Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

By Kevin C Maki, PhD and Orsolya M Palacios, PhD

 

Our group recently collaborated with scientists from the University of Cincinnati to conduct meta-regression analyses that investigated the dose-response relationships between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol levels.  The results from these analyses were presented in June at the American Society for Nutrition’s annual Nutrition 2018 meetings,1,2 and have also recently been accepted for publication in the American Journal of Clinical Nutrition.This summary is also available in the Fall 2018 Newsletter of MB Clinical Research.

 

Elevated low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, and there is a strong inverse association between high-density lipoprotein cholesterol (HDL-C) concentration and cardiovascular risk.4  Dietary guidance generally recommends reducing intakes of saturated fatty acids (SFA) and trans fatty acids (TFA) to reduce LDL-C levels, but in recent years there has been a step back from making specific quantitative recommendations with regard to limiting dietary cholesterol intake.5,6  A key recommendation from the 2010 Dietary Guidelines was to limit consumption of dietary cholesterol to <300 mg/day, but this was not included in the 2015-2020 Dietary Guidelines, although they did explain that “this change does not suggest that dietary cholesterol is no longer important to consider when building healthy eating patterns.”6  The 2015 guidelines stated “Strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include lower intake of dietary cholesterol are associated with reduced risk of CVD…”.6  However, the committee concluded that “More research is needed regarding the dose-response relationship between dietary cholesterol and blood cholesterol levels.  Adequate evidence is not available for a quantitative limit for dietary cholesterol specific to the Dietary Guidelines.” 6  The 2013 American Heart Association/American College of Cardiology Lifestyle Management Guideline also concluded “There is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C.”5  One problem with the available evidence is that there are limited data examining how much of an impact on lipoprotein lipid levels is attributable to dietary cholesterol after controlling for intakes of dietary fatty acids (i.e., SFA, TFA, polyunsaturated fatty acids [PUFA] and monounsaturated fatty acids [MUFA]).

 

Therefore, the goal of these meta-regression analyses was to examine the impacts of changes in dietary cholesterol on lipoprotein cholesterol levels, after accounting for dietary fatty acids.1,2  This meta-regression examined results from 55 randomized controlled dietary intervention trials (n = 2652 subjects) using a Bayesian approach (with Markov chain Monte Carlo techniques) and adjustment for dietary fatty acids to determine the best fitting mathematical models to the data.7  No significant associations were observed between change in dietary cholesterol intake and change in triglyceride or very low density lipoprotein cholesterol level.

 

For LDL-C, the meta-regression results indicated a positive correlation using a linear model and two non-linear models (Michaelis-Menten and Hill models), even after accounting for intakes of SFA, PUFA, MUFA and, where possible, TFA.  The relationship was best characterized by the non-linear models across the full range of cholesterol changes (0-1500 mg/day).  A 100 mg/day dietary cholesterol change was predicted to be associated with an increase in LDL-C of ~ 4.5 mg/dL in LDL-C.  Baseline cholesterol intake was not a significant predictor of the LDL-C response to a change in dietary cholesterol.  The relationship between baseline LDL-C and LDL-C response was unclear, and needs further exploration.  For HDL-C, the meta-regression analyses did not indicate a clear relationship between the change in dietary cholesterol intake and the change in HDL-C levels when both men and women were included.  However, when analyzed according to sex, the linear model and the Michaelis-Menten non-linear model demonstrated an inverse relationship in men, and a positive relationship in women.  This suggests a possible interaction between sex and HDL-C response to dietary cholesterol.

 

Using the Mensink et al. equation, which is designed to calculate the effects of changes in carbohydrate and fatty acid intakes on serum lipid and lipoprotein levels, each 1% increase in SFA in exchange for carbohydrate is predicted to increase LDL-C by 1.23 mg/dL.8  These findings suggest that increasing dietary cholesterol by 100 mg/day or 200 mg/day would have effects comparable to increasing dietary SFA by 3.7% and 5.5%, respectively.

