3 supplements appear safe in children at a dose of 4 g/d, but only reduce the triglyceride level by about 50 mg/dL and were marginally significant compared with placebo [84, 85]. There is no data on the use of niacin in children with DM and hypertriglyceridemia. 6. Conclusion There is an improved understanding of the role of hypertriglyceridemia in adult patients with DM in the development of CVD; however, specific treatments to prevent CVD continue to be directed toward statins. The implications of hypertriglyceridemia in children and adolescents with DM remain unknown and are of critical importance given the potential for lifelong exposure to elevated levels. Current pediatric guidelines consider DM as a major CVD risk factor and recommend focusing treatment on lowering LDL-C with statins and using lower LDL-C thresholds for initiating medication (130 to 160 mg/dL depending on the presence of other risk factors) [11–13]. Although fibrates, niacin, and supplemental omega-3 fatty acids are effective at lowering triglyceride levels, the data supporting their use in reducing CVD risk is rather weak and data on use in children is lacking. Specifically targeting triglyceride levels, however, remains important in the prevention and treatment of triglyceride-induced pancreatitis for both children and adults. Further research on hypertriglyceridemia in children and adolescents with DM is needed to sufficiently prevent future CVD in this population. Abbreviations: Abbreviations: CVD cardiovascular disease DKA diabetic ketoacidosis DM diabetes mellitus EPA eicosapentaenoic acid HDL-C high-density lipoprotein cholesterol LDL-C low-density lipoprotein cholesterol T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus VLDL very low-density lipoprotein Acknowledgments Disclosure Summary: The authors have nothing to disclose. References and Notes 1. Goldberg IJ . Clinical review 124: diabetic dyslipidemia: causes and consequences . J Clin Endocrinol Metab . 2001 ; 86 ( 3 ): 965 – 971 . Google Scholar CrossRef Search ADS PubMed 2. American Diabetes Association . Classification and diagnosis of diabetes - 2017 . Diabetes Care . 2017 ; 40 ( Suppl 1 ): S11 – S24 . CrossRef Search ADS PubMed 3. de Ferranti SD , de Boer IH , Fonseca V , Fox CS , Golden SH , Lavie CJ , Magge SN , Marx N , McGuire DK , Orchard TJ , Zinman B , Eckel RH . Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association . Diabetes Care . 2014 ; 37 ( 10 ): 2843 – 2863 . Google Scholar CrossRef Search ADS PubMed 4. Maahs DM , Daniels SR , de Ferranti SD , Dichek HL , Flynn J , Goldstein BI , Kelly AS , Nadeau KJ , Martyn-Nemeth P , Osganian SK , Quinn L , Shah AS , Urbina E ; American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council for High Blood Pressure Research, and Council on Lifestyle and Cardiometabolic Health . Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association . Circulation . 2014 ; 130 ( 17 ): 1532 – 1558 . Google Scholar CrossRef Search ADS PubMed 5. Cullen P . Evidence that triglycerides are an independent coronary heart disease risk factor . Am J Cardiol . 2000 ; 86 ( 9 ): 943 – 949 . Google Scholar CrossRef Search ADS PubMed 6. Singh AK , Singh R . Triglyceride and cardiovascular risk: a critical appraisal . Indian J Endocrinol Metab . 2016 ; 20 ( 4 ): 418 – 428 . Google Scholar CrossRef Search ADS PubMed 7. Mazzone T , Chait A , Plutzky J . Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies . Lancet . 2008 ; 371 ( 9626 ): 1800 – 1809 . Google Scholar CrossRef Search ADS PubMed 8. Maahs DM , Dabelea D , D'Agostino RB Jr , Andrews JS , Shah AS , Crimmins N , Mayer-Davis EJ , Marcovina S , Imperatore G , Wadwa RP , Daniels SR , Reynolds K , Hamman RF , Dolan LM . Glucose control predicts 2-year change in lipid profile in youth with type 1 diabetes . J Pediatr . 2013 ; 162 : 101 – 107 e101 . Google Scholar CrossRef Search ADS PubMed 9. TODAY Study Group . Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial . Diabetes Care . 2013 ; 36 ( 6 ): 1758 – 1764 . CrossRef Search ADS PubMed 10. Stone NJ , Robinson JG , Lichtenstein AH , Bairey Merz CN , Blum CB , Eckel RH , Goldberg AC , Gordon D , Levy D , Lloyd-Jones DM , McBride P , Schwartz JS , Shero ST , Smith SC Jr , Watson K , Wilson PW , Eddleman KM , Jarrett NM , LaBresh K , Nevo L , Wnek J , Anderson JL , Halperin JL , Albert NM , Bozkurt B , Brindis RG , Curtis LH , DeMets D , Hochman JS , Kovacs RJ , Ohman EM , Pressler SJ , Sellke FW , Shen WK , Smith SC Jr , Tomaselli GF ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines . 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . Circulation . 2014 ; 129 ( 25 , Suppl 2 ) S1 – S45 . Google Scholar CrossRef Search ADS PubMed 11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) . Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report . Circulation . 2002 ; 106 ( 25 ): 3143 – 3421 . PubMed 12. Berglund L , Brunzell JD , Goldberg AC , Goldberg IJ , Sacks F , Murad MH , Stalenhoef AFH ; Endocrine society . Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2012 ; 97 ( 9 ): 2969 – 2989 . Google Scholar CrossRef Search ADS PubMed 13. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and AdolescentsNational Heart, Lung, and Blood Institute . Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report . Pediatrics . 2011 ; 128 ( Suppl 5 ): S213 – S256 . CrossRef Search ADS PubMed 14. Guy J , Ogden L , Wadwa RP , Hamman RF , Mayer-Davis EJ , Liese AD , D’Agostino R Jr , Marcovina S , Dabelea D . Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case-control study . Diabetes Care . 2009 ; 32 ( 3 ): 416 – 420 . Google Scholar CrossRef Search ADS PubMed 15. Miller M , Stone NJ , Ballantyne C , Bittner V , Criqui MH , Ginsberg HN , Goldberg AC , Howard WJ , Jacobson MS , Kris-Etherton PM , Lennie TA , Levi M , Mazzone T , Pennathur S ; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism Council on Arteriosclerosis, Thrombosis and Vascular Biology Council on Cardiovascular Nursing Council on the Kidney in Cardiovascular Disease . Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association . Circulation . 2011 ; 123 ( 20 ): 2292 – 2333 . Google Scholar CrossRef Search ADS PubMed 16. Ievers-Landis CE , Walders-Abramson N , Amodei N , Drews KL , Kaplan J , Levitt Katz LE , Lavietes S , Saletsky R , Seidman D , Yasuda P ; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group . Longitudinal correlates of health risk behaviors in children and adolescents with type 2 diabetes . J Pediatr . 2015 ; 166 ( 5 ): 1258 – 1264.e3 . Google Scholar CrossRef Search ADS PubMed 17. Adiels M , Olofsson S-O , Taskinen M-R , Borén J . Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome . Arterioscler Thromb Vasc Biol . 2008 ; 28 ( 7 ): 1225 – 1236 . Google Scholar CrossRef Search ADS PubMed 18. Kushner PA , Cobble ME . Hypertriglyceridemia: the importance of identifying patients at risk . Postgrad Med . 2016 ; 128 ( 8 ): 848 – 858 . Google Scholar CrossRef Search ADS PubMed 19. Cooper AD . Hepatic uptake of chylomicron remnants . J Lipid Res . 1997 ; 38 ( 11 ): 2173 – 2192 . Google Scholar PubMed 20. Ginsberg HN . Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis . Diabetes Care . 1991 ; 14 ( 9 ): 839 – 855 . Google Scholar CrossRef Search ADS PubMed 21. Subramanian S , Chait A . Hypertriglyceridemia secondary to obesity and diabetes . Biochim Biophys Acta . 2012 ; 1821 ( 5 ): 819 – 825 . Google Scholar CrossRef Search ADS PubMed 22. Kumar P , Sakwariya A , Sultania AR , Dabas R . Hypertriglyceridemia-induced acute pancreatitis with diabetic ketoacidosis: a rare presentation of type 1 diabetes mellitus . J Lab Physicians . 2017 ; 9 ( 4 ): 329 – 331 . Google Scholar CrossRef Search ADS PubMed 23. Jaiswal M , Schinske A , Pop-Busui R . Lipids and lipid management in diabetes . Best Pract Res Clin Endocrinol Metab . 2014 ; 28 ( 3 ): 325 – 338 . Google Scholar CrossRef Search ADS PubMed 24. Ginsberg HN , Zhang YL , Hernandez-Ono A . Regulation of plasma triglycerides in insulin resistance and diabetes . Arch Med Res . 2005 ; 36 ( 3 ): 232 – 240 . Google Scholar CrossRef Search ADS PubMed 25. Nordestgaard BG . A test in context: lipid profile, fasting versus nonfasting . J Am Coll Cardiol . 2017 ; 70 ( 13 ): 1637 – 1646 . Google Scholar CrossRef Search ADS PubMed 26. Di Angelantonio E , Sarwar N , Perry P , Kaptoge S , Ray KK , Thompson A , Wood AM , Lewington S , Sattar N , Packard CJ , Collins R , Thompson SG , Danesh J ; Emerging Risk Factors Collaboration . Major lipids, apolipoproteins, and risk of vascular disease . JAMA . 2009 ; 302 ( 18 ): 1993 – 2000 . Google Scholar CrossRef Search ADS PubMed 27. Nordestgaard BG , Benn M , Schnohr P , Tybjaerg-Hansen A . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women . JAMA . 2007 ; 298 ( 3 ): 299 – 308 . Google Scholar CrossRef Search ADS PubMed 28. Ai M , Tanaka A , Ogita K , Sekinc M , Numano F , Numano F , Reaven GM . Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes . J Am Coll Cardiol . 2001 ; 38 ( 6 ): 1628 – 1632 . Google Scholar CrossRef Search ADS PubMed 29. Sathiyakumar V , Park J , Golozar A , Lazo M , Quispe R , Guallar E , Blumenthal RS , Jones SR , Martin SS . Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy . Circulation . 2018 ; 137 ( 1 ): 10 – 19 . Google Scholar CrossRef Search ADS PubMed 30. Nordestgaard BG , Varbo A . Triglycerides and cardiovascular disease . Lancet . 2014 ; 384 ( 9943 ): 626 – 635 . Google Scholar CrossRef Search ADS PubMed 31. Musunuru K . Atherogenic dyslipidemia: cardiovascular risk and dietary intervention . Lipids . 2010 ; 45 ( 10 ): 907 – 914 . Google Scholar CrossRef Search ADS PubMed 32. Reiner Ž . Hypertriglyceridaemia and risk of coronary artery disease . Nat Rev Cardiol . 2017 ; 14 ( 7 ): 401 – 411 . Google Scholar CrossRef Search ADS PubMed 33. Gotto AMJ Jr , Whitney E , Stein EA , Shapiro DR , Clearfield M , Weis S , Jou JY , Langendörfer A , Beere PA , Watson DJ , Downs JR , de Cani JS . Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) . Circulation . 2000 ; 101 ( 5 ): 477 – 484 . Google Scholar CrossRef Search ADS PubMed 34. Robins SJ , Collins D , Wittes JT , Papademetriou V , Deedwania PC , Schaefer EJ , McNamara JR , Kashyap ML , Hershman JM , Wexler LF , Rubins HB ; VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial . Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial . JAMA . 2001 ; 285 ( 12 ): 1585 – 1591 . Google Scholar CrossRef Search ADS PubMed 35. Sarwar N , Danesh J , Eiriksdottir G , Sigurdsson G , Wareham N , Bingham S , Boekholdt SM , Khaw KT , Gudnason V . Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies . Circulation . 2007 ; 115 ( 4 ): 450 – 458 . Google Scholar CrossRef Search ADS PubMed 36. Rosenson RS , Davidson MH , Hirsh BJ , Kathiresan S , Gaudet D . Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease . J Am Coll Cardiol . 2014 ; 64 ( 23 ): 2525 – 2540 . Google Scholar CrossRef Search ADS PubMed 37. Sarwar N , Sandhu MS , Ricketts SL , Butterworth AS , Di Angelantonio E , Boekholdt SM , Ouwehand W , Watkins H , Samani NJ , Saleheen D , Lawlor D , Reilly MP , Hingorani AD , Talmud PJ , Danesh J ; Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration . Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies . Lancet . 2010 ; 375 ( 9726 ): 1634 – 1639 . Google Scholar CrossRef Search ADS PubMed 38. Assmann G , Schulte H , von Eckardstein A . Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men . Am J Cardiol . 1996 ; 77 ( 14 ): 1179 – 1184 . Google Scholar CrossRef Search ADS PubMed 39. Thomsen M , Varbo A , Tybjærg-Hansen A , Nordestgaard BG . Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study . Clin Chem . 2014 ; 60 ( 5 ): 737 – 746 . Google Scholar CrossRef Search ADS PubMed 40. Simes RJ , Marschner IC , Hunt D , Colquhoun D , Sullivan D , Stewart RA , Hague W , Keech A , Thompson P , White H , Shaw J , Tonkin A , Investigators LS ; LIPID Study Investigators . Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels ? Circulation . 2002 ; 105 ( 10 ): 1162 – 1169 . Google Scholar CrossRef Search ADS PubMed 41. Puri R , Nissen SE , Shao M , Elshazly MB , Kataoka Y , Kapadia SR , Tuzcu EM , Nicholls SJ . Non-HDL cholesterol and triglycerides. Implications for coronary atheroma progression and clinical events . Arterioscler Thromb Vasc Biol . 2016 ; 36 ( 11 ): 2220 – 2228 . Google Scholar CrossRef Search ADS PubMed 42. Miller M , Cannon CP , Murphy SA , Qin J , Ray KK , Braunwald E ; PROVE IT-TIMI 22 Investigators . Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial . J Am Coll Cardiol . 2008 ; 51 ( 7 ): 724 – 730 . Google Scholar CrossRef Search ADS PubMed 43. Schwartz GG , Abt M , Bao W , DeMicco D , Kallend D , Miller M , Mundl H , Olsson AG . Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins . J Am Coll Cardiol . 2015 ; 65 ( 21 ): 2267 – 2275 . Google Scholar CrossRef Search ADS PubMed 44. Watts GF , Karpe F . Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient . Heart . 2011 ; 97 ( 5 ): 350 – 356 . Google Scholar CrossRef Search ADS PubMed 45. Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology . Circ Res . 2016 ; 118 ( 4 ): 547 – 563 . Google Scholar CrossRef Search ADS PubMed 46. Quispe R , Manalac RJ , Faridi KF , Blaha MJ , Toth PP , Kulkarni KR , Nasir K , Virani SS , Banach M , Blumenthal RS , Martin SS , Jones SR . Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: the Very Large Database of Lipids-4 (VLDL-4) study . Atherosclerosis . 2015 ; 242 ( 1 ): 243 – 250 . Google Scholar CrossRef Search ADS PubMed 47. Pacifico L , Bonci E , Andreoli G , Romaggioli S , Di Miscio R , Lombardo CV , Chiesa C . Association of serum triglyceride-to-HDL cholesterol ratio with carotid artery intima-media thickness, insulin resistance and nonalcoholic fatty liver disease in children and adolescents . Nutr Metab Cardiovasc Dis . 2014 ; 24 ( 7 ): 737 – 743 . Google Scholar CrossRef Search ADS PubMed 48. Di Bonito P , Moio N , Scilla C , Cavuto L , Sibilio G , Sanguigno E , Forziato C , Saitta F , Iardino MR , Di Carluccio C , Capaldo B . Usefulness of the high triglyceride-to-HDL cholesterol ratio to identify cardiometabolic risk factors and preclinical signs of organ damage in outpatient children . Diabetes Care . 2012 ; 35 ( 1 ): 158 – 162 . Google Scholar CrossRef Search ADS PubMed 49. Gidding SS , Keith SW , Falkner B . Adolescent and adult African Americans have similar metabolic dyslipidemia . J Clin Lipidol . 2015 ; 9 ( 3 ): 368 – 376 . Google Scholar CrossRef Search ADS PubMed 50. DeLoach S , Keith SW , Gidding SS , Falkner B . Obesity associated inflammation in African American adolescents and adults . Am J Med Sci . 2014 ; 347 ( 5 ): 357 – 363 . Google Scholar CrossRef Search ADS PubMed 51. Boden WE , Probstfield JL , Anderson T , Chaitman BR , Desvignes-Nickens P , Koprowicz K , McBride R , Teo K , Weintraub W ; AIM-HIGH Investigators . Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy . N Engl J Med . 2011 ; 365 ( 24 ): 2255 – 2267 . Google Scholar CrossRef Search ADS PubMed 52. Landray MJ , Haynes R , Hopewell JC , Parish S , Aung T , Tomson J , Wallendszus K , Craig M , Jiang L , Collins R , Armitage J ; HPS2-THRIVE Collaborative Group . Effects of extended-release niacin with laropiprant in high-risk patients . N Engl J Med . 2014 ; 371 ( 3 ): 203 – 212 . Google Scholar CrossRef Search ADS PubMed 53. Schwartz GG , Olsson AG , Abt M , Ballantyne CM , Barter PJ , Brumm J , Chaitman BR , Holme IM , Kallend D , Leiter LA , Leitersdorf E , McMurray JJ , Mundl H , Nicholls SJ , Shah PK , Tardif JC , Wright RS ; dal-OUTCOMES Investigators . Effects of dalcetrapib in patients with a recent acute coronary syndrome . N Engl J Med . 2012 ; 367 ( 22 ): 2089 – 2099 . Google Scholar CrossRef Search ADS PubMed 54. Barter PJ , Caulfield M , Eriksson M , Grundy SM , Kastelein JJ , Komajda M , Lopez-Sendon J , Mosca L , Tardif JC , Waters DD , Shear CL , Revkin JH , Buhr KA , Fisher MR , Tall AR , Brewer B ; ILLUMINATE Investigators . Effects of torcetrapib in patients at high risk for coronary events . N Engl J Med . 2007 ; 357 ( 21 ): 2109 – 2122 . Google Scholar CrossRef Search ADS PubMed 55. Bowman L , Hopewell JC , Chen F , Wallendszus K , Stevens W , Collins R , Wiviott SD , Cannon CP , Braunwald E , Sammons E , Landray MJ ; HPS3/TIMI55–REVEAL Collaborative Group . Effects of anacetrapib in patients with atherosclerotic vascular disease . N Engl J Med . 2017 ; 377 ( 13 ): 1217 – 1227 . Google Scholar CrossRef Search ADS PubMed 56. Voight BF , Peloso GM , Orho-Melander M , Frikke-Schmidt R , Barbalic M , Jensen MK , Hindy G , Hólm H , Ding EL , Johnson T , Schunkert H , Samani NJ , Clarke R , Hopewell JC , Thompson JF , Li M , Thorleifsson G , Newton-Cheh C , Musunuru K , Pirruccello JP , Saleheen D , Chen L , Stewart A , Schillert A , Thorsteinsdottir U , Thorgeirsson G , Anand S , Engert JC , Morgan T , Spertus J , Stoll M , Berger K , Martinelli N , Girelli D , McKeown PP , Patterson CC , Epstein SE , Devaney J , Burnett MS , Mooser V , Ripatti S , Surakka I , Nieminen MS , Sinisalo J , Lokki ML , Perola M , Havulinna A , de Faire U , Gigante B , Ingelsson E , Zeller T , Wild P , de Bakker PI , Klungel OH , Maitland-van der Zee AH , Peters BJ , de Boer A , Grobbee DE , Kamphuisen PW , Deneer VH , Elbers CC , Onland-Moret NC , Hofker MH , Wijmenga C , Verschuren WM , Boer JM , van der Schouw YT , Rasheed A , Frossard P , Demissie S , Willer C , Do R , Ordovas JM , Abecasis GR , Boehnke M , Mohlke KL , Daly MJ , Guiducci C , Burtt NP , Surti A , Gonzalez E , Purcell S , Gabriel S , Marrugat J , Peden J , Erdmann J , Diemert P , Willenborg C , König IR , Fischer M , Hengstenberg C , Ziegler A , Buysschaert I , Lambrechts D , Van de Werf F , Fox KA , El Mokhtari NE , Rubin D , Schrezenmeir J , Schreiber S , Schäfer A , Danesh J , Blankenberg S , Roberts R , McPherson R , Watkins H , Hall AS , Overvad K , Rimm E , Boerwinkle E , Tybjaerg-Hansen A , Cupples LA , Reilly MP , Melander O , Mannucci PM , Ardissino D , Siscovick D , Elosua R , Stefansson K , O’Donnell CJ , Salomaa V , Rader DJ , Peltonen L , Schwartz SM , Altshuler D , Kathiresan S . Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study . Lancet . 2012 ; 380 ( 9841 ): 572 – 580 . Google Scholar CrossRef Search ADS PubMed 57. Varbo A , Benn M , Tybjærg-Hansen A , Nordestgaard BG . Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation . Circulation . 2013 ; 128 ( 12 ): 1298 – 1309 . Google Scholar CrossRef Search ADS PubMed 58. Sandhu S , Al-Sarraf A , Taraboanta C , Frohlich J , Francis GA . Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study . Lipids Health Dis . 2011 ; 10 ( 1 ): 157 . Google Scholar CrossRef Search ADS PubMed 59. Fick T , Jack J , Pyle-Eilola AL , Henry RK . Severe hypertriglyceridemia at new onset type 1 diabetes mellitus . J Pediatr Endocrinol Metab . 2017 ; 30 ( 8 ): 893 – 897 . Google Scholar CrossRef Search ADS PubMed 60. Henderson SR , Maitland R , Mustafa OG , Miell J , Crook MA , Kottegoda SR . Severe hypertriglyceridaemia in Type 2 diabetes mellitus: beneficial effect of continuous insulin infusion . QJM . 2013 ; 106 ( 4 ): 355 – 359 . Google Scholar CrossRef Search ADS PubMed 61. Thuzar M , Shenoy VV , Malabu UH , Schrale R , Sangla KS . Extreme hypertriglyceridemia managed with insulin . J Clin Lipidol . 2014 ; 8 ( 6 ): 630 – 634 . Google Scholar CrossRef Search ADS PubMed 62. Nair S , Yadav D , Pitchumoni CS . Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA . Am J Gastroenterol . 2000 ; 95 ( 10 ): 2795 – 2800 . Google Scholar CrossRef Search ADS PubMed 63. Whayne TFJ Jr . Concerns about heparin therapy for hypertriglyceridemia . Arch Intern Med . 2010 ; 170 ( 1 ): 108 – 109, author reply 109 . Google Scholar CrossRef Search ADS PubMed 64. Valdivielso P , Ramírez-Bueno A , Ewald N . Current knowledge of hypertriglyceridemic pancreatitis . Eur J Intern Med . 2014 ; 25 ( 8 ): 689 – 694 . Google Scholar CrossRef Search ADS PubMed 65. Gerstein HC , Miller ME , Byington RP , Goff DC Jr , Bigger JT , Buse JB , Cushman WC , Genuth S , Ismail-Beigi F , Grimm RH Jr , Probstfield JL , Simons-Morton DG , Friedewald WT ; Action to Control Cardiovascular Risk in Diabetes Study Group . Effects of intensive glucose lowering in type 2 diabetes . N Engl J Med . 2008 ; 358 ( 24 ): 2545 – 2559 . Google Scholar CrossRef Search ADS PubMed 66. Soedamah-Muthu SS , Chaturvedi N , Toeller M , Ferriss B , Reboldi P , Michel G , Manes C , Fuller JH ; EURODIAB Prospective Complications Study Group . Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study . Diabetes Care . 2004 ; 27 ( 2 ): 530 – 537 . Google Scholar CrossRef Search ADS PubMed 67. Nathan DM , Cleary PA , Backlund JY , Genuth SM , Lachin JM , Orchard TJ , Raskin P , Zinman B ; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group . Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes . N Engl J Med . 2005 ; 353 ( 25 ): 2643 – 2653 . Google Scholar CrossRef Search ADS PubMed 68. Nathan DM , Genuth S , Lachin J , Cleary P , Crofford O , Davis M , Rand L , Siebert C ; Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus . N Engl J Med . 1993 ; 329 ( 14 ): 977 – 986 . Google Scholar CrossRef Search ADS PubMed 69. Ueyama C , Horibe H , Yamase Y , Fujimaki T , Oguri M , Kato K , Yamada Y . Association of smoking with prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals . Biomed Rep . 2017 ; 7 ( 5 ): 429 – 438 . Google Scholar CrossRef Search ADS PubMed 70. Watts GF , Ooi EM , Chan DC . Demystifying the management of hypertriglyceridaemia . Nat Rev Cardiol . 2013 ; 10 ( 11 ): 648 – 661 . Google Scholar CrossRef Search ADS PubMed 71. Estruch R , Ros E , Salas-Salvadó J , Covas MI , Corella D , Arós F , Gómez-Gracia E , Ruiz-Gutiérrez V , Fiol M , Lapetra J , Lamuela-Raventos RM , Serra-Majem L , Pintó X , Basora J , Muñoz MA , Sorlí JV , Martínez JA , Martínez-González MA ; PREDIMED Study Investigators . Primary prevention of cardiovascular disease with a Mediterranean diet . N Engl J Med . 2013 ; 368 ( 14 ): 1279 – 1290 . Google Scholar CrossRef Search ADS PubMed 72. Sacks FM , Bray GA , Carey VJ , Smith SR , Ryan DH , Anton SD , McManus K , Champagne CM , Bishop LM , Laranjo N , Leboff MS , Rood JC , de Jonge L , Greenway FL , Loria CM , Obarzanek E , Williamson DA . Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates . N Engl J Med . 2009 ; 360 ( 9 ): 859 – 873 . Google Scholar CrossRef Search ADS PubMed 73. Larsen RN , Mann NJ , Maclean E , Shaw JE . The effect of high-protein, low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial . Diabetologia . 2011 ; 54 ( 4 ): 731 – 740 . Google Scholar CrossRef Search ADS PubMed 74. Wing RR , Lang W , Wadden TA , Safford M , Knowler WC , Bertoni AG , Hill JO , Brancati FL , Peters A , Wagenknecht L ; Look AHEAD Research Group . Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes . Diabetes Care . 