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 NEWSLETTER

Volume 5; Issue 4

 

Improving health through research on chronic disease prevention and treatment

 

www.mbclinicalresearch.com

 

Scientific Contributions

 

Searching for Answers to Explain the Contrasting Results in REDUCE-IT and STRENGTH

Two large-scale cardiovascular outcomes trials conducted with higher dosages of omega-3 fatty acids than previous investigations and in populations with elevated triglycerides (TG) and higher risk of atherosclerotic cardiovascular disease (ASCVD), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH), produced markedly different results.1,2  In REDUCE-IT, 4 g/d icosapent ethyl (Vascepa®; an ethyl ester formulation of eicosapentaenoic acid [EPA]) produced a 25% reduction in the incidence of the primary composite outcome over a median follow-up of 4.9 y.  In contrast, STRENGTH, which administered 4 g/d EPA + docosahexaenoic acid (DHA) carboxylic acids (Epanova®), was terminated early due to futility, after an interim analysis indicated that there was a 1%, non-significant, lower incidence of the primary composite outcome after a median follow-up of 3.5 y.  These findings have sparked intense debate and led to further research into possible explanations for the disparity.

One such investigation conducted by Doi et al. was recently published in the European Heart Journal.3 Using data from the Copenhagen General Population Study, the investigators selected cohorts that met the key inclusion criteria for REDUCE-IT and STRENGTH.  They applied Cox proportional hazards models to investigate relationships between TG, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP) and ASCVD risk within the cohorts, and to estimate the effects of observed changes in these biomarkers in the active and control arms in each trial.  The estimated changes in ASCVD risk were then compared with the actual differences in ASCVD incidence.  Results demonstrated that there were no differences between active treatments in the modeled effects on ASCVD risk, but there were differences in the modeled effects of the control oils:  an adverse effect for mineral oil in REDUCE-IT and a neutral effect for corn oil in STRENGTH. Therefore, the authors concluded that the contrasting results in REDUCE-IT and STRENGTH could partly be explained by a difference in the effects of the comparator oils, but not of the active oils, on TG, LDL-C, and hs-CRP.

Kevin C. Maki, PhD was invited to prepare an editorial to accompany this article, and recorded a podcast for ESC Cardio Talk in which he discussed the editorial with his colleague, Carl E. Orringer, MD, of the University of Miami Miller School of Medicine.4  In the editorial, Dr. Maki further explored the possibility that the different control oils accounted for part of the difference in results between REDUCE-IT and STRENGTH.  Corn oil, which is high in linoleic acid, an omega-6 polyunsaturated fatty acid (PUFA), may have produced a benefit on ASCVD risk in STRENGTH through mechanisms beyond effects on lipids and hs-CRP.  Results from observational studies indicate lower ASCVD risk with higher omega-6 PUFA intake or status.5-8  Adverse effects of mineral oil on lipids, such as its potential to interfere with statin absorption, and hs-CRP might explain approximately one-quarter of the observed difference between control and active oils in REDUCE-IT, which also leaves a substantial portion of the benefit for Vascepa unexplained by these mechanisms alone.  Higher on-treatment plasma EPA with Vascepa in REDUCE-IT compared with the levels achieved with the active treatment in STRENGTH may be involved in the disparity in results between these two trials.  There was a strong dose-response association of plasma EPA with lower ASCVD risk in REDUCE-IT, especially in the range of 130-200 µg/mL.  Higher plasma EPA has potential antiplatelet effects, as indicated by increased bleeding events in REDUCE-IT,1 but not in STRENGTH, as well as other antiatherosclerotic and antioxidant impacts.9-11  Dr. Maki broke down the possible explanations for the 25% difference in cardiovascular events between Vascepa and mineral oil groups in REDUCE-IT into 7% due to effects of mineral oil on TG, LDL-C, and hs-CRP; 5% due to effects of icosapent ethyl on TG, LDL-C, and hs-CRP; and 13% related to unexplained possible beneficial effects of EPA (e.g., antiplatelet, antiatherosclerotic, antioxidant) or adverse effects of mineral oil.