 

These results suggest that there is a clinically meaningful effect of dietary cholesterol on LDL-C concentration.  This finding from a pooled analysis of results from 55 studies aligns with those from the best-controlled individual studies, such as two published by Ginsberg et al.9,10  This dose-response analysis provides reference for clinicians and nutrition scientists on how changes in dietary cholesterol intake may impact plasma cholesterol levels, although considerable interindividual variability should be expected.9-11  The clinical implications of changes in HDL-C associated with increased dietary cholesterol intake remain uncertain.

 

References:

  1. Vincent MJ, Allen B, Maki KC, Palacios OM, Haber LT. Non-linear models best characterize the relationship between dietary cholesterol intake and circulating low-density lipoprotein cholesterol levels. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  2. Palacios OM, Vincent MJ, Allen B, Haber LT, Maki KC. The effect of dietary cholesterol on high-density lipoprotein cholesterol levels in men and women: a meta-analysis of randomized controlled trials. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  3. Vincent MJ, Allen B, Palacios OM, Haber LT, Maki KC. Meta-regression analysis of the effects of dietary cholesterol intake on low- and high-density lipoprotein cholesterol. Am J Clin Nutr. 2018; In Press.
  4. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.
  5. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr., Svetkey LP, Wadden TA, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle managemnet to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2960-2984.
  6. U.S. Department of Health and Human Services and U.S Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. December 2015. Available at https://health.gov/dietaryguidelines/2015/resources/2015-2020_Dietary_Guidelines.pdf.
  7. The Stan Development Team. RStan: the R interface to Stan. R package version 2.16.2. 2017. Available at http://mc-stan.org.
  8. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146-1155.
  9. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Rumsey SC, Deckelbaum RJ, Blaner WS, Ramakrishnan R. A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arterioscler Thromb. 1994;14:576-586.
  10. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Blaner WS, Ramakrishnan R. Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women. Arterioscler Thromb Vasc Biol. 1995;15:169- 178.
  11. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, La Forge R, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Underberg JA, NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122.
Photo by Kelly Sikkema

Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia1

Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia

By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD

 Background:

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death in persons with type 2 diabetes2 and the incidence of cardiovascular events is elevated in patients with type 2 diabetes compared with those without diabetes.3,4 Abnormalities in lipid metabolism often accompany type 2 diabetes mellitus and are associated with insulin resistance, including:

  • Elevated triglyceride (TG) levels with delayed clearance of TG-rich lipoproteins from the circulation;
  • Reduced high-density lipoprotein cholesterol (HDL-C) levels;
  • An increased proportion of small, dense low-density lipoprotein (LDL) particles.

Several large-scale clinical trials, including the Collaborative Atorvastatin Diabetes Study (CARDS) and a Cholesterol Treatment Trialists’ (CTT) meta-analysis, have shown that effective management of dyslipidemia through LDL cholesterol (LDL-C)-lowering therapy with statins results in reduced cardiovascular risk in patients with diabetes.5,6 Other studies in people with diabetes have also identified risk factors for developing coronary heart disease including the Japan Diabetes Complication Study (JDCS), which noted high LDL-C and TG levels as risk factors, and the UK Prospective Diabetes Study (UKPDS), which showed that high LDL-C and low HDL-C are associated with elevated cardiovascular disease risk.7,8

Studies with fibrates have shown the expected decreases in TG and increases in HDL-C, but have shown inconsistent results regarding reductions in ASCVD risk in patients with type 2 diabetes. A meta-analysis completed by our group9 showed evidence that fibrates and other drugs that primarily lower TG and TG-rich lipoproteins (omega-3 fatty acid concentrates and niacin) reduce ASCVD events in participants with elevated TG, particularly if also accompanied by low HDL-C.

