lipidspin...4 lipidspin • volume 18, issue 1 • february 2020from the mwla president: branching...

Volume 18 Issue 1 2020visit www.lipid.org

Also in this issue:

Pediatric Metabolic Syndrome – Difficult to Define, Important to Treat

Lipid Metabolism and Cardiovascular Disease in Patients with Renal Disease

Recognition and Treatment for Fabry’s Disease and Morquio A Syndrome

This issue is sponsored by the Midwest Lipid Association.

Lipids Beyond the Cardiovascular Tree

Official Publication of the National Lipid Association

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LIPID SPECIALISTS.Whether your medical discipline is as a physician in Internal Medicine, Cardiology, Endocrinology, or Family Practice, or as a pharmacist, advanced nurse practitioner, nurse, dietitian, or other healthcare professional, earning certification as a Lipid Specialist is your pathway to professional excellence and career opportunities.

The credentialing process and assessment exams ensure that those who gain certification are committed to the highest standards and requirements of professional improvement.

Plus, certification is confirmation that you have the distinct and specialized knowledge, advanced training and level of expertise necessary to deliver superior patient care.

Take the first step today to become a Lipid Specialist. Learn more at:

www.lipid.org/lipidspecialist

Consider this your invitation

to join an elite collection

of certified

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2 From the NLA PresidentYour NLA New Year’s Check-In & Check List— Antonio M. Gotto, Jr., MD, DPhil, FNLA*

4 From the MWLA PresidentBranching Out: The Tree of Lipidology Continues to Grow— Ann Liebeskind, MD, FAAP, FNLA*

5 Editor’s CornerDon’t Miss the Forest for the Trees— Kaye-Eileen Willard MD, FNLA*

6 Clinical FeatureNonalcoholic Fatty Liver Disease: The Hepatic Complication of Metabolic Dysmetabolism— Maya Balakrishnan, MD— David Neff, DO

11 EBM Tools for PracticePediatric Metabolic Syndrome: Difficult to Define, Important to Treat — Kristen A. Marten, DO— Amy L. Peterson, MD*

13 Lipid LuminationsRisk Reduction: DECLARE-TIMI 58 Outcomes— Sara Lynn Peterson, PharmD

15 Practical PearlsRecognition and Treatment for Fabry’s Disease and Morquio A Syndrome— Mrinali Shetty, MD— David Davidson, MD, FACC, FNLA*

17 Case StudyElevated LDL Secondary to Multiple Myeloma— Abigail F. Rabatin, PharmD, BCACP, CLS— Elisa M. Baddour, PharmD, BCACP— Kelly M. Bartsch, PharmD, BCPS, CLS— Laxmi S. Mehta, MD, FACC*

20 Chapter UpdateThe MWLA Three-Year Plan— Ann Liebeskind, MD, FAAP, FNLA*

21 Specialty CornerLipid Metabolism and Cardiovascular Disease in Patients with Renal Disease— Kaveh Rezaei Bookani, MD— David Davidson, MD, FACC, FNLA*— Marlys L. Koschinsky, PhD, FNLA

23 Women’s HealthGuidelines for Lipid-Lowering in Women: What Have we Learned?— Eugenia Gianos, MD, FACC, FASE, FNLA*— Merle Myerson, MD, EdD, FACC, FNLA*— Sasha De Jesus, MD

28 BackspinNew Cholesterol Guidelines: Coronary Artery Calcium Scores a Win— Douglas Jacoby, MD, FNLA*— Michael Ayers, MD

31 Guest EditorialPostprandial Dysmetabolism: Understanding the Impact of Elevated Postprandial Glucose and Triglycerides with the Potential to Prevent or Intervene Early— Kevin Maki, PhD, CLS, FACN, FNLA— Mary R. Dicklin, PhD— Maya Balakrishnan, MD— David R. Neff, DO

34 References

37 NLA Tear SheetStatin Intolerance and What to Do About It

In This Issue: 2020(Volume 18, Issue 1)

EditorsDANIEL E. SOFFER, MD, FNLA*Clinical Associate Professor of MedicineUniversity of PennsylvaniaInternal Medicine and Preventive CardiologyUniversity of Pennsylvania Health SystemPhiladelphia, PA

KAYE-EILEEN WILLARD, MD, FNLA*Medical Director, Lipid Clinic and Physician AdvisorAscension Wisconsin All SaintsRacine, WI

Associate Editors Lori A. Alexander, MSHS, RD, CCRC, CLS, FNLA; Christie M. Ballantyne, MD, FNLA*; Thomas A. Barringer, MD, FNLA*; Carolyn Burns, MD*; Ashley D. Davila, RN, MSN, CNS, CLS, FNLA; Daniel A. Duprez, MD, PhD, FNLA; Debra A. Friedrich, DNP, ARNP, FNP, BC, CLS, FNLA; Raymond A. Gaskins, MD*; Douglas S. Jacoby, MD, FNLA*; Laney K. Jones, PharmD, MPH; Matthew D. Kostoff, PharmD, CLS, FNLA; Spencer D. Kroll, MD, PhD, FNLA*; Merle Myerson, MD, EdD, FNLA*; Hal Roseman, MD, FNLA*; Khalid H. Sheikh, MD, FNLA*; Mark Sherman, MD, FNLA*; Leandro Slipczuk, MD, PhD; and Nathan D. Wong, PhD, FNLA

Executive DirectorBRIAN HART, JD National Lipid Association

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Letter from the NLA President: Your NLA New Year’s Check-In & Check List

I would like to wish everyone a Happy New Year! With the new year upon us and being more than halfway through my term as President, I wanted to thank the membership for the opportunity to provide a reminder of a few key initiatives of the NLA and make sure you complete your 2020 NLA checklist:

• Pay dues – lipid.org/dues/payment

• Recruit a colleague – lipid.org/membership/new-

members

• Register for a meeting – lipid.org/conferences

• Join a committee – lipid.org/contact/question

• Become a Lipid Specialist – lipid.org/lipidspecialist

Membership Recruitment CompetitionThe NLA Membership Recruitment Competition is underway through March 31, 2020. The chapter and individual who recruit the greatest number of new qualifying members will receive a $2,500 award. New members who join prior to March 31, 2020 are included in the calculation. To be eligible to win the individual award, you must recruit at least 10 qualifying members as provided below.

Qualifying Recruits for the Chapter Award of $2,500: All new member applicants, including those eligible for Associate Member status, who have not held an NLA member designation within the last 10 years.

Qualifying Recruits for Individual Award of $2,500: Dues-paying members who have not held an NLA member designation from the NLA within the last 10 years. Associate members, who receive complimentary dues, are excluded from the individual competition, but not the chapter competition.

