Weight gain trajectories and obesity rates in intensive and conventional treatments of type 1 diabetes from the DCCT compared with a control population without diabetes.

AIM: Obesity is a significant health issue for participants with type 1 diabetes undergoing intensive diabetes management. The temporal pattern and factors associated with weight gain after treatment initiation remain poorly understood including how weight gain in participants with and without type I diabetes compare. Our aim was to compare weight gain in those receiving intensive (INT) and conventional (CONV) type 1 diabetes treatment to a population without diabetes. METHODS: Participants included men and women of 18 years and older in the Diabetes Control and Complications Trial (DCCT) randomized to INT (n = 562) or CONV (n = 568) and a prospective, observational cohort without diabetes from the Coronary Artery Development in Young Adults (CARDIA, controls) study (n = 2446). Body mass index (BMI) trajectories and obesity prevalence were compared between groups and candidate metabolic and therapeutic moderators investigated. RESULTS: Annual weight gain with INT peaked 1.3 years after initiation and was greater than both CONV and controls before and after this peak. Obesity prevalence with INT was lower than controls at baseline, was similar to controls at 2 years and surpassed controls by 5 years. Obesity rates with CONV remained below controls at all time points. Greater annual weight gain in the DCCT was associated with lower haemoglobin A1c , higher insulin dose and family history of type 2 diabetes. CONCLUSIONS: Greater weight gain accompanying INT therapy occurs in two stages, leads to similar or greater obesity rates than controls after 2 years and is primarily modified by glucose control and family history, supportive of a therapeutic-genetic influence on weight trajectories.

Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus.

Objective- Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results- In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate ( P<10-6). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43-0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40-0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions- Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. Moreover, low concentrations of the antiatherosclerotic protein PON1 in HDL associated with both albuminuria and coronary artery calcification, raising the possibility that alterations in HDL protein cargo mediate, in part, the known association of albuminuria with cardiovascular risk in type 1 diabetes mellitus. Visual Overview- An online visual overview is available for this article.

Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

OBJECTIVE: Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS: Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS: The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1-3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1-3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1-3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS: For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential. METHODS: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. RESULTS: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%). CONCLUSION: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.

BACKGROUND: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. RESULTS: A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. CONCLUSIONS: We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).

Intraabdominal fat, insulin sensitivity, and cardiovascular risk factors in postpartum women with a history of preeclampsia.

OBJECTIVE: Women who develop preeclampsia have a higher risk of future cardiovascular disease and diabetes compared to women who have uncomplicated pregnancies. We hypothesized that women with prior preeclampsia would have increased visceral adiposity that would be a major determinant of their metabolic and cardiovascular risk factors. STUDY DESIGN: We compared intraabdominal fat (IAF) area, insulin sensitivity index (SI), fasting lipids, low-density lipoprotein relative flotation rate, and brachial artery flow-mediated dilatation in 49 women with prior preeclampsia and 22 controls who were at least 8 months postpartum and matched for age, parity, body mass index, and months postpartum. Women were eligible if they did not smoke tobacco, use hormonal contraception, have chronic hypertension, or have a history of gestational diabetes. RESULTS: The groups were similar for age (mean ± SD: prior preeclampsia 33.4 ± 6.6 vs control 34.6 ± 4.3 years), parity (median: 1 for both), body mass index (26.7 ± 5.9 vs 24.0 ± 7.3 kg/m(2)), and months postpartum (median [25th-75th percentile]: 16 [13-38] vs 16.5 [13-25]). There were no significant differences in IAF area and SI. Despite this, women with preeclampsia had lower high-density lipoprotein (46.0 ± 10.7 vs 51.3 ± 9.3 mg/dL; P < .05), smaller/denser low-density lipoprotein relative flotation rate (0.276 ± 0.022 vs 0.289 ± 0.016; P = .02), higher systolic (114.6 ± 10.9 vs 102.3 ± 7.5 mm Hg) and diastolic (67.6 ± 7.5 vs 60.9 ± 3.6 mm Hg; P < .001) blood pressures, and impaired flow-mediated dilatation (4.5 [2-6.7] vs 8.8 [4.5-9.1] percent change, P < .05) compared to controls. In a subgroup analysis, women with nonsevere preeclampsia (n = 17) had increased IAF (98.3 [60.1-122.2]) vs 63.1 [40.1-70.7] cm(2); P = .02) and decreased SI (4.18 [2.43-5.25] vs 5.5 [3.9-8.3] × 10(-5) min(-1)/pmol/L; P = .035) compared to the controls, whereas women with severe preeclampsia (n = 32) were not different for IAF and SI. IAF was negatively associated with SI and positively associated with cardiovascular risk factors even after adjusting for the matching variables and total body fat. CONCLUSION: Women with prior preeclampsia have an atherogenic lipid profile and endothelial dysfunction compared to matched control subjects despite having similar adiposity and insulin sensitivity, suggesting that there are mechanisms separate from obesity and insulin resistance that lead to their cardiovascular risk factors. Visceral adiposity may have a role in contributing to these risk factors in the subgroup of women who have preeclampsia without severe features.

