Partial Clinical Remission Reduces Lipid-Based Cardiovascular Risk in Adult Patients With Type 1 Diabetes

ImportanceRisk factors for atherosclerotic cardiovascular disease (ASCVD) are well established in type 2 diabetes (T2D), but not in type 1 diabetes (T1D). The impact of partial clinical remission (PR) on short-term ASCVD risk in T1D is unclear.AimTo investigate the impact of PR on the earliest ASCVD risk phenotype in adult T1D using factor analysis to compare the lipid phenotypes of T1D, T2D and controls after stratifying the T1D cohort into remitters and non-remitters.Subjects and MethodsA study of 203 adults subjects consisting of 86 T2D subjects, and 77 T1D subjects stratified into remitters (n=49), and non-remitters (n=28). PR was defined as insulin-dose adjusted HbA1c of ≤9, and obesity as a BMI ≥30 kg/m2. Factor analysis was used to stratify the groups by ASCVD risk by factorizing seven lipid parameters (TC, LDL, HDL, non-HDL, TC/HDL, TG, TG/HDL) into 2 orthogonal factors (factor 1: TC*LDL; factor 2: HDL*TG) that explained 90% of the variance in the original seven parameters.ResultsThe analysis of individual lipid parameters showed that TC/HDL was similar between the controls and remitters (p=NS) but was significantly higher in the non-remitters compared to the remitters (p=0.026). TG/HDL was equally similar between the controls and remitters (p=NS) but was lower in the remitters compared to the non-remitters (p=0.007). TG was significantly lower in the remitters compared to T2D subjects (p<0.0001) but was similar between T2D subjects and non-remitters (p=NS). Non-HDL was significantly lower in the controls versus non-remitters (p=0.0003) but was similar between the controls and remitters (p=NS). Factor analysis showed that the means of factor 1 and factor 2 composite scores for dyslipidemia increased linearly from the controls, remitters, non-remitters to T2D, p value 0.0042 for factor 1, and <0.0001 for factor 2, with remitters having similar lipid phenotype as controls, while non-remitters were similar to T2D.ConclusionsPartial clinical remission of T1D is associated with a favorable early lipid phenotype which could translate to reduced long-term CVD risk in adults.

Abstract 16278: Discordant Lipid Phenotype and Other Determinants of Statin Response in the Pravastatin Inflammation/crp Evaluation (PRINCE) Trial

Introduction: Wide variability in LDL-C change is observed with statins, yet determinants of statin response are uncertain. Methods: Participants were selected from the primary prevention cohort of the Pravastatin Inflammation/CRP Evaluation double-blind trial that randomized participants to pravastatin 40 mg/d or placebo over 24 weeks. Baseline and 24-week levels of LDL-C and 15 other biomarkers were measured in 495 participants. We defined optimal statin response as >=30% LDL-C reduction and suboptimal response as <30% reduction. Sub-optimal hs-CRP response was defined as >=median (14%) decline in hs-CRP from baseline to 24 weeks and non-response as no decrease or an increase in hs-CRP. χ 2 , t-tests and ANOVA were used to compare variables across optimal statin response (N=166) and suboptimal response (N=287). Multivariable logistic regression models evaluated associations of determinants of statin response. Forward selection identified variables that associated with response. Xgboost was used to train and validate the models using 2/3 and 1/3 of the data respectively. Results: Significant determinants of optimal statin response included older age, and higher baseline levels of LDL-C and triglyceride-rich lipoproteins. By contrast, female sex, alcohol intake >=1 drink/day, diabetes, higher baseline levels of apo B and lipoprotein(a) were associated with decreased response, as was hs-CRP non-response (Table). Race, baseline hs-CRP and sub-optimal hs-CRP response, smoking, HDL-C and BMI had no significant effect on statin LDL-C response. Training and validation of models predicted suboptimal LDL-C response with an AUC of 0.71. Similarly, training and validation of models using Xgboost yielded an AUC of 0.85. Conclusion: This study identified discordant lipid phenotype and other determinants of moderate-intensity statin response and suggests other pathways of CVD risk beyond those addressed by statin treatment that require further investigation.

Risk factors for the presence and development of Familial Dysbetalipoproteinemia in subjects from the general population with an APOE2E2 genotype