This is an exciting time for Clinical Lipidology with the development of new

therapies technologies, and educational opportunities. We want you to bring your colleagues into our organization and show them the great value and opportunity within our organization. For more information on the competition, visit lipid.org/refer.

Lipid Specialist & Pursuit of CMS RecognitionThe NLA has started its pursuit of recognition of Lipid Specialist by the Centers for Medicare & Medicaid Services. In our pursuit, we will persuade CMS recognize Lipid Specialist in the taxonomy of medicine and be eligible to bill for payable services using a new provider specialty code. The NLA defines Lipid Specialist as an individual certified by the American Board of Clinical Lipidology (lipidboard.org) or Accreditation Council for Clinical Lipidology (lipidspecialist.org) specializing in the identification and management of dyslipidemia and related metabolic disorders which lead to atherosclerotic cardiovascular disease (ASCVD) and other morbidities, so be sure to certify. For more information, visit lipid.org/lipidspecialist.

Discuss this article at www.lipid.org/lipidspin

ANTONIO M. GOTTO, JR., MD, DPhil, FNLAPresident, National Lipid AssociationDean Emeritus, Weill Cornell MedicineProvost for Medical Affairs Emeritus, Cornell UniversityNew York, NY

Diplomate, American Board of Clinical Lipidology

2 LipidSpin • Volume 18, Issue 1 • February 2020

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Scientific StatementsThe NLA is the international leader in lipidology and we want to stay ahead of the science while also providing value to our membership and the lipid community. Our scientific statement topics are carefully selected to help guide healthcare providers in the rapidly growing landscape of lipidology, and are written by experts in the field. In 2019, the NLA was proud to release the following statements, each available on the NLA website with additional resources at lipid.org/practicetools/documents, on the Journal of Clinical Lipidology website:

• NLA Scientific Statement on the Use of Icosapent Ethyl in Statin-treated Patients with Elevated Triglycerides and High or Very High ASCVD Risk

• Review of Current Evidence and Clinical Recommendations on the Effects of Low-Carbohydrate and Very-Low-Carbohydrate (including Ketogenic) Diets for the Management of Body Weight and other Cardiometabolic Risk Factors

• Use of Lipoprotein(a) in Clinical Practice: A Biomarker Whose Time Has Come.

• Enhancing the Value of PCSK9 Monoclonal Antibodies by Identifying Patients Most Likely to Benefit

You should anticipate the following scientific statements and manuscripts from the NLA in 2020 & beyond:

• Genetic Testing

• Lipid Laboratory Testing

• Dietary Management of Disorders of Lipid and Lipoprotein Metabolism in Youth (<18 years of age)

• Clinical Utility of Coronary Artery Calcium (CAC)

• Statements to Supplement the 2018 Cholesterol Guideline

We look forward to seeing you at one of our conferences in 2020, whether it is the Spring Clinical Lipid Update in Denver, Colorado, the Scientific Sessions in Chicago, Illinois or the Fall Clinical Lipid Update in Washington, DC. Each meeting provides a wonderful opportunity to learn and network in the Clinical Lipidology community. Visit lipid.org/conferences for more information on the 2020 meeting series.

The NLA continues to develop as an organization, and we look to you as the membership to inform us how we are meeting your needs and how we can continue to serve you. Please feel free to contact me at [email protected]. I look forward to hearing from you. n

“Each meeting provides a wonderful opportunity to learn and network in the Clinical Lipidology

community.”

https://www.lipid.org/practicetools/documents

https://www.lipid.org/practicetools/documents

https://www.lipid.org/conferences

mailto:[email protected]


From the MWLA President: Branching Out: The Tree of Lipidology Continues to Grow

While expertise in lipids management has evolved over many decades, our field of lipidology truly took flight in 2006 with the American Board of Clinical Lipidology certification process. Since those early days, we have slowly but steadily raised awareness of the value of the care we provide as lipid specialists. It is likely that each and every one of you has had to explain what a lipid specialist is, or does, more than once in your career. While our role in treating lipid disorders is clear to most, it is much more difficult to detail the many ways that we provide expertise beyond the lipid particle or the cardiovascular tree. This edition of the LipidSpin sheds light on the expanding role we enjoy as lipid specialists, from the increasingly common cases of nonalcoholic fatty liver disease to the less common secondary dyslipidemia of

paraproteinemias or the rare condition of mucopolysaccharidoses. Our breadth of knowledge continues to widen.

While the public often thinks of high cholesterol as a problem of adulthood, we know that is far from the truth. We welcome our pediatric lipid colleagues to the National Lipid Association membership in growing numbers. Their experiences with the struggles in managing inborn errors of metabolism, such as Morquio Syndrome and Fabry’s Disease, give our field important depth and perspective as we look to the future of potential enzyme replacement therapies.

Far more common is the struggle with early insulin resistance and dyslipidemia in children (and adults). While the definition of pediatric metabolic syndrome may be cloudy, our experiences across the age spectrum teach us more and more about the pathophysiology and potential prevention and treatment options. We are certainly entering a new era in the understanding of insulin resistance and the interplay with postprandial dysmetabolism, as so thoroughly discussed in this edition.

This insight brings new opportunities for risk identification and primordial prevention.

We also see a growing toolbox of medication options for lipid specialists. The Lipid Luminations review in this edition turns our attention to the potential utility of SGLT2 inhibitors in risk reduction.

Lipidology looks like a very different field than when I first joined the ranks in 2006. As our field grows wider and deeper, I can’t wait to see what the future holds. Thank you for taking the time to explore this edition of LipidSpin and for helping this dynamic field grow and thrive! n


ANN LIEBESKIND, MD, FAAP, FNLA President, Midwest Lipid AssociationFaculty, Foundations of Lipidology CourseFounder, Mobile Health Team Lipids ClinicAdjunct Assistant Professor of Pediatrics, University of Wisconsin School of Medicine and Public HealthNeenah and Wauwatosa, WI




Editor’s Corner: Don’t Miss the Forest for the Trees

“People who believe they are ignorant of nothing have neither looked for nor stumbled upon the boundary between what is known and unknown in the universe”— Neil deGrasse Tyson

It is a privilege as the co-editor of the LipidSpin to write the Editor’s Corner for the Midwest (MWLA) edition of the journal.

Our membership has come to expect a high calibre, informative and instructive journal to help them with their daily practice of clinical lipidology. Consistent with a theme we have been fostering in the last year or two, this edition captures the significant role of lipid science “beyond the cardiovascular tree.” As an organization, we focus on lipids and lipoproteins, the foundation of atherosclerosis. Major clinical findings in the last few years have highlighted important non-lipid/lipoprotein issues. This MWLA edition of LipidSpin offers an opportunity to turn our focus away from the basics and emphasizes the ways in which lipoproteins are involved in the pathophysiology of disease outside the cardiovascular system.