Dr. Maki concluded his editorial to state that although results have been mixed for omega-3 fatty acid interventions, the evidence to date supports the recommendation that Vascepa should be considered for high- and very-high risk statin-treated patients with elevated TG.12,13  He further emphasized the need for additional ASCVD outcome trials and randomized controlled trials of surrogate indicators, such as coronary plaque progression, to further clarify the magnitude of the benefit of Vascepa on ASCVD incidence and the mechanisms responsible.
 

References:

1. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Jr., Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22.
2. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundstrom T, Agrawal R, Menon V, Wolski K, Nissen SE. Effect of high-dose omega-3 fatty acids vs. corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020;324:2268-2280.
3. Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J. 2021;E-pub ahead of print.
4. Maki KC. Investigating contrasting results in REDUCE-IT and STRENGTH: partial answers but questions remain. Eur Heart J. 2021;E-pub ahead of print. Podcast will be available at:  https://www.escardio.org/The-ESC/What-we-do/news/ESC-Cardio-Talk.
5. Li Y, Hruby A, Bernstein AM, Ley SH, Wang DD, Chiuve SE, Sampson L, Rexrode KM, Rimm EB, Willett WC, Hu FB. Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study. J Am Coll Cardiol. 2015;66:1538-1548.
6. Wang Q, Afshin A, Yakoob MY, Singh GM, Rehm CD, Khatibzadeh S, Micha R, Shi P, Mozaffarian D; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE). Impact of nonoptimal intakes of saturated, polyunsaturated, and trans fat on global burdens of coronary heart disease. J Am Heart Assoc. 2016;5:e002891.
7. Micha R, Penalvo JL, Cudhea F, Imamura F, Rehm CD, Mozaffarian D. Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States. JAMA. 2017;317:912-924.
8. Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, Miller M, Rimm EB, Rudel LL, Robinson JG, Stone NJ, Van Horn LV, American Heart Association. Dietary fats and cardiovascular disease: a Presidential Advisory from the American Heart Association. Circulation. 2017;136:e1-e23.
9. Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB, Le VT, May HT, Shaikh K, Shekar C, Roy SK, Tayek J, Nelson JR. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final reports of the EVAPORATE trial. Eur Heart J. 2020;41:3925-3932.
10. Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Matsuzawa Y, JELIS Investigators. Relationships between plasma fatty acid composition and coronary artery disease. J Atheroscler Thromb. 2011;18:99-107.
11. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, Seljeflot I, Arnesen H, OMEMI Investigators. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized controlled trial. Circulation. 2021;143:528-539.
12. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-188.
13. Orringer CE, Jacobson TA, Maki KC. National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J Clin Lipidol. 2019;13:860-872.

 

 

 

Recent and Upcoming Publications

Maki KC, Dicklin MR, Kirkpatrick CF. Saturated fats and cardiovascular health: current evidence and controversies. J Clin Lipidol. 2021;E-pub ahead of print.

Maki KC. Investigating contrasting results in REDUCE-IT and STRENGTH: partial answers but questions remain. Eur Heart J. 2021;E-pub ahead of print.

Baer DJ, Althouse A, Hermann M, Johnson J, Maki KC, Marklund M, Vogt L, Wesson D, Stallings VA. Targeting the dietary Na:K ratio-considerations for design of an intervention study to impact blood pressure. Adv Nutr. 2021;E-pub ahead of print.

Kirkpatrick CF, Maki KC. Dietary influences on atherosclerotic cardiovascular disease risk. Curr Atheroscler Rep. 2021;23(10):62.

Sanders LM, Maki KC. The role of appetite in mediating the relationship of whole grains and body weight. Nutr Today. 2021;56:239-245.

Weaver CM, Lichtenstein AH, Kris-Etherton PM, Maki KC, Petersen KS. At last – best practices for conducting human nutrition randomized controlled trials: a brief review and commentary. J Clin Nutr Diet. 2021;7(5):1.

Petersen KS, Kris-Etherton PM, McGabe GP, Raman G, Miller JW, Maki KC. Perspective: planning and conducting statistical analyses for human nutrition randomized, controlled trials: ensuring data quality and integrity. Adv Nutr. 2021;12:1610-1624.

Sanders LM, Zhu Y, Wilcox ML, Koecher K, Maki KC. Effects of whole grain intake, compared with refined grain, on appetite and energy intake: A systematic review and meta-analysis. Adv Nutr. 2021;12:1177-1195.