Background Subjects who carry one or two ɛ2 alleles of the APOE gene are protected from cardiovascular disease due to low LDL-cholesterol levels. However, 10–18% of ɛ2 homozygotes (ɛ2ɛ2) develop Familial Dysbetalipoproteinemia (FD), which is characterized by extensive remnant lipoprotein accumulation, making it a good model to study the effect of remnants on atherosclerosis and cardiovascular disease. Important causal factors for FD, or an “FD like phenotype” in ɛ2 heterozygotes (ɛ2ɛ3), are thought to be adiposity and insulin resistance. However, to date this relation was only evaluated in cross-sectional studies. Purpose To evaluate the cross-sectional and longitudinal association of adiposity and insulin resistance on the presence and development of FD in ɛ2ɛ2 or an “FD-like” phenotype in ɛ2ɛ3 subjects. Methods For this study we included 18042 subjects with an APOE measurement from two Dutch population-based cohorts; the PREVEND cohort (follow-up 4.1 (interquartile range (IQR) 4.0–4.4) years) and the Rotterdam Study (follow-up 10.1 (IQR 5.6–10.8) years). Subjects with an ɛ3ɛ3 genotype (n=10391) and ɛ4 carriers were excluded (n=5265). FD and “FD like” phenotype were defined as triglyceride levels &gt;3 mmol/l or use of lipid lowering medication. Logistic regression models were used to evaluate the effect of age, sex, BMI, waist circumference, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) on FD lipid phenotype. Changes in adiposity measures and insulin resistance between baseline and follow-up were compared in subjects with and without development of FD at follow-up. Results In total, 2386 subjects were included of whom 118 participants had ɛ2ɛ2 and 2268 had ɛ2ɛ3 of whom 68% completed a follow-up visit. Subjects mean age was 59±14 years and 44% were male. In ɛ2ɛ2 subjects, 19% (n=23) had FD at baseline and 16% (n=11) developed FD during follow-up. In ɛ2ɛ3 subjects 13% (n=305) had an “FD like” phenotype at baseline and 11% (n=146) at follow-up. Cross-sectional determinants for the presence of an FD or “FD like” phenotype at baseline were male sex, BMI, waist circumference and non-lipid MetS criteria. In ɛ2ɛ2 subjects who developed FD during follow-up, markers of adiposity and insulin resistance did not change compared to baseline. However, these FD patients more often had adiposity (BMI, weight and waist circumference) and T2DM at baseline, compared to those and who did not developed FD. Conclusions These results show for the first time that adiposity and insulin resistance are important risk markers for future development of FD or “FD like” phenotype in ɛ2ɛ2- and ɛ2ɛ3 subjects. The increased susceptibility of ɛ2 carriers for development of an FD lipid phenotype by adiposity and insulin resistance might be due to impaired remnant clearance consequent to decreased binding affinity of APOɛ2 to the LDL-receptor in combination with degradation of the heparan sulfate receptor by insulin resistance (mediated by sulfatase 2 activation). Odds Ratios for FD lipid phenotype Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): UMC Utrecht; Erasmus MC; UMC Groningen

Monitor Ionizing Radiation-Induced Cellular Responses with Raman Spectroscopy, Non-Negative Matrix Factorization, and Non-Negative Least Squares

Radiation therapy (RT) is one of the most commonly prescribed cancer treatments. New tools that can accurately monitor and evaluate individual patient responses would be a major advantage and lend to the implementation of personalized treatment plans. In this study, Raman spectroscopy (RS) was applied to examine radiation-induced cellular responses in H460, MCF7, and LNCaP cancer cell lines across different dose levels and times post-irradiation. Previous Raman data analysis was conducted using principal component analysis (PCA), which showed the ability to extract biological information of glycogen. In the current studies, the use of non-negative matrix factorization (NMF) allowed for the discovery of multiplexed biological information, specifically uncovering glycogen-like and lipid-like component bases. The corresponding scores of glycogen and previously unidentified lipids revealed the content variations of these two chemicals in the cellular data. The NMF decomposed glycogen and lipid-like bases were able to separate the cancer cell lines into radiosensitive and radioresistant groups. A further lipid phenotype investigation was also attempted by applying non-negative least squares (NNLS) to the lipid-like bases decomposed individually from three cell lines. Qualitative differences found in lipid weights for each lipid-like basis suggest the lipid phenotype differences in the three tested cancer cell lines. Collectively, this study demonstrates that the application of NMF and NNLS on RS data analysis to monitor ionizing radiation-induced cellular responses can yield multiplexed biological information on bio-response to RT not revealed by conventional chemometric approaches.

Exon 9-deleted CETP inhibits full length-CETP synthesis and promotes cellular triglyceride storage

Cholesteryl ester transfer protein (CETP) exists as full-length (FL) and exon 9 (E9)-deleted isoforms. The function of E9-deleted CETP is poorly understood. Here, we investigated the role of E9-deleted CETP in regulating the secretion of FL-CETP by cells and explored its possible role in intracellular lipid metabolism. CETP overexpression in cells that naturally express CETP confirmed that E9-deleted CETP is not secreted, and showed that cellular FL- and E9-deleted CETP form an isolatable complex. Coexpression of CETP isoforms lowered cellular levels of both proteins and impaired FL-CETP secretion. These effects were due to reduced synthesis of both isoforms; however, the predominate consequence of FL- and E9-deleted CETP coexpression is impaired FL-CETP synthesis. We reported previously that reducing both CETP isoforms or overexpressing FL-CETP impairs cellular triglyceride (TG) storage. To investigate this further, E9-deleted CETP was expressed in SW872 cells that naturally synthesize CETP and in mouse 3T3-L1 cells that do not. E9-deleted CETP overexpression stimulated SW872 triglyceride synthesis and increased stored TG 2-fold. Expression of E9-deleted CETP in mouse 3T3-L1 cells produced a similar lipid phenotype. In vitro, FL-CETP promotes the transfer of TG from ER-enriched membranes to lipid droplets. E9-deleted CETP also promoted this transfer, although less effectively, and it inhibited the transfer driven by FL-CETP. We conclude that FL- and E9-deleted CETP isoforms interact to mutually decrease their intracellular levels and impair FL-CETP secretion by reducing CETP biosynthesis. E9-deleted CETP, like FL-CETP, alters cellular TG metabolism and storage but in a contrary manner.

Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.