Dyslipidemia may indeed be a harbinger of disease involving organ systems other thancardiovascular, and this awareness may lead the clinician to earlier diagnosis of conditions such as renal, liver, hematologic diseases, hormonal changes and others.

Neil deGrasse Tyson’s words guide me when I am seeing patients. I know what is known today was not widely known a generation ago, and that I can do more for my patients. I also realize what will be known in another generation will be an improvement from what I offer my patients today.

Recently, I attended a holiday party with former colleagues from my training at University of Washington, and my earlier practice years. In particular, one couple with whom I shared a partnership — a cardiologist and nephrologist — voiced their appreciation of the evolving role of the clinical lipidologist in disease prevention and our potential to impact other aspects of health care. This includes everything from comprehensive patient assessments to our role over time in pre-empting end-stage disease, reducing

suffering and even mitigating healthcare cost. Our work in clinical lipidology gives all of us the opportunity to not miss the ‘forest for the trees’ in our daily patient care interactions, and see that the whole is often greater than the sum of the parts!

We hope you will enjoy the content of this edition of the journal, and our thanks to all the hard work of the contributing authors, editors and staff. n

KAYE-EILEEN WILLARD, MD, FNLAEditor, LipidSpin

Medical Director, Lipid Clinic and Physician AdvisorAscension Wisconsin All Saints

Racine, WI





Clinical Feature: Nonalcoholic Fatty Liver Disease: The Hepatic Complication of Metabolic Dysmetabolism

MAYA BALAKRISHNAN, MDSection of Gastroenterology & HepatologyBaylor College of Medicine Houston, TX

Nonalcoholic fatty liver disease (NAFLD) is the main hepatic complication of obesity, diabetes and metabolic syndrome. Its prevalence has risen dramatically since 1980, when it was a perplexing and sporadically-observed disease as first

reported by Ludwig and colleagues (1), to a current estimated 25% global prevalence.(2) NAFLD represents the leading cause of chronic liver disease and is the second leading indication for liver transplantation in the United States.(3) Its rise parallels the obesity epidemic and is attributed to the concomitant rise in the prevalence of type 2 diabetes and metabolic syndrome. Its strongest risk factors are similar to those of cardiovascular disease (CVD). There is growing evidence that combined postprandial hyperglycemia

and hypertriglyceridemia (postprandial dysmetabolism) are likely to play a significant role toward inducing NAFLD.

More recent evidence utilizing a systems biology and metagenomics approach reveals NAFLD is likely to be a component of a more systemic disease, and the pathophysiology within the liver contributes significantly to overall progression.(4-9) Other organ systems include dysfunction of the adipose tissue, skeletal muscle, pancreas, intestine and central nervous system (Figure 1). The challenge for clinicians, payers and public health officials grappling with the condition is to identify who among those with NAFLD are at greatest necessity to treat.

DISEASE SUBTYPES, NATURAL HISTORY AND COMPLICATIONS NAFLD is fundamentally defined as an abnormal accumulation of hepatic fat in > 5% of hepatocytes. It consists of two main subtypes: simple steatosis and nonalcoholic steatohepatitis (NASH). The two subtypes are defined by specific liver histologic findings, possess different pathophysiological underpinnings and have

DAVID R. NEFF, DOPast President, Midwest Lipid AssociationMichigan State UniversityCollege of Osteopathic MedicineAssociate Clinical ProfessorDepartment of Family & Community MedicineIngham Regional Medical CenterLansing, MI

Figure 1. NAFLD is a component of a multisystemic diseaseAdapted from Int. J. Mol. Sci. 2019, 20, 1948; doi:10.3390/ijms20081948




very different clinical outcomes.

Simple steatosis is characterized by the presence of isolated hepatic steatosis without necro-inflammatory features on biopsy. It is associated with a very low risk of progressive liver disease and liver-related mortality.

NASH is characterized by the presence of hepatic steatosis accompanied by ballooned hepatocytes, which represent inflamed, injured and degenerating hepatocytes. While simple steatosis rarely leads to progressive liver injury, NASH can undergo fibrotic progression and develop into cirrhosis among 20% of affected persons.

The pathogenesis of NASH is complex and is thought to encompass dual or multiple pathogenic hits(10) (Figure 2). The first hit, postprandial dysmetabolism, serves as a permissive factor leading to triglyceride accumulation within hepatocytes. A concomitant second insult, inflammatory and oxidative stress triggers, occurs in

approximately 30% of persons leading to a dysfunctional hepatic response to excess free fatty acids, culminating in the necro-inflammatory form of disease, NASH. The exact nature of the additional hit has not been fully elucidated; however, genetic factors, environmental (i.e. smoking, pollution and the intestinal microbiome), hormonal and dietary factors have been proposed. Advanced glycation end-products (AGE’s) and lipid peroxidation contribute significantly to its progression. Liver fibrosis severity is the strongest independent predictor for all-cause mortality among patients with NASH. Fibrosis is measured histologically using the METAVIR staging system that ranges from 0 (no fibrosis) and increases to stage 4 (which represents hepatic cirrhosis). Retrospective cohort studies have repeatedly demonstrated that overall mortality is increased among patients with advanced fibrosis (stage 3-4) compared with no/early fibrosis (stage 0-2) irrespective of the extent of steatosis,

ballooning and inflammation.

Patients with simple steatosis are at an increased risk of cardiovascular complications compared to patients without NAFLD, particularly if there is concomitant diabetes.(11) NASH is associated with greater risk of cardiovascular complications than simple steatosis, an association that may be explained by shared risk factors.(12) The increased mortality seen among patients with advanced liver fibrosis is also associated with complications of metabolic syndrome, cardiovascular disease, chronic kidney disease and cancer.(13)

DIAGNOSIS Making an initial diagnosis of NAFLD requires meeting two criteria: demonstration of hepatic steatosis (by imaging or liver biopsy) and exclusion of secondary causes of hepatic steatosis or alternate causes of liver disease (Table 1). Abdominal ultrasound is favored for determining the presence of hepatic steatosis. After the presence of hepatic fat is confirmed, a thorough evaluation should be done to exclude alternative causes of hepatic steatosis and chronic liver disease (if elevated liver enzymes are present) as outlined in Table 1. The most frequent secondary causes of hepatic steatosis include hepatitis C infection, excessive alcohol intake and specific medications including amiodarone, tamoxifen, methotrexate and steroids. Multiple causes might be identified but difficult to tease apart.