Wilcox M, Edirisinghe I, Dicklin M, Xiao D, Burton-Freeman B, Maki K. Comparison of two methods for assessing small, dense LDL cholesterol. In: Scientific Poster Abstracts Selected for National Lipid Association 2020 Scientific Sessions, December 13-16, 2020, Chicago, IL. J Clin Lipidol. 2020;In press.

Chen O, Rogers GT, McKay DL, Maki KC, Blumberg JB. The effect of multi-vitamin/multi-mineral supplementation on nutritional status in older adults receiving drug therapies: a double-blind, placebo-controlled trial. J Diet Suppl. 2020;E-pub ahead of print.
 

Bolded individuals are from MB Clinical Research or Great Lakes Clinical Trials.

 

SARS-CoV-2/Covid-19 Pandemic

Comments from our Chief Scientist, Epidemiologist Kevin C. Maki, PhD as of October 4, 2021

Delta variant.  The southern United States seems to be at the tail end of the delta variant wave of SARS-CoV-2 infections.  The delta variant wave appears to be moving northward and I anticipate that there will be a relatively large number of cases in the midwestern and northern states as the weather cools and people spend more time indoors. Alaska, the most northern state, is currently showing high cases and hospitalizations.  The delta variant is highly contagious with an R0 of perhaps 6.0 to 7.0, indicating that each infected person would be expected to infect 6 to 7 additional individuals in a population completely naïve to the virus.  A large majority of hospitalizations and deaths occurring during the delta wave are among unvaccinated individuals.

The delta variant is so contagious that it has dampened hopes for a high level of herd immunity. Herd immunity does not mean that the virus goes away but does mean that rapid spread is less likely. The traditional formula for the herd immunity threshold is 1 – 1/ R0.  With an R0 value as high as 7.0, that would mean nearly 86% of the population would need to have been infected or vaccinated to reach herd immunity.  Given that children under 12 years of age are not currently eligible for vaccination and breakthrough infections are clearly occurring among the vaccinated, herd immunity is unlikely to markedly dampen the spread of this virus, which is likely to remain endemic in the US for years to come.

Breakthrough infections.  It has become clear from the US experience, as well as that in other countries such as the UK and Israel, that vaccination does not provide near 100% protection against infection with SARS-CoV-2 for more than a relatively short period.  Immune protection appears to begin waning after a few months.  Preliminary evidence suggests that this is true to a larger extent with the Pfizer vaccine than with the Moderna vaccine.  This is not entirely surprising because each dose of Pfizer vaccine contains 30 µg of mRNA, whereas each dose of the Moderna vaccine contains 100 µg.  Both use a 2-dose regimen.  The Johnson & Johnson single-dose regimen vaccine provides more moderate protection from symptomatic SARS-CoV-2 infection (roughly 70%), which appears to be relatively stable over time, out to several months.  However, it should be emphasized that most breakthrough infections in vaccinated individuals are mild and do not require hospitalization.  The vaccines also remain very effective against death from Covid-19, particularly among healthy individuals who are not immunocompromised.  

The FDA recently approved the application by Pfizer for Emergency Use Authorization of a booster vaccination (3rd dose) for their SARS-CoV-2 vaccine to be administered at least six months after completion of the primary series in:

   individuals 65 years of age and older;
-    individuals 18 through 64 years of age 
     at high risk of severe COVID-19; and 
-    individuals 18 through 64 years of age 
     whose frequent institutional or occupational
     exposure to SARS-CoV-2 puts them at high 
     risk of serious complications of COVID-19 
     including severe COVID-19.

Both Moderna and Johnson & Johnson have applied to the FDA for approval of booster doses for their SARS-CoV-2 vaccines, and approval is expected within a few weeks for each.  In addition, Pfizer has released data from a study in children 5-11 years of age for a lower dose (10 µg), two-vaccination series.  Studies are also underway for younger children, 6 months to <5 years.  Emergency Use Authorization for children 5-11 years of age could be granted by the FDA before the end of the year.

Natural immunity.  The available evidence for natural immunity after infection continues to be reassuring.  Infection and recovery from SARS-CoV-2 infection is associated with strong protection from Covid-19 hospitalization and death for at least several months.  Data from observational studies suggest that vaccination after recovery provides additional protection, although results from randomized, controlled trials are needed to strengthen that conclusion.  