2011 ; 34 ( 7 ): 1481 – 1486 . Google Scholar CrossRef Search ADS PubMed 75. Wing RR , Bolin P , Brancati FL , Bray GA , Clark JM , Coday M , Crow RS , Curtis JM , Egan CM , Espeland MA , Evans M , Foreyt JP , Ghazarian S , Gregg EW , Harrison B , Hazuda HP , Hill JO , Horton ES , Hubbard VS , Jakicic JM , Jeffery RW , Johnson KC , Kahn SE , Kitabchi AE , Knowler WC , Lewis CE , Maschak-Carey BJ , Montez MG , Murillo A , Nathan DM , Patricio J , Peters A , Pi-Sunyer X , Pownall H , Reboussin D , Regensteiner JG , Rickman AD , Ryan DH , Safford M , Wadden TA , Wagenknecht LE , West DS , Williamson DF , Yanovski SZ ; Look AHEAD Research Group . Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes . N Engl J Med . 2013 ; 369 ( 2 ): 145 – 154 . Google Scholar CrossRef Search ADS PubMed 76. Nield L , Moore HJ , Hooper L , Cruickshank JK , Vyas A , Whittaker V , Summerbell CD . Dietary advice for treatment of type 2 diabetes mellitus in adults . Cochrane Database Syst Rev . 2007 ; ( 3 ): CD004097 . 77. Keech AC , Jenkins AJ . Triglyceride-lowering trials . Curr Opin Lipidol . 2017 ; 28 ( 6 ): 477 – 487 . Google Scholar CrossRef Search ADS PubMed 78. Jakob T , Nordmann AJ , Schandelmaier S , Ferreira-González I , Briel M . Fibrates for primary prevention of cardiovascular disease events . Cochrane Database Syst Rev . 2016 ; 11 : CD009753 . Google Scholar PubMed 79. Keech A , Simes RJ , Barter P , Best J , Scott R , Taskinen MR , Forder P , Pillai A , Davis T , Glasziou P , Drury P , Kesäniemi YA , Sullivan D , Hunt D , Colman P , d’Emden M , Whiting M , Ehnholm C , Laakso M ; FIELD study investigators . Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial . Lancet . 2005 ; 366 ( 9500 ): 1849 – 1861 . Google Scholar CrossRef Search ADS PubMed 80. Ginsberg HN , Elam MB , Lovato LC , Crouse JR III , Leiter LA , Linz P , Friedewald WT , Buse JB , Gerstein HC , Probstfield J , Grimm RH , Ismail-Beigi F , Bigger JT , Goff DC Jr , Cushman WC , Simons-Morton DG , Byington RP ; ACCORD Study Group . Effects of combination lipid therapy in type 2 diabetes mellitus . N Engl J Med . 2010 ; 362 ( 17 ): 1563 – 1574 . Google Scholar CrossRef Search ADS PubMed 81. Sacks FM , Carey VJ , Fruchart JC . Combination lipid therapy in type 2 diabetes . N Engl J Med . 2010 ; 363 ( 7 ): 692 – 694, author reply 694–695 . Google Scholar CrossRef Search ADS PubMed 82. Roussel R , Chaignot C , Weill A , Travert F , Hansel B , Marre M , Ricordeau P , Alla F , Allemand H . Use of fibrates monotherapy in people with diabetes and high cardiovascular risk in primary care: a French nationwide cohort study based on national administrative databases . PLoS One . 2015 ; 10 ( 9 ): e0137733 . Google Scholar CrossRef Search ADS PubMed 83. Backes J , Anzalone D , Hilleman D , Catini J . The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia . Lipids Health Dis . 2016 ; 15 ( 1 ): 118 . Google Scholar CrossRef Search ADS PubMed 84. de Ferranti SD , Milliren CE , Denhoff ER , Steltz SK , Selamet Tierney ES , Feldman HA , Osganian SK . Using high-dose omega-3 fatty acid supplements to lower triglyceride levels in 10- to 19-year-olds . Clin Pediatr (Phila) . 2014 ; 53 ( 5 ): 428 – 438 . Google Scholar CrossRef Search ADS PubMed 85. Gidding SS , Prospero C , Hossain J , Zappalla F , Balagopal PB , Falkner B , Kwiterovich P . A double-blind randomized trial of fish oil to lower triglycerides and improve cardiometabolic risk in adolescents . J Pediatr . 2014 ; 165 ( 3 ): 497 – 503.e2 . Google Scholar CrossRef Search ADS PubMed 86. Balk EM , Lichtenstein AH , Chung M , Kupelnick B , Chew P , Lau J . Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review . Atherosclerosis . 2006 ; 189 ( 1 ): 19 – 30 . Google Scholar CrossRef Search ADS PubMed 87. Kris-Etherton PM , Harris WS , Appel LJ ; American Heart Association. Nutrition Committee . Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease . Circulation . 2002 ; 106 ( 21 ): 2747 – 2757 . Google Scholar CrossRef Search ADS PubMed 88. Ito MK . A comparative overview of prescription omega-3 fatty acid products . P&T . 2015 ; 40 ( 12 ): 826 – 857 . Google Scholar PubMed 89. Hartweg J , Perera R , Montori V , Dinneen S , Neil HA , Farmer A . Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus . Cochrane Database Syst Rev . 2008 ; 1 ( 1 ): CD003205 . 90. Grundy SM , Vega GL , McGovern ME , Tulloch BR , Kendall DM , Fitz-Patrick D , Ganda OP , Rosenson RS , Buse JB , Robertson DD , Sheehan JP ; Diabetes Multicenter Research Group . Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial . Arch Intern Med . 2002 ; 162 ( 14 ): 1568 – 1576 . Google Scholar CrossRef Search ADS PubMed 91. Yokoyama M , Origasa H , Matsuzaki M , Matsuzawa Y , Saito Y , Ishikawa Y , Oikawa S , Sasaki J , Hishida H , Itakura H , Kita T , Kitabatake A , Nakaya N , Sakata T , Shimada K , Shirato K ; Japan EPA Lipid Intervention Study (JELIS) Investigators . Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis . Lancet . 2007 ; 369 ( 9567 ): 1090 – 1098 . Google Scholar CrossRef Search ADS PubMed 92. Bosch J , Gerstein HC , Dagenais GR , Díaz R , Dyal L , Jung H , Maggiono AP , Probstfield J , Ramachandran A , Riddle MC , Rydén LE , Yusuf S ; ORIGIN Trial Investigators . n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia . N Engl J Med . 2012 ; 367 ( 4 ): 309 – 318 . Google Scholar CrossRef Search ADS PubMed 93. Rauch B , Schiele R , Schneider S , Diller F , Victor N , Gohlke H , Gottwik M , Steinbeck G , Del Castillo U , Sack R , Worth H , Katus H , Spitzer W , Sabin G , Senges J ; OMEGA Study Group . OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction . Circulation . 2010 ; 122 ( 21 ): 2152 – 2159 . Google Scholar CrossRef Search ADS PubMed 94. Bonds DE , Harrington M , Worrall BB , Bertoni AG , Eaton CB , Hsia J , Robinson J , Clemons TE , Fine LJ , Chew EY ; Writing Group for the AREDS2 Research Group . Effect of long-chain ω-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial . JAMA Intern Med . 2014 ; 174 ( 5 ): 763 – 771 . Google Scholar CrossRef Search ADS PubMed 95. Siscovick DS , Barringer TA , Fretts AM , Wu JH , Lichtenstein AH , Costello RB , Kris-Etherton PM , Jacobson TA , Engler MB , Alger HM , Appel LJ , Mozaffarian D ; American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology . Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association . Circulation . 2017 ; 135 ( 15 ): e867 – e884 . Google Scholar CrossRef Search ADS PubMed 96. Weintraub HS . Overview of prescription omega-3 fatty acid products for hypertriglyceridemia . Postgrad Med . 2014 ; 126 ( 7 ): 7 – 18 . Google Scholar CrossRef Search ADS PubMed 97. Canner PL , Berge KG , Wenger NK , Stamler J , Friedman L , Prineas RJ , Friedewald W . Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin . J Am Coll Cardiol . 1986 ; 8 ( 6 ): 1245 – 1255 . Google Scholar CrossRef Search ADS PubMed 98. Shearer GC , Pottala JV , Hansen SN , Brandenburg V , Harris WS . Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial . J Lipid Res . 2012 ; 53 ( 11 ): 2429 – 2435 . Google Scholar CrossRef Search ADS PubMed 99. Taylor AJ , Lee HJ , Sullenberger LE . The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3 . Curr Med Res Opin . 2006 ; 22 ( 11 ): 2243 – 2250 . Google Scholar CrossRef Search ADS PubMed 100. Sonne DP , Hemmingsen B . Comment on American Diabetes Association. Standards of medical care in diabetes-2017 . Diabetes Care . 2017 ; 40 ( 7 , Suppl 1 ): e92 – e93 . Google Scholar CrossRef Search ADS PubMed 101. Guyton JR , Fazio S , Adewale AJ , Jensen E , Tomassini JE , Shah A , Tershakovec AM . Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial . Diabetes Care . 2012 ; 35 ( 4 ): 857 – 860 . Google Scholar CrossRef Search ADS PubMed 102. Guyton JR . Niacin in cardiovascular prevention: mechanisms, efficacy, and safety . Curr Opin Lipidol . 2007 ; 18 ( 4 ): 415 – 420 . Google Scholar CrossRef Search ADS PubMed 103. Elam MB , Hunninghake DB , Davis KB , Garg R , Johnson C , Egan D , Kostis JB , Sheps DS , Brinton EA . Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial . JAMA . 2000 ; 284 ( 10 ): 1263 – 1270 . Google Scholar CrossRef Search ADS PubMed 104. American Diabetes Association . Standards of medical care in diabetes 2018 . Diabetes Care . 2018 ; 41 ( Suppl 1 ). 105. Bremer AA , Auinger P , Byrd RS . Relationship between insulin resistance-associated metabolic parameters and anthropometric measurements with sugar-sweetened beverage intake and physical activity levels in US adolescents: findings from the 1999-2004 National Health and Nutrition Examination Survey . Arch Pediatr Adolesc Med . 2009 ; 163 ( 4 ): 328 – 335 . Google Scholar CrossRef Search ADS PubMed 106. Canas JA , Ross JL , Taboada MV , Sikes KM , Damaso LC , Hossain J , Caulfield MP , Gidding SS , Mauras N . A randomized, double blind, placebo-controlled pilot trial of the safety and efficacy of atorvastatin in children with elevated low-density lipoprotein cholesterol (LDL-C) and type 1 diabetes . Pediatr Diabetes . 2015 ; 16 ( 2 ): 79 – 89 . Google Scholar CrossRef Search ADS PubMed 107. Lauer RM , Obarzanek E , Hunsberger SA , Van Horn L , Hartmuller VW , Barton BA , Stevens VJ , Kwiterovich PO Jr , Franklin FA Jr , Kimm SY , Lasser NL , Simons-Morton DG . Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children . Am J Clin Nutr . 2000 ; 72 ( 5 , Suppl ) 1332S – 1342S . Google Scholar CrossRef Search ADS PubMed 108. American Diabetes Association . Children and adolescents: standards of medical care in diabetes-2018 . Diabetes Care . 2018 ; 41 ( Suppl 1 ): S126 – S136 . CrossRef Search ADS PubMed 109. Lambert M , Lupien PJ , Gagné C , Lévy E , Blaichman S , Langlois S , Hayden M , Rose V , Clarke JT , Wolfe BM , Clarson C , Parsons H , Stephure DK , Potvin D , Lambert J ; Canadian Lovastatin in Children Study Group . Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin . Pediatrics . 1996 ; 97 ( 5 ): 619 – 628 . Google Scholar PubMed 110. Knipscheer HC , Boelen CC , Kastelein JJ , van Diermen DE , Groenemeijer BE , van den Ende A , Büller HR , Bakker HD . Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia . Pediatr Res . 1996 ; 39 ( 5 ): 867 – 871 . Google Scholar CrossRef Search ADS PubMed 111. McCrindle BW , Ose L , Marais AD . Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial . J Pediatr . 2003 ; 143 ( 1 ): 74 – 80 . Google Scholar CrossRef Search ADS PubMed 112. Avis HJ , Vissers MN , Stein EA , Wijburg FA , Trip MD , Kastelein JJ , Hutten BA . A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia . Arterioscler Thromb Vasc Biol . 2007 ; 27 ( 8 ): 1803 – 1810 . Google Scholar CrossRef Search ADS PubMed 113. Haller MJ , Stein JM , Shuster JJ , Theriaque D , Samyn MM , Pepine C , Silverstein JH . Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus . J Pediatr Endocrinol Metab . 2009 ; 22 ( 1 ): 65 – 68 . Google Scholar CrossRef Search ADS PubMed 114. Tehrani S , Mobarrez F , Antovic A , Santesson P , Lins PE , Adamson U , Henriksson P , Wallén NH , Jörneskog G . Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia . Thromb Res . 2010 ; 126 ( 3 ): e225 – e231 . Google Scholar CrossRef Search ADS PubMed 115. Bjornstad P , Wadwa RP . Risks and benefits of statin use in young people with type 1 diabetes . Curr Diab Rep . 2014 ; 14 ( 7 ): 499 . Google Scholar CrossRef Search ADS PubMed 116. Wheeler KA , West RJ , Lloyd JK , Barley J . Double blind trial of bezafibrate in familial hypercholesterolaemia . Arch Dis Child . 1985 ; 60 ( 1 ): 34 – 37 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Endocrine Society Oxford University Press

Hypertriglyceridemia in Diabetes Mellitus: Implications for Pediatric Care

Loading next page...
 
/lp/ou_press/hypertriglyceridemia-in-diabetes-mellitus-implications-for-pediatric-HDhIQ7rPTR
Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
eISSN
2472-1972
D.O.I.