Elevated liver enzymes are common in NAFLD but not a necessary diagnostic feature. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) typically range from normal to 250 IU/mL, with an AST/ALT enzyme ratio < 1. More significantly elevated liver enzymes should raise the possibility of an alternative

Figure 2. Transition of NAFLD to NASH – The “Two Hit” HypothesisAdapted from Drug Discov Today. 2019 Feb;24(2):560-566. doi: 10.1016/j.drudis.2018.09.020. Epub 2018 Oct 3.


diagnosis and an AST/ALT ratio > 1 may indicate the presence of cirrhosis. ALT and AST levels are not reliable indicators of the presence or severity of NAFLD.(14)

RISK STRATIFICATION Liver biopsy is the gold standard to stratify NAFLD and the only way to identify histologic ballooning to diagnose NASH. However, it is impractical to biopsy everyone with NAFLD. Fortunately, there are reliable noninvasive methods for prediction of advanced fibrosis. Noninvasive testing is used as the first line approach to identify patients at highest risk for advanced fibrosis and biopsy is offered

to select patients who will be offered liver specific therapies.

The NAFLD fibrosis score (NFS) is the best validated and most widely used clinical prediction model. It is a formula consisting of age, body-mass-index, presence of hyperglycemia, AST/ALT ratio, platelet count and albumin (http://nafldscore.com/). An NFS score below -1.455 and above 0.676 identifies patients at a low risk and high risk for advanced fibrosis (F3/F4), respectively. Those in between are considered to be at intermediate risk. Nevertheless, the intermediate category in addition to high risk has been shown to increase the likelihood of liver related events and outcome of death or liver transplantation.(15) When the NFS score is used to choose candidates for liver biopsy, an intermediate or high risk scores (NFS score > -1.455) is used as the threshold for liver biopsy.

Transient elastography (TE) is a noninvasive ultrasound-based technique that uses mechanical vibrations to correlate increasing liver stiffness with worsening

liver fibrosis. TE can be performed in an office setting and has reasonably good accuracy for predicting advanced fibrosis. However, its use is limited in persons with BMI ≥35kg/m2. Magnetic resonance elastography is more reliable than TE for estimating liver fibrosis and can be used in the setting of morbid obesity, but it may not be widely available at all centers.

TREATMENTThe contemporary management of NAFLD should consist of treating liver disease as well as the associated metabolic comorbidities. Pharmacological treatments target primarily biopsy-proven NASH and fibrosis. Treatment considerations from the 2018 Practice Guidance from the American Association for the Study of Liver Disease (AASLD) and more recent literature reviews are provided below.(4,16-19)

Promote Healthy Lifestyle - Weight Loss, Diet and Exercise Weight reduction is the cornerstone of therapy. A loss of 5% of the patient’s baseline weight is associated with

Cause Method of Screening Abnormal values that should trigger further workup for alternative causes of liver disease

Alcohol History Heavy alcohol use defined as:> 21 drinks/week for men> 14 drinks/week for women for ≥ 2 years

Medications Medication review for:amiodarone, tamoxifen, corticosteroids, methotrexate, valproate, highly active anti-retroviral therapy

Positive medication review

Infections Hepatitis C antibodyHepatitis B surface antigen, Hepatitis B core antibodyHIV

Positive serology

Wilson’s Disease(screen patients < 45 years)

Cerruloplasmin Cerruloplasmin < 20mg/dL

Autoimmune Hepatitis Anti-nuclear antibodysmooth muscle antibody

Positive serology

Iron Overload FerritinTransferrin saturation

Transferrin saturation > 45%

Table 1. Secondary causes of hepatic steatosis and liver disease - workup

“ALT and AST levels are not reliable indicators of the

presence or severity of NAFLD.”

http://nafldscore.com/

http://nafldscore.com/


reduction in hepatic steatosis, 7% with improvement in NASH histology, and 10% with fibrosis regression. A combination of a hypocaloric diet (daily reduction by 500-1,000 kcal) and moderate-intensity exercise is likely to provide the best likelihood of sustaining weight loss over time. While firm recommendations regarding specific dietary patterns are lacking, the Mediterranean diet is the most suggested for patients with NAFLD. Exercise alone in adults with NAFLD may prevent or reduce hepatic steatosis, but its ability to improve other aspects of liver histology remains unknown.

Control Factors That Degrade Hepatic and Overall Health - Smoking, Alcohol and Infectious DiseaseSmoking is linked to progression of fibrosis so cessation should be strongly encouraged. Alcohol exposure may

exacerbate NAFLD related liver disease and increase the risk of cirrhosis. There are insufficient data to make concrete recommendations with regard to how much alcohol use is safe among individuals with NAFLD. Therefore, in clinical practice, the approach is to counsel patients regarding the risk of concomitant alcohol exposure and NAFLD and to advise alcohol avoidance. In addition, all patients with NAFLD should be vaccinated for hepatitis A and B to minimize risk of additional hepatic injury.

Manage Risk Co-Factors for CVD and CKDPatients with NAFLD are at high risk for cardiovascular and renal morbidity and mortality. Along with lifestyle changes, aggressive glucose, blood pressure and lipid management should be considered in all patients with NAFLD.

Surgery - Bariatric Surgery and Liver TransplantNAFLD is not an indication for bariatric surgery. More investigation is required to understand the full clinical utility of bariatric surgical management for management of NAFLD. However, foregut bariatric surgery can be selectively considered in otherwise eligible obese individuals with NAFLD but without advanced cirrhosis. Liver Transplant is Class 1-A indication for advanced decompensated NASH cirrhosis.

Pharmacologic TherapyCare should be taken to avoid adverse effects of drugs that could potentially injure the liver, kidney or heart. Overall, solid data for existing drugs is lacking so care should be taken until further evidence is obtained.

Vitamin E Vitamin E (a-tocopherol) administered at a daily dose of 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH and therefore may be considered for this patient population. Vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis or cryptogenic cirrhosis.

Management Hepatic Steatosis NAFLDCirrhosis

secondary to steatohepatitis

Weight loss Yes(5% weight loss)

Yes(7-10% weight

loss)Yes

Dietary modification Yes Yes Yes

Exercise Yes Yes Yes

Alcohol Avoidance Yes Yes Yes

Hepatitis A and B vaccination Yes Yes Yes

Pharmacological treatment for steatohepatitis

No Yes No

Screening for hepatocellular carcinoma

No Need better data on risk prediction Yes

Screening for varices No No Yes

Bariatric surgery If morbidly obese If morbidly obeseIn select patients without advanced

cirrhosis

Liver transplantation No NoFor advanced

decompensated cirrhosis

Table 2. Management of NAFLD

“The disease spectrum of NAFLD

encompasses a wide range of patients,

and it will continue to represent a growing

public health burden of epidemic proportion.”