Treatments.  Results continue to be encouraging for trials of monoclonal antibody therapies if delivered early in the course of a SARS-CoV-2 infection.  The studies have shown 70% or higher reductions in hospitalization and protection against symptomatic infection if administered prophylactically to those who have been exposed to an infected individual.

Also, three companies (Pfizer, Merck with Ridgeback Biotherapeutics, and Attea in partnership with Roche) are developing oral antiviral drugs that are protease and/or polymerase inhibitors intended to reduce viral replication.  Merck and Ridgeback Biotherapeutics announced preliminary findings from a trial that was stopped early because of favorable results.  The preliminary findings indicate that their experimental oral antiviral drug molnupiravir reduced the risk of hospitalization for Covid-19 from 14.1% to 7.3% (a 48% relative risk reduction).  Merck plans to request Emergency Use Authorization for the drug very soon and approval could come later in the year.  Notably, these antiviral agents may prove to also prevent colds caused by coronaviruses, although more data are needed to confirm this effect.  Coronaviruses are responsible for approximately 25% of common cold cases in the US each year.

Currently, the only antiviral agent approved by the FDA for treating SARS-CoV-2 is remdesivir, which is administered to hospitalized patients via infusion, although an oral version of remdesivir is under study.  The availability of at least one antiviral agent that is effective at shortening the course and reducing the severity of SARS-CoV-2 infection, and that can be taken at home orally, would be a significant advance.

In This Issue

Scientific Contributions

 

Recent Publications

 

SARS-CoV-2/Covid-19 Pandemic

 

Announcements

 

Recent and Upcoming Presentations

 

 

Announcements

 

Kevin C. Maki, PhD was the recipient of the 2021 Honorary Membership Award from the Academy of Nutrition and Dietetics:  Link

 

Kevin C. Maki, PhD was recognized as an Expertscape Expert in Hypertriglyceridemia. A list of these experts is available at: Link

 

Recent and Upcoming

Presentations

 

Kevin C. Maki, PhD will moderate a webinar for the Pacific Lipid Association on “Working with Patients Following Very-Low Carbohydrate and/or Ketogenic Diets” to be held October 27, 2021.

 

An abstract titled “An open-label, crossover study comparing EPA+DPA-free fatty acids and EPA-ethyl esters in adults with elevated triglycerides: ENHANCE-IT” based on an investigation sponsored by Matinas BioPharma and authored by Kevin C. Maki, Harold E. Bays, Christie M. Ballantyne, James A. Underberg, John J.P. Kastelein, Judith B. Johnson, and James J. Ferguson, was presented at the National Lipid Association’s 2021 Annual Scientific Sessions held September 24-26, 2021 in Orlando, FL.

 

Kevin C. Maki, PhD presented two lectures titled “Cardiovascular Outcome Trials: An Update” and “Relationships Between Triglycerides, Non-HDL-C and Cardiovascular Risk” at the National Lipid Association’s 2021 Annual Scientific Sessions held September 24-26, 2021 in Orlando, FL.  Dr. Maki also presented a poster at the meeting titled “An open-label, crossover study comparing EPA+DPA-free fatty acids and EPA-ethyl esters in adults with elevated triglycerides: ENHANCE-IT” based on an investigation sponsored by Matinas BioPharma and authored by Kevin C. Maki, Harold E. Bays, Christie M. Ballantyne, James A. Underberg, John J.P. Kastelein, Judith B. Johnson, and James J. Ferguson.

 

Kevin C. Maki, PhD was a faculty member for the National Lipid Association’s Masters in Lipidology Course held September 22-23, 2021 in Orlando, FL.

 

Kevin C. Maki, PhD presented a plenary session titled “Diet and Prevention of Type 2 Diabetes Mellitus – Beyond Weight Loss and Exercise” at the Indiana University School of Medicine’s Center for Diabetes and Metabolic Diseases Annual Symposium that was held virtually August 6, 2021.

 

Kevin C. Maki, PhD was a faculty member of the American Society of Nutrition’s online course on Best Practices for Human Nutrition RCTs, based on a series of articles that originated from the Nutrition Intervention Research (NURISH) project.  He presented a webinar titled “Data Management Planning and Execution” at the virtual meeting held on July 20, 2021. Access to the course materials is available at:  Link

 

 

 

 

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