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The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

ABSTRACT: The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C is attenuated in low LDL-C levels. This report examined this possibility in 1,508 patients with type 2 diabetes and 670 healthy controls. LDL-C ranges were classified as ≤69, 70-99, 100-139 and 140≤ mg/dL. The slope of the regression curve between sdLDL-C and TG was found to flatten as LDL-C decreased; 0.18, 0.13, 0.10 and 0.04 for controls, and 0.18, 0.13, 0.09 and 0.07 for diabetes patients. Correspondingly, the lower the LDL-C range, the lower the sdLDL-C/TG ratio. These results suggest that when LDL-C is tightly controlled, TG-lowering has only a weak inhibitory effect on sdLDL-C.

SUBMITTER: Hirano T

PROVIDER: S-EPMC10286789 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

Hirano Tsutomu T Ito Yasuki Y

Journal of diabetes investigation 20230404 7

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C i ...[more]

PMID: 37016542

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Project description:Background Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. Methods and Results Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cholesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL-C were confirmed by adjusted discordance analysis versus calculated non-high-density lipoprotein cholesterol, in contrast to LDL triglycerides. Conclusions sdLDL-C, direct LDL-C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL-C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter.

Project description:BackgroundMixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM.MethodsThe previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women).ResultsAlirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed.ConclusionsAlirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.

Dataset Information

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

Publications

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

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