Target Molecule Status

Peroxisome proliferator-activated receptor (PPAR) a/δ agonist Elafibranor (GFT505) Phase III

Farnesoid X receptor (FXR) ligand Obeticholic acid (OCA) Phase III

Non-steroidal farnesoid X receptor (FXR) agonist Cilofexor (GS-9674) Phase II

The thyroid hormone receptor β (THRβ) agonist Resmetirom Phase III

C-C motif chemokine receptor-2/5 (CCR2/5) antagonist Cenciviroc CVC) Phase III

Apoptosis signal-regulating kinase 1 (ASK-1) inhibitor Selonsertib (SEL) Phase III

Galectin-3 protein inhibitor Galactoarabino-rhamnogalaturonan (GR-MD-02) Phase II

Steroyl-CoA desaturase-1 inhibitor Aramchol Phase II

Fibroblast Growth Factor 19 (FGF19) analogue NGM282 Phase II

Pegylated Fibroblast Growth Factor 21 (FGF21) analogue Pegbelfermin (BMS-986036) Phase II

Acetyl-CoA carboxylase (ACC) inhibitor Firsocostat Phase II

β-Klotho/FGFR1c receptor complex agonist monoclonal antibody MK-3655 Phase II

Integrin aVβ1 inhibitor PLN-1474 Preclinical

Table 3. Drugs in Development to Treat NASH

Diabetes AgentsPioglitazone, a PPAR-γ agonist, improves liver histology in patients with and without T2DM with biopsy-proven NASH. However, heart failure, fluid retention, subcutaneous fat weight gain, bone demineralization and anemia are known adverse effects. At this time, pioglitazone should be used to only treat biopsy-proven NASH. GLP-1 agonists are promising agents but cannot specifically be recommended for NASH at this time. Metformin and other antidiabetic agents are not recommended specifically to treat NAFLD or NASH but may be used if otherwise indicated.

Statins and Other Lipid Lowering Agents Patients with NAFLD or NASH are not at higher risk for serious liver injury from statins, so they can be used to treat dyslipidemia in patients with NAFLD and NASH. However, they should be avoided with decompensated cirrhosis. Fenofibrate, a PPAR a agonist, may convey benefit but further studies are required. Ezetimibe and omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but

they may be considered in patients with dyslipidemias. Initial studies evaluating PCKS9 Inhibitors are promising but no recommendation can be made.

Weight Loss AgentsOrlistat and other weight loss drugs are not recommended to specifically treat NASH.

Future Drugs in Development While lifestyle intervention can reverse NASH and fibrosis, only a minority of patients can achieve sufficient weight reduction and histological improvement. A variety of drug targets are being pursued (Table 3) both as monotherapy and in combination with 2-3 other agents. At present, five drugs have entered phase 3 development for the treatment of NASH, but the selonsertib Phase 3 program has been recently discontinued.

CONCLUSIONThe disease spectrum of NAFLD encompasses a wide range of patients, and it will continue to represent a growing public health burden of epidemic proportions. Prevention and lifestyle

management are still the foundation of current therapy. Therapies aimed at controlling metabolic syndrome and reducing cardiovascular and renal risk should be utilized throughout all stages for NAFLD and NASH. Unfortunately, the current therapies have limited efficacy, although sustained weight loss can alter the natural history of disease. Although all patients with NAFLD should receive thoughtful clinical and supportive care, patients with NASH should be treated more aggressively, due to the natural course of this disease. Future pharmacologic strategies to treat NASH are underway with the first new agent being potentially released in 2020. They will target metabolic pathways that impact insulin sensitivity, fatty acid synthesis and oxidation, and various mechanisms that decrease inflammation and fibrosis. Ultimately, the horizon is bright for better and more precise treatment options. n

Disclosure statement: Dr. Balakrishnan received honoraria from Intercept, Gilead, and Ebix Reviews. Dr. Neff has no financial disclosures to report.

References are listed on page 34.


Although there is debate over the definition of metabolic syndrome in adults, the picture is even more clouded in pediatrics. Metabolic syndrome in adults is defined as having at least three of the following five cardiometabolic risk factors: hyperglycemia, increased central adiposity, elevated triglycerides, decreased HDL cholesterol and elevated blood pressure.(1) In pediatrics, there have been up to 40 definitions of metabolic syndrome proposed. The most commonly used definitions are quite similar to the adult definition; the primary difference is that only two criteria are needed (see Table

1).(2,3) Typically, metabolic syndrome in children is not formally diagnosed until the age of 10, but many children have risk factors which can and should be addressed prior to a formal diagnosis.(2)

The prevalence of pediatric metabolic syndrome is about 4%, but this is heavily dependent on the definition used. Not surprisingly, the prevalence is higher in overweight and obese children (33%). In pediatrics, obesity is defined as a BMI greater than the 95th percentile based on age and gender. Approximately 1% of children with normal weight have

metabolic syndrome, but up to 1/3 of normal weight children will have at least one of the components of metabolic syndrome.(4) Mexican American teens have the highest rate of metabolic syndrome at 5.6%, followed by African Africans and those of European ancestry at 4.8% and 2%, respectively.(5) Although the rate of metabolic syndrome has remained stable over recent years, obesity continues to trend upward, placing many children at risk.(4,6,7) Other risk factors for the development of pediatric metabolic syndrome are shown in Table 2.(3)

Rather than debating the exact definition of pediatric metabolic syndrome, some organizations have proposed that the focus should be on identifying and treating specific cardiometabolic risk

EBM Tools for Practice: Pediatric Metabolic Syndrome: Difficult to Define, Important to Treat