10.1210/js.2018-00079
Publisher site
See Article on Publisher Site

Abstract

Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). It is estimated that the risk of CVD in diabetes mellitus (DM) is 2 to 10 times higher than in the general population. Much of this increased risk is thought to be related to the development of an atherogenic lipid profile, in which hypertriglyceridemia is an essential component. Recent studies suggest that dyslipidemia may be present in children and adolescents with DM, particularly in T2DM and in association with poor control in T1DM. However, the role of hypertriglyceridemia in the development of future CVD in youth with DM is unclear, as data are scarce. In this review, we will evaluate the pathophysiology of atherogenic hypertriglyceridemia in DM, the evidence regarding an independent role of triglycerides in the development of CVD, and the treatment of hypertriglyceridemia in patients with DM, highlighting the potential relevance to children and the need for more data in children and adolescents to guide clinical practice. diabetes mellitus type 1, diabetes mellitus type 2, hyperlipidemia, triglycerides Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) [1–3]. It is estimated that the risk of CVD in diabetes mellitus (DM) is 2 to 10 times higher than in the general population [4–6]. Much of this increased risk is thought to be related to the development of an atherogenic lipid profile, in which hypertriglyceridemia is an essential component [7]. Recent studies suggest that dyslipidemia may be present in children and adolescents with DM, particularly in T2DM and in association with poor control in T1DM [8, 9]. However, the role of hypertriglyceridemia in the development of future CVD in youth with DM is unclear as data are scarce. Current guidelines recommend a primary treatment goal to lower triglyceride levels, only in the prevention and treatment of triglyceride-induced pancreatitis [10–13]. Studies in childhood DM highlight the importance of understanding the relationship of triglycerides to CVD risk [4, 9]. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial, dyslipidemia worsened over the nearly 4 years of the study, including in those who were started on metformin; increasing hemoglobin A1c was associated with worsening dyslipidemia [9]. In the SEARCH for Diabetes in Youth Case-Control Study, patients with T1DM and T2DM who had excellent glucose control had lower triglyceride levels and higher high-density lipoprotein cholesterol (HDL-C) compared with those with poor control [14]. In this review, we will evaluate the pathophysiology of atherogenic hypertriglyceridemia in DM, the evidence regarding an independent role of triglycerides in the development of CVD, and the treatment of hypertriglyceridemia in patients with DM, highlighting the potential relevance to children and the need for more data in children and adolescents to guide clinical practice. Although this paper is not a systematic review, relevant literature was found by searching MEDLINE, Google Scholar, the Cochrane Library, and Web of Science for references published up to December 2017. In addition, we searched the references listed in the relevant publications. There were no language restrictions. The search terms were kept general and included hypertriglyceridemia, cardiovascular disease, diabetes mellitus, insulin resistance, diet, hyperglycemia, physical activity, statins, fibrates, omega-3 fatty acids, and combinations of these search terms. 1. Pathophysiology Dyslipidemia is not an obligatory component of DM. In fact, in well-controlled T1DM, the lipid profile is often normal [14, 15]. However, in poorly controlled T1DM and T2DM, or in obese patients who develop T2DM, an atherogenic triad of lipid abnormalities consisting of elevated triglycerides, low levels of HDL-C, and an increased prevalence of small, dense low-density lipoprotein particles is often found [7, 16]. The link among these various components of dyslipidemia is likely secondary to the increase in circulating very low-density lipoprotein (VLDL) remnant particles and chylomicron remnants, which is often clinically estimated by measuring apolipoprotein B levels or by non-HDL-C [17]. Increased VLDL levels can be the result of increased VLDL production in the liver, reduced catabolism, or both [12, 18]. The mechanisms relating to this process are complex, but can be reduced to three pathways. First, in patients with insulin resistance, lipolysis of triglycerides in adipocytes and myocytes is unchecked, leading to a flood of fatty acids returning to the liver [19–21]. The increase in fatty acids returning to the liver stimulates increased VLDL production by the liver [15, 22]. Second, insulin resistance indirectly leads to an overproduction of both apolipoprotein B and VLDL, by failing to initiate degradation of apolipoprotein B in the liver [21, 23]. Thirdly, there is evidence that increased expression of apolipoprotein CIII in the setting of insulin resistance contributes to the overproduction of VLDL [24]. Higher insulin levels contribute to the decreased uptake up of VLDL particles, leading to prolonged circulation of these atherogenic particles [15, 17]. As VLDL and chylomicron remnants are cleared by the same mechanisms, the persistence of VLDL remnants prevents efficient clearance of chylomicron remnants, leading to the characteristic postprandial hyperlipidemia seen in patients with DM [17, 24]. Another mechanism of reduced catabolism of triglycerides is through the reduced function of lipoprotein lipase in muscle and adipose, leading to decreased uptake of free fatty acids by these cells and thus increased free fatty acids contributing to the cycle of VLDL overproduction [24]. 2. Role of Triglycerides in CVD, Adult Studies Hypertriglyceridemia is generally defined by fasting levels (Table 1). According to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [11], a normal fasting triglyceride level is less than 150 mg/dL, but an optimal level is considered to be less than 100 mg/dL. Triglyceride levels from 150 to 199 mg/dL are defined as borderline, whereas levels from 200 to 499 mg/dL are defined as high, and levels greater than 500 mg/dL are considered very high [15]. Table 1. Categories of Triglyceride Levels Under Fasting Conditions NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL Fasting is defined as having a sample drawn after a patient has fasted for 8 to 12 hours. Abbreviations: NCEP-ATP, Third Report of the National Cholesterol Education Program-Adult Treatment Panel; NHLBI, National Heart Lung and Blood Institute. View Large Table 1. Categories of Triglyceride Levels Under Fasting Conditions NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL NCEP-ATP III [11] Endocrine Society [12] NHLBI Expert Panel in Children and Adolescents [13] Normal <150 mg/dL Normal <150 mg/dL Acceptable 0–9 years <75 mg/dL Borderline 150–199 mg/dL Mild 150–199 mg/dL 10–19 years <90 mg/dL High 200–499 mg/dL Moderate 200–999 mg/dL Borderline high 0–9 years 75–99 mg/dL Very high >500 mg/dL Severe 1000–1999 mg/dL 10–19 years 90–130 mg/dL Very severe >2000 mg/dL High 0–9 years ≥100 mg/dL 10–19 years >130 mg/dL Fasting is defined as having a sample drawn after a patient has fasted for 8 to 12 hours. Abbreviations: NCEP-ATP, Third Report of the National Cholesterol Education Program-Adult Treatment Panel; NHLBI, National Heart Lung and Blood Institute. View Large In most studies assessing the role of triglycerides in the development of CVD in patients with DM, triglyceride levels are obtained following an 8- to 12-hour fast. A possibly more convenient measurement is to obtain a nonfasting triglyceride level. Nonfasting lipid profiles, on average, result in an increase in triglycerides of 26 mg/dL above fasting levels, increased total cholesterol of 8 mg/dL, and a decrease of 8 mg/dL for both low-density lipoprotein cholesterol (LDL-C) and HDL-C [25]. Evidence suggests that postprandial (nonfasting) triglyceride levels may have a stronger association with CVD than fasting levels [26]. For instance, in the Women’s Health Study, nonfasting triglyceride levels were found to be independently associated with CVD events, but fasting triglycerides were not [27]. This finding is especially relevant to those with DM as deranged postprandial lipid metabolism is more common in those with insulin resistance [28]. Although there is concern that nonfasting levels may misclassify some patients, updated LDL-C modeling using nonfasting samples may actually perform better in predicting future CVD events and have been the standard in Denmark since 2009 [6, 29, 30]. Although an atherogenic triad composed of hypertriglyceridemia, low HDL-C, and increased prevalence of small, dense low-density lipoprotein particles is associated with an increased risk of CVD [31], the independent role of hypertriglyceridemia in CVD has been controversial. The independent association between triglycerides and CVD often is muted once models control for HDL-C and LDL-C [5, 15, 26, 32]. For example, for patients being treated with statins, triglyceride level was not associated with CVD risk in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [33] nor were they predictive of CVD events in the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) [34]. In addition, the risk of CVD does not appear to be elevated in patients with inherited forms of severe hypertriglyceridemia, unless the inherited form is associated with increased apolipoprotein production or associated with an increase in triglyceride-rich remnant particles [6, 15]. In fact, the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults does not suggest targeting triglycerides with the goal to reduce CVD risk, only to reduce the risk of triglyceride-induced pancreatitis [10]. However, there is also increasing evidence of an independent role of hypertriglyceridemia in the development of CVD [26, 32, 35–39]. For instance, in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID), each 89 mg/dL decrease in triglycerides reduced the risk of CVD by 11% in those taking pravastatin [40]. Similarly, a 2016 study that controlled for body mass index demonstrated that an elevated triglyceride level was associated with increased coronary plaque development in patients whose LDL-C was well controlled with lipid-lowering therapy [41]. Further, there is evidence that triglycerides are independent markers of risk of recurrent disease after myocardial infarctions, even in those with well-controlled LDL-C and controlling for body mass index [42, 43]. In a large Mendelian randomization study, a technique that can help inform decisions on causality, nonfasting triglycerides were associated with an increased risk of CVD of 2.8 times for each 1 mmol/L (89 mg/dL) increase in triglyceride levels [44, 45]. The ratio of triglycerides to HDL-C has been associated with an increased risk of CVD [46]. Various cutoff points have been used, varying from 2.5 for men and 2 for women [15] to 3.5 for both sexes [46]. A ratio as low as 2:1 has been used in children to identify risk factors for metabolic syndrome, with studies in children and adolescents indicating that a higher ratio is associated with increased number of markers of CVD [47, 48]. African Americans, both adolescents and adults, tend to have a higher HDL-C and lower triglycerides than whites, but a higher rate of CVD. It appears that the ratio in which an atherogenic dyslipidemia develops is lower in African Americans and closer to 2:1. After controlling for the triglyceride-to-HDL-C ratio, adolescents and adults have similar levels of obesity and inflammatory markers, suggesting a similar atherogenic substrate related to high triglycerides at a much younger age [49, 50]. The Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial [51] and the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) [52] suggest the association between HDL-C and CVD is much less than previously thought and strengthens the argument that hypertriglyceridemia has a causal role in atherosclerosis [6, 52]. Similarly, only one trial investigating cholesteryl ester transfer protein inhibitors has demonstrated reduction in CVD risk, even with meaningful elevations in HDL-C [53–55]. Non-HDL-C appears to improve risk prediction and progression of atherosclerosis than LDL-C. Non-HDL-C measures all lipoproteins containing apolipoprotein B, including the triglyceride-rich lipoproteins. In a study of adults on statins, non-HDL-C had a stronger association with plaque progression than LDL-C [41]. This is further supported by the Mendelian randomization studies on triglycerides that help control for the very high day-to-day variability of triglycerides in the general population, a factor that can confound traditional epidemiologic analysis [45, 56]. Another factor increasing the relevance of hypertriglyceridemia in DM is a better understanding of the role of triglycerides in the development of atherosclerosis. Although triglycerides are absent in atherosclerotic plaques, remnant particles, which are triglyceride rich, likely contribute to the inflammatory component of atherosclerosis and do enter developing plaques similar to LDL-C [45]. For example, in patients with genetically high LDL-C, this inflammation is absent, suggesting the inflammation is not primarily