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity.

Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 × 10(-9)), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10(-5)), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10(-7)), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.

Paraoxonase-3 is depleted from the high-density lipoproteins of autoimmune disease patients with subclinical atherosclerosis.

Patients with autoimmune diseases have a significantly increased risk of developing cardiovascular disease. In disease, high-density lipoprotein (HDL) particles lose their anti-inflammatory and antioxidant properties and become dysfunctional. The purpose of this study was to test the hypothesis that alterations in the HDL proteomic profile are associated with subclinical atherosclerosis and HDL dysfunction in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes. Targeted proteomics was used to quantify the relative abundance of 18 proteins in HDL from SLE patients with and without atherosclerotic plaque detectable by carotid ultrasound. Changes in the proteomic profile were compared against the in vitro ability of HDL to protect against lipid oxidation. The same proteins were quantified in HDL from patients with type 1 diabetes with or without coronary artery calcification as determined by computed tomography. In each population, paraoxonase-3 (PON3), a potent antioxidant protein, was depleted from the HDL of patients with subclinical atherosclerosis. PON3 expression in HDL was positively correlated with HDL antioxidant function. These results suggest that PON3 may be an important protein in preventing atherosclerosis and highlight the importance of antioxidant proteins in the prevention of atherosclerosis in vivo.

Treatment options for hypertriglyceridemia: from risk reduction to pancreatitis.

While there has been considerable focus on the role and treatment of LDL cholesterol levels, a definitive role of triglycerides in the management of cardiovascular disease has been uncertain. Notably, with increasing triglyceride levels, there is a parallel increase in cholesterol levels carried by triglyceride-rich lipoproteins, which has prompted interest in the use of non-HDL cholesterol levels as a tool guiding interventions. Recent studies have provided evidence for an independent role of triglyceride levels as a cardiovascular risk factor, and recently, an Endocrine Society guideline was published for treatment of hypertriglyceridemia. In contrast to the relative uncertainty regarding triglycerides and cardiovascular disease, a role of very high triglyceride levels as a risk factor for pancreatitis has been well known. The present paper summarizes the underlying evidence for a risk role for triglyceride levels in cardiovascular disease and pancreatitis, current treatment recommendations and areas of future research.

Effects of niacin combination therapy with statin or bile acid resin on lipoproteins and cardiovascular disease.

Two large studies in populations selected for cardiovascular disease (CVD) demonstrated that raising high-density lipoprotein (HDL) cholesterol with niacin added to statin therapy did not decrease CVD. We examine the association of lipoprotein subfractions with niacin and changes in coronary stenosis and CVD event risk. One hundred and seven patients from 2 previous studies using niacin in combination with either statin or bile acid-binding resin were selected to evaluate changes in lipoproteins separated by density-gradient ultracentrifugation to progression of coronary artery disease as assessed by quantitative coronary angiography. Improvement in coronary stenosis was significantly associated with the decrease of cholesterol in the dense low-density lipoprotein (LDL) particles and across most of the intermediate density lipoprotein (IDL) and very low density lipoprotein particle density range, but, not with any of the HDL fraction or of the more buoyant LDL fractions. Event-free survival was significantly associated with the decrease of cholesterol in the dense LDL and IDL; there was no association with changes in cholesterol in the HDL and buoyant LDL fractions. Niacin combination therapy raises HDL cholesterol and decreases dense LDL and IDL cholesterol levels. Changes in LDL and IDL are related to improvement in CVD. Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in combination with statins.

Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia.

Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer's disease brains.

Lipoprotein lipase (LPL) is involved in regulation of fatty acid metabolism, and facilitates cellular uptake of lipoproteins, lipids and lipid-soluble vitamins. We evaluated LPL distribution in healthy and Alzheimer's disease (AD) brain tissue and its relative levels in cerebrospinal fluid. LPL immunostaining is widely present in different neuronal subgroups, microglia, astrocytes and oligodendroglia throughout cerebrum, cerebellum and spinal cord. LPL immunoreactivity is also present in leptomeninges, small blood vessels, choroid plexus and ependymal cells, Schwann cells associated with cranial nerves, and in anterior and posterior pituitary. In vitro studies have shown presence of secreted LPL in conditioned media of human cortical neuronal cell line (HCN2) and neuroblastoma cells (SK-N-SH), but not in media of cultured primary human astrocytes. LPL was present in cytoplasmic and nuclear fractions of neuronal cells and astrocytes in vitro. LPL immunoreactivity strongly associates with AD-related pathology, staining diffuse plaques, dystrophic and swollen neurites, possible Hirano bodies and activated glial cells. We observed no staining associated with neurofibrillary tangles or granulovacuolar degeneration. Granule cells of the dentate gyrus and the associated synaptic network showed significantly reduced staining in AD compared to control tissue. LPL was also reduced in AD CSF samples relative to those in controls.

Circulating vitamin D metabolites and subclinical atherosclerosis in type 1 diabetes.

OBJECTIVE: People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study. RESEARCH DESIGN AND METHODS: We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT. RESULTS At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower-not higher-with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68-0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT. CONCLUSIONS: We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.

The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study.

BACKGROUND: Intensive diabetes mellitus therapy of type 1 diabetes mellitus reduces diabetes mellitus complications but can be associated with excess weight gain, central obesity, and dyslipidemia. The purpose of this study was to determine whether excessive weight gain with diabetes mellitus therapy of type 1 diabetes mellitus is prospectively associated with atherosclerotic disease. METHODS AND RESULTS: Subjects with type 1 diabetes mellitus (97% white, 45% female, mean age 35 years) randomly assigned to intensive or conventional diabetes mellitus treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (n = 1015) and coronary artery calcium score (n = 925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Intensive treatment subjects were classified by quartile of body mass index change during the DCCT. Excess gainers (4th quartile, including conventional treatment subjects meeting this threshold) maintained greater body mass index and waist circumference, needed more insulin, had greater intima-media thickness (+5%, P < 0.001 EDIC year 1, P = 0.003 EDIC year 6), and trended toward greater coronary artery calcium scores (odds ratio, 1.55; confidence interval, 0.97 to 2.49; P = 0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for waist circumference and blood pressure had greater intima-media thickness in both EDIC years (P = 0.02 to < 0.001); those meeting high-density lipoprotein criteria had greater coronary artery calcium scores (odds ratio, 1.6; confidence interval, 1.1 to 2.4; P = 0.01) during follow-up. Increasing frequency of a family history of diabetes mellitus, hypertension, and hyperlipidemia was associated with greater intima-media thickness with intensive but not conventional treatment. CONCLUSIONS: Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC. CLINICAL TRIAL REGISTRATION: URL for DCCT: http://clinicaltrials.gov; Unique identifier: NCT00360815. URL for EDIC: http://clinicaltrials.gov; Unique identifier: NCT00360893.

Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.

OBJECTIVE: The aim was to develop clinical practice guidelines on hypertriglyceridemia. PARTICIPANTS: The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS: The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150-999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of > 1000 mg/dl) be considered a risk for pancreatitis. The Task Force also recommends that patients with hypertriglyceridemia be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease. The Task Force recommends that the treatment goal in patients with moderate hypertriglyceridemia be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate should be used as a first-line agent.