KRISTEN A. MARTEN, DODepartment of Pediatrics

University of Wisconsin School of Medicine and Public Health

Madison, WI

AMY L. PETERSON, MDDepartment of Pediatrics

University of Wisconsin School of Medicine and Public HealthMadison, WI


Diagnosis of Metabolic Syndrome

Adult Criteria3+ criteria

Pediatric Criteria2+ criteria

WC > 102 cm (men) or 88 cm (women) WC ≥ 90th percentile for age and gender

Triglycerides ≥ 150 mg/dL Triglycerides ≥ 150 mg/dL

HDL-C < 40 (men) or < 50 (women) HDL-C < 40 mg/dL

Systolic BP > 130 mmHg or > 85 mmHg diastolic

Systolic BP ≥ 130 or diastolic ≥ 85 mmHg

Fasting glucose ≥ 100 mg/dLOr known T2DM

Fasting glucose ≥ 100 mg/dLOr known T2DM

Table 1. Diagnostic criteria for adult and pediatric metabolic syndrome. Pediatric criteria established for ages 10-16. Adolescents over age of 16 are diagnosed based on adult criteria. The most common lab abnormalities in children ages 10-16 were elevated triglycerides and low HDL-C.(1,3,5,18) WC = waist circumference, BP = blood pressure, T2DM = Type 2 Diabetes Mellitus




factors. Regardless of the definition, the constellation of findings known as metabolic syndrome has significant implications for lifelong health including: increased risk of heart attack and stroke in adulthood as well as polycystic ovarian syndrome, obstructive sleep apnea, and type II diabetes.(3) Studies show that pediatric metabolic syndrome increases the risk of adulthood metabolic syndrome by 6 fold (Odds Ratio 6.2 [CI 2.8-13.8, p<0.001]) and cardiovascular disease in adulthood almost 15 fold (OR 14.6 [CI 4.8-45.3, P<0.0001]).(8) Regardless of the diagnosis, cluster tracking studies revealed that cardiovascular risk factors in childhood persist into adulthood in 25-60% of cases.(5)

What makes pediatric metabolic syndrome different from adult metabolic syndrome has been explored. Childhood is a period of rapid growth with physiologic fluctuations in lipid levels and insulin resistance. Many children defined as having metabolic syndrome do not meet diagnostic criteria 3-6 years later, although their metabolic risk factors remain consistent.(9) One study found that the diagnosis of metabolic syndrome was unstable in up to 1/3 of pediatric cases.(10) Due to this constant flux, the terms “metabolically healthy” or “metabolically unhealthy” in the obese pediatric population rather than “metabolic syndrome” are occasionally used. Unfortunately, “metabolically healthy”

status in a prepubertal child does not guarantee a healthy child during or after puberty. Puberty is a period of natural insulin resistance and increases a child’s risk of developing metabolically syndrome, independently of a child’s BMI.(9,11-14) Alternatively, some children with risk factors during puberty may have normal findings at the end of puberty without intervention.(11,12) Obesity has been found to be a more stable trait throughout childhood, although waist circumference ≥ 90th percentile for age and gender better predicted cardiometabolic risk than BMI percentile alone.(15) Obesity does not guarantee the presence of cardiovascular risk factors, but it should prompt further investigation.

Ultimately, efforts should focus on identifying non-modifiable cardiometabolic risk factors, including birth history and family history, and treating lifestyle factors such as diet, physical activity, and sleep

habits.(3, 16) Despite the disagreement on definition, it is well established that prevention and treatment of obesity is the first line approach to minimizing a child’s risk.(12) Lifestyle interventions of diet and exercise modification have been shown to produce significant improvements in obesity, LDL cholesterol, triglycerides, fasting insulin and blood pressure. Some studies have shown that this can be maintained, but data are mixed.(14) In pediatrics, involvement of the entire family is critical for success, and establishing regular family meal times, limiting “screen time” and group physical activity are key interventions for lasting lifestyle modifications.(14,17)

In summary, the definition of metabolic syndrome in children is elusive, but the long-term risks are not. As health care providers, our focus should be on identifying pediatric patients and their families with risk factors and providing the tools they need to protect their health. If we do not look for it, we will not find it. n

Disclosure statement: Dr. Marten has no financial disclosures to report. Dr. Peterson has no financial disclosures to report.


Pediatric Metabolic Syndrome Risk Factors

Non-modifiable Modifiable

Maternal gestational diabetes Excessive screen time

Low birth weight (with rapid catch-up growth) Low physical activity

Family history of obesity Short sleep duration

Family history of atherosclerotic CVD Lack of fiber intake

Socioeconomic status Intake of sugar sweetened beverages

Hispanic ethnicity Tobacco exposure

Table 2. Risk factors associated with development of metabolic syndrome in children (3, 19-24)

5 ways to prevent AND treatpediatric metabolic syndrome

1. Limit sugar sweetened beverages

2. Aim for 7-9 hours of sleep 3. Don’t eat in front of a screen4. Be active every day5. Incorporate fiber in your diet

every day


Lipid Luminations: Risk Reduction: DECLARE-TIMI 58 Outcomes

SARA LYNN PETERSON, PharmDComplex Lipids Clinic

Mobile Health TeamNeenah, WI

Results from multiple trials prompted the Food and Drug Administration’s (FDA) approval of empagliflozin (Jardiance) for reducing cardiovascular (CV) death and canagliflozin (Invokana) for reducing CV death and CV events, in patients with cardiovascular disease and type II diabetes (T2D).(1-6) The FDA’s expanded approval of empagliflozin and canagliflozin led to the American College of Cardiology (ACC) and the American Diabetes Association (ADA) incorporating sodium–glucose cotransporter 2 (SGLT2) inhibitors into decision pathways for patients with T2D and atherosclerotic cardiovascular disease (ASCVD).(7,8) These pathways create a renewed focus on clinicians utilizing all available comprehensive CV risk reduction strategies.

Wiviott et al. (2019) questioned the CV benefits of the third SGLT2 inhibitor, dapagliflozin, in the randomized, double-blinded, placebo-controlled trial, dapagliflozin (Farxiga) Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58).(9) We review the findings of DECLARE-TIMI 58 and its implications in clinical practice.

DECLARE-TIMI 58 included 17,160 patients with T2D, of which, 10,186 (59.4%) were without established ASCVD.(9) Patients with T2D and a creatinine clearance (CrCl) of 60 mL or more per minute, who also had multiple risk factors for ASCVD or established ASCVD, were eligible and followed for a median of 4.2 years. The primary safety outcome was a composite of major adverse CV events (MACE), defined as CV death, myocardial infarction or ischemic stroke. Researchers added two efficacy outcomes after results of another SGLT2 inhibitor trial were released: MACE and a composite of CV death or hospitalization from heart failure (HF).(1) Secondary efficacy outcomes were death from any cause and a renal composite (≥40% decrease in estimated glomerular filtration rate to < 60 mL per minute, new end-stage renal disease, or death from renal or CV causes).

DECLARE-TIMI 58 did not show a significant reduction in MACE between treatment (dapagliflozin 10 mg daily) and placebo groups (8.8% and 9.4%, respectively; P = 0.17) but did in reduction of the composite end point of CV death or hospitalization for HF (4.9%

vs. 5.8%, respectively; P = 0.005).(9) The significant reduction of the latter was attributed to a lowered hospitalization rate for HF in the treatment group (hazard ratio [HR], 0.73; 95% CI, 0.61 to 0.88). No difference between groups was found for CV death alone (HR, 0.98; 95% CI, 0.82 to 1.17).