a result of LDL-C [57]. To summarize, the role of triglycerides in the development of CVD remains unresolved, but recent evidence using more sophisticated methods suggests that triglycerides may have a more important role in the development of CVD in patients with DM. 3. Treatment Recommendations for Adults Treatment of hypertriglyceridemia in T1DM and T2DM depends on the degree of elevation of triglycerides. For those with less than very high hypertriglyceridemia (<500 mg/dL) [15], the focus of treatment has been on reducing CVD risk, rather than the triglyceride level. However, for those with significantly higher levels, triglyceride-induced pancreatitis is a potentially serious complication. Although it can occur at lower levels, patients with triglyceride levels greater than 800 mg/dL are thought to be at the highest risk. In one study, 15% of patients with a triglyceride level >20 mmol/L (1770 mg/dL) had triglyceride-induced pancreatitis, whereas the prevalence dropped to 3% when the triglyceride level ranged from 10 to 20 mmol/L (885 to 1770 mg/dL) [58]. For patients with triglycerides levels in this range, the goal of treatment should be to lower the triglyceride level quickly. In the prevention and treatment of triglyceride-induced pancreatitis, fat should be eliminated or severely restricted. For those with symptoms of pancreatitis, patients should fast until they improve. After improvement, a nonfat diet should be implemented slowly. For many patients with DM, poor glucose control will be the primary driver of hypertriglyceridemia and may actually be a presenting symptom at diagnosis of DM [59]. In these patients, insulin can rapidly lower triglyceride levels in concert with stabilizing blood glucose levels, particularly in patients presenting concurrently with triglyceride-induced pancreatitis and diabetic ketoacidosis (DKA) [60, 61]. In one of the largest studies of triglyceride-induced pancreatitis in patients with DKA, at least 11% of patients with DKA had evidence of pancreatitis, with the risk of pancreatitis being associated with the severity of acidosis and hyperglycemia [62]. Once patients are able to tolerate oral intake, fibrates and/or omega-3 fatty acid supplements can be useful in reducing triglyceride levels in the long term (Table 2). The American Heart Association states it is reasonable to start triglyceride-lowering medications once triglyceride levels are over 500 mg/dL [15]. If the pancreatitis or hypertriglyceridemia persist, despite medical management, plasmapheresis is one potential option. Plasmapheresis is preferred over more selective forms of apheresis because filtering of triglycerides often leads to clogging of apheresis filters. Of note, intravenous heparin was once used in the treatment of very high triglyceride levels but should now be avoided. Although heparin is able to release lipoprotein lipase from the endothelium and therefore increases triglyceride hydrolysis, this effect is temporary and increases the risk of rebound hypertriglyceridemia [63, 64]. Table 2. Triglyceride-Lowering Effects of Common Lipid-Lowering Medications [15] Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% a In children, 4 g per day lowers triglycerides by approximately 50 mg/dL [84, 85] and by 15% to 30% in adults [86–88]. View Large Table 2. Triglyceride-Lowering Effects of Common Lipid-Lowering Medications [15] Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% Medication Triglyceride Reduction Fibrates 30%–50% Niacin 20%–50% Omega-3 supplementsa 20%–50% Statins 10%–30% Ezetimibe 5%–10% a In children, 4 g per day lowers triglycerides by approximately 50 mg/dL [84, 85] and by 15% to 30% in adults [86–88]. View Large 4. Moderately Increased Triglycerides A. Role of Glucose Control Poor glucose control is central to many of the consequences of T1DM and T2DM. However, tightly controlling glucose will likely be insufficient to reduce all CVD risk and may actually increase risk, as was demonstrated in Action to Control Cardiovascular Risk in Diabetes (ACCORD) [4, 65, 66]. One potential explanation for this counterintuitive finding is that tight glucose control is most important in the early stages of T1DM and T2DM and that the increased possibility of hypoglycemia with tight glucose regulation in older adults is associated with excessive risk. Only in the Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, in which tight glucose control was started early in the course of the illness, did a reduction in CVD risk occur [4, 67, 68]. Glucose control appears to be of most importance in the prevention and treatment of triglyceride-induced pancreatitis, rather than in reducing CVD risk factors [65]. B. Role of Diet and Physical Activity A healthy diet, sufficient physical activity, smoking cessation, and moderation in the use of alcohol remain first-line treatments for hypertriglyceridemia, particularly for patients with DM (Table 3)[2, 4, 12, 69]. In adult trials, a modest reduction in weight by 5% to 10% can lead to a decrease of triglyceride levels by approximately 20% [70]. For patients with DM and hypertriglyceridemia, reducing carbohydrates may be the most effective strategy to reduce triglycerides and improve the atherogenic triad [26]. Substantial reduction in calories from carbohydrates, especially those from foods and beverages with added sugar, can lead to a 10% to 20% reduction in triglyceride levels [4]. In the large Primary Prevention of Cardiovascular Disease With a Mediterranean Diet (PREDIMED), a diet high in nuts and polyunsaturated fatty acids reduced hypertriglyceridemia and the risk of CVD in adults [71]. A subgroup analysis of patients with DM also showed an improvement in hypertriglyceridemia [71]. However, in comprehensive review of diets with different macronutrient compositions, the primary driver for improved triglyceride levels was caloric restriction, rather than the macronutrient content [72]. In adults, aerobic exercise also can reduce triglycerides by 20% if a low-calorie diet is followed [70]. Taken together, reductions of 50% or more in triglyceride levels could potentially be attained through intensive therapeutic lifestyle change [15, 73]. Table 3. Treatment of Hypertriglyceridemia in Adults With DM [11, 12] TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction Abbreviation: TG, triglyceride. View Large Table 3. Treatment of Hypertriglyceridemia in Adults With DM [11, 12] TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction TG Level Management Focus 150–499 mg/dL CVD risk reduction by achieving LDL-C goals 6-month trial of lifestyle modifications followed by the addition of a statin if indicated 200–499 mg/dL (goal LDL-C) CVD risk reduction by achieving non-HDL-C goals Intensify statin therapy Start a fibrate, omega-3 supplement, or niacin ≥500 mg/dL Reduce risk of pancreatitis Restrict dietary fat to <15% of total calories Start a fibrate, omega-3 supplement, or niacin Intensifying the insulin regimen may be beneficial in patients with DM who require insulin Once TG level <500 mg/dL, return focus to CVD risk reduction Abbreviation: TG, triglyceride. View Large However, the role of lifestyle interventions in patients with DM is not conclusive. Findings from the 2013 Look Action for HEAlth in Diabetes (Look AHEAD) did not find that moderate weight loss in obese patients with T2DM led to a reduction in CVD risk factors [74]. Similarly, an intensive lifestyle intervention in patients with DM did not result in reduced risk of CVD and was stopped prematurely, with average follow-up of over 8 years [75]. A systematic review by Nield et al. [76] did not find evidence of a benefit of nutrition interventions in adults with DM, although the lack of high-quality studies was noted. In the absence of long-term results, it is difficult to determine the impact of lifestyle interventions if they are started at young age. C. Statins Statins are the most effective of the lipid-lowering medications in reducing the risk of CVD in patients with DM and hypertriglyceridemia [15]. Statins generally reduce triglycerides by 10% to 15%, depending on baseline triglyceride level, specific statin, and its dose [12, 70]. In LIPID, each 89 mg/dL decrease in triglycerides reduced the risk of CVD by 11% in those taking pravastatin [40]. However, much of the risk reduction in CVD is related to statin’s ability to lower LDL-C and the triglyceride-lowering effect remains modest. As a result, the 2013 ACC/AHA guidelines on reducing CVD and the Endocrine Society guidelines on hypertriglyceridemia in DM do not suggest the use of statins to reduce triglycerides and only recommend statins for reducing CVD [10, 12]. There is a growing body of literature suggesting statins should be first line to reduce CVD in patients with hypertriglyceridemia, especially if the apolipoprotein B level is high [15]. Unfortunately, patients with hypertriglyceridemia are typically excluded from statin trials; in addition, no clinical trial has evaluated the use of non-HDL-C or apolipoprotein b as primary risk factors for CVD, and the evidence to use these markers as therapy targets is limited to secondary analysis [6, 45]. D. Fibrates Fibrates are the most potent of the lipid-lowering therapies with regard to triglycerides. They reduce triglycerides by decreasing VLDL production and increase the activity of lipoprotein lipase [12]. Studies suggest fibrates decrease triglyceride levels by 30% to 50% and lead to small increases in HDL-C, but generally have no effect on LDL-C [12]. Fibrates have been demonstrated to reduce microvascular complications of DM, such as retinopathy, nephropathy, and amputations [77]. The efficacy of fibrates in reducing CVD in patients with DM has been disappointing, and fibrates likely do not lower all-cause mortality [12, 78]. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, there was no effect of fenofibrate on CVD events [79]. Similar results were reported by the ACCORD trial, which added a fenofibrate to statin therapy [65]. However, in ACCORD, fibrates reduced CVD events in the subgroup with triglyceride levels greater than 204 mg/dL and HDL-C less than 35 mg/dL [80, 81]. In summary, there is scant evidence that fibrates used in patients with DM have worse outcomes compared with statins [82]. E. Omega-3 Fatty Acids Omega-3 fatty acids lower triglycerides primarily through reducing triglyceride synthesis in the liver, inhibiting VLDL production, and increasing clearance of triglycerides [83]. Omega-3 fatty acid supplements are well tolerated, but only have a modest effect on triglyceride levels. Triglycerides are usually lowered between 15% to 30%, and LDL-C usually remains unchanged, or even slightly increases [84–88]. In a systematic review, omega-3 fatty acids decreased triglycerides in patients with DM and had no effect on glucose control [89, 90]. The effect of reducing atherosclerotic events, though, is mixed. In JELIS, a study of the effectiveness of omega-3 fatty acids in Japanese adults who were already prescribed a statin, the risk of major cardiac events was reduced by 19% [91]. However, these results were not replicated in the Outcome Reduction With Initial Glargine Intervention trial, Age-Related Eye Disease Study 2, or in the Risk Prevention Study of Omega-3 Fatty Acids [92–94]. The variability of results may depend on several factors, including dose and formulation of supplement, baseline triglyceride level, and baseline omega-3 fatty acid level in the subject of interest. Based on the available evidence, a 2017 statement from the American Heart Association found no evidence that omega-3 fatty acid supplementations reduce CVD in patients with DM [95]. Supplemental omega-3 fatty acids are available as either over-the-counter formulations or in a prescription formulation. Omega-3 fatty acid preparations typically include docosahexaenoic acid and eicosapentaenoic acid (EPA), either alone or in combination. Lovaza, Epanova, and Omtryg, which include both DHA and EPA, are approved by the Federal Drug Administration. Vascepa, a formulation of EPA only, is also approved by the Federal Drug Administration. Omega-3 fatty acids also can be obtained from the diet, such as from fish and vegetables [96]. F. Niacin Niacin was the first drug to be approved to treat dyslipidemia. Depending on dose and formulation, Niacin typically leads to a 15% to 30% reduction in triglycerides in patients with and without DM [90, 97–99]. The reduction in triglycerides is a result of inhibition of lipolysis in adipose tissue, which reduces the return of free fatty acids to the liver [70]. Despite the decrease in triglycerides, niacin does not appear to reduce the risk of CVD as was demonstrated in AIM-HIGH [50]. In fact, in some populations, it may also increase the risk of stroke and worsen glucose control in patients with DM [100–103]. 