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor alpha (PPARɑ) modulator approved for the treatment of dyslipidemia.10 Ishibashi et al. performed a dose-finding phase 2 trial of pemafibrate in patients with atherogenic dyslipidemia (elevated TG and low HDL-C) and noted significant reductions in TG and increases in HDL-C with rates of adverse events (AEs) similar to placebo. Because type 2 diabetes and atherogenic dyslipidemia often coexist, many of the patients who receive treatment with pemafibrate (once approved for marketing) are expected to also have type 2 diabetes. This summary reports on the initial 24-week treatment period for a Phase III clinical trial comparing the effects of pemafibrate and placebo in patients with elevated TG and type 2 diabetes. The primary end point of the study was the percentage change in fasting serum TG level from baseline to the end point of 24 weeks. Secondary endpoints included the percentage changes or changes from baseline in fasting and postprandial lipid-related and glycemic parameters. The primary safety end points were the incidence rates of AEs and adverse drug reactions after the study drug usage.

 Methods:

This was a multicenter, placebo-controlled, randomized, double-blind, parallel group study that was completed in 34 medical institutions in Japan from February 20, 2014 through April 30, 2015. Subjects were eligible for the study if they met the following criteria:

  • Men and postmenopausal women age ≥20 years;
  • Type 2 diabetes with glycated hemoglobin (HbA1c) ≥6.2% and TG ≥150 mg/dL (1.7 mmol/L);
  • ≥12 weeks of dietary or exercise guidance before the first screening visit.

This study included participants who were randomly assigned to receive twice daily placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks. Pemafibrate is available in 0.1 mg tablets.

 Results:

Fasting serum TG significantly decreased by ~45% with pemafibrate compared with placebo (p<0.001, see table).

 

 

Fasting TG, mg/dL, mean ± standard deviation

 

Baseline

Week 24

Placebo

  284.3 ± 117.6

240.0 ± 92.2

0.2 mg/day pemafibrate

240.3 ± 93.5

129.0 ± 71.5

0.4 mg/day pemafibrate

260.4 ± 95.9

135.8 ± 71.2

Percentage changes in fasting serum TG levels from baseline to 24 weeks were -10.8% (p < 0.01), -44.3% (p < 0.001) and -45.1% (p <0.001) for placebo, 0.2 mg/day and 0.4 mg/day, respectively. The pemafibrate groups also had significantly reduced levels of non-HDL-C, remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, Apo B48 and Apo C3, and significantly increased HDL-C and Apo A1 levels. LDL-C was not significantly affected by treatment with pemafibrate. The 0.2 mg/day pemafibrate group had significant reductions in homeostasis model assessment (HOMA)-insulin resistance scores compared with placebo, but no significant alterations vs. placebo were seen in fasting plasma glucose, fasting insulin, glycoalbumin or HbA1c. Rates of AEs and adverse drug reactions were similar between the two pemafibrate groups and the placebo group.

 Comment:

This is the first report of long-term (24 weeks) efficacy and safety of pemafibrate in subjects with type 2 diabetes and hypertriglyceridemia. In this study, which was conducted in Japan, pemafibrate lowered TG levels by ~45%, which was apparent within the first month of the treatment period and maintained over the entire treatment period. An ASCVD event trial with pemafibrate commenced enrollment in 2017, the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial, and is expected to complete in 2022 (https://clinicaltrials.gov/ct2/show/NCT03071692).

References:

  1. Araki E, Yamashita S, Arai H, et al. Effects of pemafibrate, a novel selective PPARalpha modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial. Diabetes Care. 2018;41(3):538-546.
  2. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732.
  3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
  4. Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database. Diabetologia. 2008;51(9):1639-1645.
  5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.
  6. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-125.
  7. Sone H, Tanaka S, Tanaka S, et al. Serum level of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab. 2011;96(11):3448-3456.
  8. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823-828.
  9. Maki KC, Guyton JR, Orringer CE, Hamilton-Craig I, Alexander DD, Davidson MH. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10(4):905-914.

10.       Ishibashi S, Yamashita S, Arai H, et al. Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36-43.

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