The primary safety outcome reported noninferiority of the treatment group to placebo (P <0.001).(9) Safety results include no evidence of a higher risk of stroke, amputations, Fournier’s gangrene or fractures with dapagliflozin than with placebo. As previously reported with SGLT2 inhibitors, a higher incidence of ketoacidosis and genital infections with dapagliflozin was noted.(2,10)

Secondary outcomes showed no significant difference in rate of death from any cause




(HR, 0.93; 95% CI, 0.82 to 1.04) but renal composite outcome was significant with 4.3% in the dapagliflozin group and 5.6% in the placebo group (HR, 0.76; 95% CI, 0.67 to 0.87).(9)

With other SGLT2 inhibitor trials reporting reductions in MACE and CV death, one could point to differences between drugs within the class, but differences in eligibility criteria between trials (i.e. DECLARE-TIMI 58 excluded patients with CrCl < 60 mL per minute and majority were without clinical ASCVD) and the change in primary outcome without increase in sample size (possibly reducing statistical power) may account for the lack of reduction in MACE and CV death.(1,2,9)

The ACC’s “Expert Consensus Decision Pathway” pushes us out of our comfort

zone and into shared decision making to tackle residual risk.(7) Despite DECLARE-TIMI 58 CV results inconsistency with other SGLT2 inhibitor trials, SGLT2 inhibitors are now part of our toolbox and how integral they become is still unclear.(1-6) This trial and others have created a drive for knowledge and pursuit of new FDA approvals as six trials are currently evaluating safety and efficacy in HF and chronic kidney disease in patients with and without T2D.(7,11) n

Disclosure statement: Dr. Peterson has no financial disclosures to report.



Practical Pearls: Recognition and Treatment For Fabry’s Disease and Morquio A Syndrome

MRINALI SHETTY, MDCardiology Fellow-In-Training

University of Chicago (NorthShore) ProgramEvanston, IL

Fabry’s Disease and Morquio A syndrome are two rare genetic diseases that lead to a diverse series of problems including cardiovascular.(1,30) Until recently, treatment options have been limited to treat these conditions. Now that there are available therapies to help improve quality and quantity of life, (20,46) it is important to be able to recognize these conditions in clinical practice to help initiate treatment earlier. The goal of this “Practical Pearl” is to help identify these conditions earlier to help improve patient outcomes.

Mucopolysaccharidoses (MPA) type IV A, also known as Morquio A syndrome, is an autosomal recessive inherited deficiency of the lysosomal enzyme N-acetylegalactosamine-6-sulphate sulphatase (GALNS). The syndrome is characterized by the accumulation of keratan sulphate and chondroitin-6-sulphate.(1,2) The presentation ranges from mild to severe phenotypes due to over 220 mutations linked to the GALNS gene on chromosome 16q24.3.(3-5) Given its rarity, it is common for diagnosis to be delayed or missed with reported incidence ranging from 1 in 76,000 to 1 in 640,000

live births.(6-8)

Infants usually appear normal at birth and develop signs and symptoms over time due to the accumulation of glycosaminoglycans in organs. The condition is characterized by skeletal dysplasia. Findings include a short stature, odontoid hypoplasia, cervical spinal cord compression, pectus carinatum, abnormal gait, hypermobile joints, genu valga, platyspondyly, kyphoscoliosis, thickened heart valves and preserved intellect.(9-14) Left ventricular hypertrophy is associated with a decrease in stroke volume and compensatory higher resting heart rates, which should be allowed to remain elevated to help preserve cardiac output.(15) Spinal cord injury and respiratory failure result in significant mortality with patients often becoming wheelchair dependent in the second decade and not surviving past the third decade of life.(16,17) Given the progressive nature of the disease, early referral to a genetic center for definitive diagnosis is crucial in optimizing patient outcomes. Enzyme activity testing in dried blood and urinary glycosaminoglycan testing may serve as screening tools but

definitive diagnosis is by demonstration of reduced GALNS activity in fibroblasts or leukocytes. In cases with strong clinical suspicion for the disease but inconclusive enzyme results, molecular analysis clinches the diagnosis.(15,18)

Until recently, treatment for Morquio A syndrome was supportive and symptom-driven. However, the approval of enzyme replacement therapy with elosulfase alpha, a recombinant human GALNS administered as weekly infusions, has proven to be effective with a favorable safety profile. Treatment should be implemented as soon as diagnosis is confirmed.(15,19-21) Valve replacement surgery may be considered per standard guidelines.(22,23) Anesthesia for surgery should be carried out by an anesthesiologist familiar with the disease

DAVID DAVIDSON, MD, FACC, FNLA Director, Lipid Clinic

NorthShore University Health System Clinical Instructor

University of ChicagoChicago, IL





as deposition of mucopolysaccharides in the oro-pharynx complicates intubation and atlanto-axial instability raises the risk of subluxation and quadriparesis.(24)

Fabry’s disease is an X-linked lysosomal storage disorder caused by the deposition of globotriaosylceramide (ceramide trihexoside), a lipid material, throughout the body. This is due to deficiency of the enzyme alpha-galactosidase.(25,26)Males are more commonly and severely affected than females who usually manifest at a later age.(27) Carrier females may remain asymptomatic or manifest as full-blown disease.(28) The incidence of the classic manifestation of Fabry’s disease is reported to be 1:22,000 to 1:40,000 in males.(29-31) Glycosphingolipid accumulation in vascular endothelium results in ischemia and infarction (systemic, but uniquely effects the renal vasculature) culminating in early death.