5. Treatment Recommendations for Children Data in children and adolescents is much less robust than it is in adults with DM. Current pediatric guidelines focus on treating hypertriglyceridemia as the primary treatment goal only in regards to prevention and treatment of triglyceride-induced pancreatitis (Table 4) [13]. It should be noted, though, that non-HDL-C is recommended as a secondary target for those with elevated triglycerides despite reaching LDL-C goals. For all degrees of hypertriglyceridemia, treatment in children and adolescents is based on small studies and/or extrapolated from trials in adults. The 2011 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (2011 Expert Panel) has different thresholds for hypertriglyceridemia for those <10 years old and for those ≥10 years old (Table 1) [13]. To ensure an accurate diagnosis, classification of hypertriglyceridemia should be based on at least two fasting lipid panels, unless the initial value is >1000 mg/dL [13]. Table 4. Treatment Recommendations for Hypertriglyceridemia in Children and Adolescents [13] TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 Abbreviations: omega-3, omega-3 fatty acid supplement; TG, triglyceride level. a 10 to 19 years old. b <10 years old. View Large Table 4. Treatment Recommendations for Hypertriglyceridemia in Children and Adolescents [13] TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 TG ≥130 mg/dLa TG ≥200–499 mg/dL TG ≥1000 mg/dL or Average TG ≥500 mg/dL TG ≥100 mg/dLb Step 1 CHILD-1 CHILD-1 CHILD-2 Step 2 CHILD-2 CHILD-2; consider omega-3; consider statin if non-HDL-C ≥145 mg/dL Consider fibrate, niacin, or omega-3; consider statin if non-HDL-C ≥145 mg/dL Goal TG < 130a Non-HDL-C <145 mg/dL Acutely lower TG to prevent pancreatitis TG < 100b TG < 130 Abbreviations: omega-3, omega-3 fatty acid supplement; TG, triglyceride level. a 10 to 19 years old. b <10 years old. View Large Except in patients at risk for triglyceride-induced pancreatitis, the initial treatment of patients with DM and hypertriglyceridemia is a 6-month trial of lifestyle modifications. The 2011 Expert Panel [13] suggests using the Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) if the triglyceride level is ≥100 mg/dL for children less than 10 years old or ≥130 mg/dL for those ≥10 years old [13]. In contrast, the American Diabetes Association Standards of Medical Care in Diabetes-2018 recommends the Step 2 American Heart Association diet [104]. Both the CHILD-1 and Step 2 American Heart Association diets recommend that total fat intake be <30% of total calories, trans fatty acids be eliminated, and saturated fat limited to 8% to 10% of total calories. If the CHILD-1 diet is insufficient, or the initial triglyceride level is ≥500 mg/dL, the more restrictive CHILD-2 diet is recommended. Although the CHILD-1 and CHILD-2 diets are very similar, the CHILD-2 diet restricts saturated fat to <7% of total calories and specifically recommends that 10% of total calories are from monounsaturated fat [13]. Per the 2011 Expert Panel, sufficient physical activity is defined as having at least 1 hour each day of moderate-to-vigorous activity and at least 3 days per week with 1 hour of vigorous-intensity physical activity [13]. In one study, a reduction in sugar-sweetened beverages coupled with increased physical activity levels was associated with lower triglyceride levels and reduced insulin resistance in boys, but not girls [105]. For most children and adolescents, weight loss, increased physical activity, and following the CHILD-1 or CHILD-2 diets should be effective in improving triglyceride levels. However, dietary intervention trials have failed to find that diet alone is adequate [106, 107]. In those in whom it fails, guidelines recommend medication referral to a lipid specialist, intensifying glucose control, and consideration of lipid-lowering therapy. In children and adolescents with DM, poor glucose control is associated with a more atherogenic lipid profile [8, 108]. Although adequate glucose control is of the utmost importance in DM, it often is insufficient to normalize the lipid profile [108]. Until the LDL-C is normalized, statins are recommended as the initial medication in patients with DM and dyslipidemia [13]. As opposed to adult guidelines that focus on reducing risk profiles, guidelines in pediatrics continue to use level-driven goals. As DM is considered a high-risk condition, statins are recommended if the LDL-C is ≥130 mg/dL and goal LDL-C levels are <100 mg/dL. Unfortunately, data on the long-term efficacy and safety of statins in reducing CVD risk in children and adolescents with DM is limited. However, studies of children and adolescents with familial hypercholesterolemia provide evidence that statins are safe and can effectively improve the lipid profile and markers of CVD risk [109–112]. Studies of the use of statins in children and adolescents with DM have found similar results, including benefits beyond LDL-C lowering [113–115]. Although there are concerns of worsening insulin sensitivity with the use of statins in adults, in a randomized control trial in adolescents with T1DM and elevated LDL-C, atorvastatin was not found to increase insulin resistance. Further, this pilot study found atorvastatin was associated with lower levels of LDL-C, apolipoprotein B, and atherogenic lipoprotein subparticles [106]. In the most recent guidelines, the use of fish oil supplements, fibrates, or niacin can be considered if triglycerides or non-HDL-C remains elevated. However, the guidelines do not provide specific recommendations in regards to treatment thresholds or doses [13]. As mentioned, fibrates are recommended in adults only to prevent triglyceride-induced pancreatitis. In children and adolescents, the safety and efficacy of fibrates is limited to a single study in youth with familial hypercholesterolemia, which demonstrated similar safety and efficacy for reducing CVD risk as in adults [116]. There also is limited data on omega-3 supplements. In two small studies, omega-3 supplements appear safe in children at a dose of 4 g/d, but only reduce the triglyceride level by about 50 mg/dL and were marginally significant compared with placebo [84, 85]. There is no data on the use of niacin in children with DM and hypertriglyceridemia. 6. Conclusion There is an improved understanding of the role of hypertriglyceridemia in adult patients with DM in the development of CVD; however, specific treatments to prevent CVD continue to be directed toward statins. The implications of hypertriglyceridemia in children and adolescents with DM remain unknown and are of critical importance given the potential for lifelong exposure to elevated levels. Current pediatric guidelines consider DM as a major CVD risk factor and recommend focusing treatment on lowering LDL-C with statins and using lower LDL-C thresholds for initiating medication (130 to 160 mg/dL depending on the presence of other risk factors) [11–13]. Although fibrates, niacin, and supplemental omega-3 fatty acids are effective at lowering triglyceride levels, the data supporting their use in reducing CVD risk is rather weak and data on use in children is lacking. Specifically targeting triglyceride levels, however, remains important in the prevention and treatment of triglyceride-induced pancreatitis for both children and adults. Further research on hypertriglyceridemia in children and adolescents with DM is needed to sufficiently prevent future CVD in this population. Abbreviations: Abbreviations: CVD cardiovascular disease DKA diabetic ketoacidosis DM diabetes mellitus EPA eicosapentaenoic acid HDL-C high-density lipoprotein cholesterol LDL-C low-density lipoprotein cholesterol T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus VLDL very low-density lipoprotein Acknowledgments Disclosure Summary: The authors have nothing to disclose. References and Notes 1. Goldberg IJ . Clinical review 124: diabetic dyslipidemia: causes and consequences . J Clin Endocrinol Metab . 2001 ; 86 ( 3 ): 965 – 971 . Google Scholar CrossRef Search ADS PubMed 2. American Diabetes Association . Classification and diagnosis of diabetes - 2017 . Diabetes Care . 2017 ; 40 ( Suppl 1 ): S11 – S24 . CrossRef Search ADS PubMed 3. de Ferranti SD , de Boer IH , Fonseca V , Fox CS , Golden SH , Lavie CJ , Magge SN , Marx N , McGuire DK , Orchard TJ , Zinman B , Eckel RH . Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association . Diabetes Care . 2014 ; 37 ( 10 ): 2843 – 2863 . Google Scholar CrossRef Search ADS PubMed 4. Maahs DM , Daniels SR , de Ferranti SD , Dichek HL , Flynn J , Goldstein BI , Kelly AS , Nadeau KJ , Martyn-Nemeth P , Osganian SK , Quinn L , Shah AS , Urbina E ; American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council for High Blood Pressure Research, and Council on Lifestyle and Cardiometabolic Health . Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association . Circulation . 2014 ; 130 ( 17 ): 1532 – 1558 . Google Scholar CrossRef Search ADS PubMed 5. Cullen P . Evidence that triglycerides are an independent coronary heart disease risk factor . Am J Cardiol . 2000 ; 86 ( 9 ): 943 – 949 . Google Scholar CrossRef Search ADS PubMed 6. Singh AK , Singh R . Triglyceride and cardiovascular risk: a critical appraisal . Indian J Endocrinol Metab . 2016 ; 20 ( 4 ): 418 – 428 . Google Scholar CrossRef Search ADS PubMed 7. Mazzone T , Chait A , Plutzky J . Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies . Lancet . 2008 ; 371 ( 9626 ): 1800 – 1809 . Google Scholar CrossRef Search ADS PubMed 8. Maahs DM , Dabelea D , D'Agostino RB Jr , Andrews JS , Shah AS , Crimmins N , Mayer-Davis EJ , Marcovina S , Imperatore G , Wadwa RP , Daniels SR , Reynolds K , Hamman RF , Dolan LM . Glucose control predicts 2-year change in lipid profile in youth with type 1 diabetes . J Pediatr . 2013 ; 162 : 101 – 107 e101 . Google Scholar CrossRef Search ADS PubMed 9. TODAY Study Group . Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial . Diabetes Care . 2013 ; 36 ( 6 ): 1758 – 1764 . CrossRef Search ADS PubMed 10. Stone NJ , Robinson JG , Lichtenstein AH , Bairey Merz CN , Blum CB , Eckel RH , Goldberg AC , Gordon D , Levy D , Lloyd-Jones DM , McBride P , Schwartz JS , Shero ST , Smith SC Jr , Watson K , Wilson PW , Eddleman KM , Jarrett NM , LaBresh K , Nevo L , Wnek J , Anderson JL , Halperin JL , Albert NM , Bozkurt B , Brindis RG , Curtis LH , DeMets D , Hochman JS , Kovacs RJ , Ohman EM , Pressler SJ , Sellke FW , Shen WK , Smith SC Jr , Tomaselli GF ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines . 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . Circulation . 2014 ; 129 ( 25 , Suppl 2 ) S1 – S45 . Google Scholar CrossRef Search ADS PubMed 11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) . Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report . Circulation . 2002 ; 106 ( 25 ): 3143 – 3421 . PubMed 12. Berglund L , Brunzell JD , Goldberg AC , Goldberg IJ , Sacks F , Murad MH , Stalenhoef AFH ; Endocrine society . Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2012 ; 97 ( 9 ): 2969 – 2989 . Google Scholar CrossRef Search ADS PubMed 13. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and AdolescentsNational Heart, Lung, and Blood Institute . Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report . Pediatrics . 2011 ; 128 ( Suppl 5 ): S213 – S256 . CrossRef Search ADS PubMed 14. Guy J , Ogden L , Wadwa RP , Hamman RF , Mayer-Davis EJ , Liese AD , D’Agostino R Jr , Marcovina S , Dabelea D . Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case-control study . Diabetes Care . 2009 ; 32 ( 3 ): 416 – 420 . Google Scholar CrossRef Search ADS PubMed 15. Miller M , Stone NJ , Ballantyne C , Bittner V , Criqui MH , Ginsberg HN , Goldberg AC , Howard WJ , Jacobson MS , Kris-Etherton PM , Lennie TA , Levi M , Mazzone T , Pennathur S ; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism Council on Arteriosclerosis, Thrombosis and Vascular Biology Council on Cardiovascular Nursing Council on the Kidney in Cardiovascular Disease . Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association . Circulation . 2011 ; 123 ( 20 ): 2292 – 2333 . Google Scholar CrossRef Search ADS PubMed 16. Ievers-Landis CE , Walders-Abramson N , Amodei N , Drews KL , Kaplan J , Levitt Katz LE , Lavietes S , Saletsky R , Seidman D , Yasuda P ; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group . Longitudinal correlates of health risk behaviors in children and adolescents with type 2 diabetes . J Pediatr . 2015 ; 166 ( 5 ): 1258 – 1264.e3 . Google Scholar CrossRef Search ADS PubMed 17. Adiels M , Olofsson S-O , Taskinen M-R , Borén J . Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome . Arterioscler Thromb Vasc Biol . 2008 ; 28 ( 7 ): 1225 – 1236 . Google Scholar CrossRef Search ADS PubMed 18. Kushner PA , Cobble ME . Hypertriglyceridemia: the importance of identifying patients at risk . Postgrad Med . 2016 ; 128 ( 8 ): 848 – 858 . Google Scholar CrossRef Search ADS PubMed 19. Cooper AD . Hepatic uptake of chylomicron remnants . J Lipid Res . 1997 ; 38 ( 11 ): 2173 – 2192 . Google Scholar PubMed 20. Ginsberg HN . Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis . Diabetes Care . 1991 ; 14 ( 9 ): 839 – 855 . Google Scholar CrossRef Search ADS PubMed 21. Subramanian S , Chait A . Hypertriglyceridemia secondary to obesity and diabetes . Biochim Biophys Acta . 2012 ; 1821 ( 5 ): 819 – 825 . Google Scholar CrossRef Search ADS PubMed 22. Kumar P , Sakwariya A , Sultania AR , Dabas R . Hypertriglyceridemia-induced acute pancreatitis with diabetic ketoacidosis: a rare presentation of type 1 diabetes mellitus . J Lab Physicians . 2017 ; 9 ( 4 ): 329 – 331 . Google Scholar CrossRef Search ADS PubMed 23. Jaiswal M , Schinske A , Pop-Busui R . Lipids and lipid management in diabetes . Best Pract Res Clin Endocrinol Metab . 2014 ; 28 ( 3 ): 325 – 338 . Google Scholar CrossRef Search ADS PubMed 24. Ginsberg HN , Zhang YL , Hernandez-Ono A . Regulation of plasma triglycerides in insulin resistance and diabetes . Arch Med Res . 2005 ; 36 ( 3 ): 232 – 240 . Google Scholar CrossRef Search ADS PubMed 25. Nordestgaard BG . A test in context: lipid profile, fasting versus nonfasting . J Am Coll Cardiol . 2017 ; 70 ( 13 ): 1637 – 1646 . Google Scholar CrossRef Search ADS PubMed 26. Di Angelantonio E , Sarwar N , Perry P , Kaptoge S , Ray KK , Thompson A , Wood AM , Lewington S , Sattar N , Packard CJ , Collins R , Thompson SG , Danesh J ; Emerging Risk Factors Collaboration . Major lipids, apolipoproteins, and risk of vascular disease . JAMA . 2009 ; 302 ( 18 ): 1993 – 2000 . Google Scholar CrossRef Search ADS PubMed 27. Nordestgaard BG , Benn M , Schnohr P , Tybjaerg-Hansen A . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women . JAMA . 2007 ; 298 ( 3 ): 299 – 308 . Google Scholar CrossRef Search ADS PubMed 28. Ai M , Tanaka A , Ogita K , Sekinc M , Numano F , Numano F , Reaven GM . Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes . J Am Coll Cardiol . 2001 ; 38 ( 6 ): 1628 – 1632 . Google Scholar CrossRef Search ADS PubMed 29. Sathiyakumar V , Park J , Golozar A , Lazo M , Quispe R , Guallar E , Blumenthal RS , Jones SR , Martin SS . Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy . Circulation . 2018 ; 137 ( 1 ): 10 – 19 . Google Scholar CrossRef Search ADS PubMed 30. Nordestgaard BG , Varbo A . Triglycerides and cardiovascular disease . Lancet . 2014 ; 384 ( 9943 ): 626 – 635 . Google Scholar CrossRef Search ADS PubMed 31. Musunuru K . Atherogenic dyslipidemia: cardiovascular risk and dietary intervention . Lipids . 2010 ; 45 ( 10 ): 907 – 914 . Google Scholar CrossRef Search ADS PubMed 32. Reiner Ž . Hypertriglyceridaemia and risk of coronary artery disease . Nat Rev Cardiol . 2017 ; 14 ( 7 ): 401 – 411 . Google Scholar CrossRef Search ADS PubMed 33. Gotto AMJ Jr , Whitney E , Stein EA , Shapiro DR , Clearfield M , Weis S , Jou JY , Langendörfer A , Beere PA , Watson DJ , Downs JR , de Cani JS . Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) . Circulation . 2000 ; 101 ( 5 ): 477 – 484 . Google Scholar CrossRef Search ADS PubMed 34. Robins SJ , Collins D , Wittes JT , Papademetriou V , Deedwania PC , Schaefer EJ , McNamara JR , Kashyap ML , Hershman JM , Wexler LF , Rubins HB ; VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial . Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial . JAMA . 2001 ; 285 ( 12 ): 1585 – 1591 . Google Scholar CrossRef Search ADS PubMed 35. Sarwar N , Danesh J , Eiriksdottir G , Sigurdsson G , Wareham N , Bingham S , Boekholdt SM , Khaw KT , Gudnason V . Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies . Circulation . 2007 ; 115 ( 4 ): 450 – 458 . Google Scholar CrossRef Search ADS PubMed 36. Rosenson RS , Davidson MH , Hirsh BJ , Kathiresan S , Gaudet D . Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease . J Am Coll Cardiol . 2014 ; 64 ( 23 ): 2525 – 2540 . Google Scholar CrossRef Search ADS PubMed 37. Sarwar N , Sandhu MS , Ricketts SL , Butterworth AS , Di Angelantonio E , Boekholdt SM , Ouwehand W , Watkins H , Samani NJ , Saleheen D , Lawlor D , Reilly MP , Hingorani AD , Talmud PJ , Danesh J ; Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration . Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies . Lancet . 2010 ; 375 ( 9726 ): 1634 – 1639 . Google Scholar CrossRef Search ADS PubMed 38. Assmann G , Schulte H , von Eckardstein A . Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men . Am J Cardiol . 1996 ; 77 ( 14 ): 1179 – 1184 . Google Scholar CrossRef Search ADS PubMed 39. Thomsen M , Varbo A , Tybjærg-Hansen A , Nordestgaard BG . Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study . Clin Chem . 2014 ; 60 ( 5 ): 737 – 746 . Google Scholar CrossRef Search ADS PubMed 40. Simes RJ , Marschner IC , Hunt D , Colquhoun D , Sullivan D , Stewart RA , Hague W , Keech A , Thompson P , White H , Shaw J , Tonkin A , Investigators LS ; LIPID Study Investigators . Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels ? Circulation . 2002 ; 105 ( 10 ): 1162 – 1169 . Google Scholar CrossRef Search ADS PubMed 41. Puri R , Nissen SE , Shao M , Elshazly MB , Kataoka Y , Kapadia SR , Tuzcu EM , Nicholls SJ . Non-HDL cholesterol and triglycerides. Implications for coronary atheroma progression and clinical events . Arterioscler Thromb Vasc Biol . 2016 ; 36 ( 11 ): 2220 – 2228 . Google Scholar CrossRef Search ADS PubMed 42. Miller M , Cannon CP , Murphy SA , Qin J , Ray KK , Braunwald E ; PROVE IT-TIMI 22 Investigators . Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial . J Am Coll Cardiol . 2008 ; 51 ( 7 ): 724 – 730 . Google Scholar CrossRef Search ADS PubMed 43. Schwartz GG , Abt M , Bao W , DeMicco D , Kallend D , Miller M , Mundl H , Olsson AG . Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins . J Am Coll Cardiol . 2015 ; 65 ( 21 ): 2267 – 2275 . Google Scholar CrossRef Search ADS PubMed 44. Watts GF , Karpe F . Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient . Heart . 2011 ; 97 ( 5 ): 350 – 356 . Google Scholar CrossRef Search ADS PubMed 45. Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology . Circ Res . 2016 ; 118 ( 4 ): 547 – 563 . Google Scholar CrossRef Search ADS PubMed 46. Quispe R , Manalac RJ , Faridi KF , Blaha MJ , Toth PP , Kulkarni KR , Nasir K , Virani SS , Banach M , Blumenthal RS , Martin SS , Jones SR . Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: the Very Large Database of Lipids-4 (VLDL-4) study . Atherosclerosis . 2015 ; 242 ( 1 ): 243 – 250 . Google Scholar CrossRef Search ADS PubMed 47. Pacifico L , Bonci E , Andreoli G , Romaggioli S , Di Miscio R , Lombardo CV , Chiesa C . Association of serum triglyceride-to-HDL cholesterol ratio with carotid artery intima-media thickness, insulin resistance and nonalcoholic fatty liver disease in children and adolescents . Nutr Metab Cardiovasc Dis . 2014 ; 24 ( 7 ): 737 – 743 . Google Scholar CrossRef Search ADS PubMed 48. Di Bonito P , Moio N , Scilla C , Cavuto L , Sibilio G , Sanguigno E , Forziato C , Saitta F , Iardino MR , Di Carluccio C , Capaldo B . Usefulness of the high triglyceride-to-HDL cholesterol ratio to identify cardiometabolic risk factors and preclinical signs of organ damage in outpatient children . Diabetes Care . 2012 ; 35 ( 1 ): 158 – 162 . Google Scholar CrossRef Search ADS PubMed 49. Gidding SS , Keith SW , Falkner B . Adolescent and adult African Americans have similar metabolic dyslipidemia . J Clin Lipidol . 2015 ; 9 ( 3 ): 368 – 376 . Google Scholar CrossRef Search ADS PubMed 50. DeLoach S , Keith SW , Gidding SS , Falkner B . Obesity associated inflammation in African American adolescents and adults . Am J Med Sci . 2014 ; 347 ( 5 ): 357 – 363 . Google Scholar CrossRef Search ADS PubMed 51. Boden WE , Probstfield JL , Anderson T , Chaitman BR , Desvignes-Nickens P , Koprowicz K , McBride R , Teo K , Weintraub W ; AIM-HIGH Investigators . Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy . N Engl J Med . 2011 ; 365 ( 24 ): 2255 – 2267 . Google Scholar CrossRef Search ADS PubMed 52. Landray MJ , Haynes R , Hopewell JC , Parish S , Aung T , Tomson J , Wallendszus K , Craig M , Jiang L , Collins R , Armitage J ; HPS2-THRIVE Collaborative Group . Effects of extended-release niacin with laropiprant in high-risk patients . N Engl J Med . 2014 ; 371 ( 3 ): 203 – 212 . Google Scholar CrossRef Search ADS PubMed 53. Schwartz GG , Olsson AG , Abt M , Ballantyne CM , Barter PJ , Brumm J , Chaitman BR , Holme IM , Kallend D , Leiter LA , Leitersdorf E , McMurray JJ , Mundl H , Nicholls SJ , Shah PK , Tardif JC , Wright RS ; dal-OUTCOMES Investigators . Effects of dalcetrapib in patients with a recent acute coronary syndrome . N Engl J Med . 2012 ; 367 ( 22 ): 2089 – 2099 . Google Scholar CrossRef Search ADS PubMed 54. Barter PJ , Caulfield M , Eriksson M , Grundy SM , Kastelein JJ , Komajda M , Lopez-Sendon J , Mosca L , Tardif JC , Waters DD , Shear CL , Revkin JH , Buhr KA , Fisher MR , Tall AR , Brewer B ; ILLUMINATE Investigators . Effects of torcetrapib in patients at high risk for coronary events . N Engl J Med . 2007 ; 357 ( 21 ): 2109 – 2122 . Google Scholar CrossRef Search ADS PubMed 55. Bowman L , Hopewell JC , Chen F , Wallendszus K , Stevens W , Collins R , Wiviott SD , Cannon CP , Braunwald E , Sammons E , Landray MJ ; HPS3/TIMI55–REVEAL Collaborative Group . Effects of anacetrapib in patients with atherosclerotic vascular disease . N Engl J Med . 2017 ; 377 ( 13 ): 1217 – 1227 . Google Scholar CrossRef Search ADS PubMed 56. Voight BF , Peloso GM , Orho-Melander M , Frikke-Schmidt R , Barbalic M , Jensen MK , Hindy G , Hólm H , Ding EL , Johnson T , Schunkert H , Samani NJ , Clarke R , Hopewell JC , Thompson JF , Li M , Thorleifsson G , Newton-Cheh C , Musunuru K , Pirruccello JP , Saleheen D , Chen L , Stewart A , Schillert A , Thorsteinsdottir U , Thorgeirsson G , Anand S , Engert JC , Morgan T , Spertus J , Stoll M , Berger K , Martinelli N , Girelli D , McKeown PP , Patterson CC , Epstein SE , Devaney J , Burnett MS , Mooser V , Ripatti S , Surakka I , Nieminen MS , Sinisalo J , Lokki ML , Perola M , Havulinna A , de Faire U , Gigante B , Ingelsson E , Zeller T , Wild P , de Bakker PI , Klungel OH , Maitland-van der Zee AH , Peters BJ , de Boer A , Grobbee DE , Kamphuisen PW , Deneer VH , Elbers CC , Onland-Moret NC , Hofker MH , Wijmenga C , Verschuren WM , Boer JM , van der Schouw YT , Rasheed A , Frossard P , Demissie S , Willer C , Do R , Ordovas JM , Abecasis GR , Boehnke M , Mohlke KL , Daly MJ , Guiducci C , Burtt NP , Surti A , Gonzalez E , Purcell S , Gabriel S , Marrugat J , Peden J , Erdmann J , Diemert P , Willenborg C , König IR , Fischer M , Hengstenberg C , Ziegler A , Buysschaert I , Lambrechts D , Van de Werf F , Fox KA , El Mokhtari NE , Rubin D , Schrezenmeir J , Schreiber S , Schäfer A , Danesh J , Blankenberg S , Roberts R , McPherson R , Watkins H , Hall AS , Overvad K , Rimm E , Boerwinkle E , Tybjaerg-Hansen A , Cupples LA , Reilly MP , Melander O , Mannucci PM , Ardissino D , Siscovick D , Elosua R , Stefansson K , O’Donnell CJ , Salomaa V , Rader DJ , Peltonen L , Schwartz SM , Altshuler D , Kathiresan S . Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study . Lancet . 2012 ; 380 ( 9841 ): 572 – 580 . Google Scholar CrossRef Search ADS PubMed 57. Varbo A , Benn M , Tybjærg-Hansen A , Nordestgaard BG . Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation . Circulation . 2013 ; 128 ( 12 ): 1298 – 1309 . Google Scholar CrossRef Search ADS PubMed 58. Sandhu S , Al-Sarraf A , Taraboanta C , Frohlich J , Francis GA . Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study . Lipids Health Dis . 2011 ; 10 ( 1 ): 157 . Google Scholar CrossRef Search ADS PubMed 59. Fick T , Jack J , Pyle-Eilola AL , Henry RK . Severe hypertriglyceridemia at new onset type 1 diabetes mellitus . J Pediatr Endocrinol Metab . 2017 ; 30 ( 8 ): 893 – 897 . Google Scholar CrossRef Search ADS PubMed 60. Henderson SR , Maitland R , Mustafa OG , Miell J , Crook MA , Kottegoda SR . Severe hypertriglyceridaemia in Type 2 diabetes mellitus: beneficial effect of continuous insulin infusion . QJM . 2013 ; 106 ( 4 ): 355 – 359 . Google Scholar CrossRef Search ADS PubMed 61. Thuzar M , Shenoy VV , Malabu UH , Schrale R , Sangla KS . Extreme hypertriglyceridemia managed with insulin . J Clin Lipidol . 2014 ; 8 ( 6 ): 630 – 634 . Google Scholar CrossRef Search ADS PubMed 62. Nair S , Yadav D , Pitchumoni CS . Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA . Am J Gastroenterol . 2000 ; 95 ( 10 ): 2795 – 2800 . Google Scholar CrossRef Search ADS PubMed 63. Whayne TFJ Jr . Concerns about heparin therapy for hypertriglyceridemia . Arch Intern Med . 2010 ; 170 ( 1 ): 108 – 109, author reply 109 . Google Scholar CrossRef Search ADS PubMed 64. Valdivielso P , Ramírez-Bueno A , Ewald N . Current knowledge of hypertriglyceridemic pancreatitis . Eur J Intern Med . 2014 ; 25 ( 8 ): 689 – 694 . Google Scholar CrossRef Search ADS PubMed 65. Gerstein HC , Miller ME , Byington RP , Goff DC Jr , Bigger JT , Buse JB , Cushman WC , Genuth S , Ismail-Beigi F , Grimm RH Jr , Probstfield JL , Simons-Morton DG , Friedewald WT ; Action to Control Cardiovascular Risk in Diabetes Study Group . Effects of intensive glucose lowering in type 2 diabetes . N Engl J Med . 2008 ; 358 ( 24 ): 2545 – 2559 . Google Scholar CrossRef Search ADS PubMed 66. Soedamah-Muthu SS , Chaturvedi N , Toeller M , Ferriss B , Reboldi P , Michel G , Manes C , Fuller JH ; EURODIAB Prospective Complications Study Group . Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study . Diabetes Care . 2004 ; 27 ( 2 ): 530 – 537 . Google Scholar CrossRef Search ADS PubMed 67. Nathan DM , Cleary PA , Backlund JY , Genuth SM , Lachin JM , Orchard TJ , Raskin P , Zinman B ; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group . Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes . N Engl J Med . 2005 ; 353 ( 25 ): 2643 – 2653 . Google Scholar CrossRef Search ADS PubMed 68. Nathan DM , Genuth S , Lachin J , Cleary P , Crofford O , Davis M , Rand L , Siebert C ; Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus . N Engl J Med . 1993 ; 329 ( 14 ): 977 – 986 . Google Scholar CrossRef Search ADS PubMed 69. Ueyama C , Horibe H , Yamase Y , Fujimaki T , Oguri M , Kato K , Yamada Y . Association of smoking with prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals . Biomed Rep . 2017 ; 7 ( 5 ): 429 – 438 . Google Scholar CrossRef Search ADS PubMed 70. Watts GF , Ooi EM , Chan DC . Demystifying the management of hypertriglyceridaemia . Nat Rev Cardiol . 2013 ; 10 ( 11 ): 648 – 661 . Google Scholar CrossRef Search ADS PubMed 71. Estruch R , Ros E , Salas-Salvadó J , Covas MI , Corella D , Arós F , Gómez-Gracia E , Ruiz-Gutiérrez V , Fiol M , Lapetra J , Lamuela-Raventos RM , Serra-Majem L , Pintó X , Basora J , Muñoz MA , Sorlí JV , Martínez JA , Martínez-González MA ; PREDIMED Study Investigators . Primary prevention of cardiovascular disease with a Mediterranean diet . N Engl J Med . 2013 ; 368 ( 14 ): 1279 – 1290 . Google Scholar CrossRef Search ADS PubMed 72. Sacks FM , Bray GA , Carey VJ , Smith SR , Ryan DH , Anton SD , McManus K , Champagne CM , Bishop LM , Laranjo N , Leboff MS , Rood JC , de Jonge L , Greenway FL , Loria CM , Obarzanek E , Williamson DA . Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates . N Engl J Med . 2009 ; 360 ( 9 ): 859 – 873 . Google Scholar CrossRef Search ADS PubMed 73. Larsen RN , Mann NJ , Maclean E , Shaw JE . The effect of high-protein, low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial . Diabetologia . 2011 ; 54 ( 4 ): 731 – 740 . Google Scholar CrossRef Search ADS PubMed 74. Wing RR , Lang W , Wadden TA , Safford M , Knowler WC , Bertoni AG , Hill JO , Brancati FL , Peters A , Wagenknecht L ; Look AHEAD Research Group . Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes . Diabetes Care . 2011 ; 34 ( 7 ): 1481 – 1486 . Google Scholar CrossRef Search ADS PubMed 75. Wing RR , Bolin P , Brancati FL , Bray GA , Clark JM , Coday M , Crow RS , Curtis JM , Egan CM , Espeland MA , Evans M , Foreyt JP , Ghazarian S , Gregg EW , Harrison B , Hazuda HP , Hill JO , Horton ES , Hubbard VS , Jakicic JM , Jeffery RW , Johnson KC , Kahn SE , Kitabchi AE , Knowler WC , Lewis CE , Maschak-Carey BJ , Montez MG , Murillo A , Nathan DM , Patricio J , Peters A , Pi-Sunyer X , Pownall H , Reboussin D , Regensteiner JG , Rickman AD , Ryan DH , Safford M , Wadden TA , Wagenknecht LE , West DS , Williamson DF , Yanovski SZ ; Look AHEAD Research Group . Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes . N Engl J Med . 2013 ; 369 ( 2 ): 145 – 154 . Google Scholar CrossRef Search ADS PubMed 76. Nield L , Moore HJ , Hooper L , Cruickshank JK , Vyas A , Whittaker V , Summerbell CD . Dietary advice for treatment of type 2 diabetes mellitus in adults . Cochrane Database Syst Rev . 2007 ; ( 3 ): CD004097 . 77. Keech AC , Jenkins AJ . Triglyceride-lowering trials . Curr Opin Lipidol . 2017 ; 28 ( 6 ): 477 – 487 . Google Scholar CrossRef Search ADS PubMed 78. Jakob T , Nordmann AJ , Schandelmaier S , Ferreira-González I , Briel M . Fibrates for primary prevention of cardiovascular disease events . Cochrane Database Syst Rev . 2016 ; 11 : CD009753 . Google Scholar PubMed 79. Keech A , Simes RJ , Barter P , Best J , Scott R , Taskinen MR , Forder P , Pillai A , Davis T , Glasziou P , Drury P , Kesäniemi YA , Sullivan D , Hunt D , Colman P , d’Emden M , Whiting M , Ehnholm C , Laakso M ; FIELD study investigators . Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial . Lancet . 2005 ; 366 ( 9500 ): 1849 – 1861 . Google Scholar CrossRef Search ADS PubMed 80. Ginsberg HN , Elam MB , Lovato LC , Crouse JR III , Leiter LA , Linz P , Friedewald WT , Buse JB , Gerstein HC , Probstfield J , Grimm RH , Ismail-Beigi F , Bigger JT , Goff DC Jr , Cushman WC , Simons-Morton DG , Byington RP ; ACCORD Study Group . Effects of combination lipid therapy in type 2 diabetes mellitus . N Engl J Med . 2010 ; 362 ( 17 ): 1563 – 1574 . Google Scholar CrossRef Search ADS PubMed 81. Sacks FM , Carey VJ , Fruchart JC . Combination lipid therapy in type 2 diabetes . N Engl J Med . 2010 ; 363 ( 7 ): 692 – 694, author reply 694–695 . Google Scholar CrossRef Search ADS PubMed 82. Roussel R , Chaignot C , Weill A , Travert F , Hansel B , Marre M , Ricordeau P , Alla F , Allemand H . Use of fibrates monotherapy in people with diabetes and high cardiovascular risk in primary care: a French nationwide cohort study based on national administrative databases . PLoS One . 2015 ; 10 ( 9 ): e0137733 . Google Scholar CrossRef Search ADS PubMed 83. Backes J , Anzalone D , Hilleman D , Catini J . The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia . Lipids Health Dis . 2016 ; 15 ( 1 ): 118 . Google Scholar CrossRef Search ADS PubMed 84. de Ferranti SD , Milliren CE , Denhoff ER , Steltz SK , Selamet Tierney ES , Feldman HA , Osganian SK . Using high-dose omega-3 fatty acid supplements to lower triglyceride levels in 10- to 19-year-olds . Clin Pediatr (Phila) . 2014 ; 53 ( 5 ): 428 – 438 . Google Scholar CrossRef Search ADS PubMed 85. Gidding SS , Prospero C , Hossain J , Zappalla F , Balagopal PB , Falkner B , Kwiterovich P . A double-blind randomized trial of fish oil to lower triglycerides and improve cardiometabolic risk in adolescents . J Pediatr . 2014 ; 165 ( 3 ): 497 – 503.e2 . Google Scholar CrossRef Search ADS PubMed 86. Balk EM , Lichtenstein AH , Chung M , Kupelnick B , Chew P , Lau J . Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review . Atherosclerosis . 2006 ; 189 ( 1 ): 19 – 30 . Google Scholar CrossRef Search ADS PubMed 87. Kris-Etherton PM , Harris WS , Appel LJ ; American Heart Association. Nutrition Committee . Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease . Circulation . 2002 ; 106 ( 21 ): 2747 – 2757 . Google Scholar CrossRef Search ADS PubMed 88. Ito MK . A comparative overview of prescription omega-3 fatty acid products . P&T . 2015 ; 40 ( 12 ): 826 – 857 . Google Scholar PubMed 89. Hartweg J , Perera R , Montori V , Dinneen S , Neil HA , Farmer A . Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus . Cochrane Database Syst Rev . 2008 ; 1 ( 1 ): CD003205 . 90. Grundy SM , Vega GL , McGovern ME , Tulloch BR , Kendall DM , Fitz-Patrick D , Ganda OP , Rosenson RS , Buse JB , Robertson DD , Sheehan JP ; Diabetes Multicenter Research Group . Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial . Arch Intern Med . 2002 ; 162 ( 14 ): 1568 – 1576 . Google Scholar CrossRef Search ADS PubMed 91. Yokoyama M , Origasa H , Matsuzaki M , Matsuzawa Y , Saito Y , Ishikawa Y , Oikawa S , Sasaki J , Hishida H , Itakura H , Kita T , Kitabatake A , Nakaya N , Sakata T , Shimada K , Shirato K ; Japan EPA Lipid Intervention Study (JELIS) Investigators . Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis . Lancet . 2007 ; 369 ( 9567 ): 1090 – 1098 . Google Scholar CrossRef Search ADS PubMed 92. Bosch J , Gerstein HC , Dagenais GR , Díaz R , Dyal L , Jung H , Maggiono AP , Probstfield J , Ramachandran A , Riddle MC , Rydén LE , Yusuf S ; ORIGIN Trial Investigators . n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia . N Engl J Med . 2012 ; 367 ( 4 ): 309 – 318 . Google Scholar CrossRef Search ADS PubMed 93. Rauch B , Schiele R , Schneider S , Diller F , Victor N , Gohlke H , Gottwik M , Steinbeck G , Del Castillo U , Sack R , Worth H , Katus H , Spitzer W , Sabin G , Senges J ; OMEGA Study Group . OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction . Circulation . 2010 ; 122 ( 21 ): 2152 – 2159 . Google Scholar CrossRef Search ADS PubMed 94. Bonds DE , Harrington M , Worrall BB , Bertoni AG , Eaton CB , Hsia J , Robinson J , Clemons TE , Fine LJ , Chew EY ; Writing Group for the AREDS2 Research Group . Effect of long-chain ω-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial . JAMA Intern Med . 2014 ; 174 ( 5 ): 763 – 771 . Google Scholar CrossRef Search ADS PubMed 95. Siscovick DS , Barringer TA , Fretts AM , Wu JH , Lichtenstein AH , Costello RB , Kris-Etherton PM , Jacobson TA , Engler MB , Alger HM , Appel LJ , Mozaffarian D ; American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology . Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association . Circulation . 2017 ; 135 ( 15 ): e867 – e884 . Google Scholar CrossRef Search ADS PubMed 96. Weintraub HS . Overview of prescription omega-3 fatty acid products for hypertriglyceridemia . Postgrad Med . 2014 ; 126 ( 7 ): 7 – 18 . Google Scholar CrossRef Search ADS PubMed 97. Canner PL , Berge KG , Wenger NK , Stamler J , Friedman L , Prineas RJ , Friedewald W . Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin . J Am Coll Cardiol . 1986 ; 8 ( 6 ): 1245 – 1255 . Google Scholar CrossRef Search ADS PubMed 98. Shearer GC , Pottala JV , Hansen SN , Brandenburg V , Harris WS . Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial . J Lipid Res . 2012 ; 53 ( 11 ): 2429 – 2435 . Google Scholar CrossRef Search ADS PubMed 99. Taylor AJ , Lee HJ , Sullenberger LE . The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3 . Curr Med Res Opin . 2006 ; 22 ( 11 ): 2243 – 2250 . Google Scholar CrossRef Search ADS PubMed 100. Sonne DP , Hemmingsen B . Comment on American Diabetes Association. Standards of medical care in diabetes-2017 . Diabetes Care . 2017 ; 40 ( 7 , Suppl 1 ): e92 – e93 . Google Scholar CrossRef Search ADS PubMed 101. Guyton JR , Fazio S , Adewale AJ , Jensen E , Tomassini JE , Shah A , Tershakovec AM . Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial . Diabetes Care . 2012 ; 35 ( 4 ): 857 – 860 . Google Scholar CrossRef Search ADS PubMed 102. Guyton JR . Niacin in cardiovascular prevention: mechanisms, efficacy, and safety . Curr Opin Lipidol . 2007 ; 18 ( 4 ): 415 – 420 . Google Scholar CrossRef Search ADS PubMed 103. Elam MB , Hunninghake DB , Davis KB , Garg R , Johnson C , Egan D , Kostis JB , Sheps DS , Brinton EA . Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial . JAMA . 2000 ; 284 ( 10 ): 1263 – 1270 . Google Scholar CrossRef Search ADS PubMed 104. American Diabetes Association . Standards of medical care in diabetes 2018 . Diabetes Care . 2018 ; 41 ( Suppl 1 ). 105. Bremer AA , Auinger P , Byrd RS . Relationship between insulin resistance-associated metabolic parameters and anthropometric measurements with sugar-sweetened beverage intake and physical activity levels in US adolescents: findings from the 1999-2004 National Health and Nutrition Examination Survey . Arch Pediatr Adolesc Med . 2009 ; 163 ( 4 ): 328 – 335 . Google Scholar CrossRef Search ADS PubMed 106. Canas JA , Ross JL , Taboada MV , Sikes KM , Damaso LC , Hossain J , Caulfield MP , Gidding SS , Mauras N . A randomized, double blind, placebo-controlled pilot trial of the safety and efficacy of atorvastatin in children with elevated low-density lipoprotein cholesterol (LDL-C) and type 1 diabetes . Pediatr Diabetes . 2015 ; 16 ( 2 ): 79 – 89 . Google Scholar CrossRef Search ADS PubMed 107. Lauer RM , Obarzanek E , Hunsberger SA , Van Horn L , Hartmuller VW , Barton BA , Stevens VJ , Kwiterovich PO Jr , Franklin FA Jr , Kimm SY , Lasser NL , Simons-Morton DG . Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children . Am J Clin Nutr . 2000 ; 72 ( 5 , Suppl ) 1332S – 1342S . Google Scholar CrossRef Search ADS PubMed 108. American Diabetes Association . Children and adolescents: standards of medical care in diabetes-2018 . Diabetes Care . 2018 ; 41 ( Suppl 1 ): S126 – S136 . CrossRef Search ADS PubMed 109. Lambert M , Lupien PJ , Gagné C , Lévy E , Blaichman S , Langlois S , Hayden M , Rose V , Clarke JT , Wolfe BM , Clarson C , Parsons H , Stephure DK , Potvin D , Lambert J ; Canadian Lovastatin in Children Study Group . Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin . Pediatrics . 1996 ; 97 ( 5 ): 619 – 628 . Google Scholar PubMed 110. Knipscheer HC , Boelen CC , Kastelein JJ , van Diermen DE , Groenemeijer BE , van den Ende A , Büller HR , Bakker HD . Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia . Pediatr Res . 1996 ; 39 ( 5 ): 867 – 871 . Google Scholar CrossRef Search ADS PubMed 111. McCrindle BW , Ose L , Marais AD . Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial . J Pediatr . 2003 ; 143 ( 1 ): 74 – 80 . Google Scholar CrossRef Search ADS PubMed 112. Avis HJ , Vissers MN , Stein EA , Wijburg FA , Trip MD , Kastelein JJ , Hutten BA . A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia . Arterioscler Thromb Vasc Biol . 2007 ; 27 ( 8 ): 1803 – 1810 . Google Scholar CrossRef Search ADS PubMed 113. Haller MJ , Stein JM , Shuster JJ , Theriaque D , Samyn MM , Pepine C , Silverstein JH . Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus . J Pediatr Endocrinol Metab . 2009 ; 22 ( 1 ): 65 – 68 . Google Scholar CrossRef Search ADS PubMed 114. Tehrani S , Mobarrez F , Antovic A , Santesson P , Lins PE , Adamson U , Henriksson P , Wallén NH , Jörneskog G . Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia . Thromb Res . 2010 ; 126 ( 3 ): e225 – e231 . Google Scholar CrossRef Search ADS PubMed 115. Bjornstad P , Wadwa RP . Risks and benefits of statin use in young people with type 1 diabetes . Curr Diab Rep . 2014 ; 14 ( 7 ): 499 . Google Scholar CrossRef Search ADS PubMed 116. Wheeler KA , West RJ , Lloyd JK , Barley J . Double blind trial of bezafibrate in familial hypercholesterolaemia . Arch Dis Child . 1985 ; 60 ( 1 ): 34 – 37 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal

Journal of the Endocrine SocietyOxford University Press

Published: May 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off