Signs and symptoms may appear in childhood or adolescence and include acroparesthesias (pain in the extremities), “Fabry’s crises” of episodic acute pain, characteristic angiokeratomas on the skin with hypohydrosis, intolerance to extremes of temperature and proteinuria.(32-34) These patients develop left ventricular hypertrophy, valvular and coronary artery disease, arrhythmias, ascending aortic aneurysms and heart failure.(35-37) Progressive renal ischemia and dysfunction lead to dialysis dependence by the fifth decade of life.(38)

Given the spectrum of manifestations, diagnosis is often delayed. Clues to diagnosis include renal failure, cardiomyopathy with left ventricular hypertrophy, arrhythmias, heat intolerance, corneal opacities, obstructive pulmonary disease and hearing loss.(39) Initial testing includes obtaining a a-Gal A enzyme level, which if markedly deficient or absent in a

male patient is diagnostic. Female carriers may have a normal a-Gal A assay and thus should undergo molecular testing.(40) Once diagnosis is established, referral to a genetic counselor should be made to educate the patient on the course of the disease, its inheritance and treatment options including enzyme replacement therapy. Prenatal testing for a-Gal A activity can be performed on cultured amniocytes or chorionic villi.(41)

Before the development of enzyme replacement therapy (ERT), the management of Fabry’s disease was supportive and symptom-driven. Blood pressure control is essential to reduce cardiovascular, renal and cerebrovascular disease. Given there is evidence to support this is a prothrombotic state, anti-platelet agents can be considered.(42) Pain is usually the earliest manifestation and is refractory to non-steroidal anti-inflammatory agents, which may conversely hasten renal dysfunction.(43,44) Renal failure is the most common cause of death in classic Fabry’s disease and dialysis or renal transplant can prolong life. Transplanted kidneys do not develop the disease.(45)

Enzyme replacement therapy in Fabry’s disease is an area of active research. Therapy should be initiated as soon as the diagnosis has been established. Two preparations of human a-Gal A are available – gene-activated human a-Gal A (Replagal) and recombinant human a-Gal A (Fabrazyme). Both proteins have been found to be similar in structure, tolerability and activity.(46) The goal of treatment with ERT is to halt progression of the disease. Early trial data has been encouraging and clinical experience with Gaucher’s disease supports this.(47,48) The availability of ERT has put a new focus on the prompt recognition and diagnosis of Fabry’s disease.

In summary, these are two rare conditions related to abnormal accumulation of material related to enzyme deficiencies. We should be aware of these conditions and the features that can prompt an earlier diagnosis. We now have treatments beyond supportive care that show promise in treating these conditions, which makes earlier diagnosis and intervention even more important. n

Disclosure statement: Dr. Shetty has no financial disclosures to report. Dr. Davidson has received honoraria from Amgen, Sanofi, Regeneron, Akcea, and Esperion.


“Before the development of

enzyme replacement therapy (ERT), the management of Fabry’s disease

was supportive and symptom-driven.”


Case Study: Elevated LDL Secondary to Multiple Myeloma

KELLY M. BARTSCH, PharmD, BCPS, CLS

Specialty Practice Pharmacist Ambulatory Care

The Ohio State UniversityWexner Medical Center

Columbus, OH

LAXMI S. MEHTA, MD, FACC Director of Preventative Cardiology& Women’s Cardiovascular Health

Director of Lipid ClinicsProfessor of Medicine

The Ohio State University Wexner Medical Center

Columbus, OH


ABIGAIL F. RABATIN, PharmD, BCACP, CLS

Specialty Practice PharmacistAmbulatory Care

The Ohio State University Wexner Medical Center

Columbus, OH

ELISA M. BADDOUR, PharmD, BCACP Primary Care Pharmacy Specialist

Cleveland ClinicCleveland, OH

IntroductionElevated cholesterol is a well-known and modifiable risk factor for cardiovascular disease. Hyperlipidemia due to secondary causes is common and should be evaluated as part of treatment. Potential secondary causes include diabetes mellitus, excessive alcohol intake, cholestatic liver disease, hypothyroidism, chronic kidney disease, nephrotic syndrome and various classes of medications.(1)

Multiple myeloma is a malignant neoplasm characterized by proliferation of plasma cells producing a monoclonal gammopathy. Monoclonal proteins proliferate in the bone marrow and spill out into the urine or serum. Presenting symptoms frequently include weight loss, anemia, bone pain, hypercalcemia and renal impairment. Multiple myeloma can lead

to the development of osteolytic lesions, hyperviscosity syndrome and renal failure. In most patients with multiple myeloma, the serum lipid levels are either normal or decreased.(2-4) Nevertheless, there are reports of multiple myeloma accompanied with hyperlipidemia, referred to as hyperlipidemic myeloma. The mechanisms leading to hyperlipidemia in patients with multiple myeloma are not well understood, although paraproteins appear to play an important role. Potential hypotheses include: decreased lipid degradation due to paraproteins complexing with lipoproteins, impaired lipolytic activity and paraprotein binding the LDL receptor inhibiting clearance.(5)

We describe a case of a patient presenting with marked increase in LDL as the initial sign of multiple myeloma, with subsequent

improvement in lipids after diagnosis and treatment of multiple myeloma.

Case PresentationThe patient is a 72-year-old male with a past medical history of hyperlipidemia, hypertension, frequent premature ventricular contractions, osteoarthritis and hypothyroidism. Initial referral to lipid clinic was for marked increase in cholesterol over the course of one year. Prior to the presentation, the patient’s




cholesterol had been monitored by his primary care physician without need for medical therapy. Historically, his total cholesterol (TC) ranged from 150-217 mg/dL (3.88-5.61 mmol/L) with low-density lipoprotein cholesterol (LDL-C) ranging from 87-133 mg/dL (2.25- 3.44 mmol/L) over a span of fifteen years.

As seen in Table 1, prior to referral to lipid clinic, LDL-C had increased from 133 mg/dL to 252 mg/dL in the span of one year, and a lipid panel rechecked two weeks later demonstrated similar elevations. TSH remained within normal limits at 0.326 uIU/mL. The patient denied any changes in medications, diet, illnesses or exercise habits. He was started on atorvastatin 80mg daily by his primary care physician.

Labs were repeated after three months on atorvastatin, with a 55% reduction in LDL-C to 156 mg/dL. However, patient’s ALT increased from 40 to 127 U/L after initiation. Therefore, he was advised by his primary care physician to hold atorvastatin and he was referred to Lipid Clinic.

Physical examination was negative for xanthomas. The hepatic panel was repeated with improvement in ALT to 56 U/L. Given that ALT was less than three times the upper limit of normal at its peak, and his total bilirubin remained normal, atorvastatin 80mg daily was resumed in accordance with the NLA 2014 Statin Safety Task Force.(6) Additionally, ezetimibe 10mg daily was added to the regimen for additional LDL-C lowering

based on previous patient response to atorvastatin. Concurrently, a right upper quadrant ultrasound and 24-hour urine were ordered to further assess for altered hepatic function and nephrotic syndrome. The right upper quadrant ultrasound revealed hepatic steatosis with no biliary ductal dilatation or obstruction. However, the 24-hour urine collection demonstrated 3g proteinuria, and the patient was referred to Nephrology.

The evaluation revealed predominantly non-albumin proteinuria, ultimately attributed to light chains. Urine electrophoresis demonstrated lambda band restriction, serum free light chains (1,474 mg/dL) and significantly elevated monoclonal lambda protein (2,073 mg/dL), concerning for multiple myeloma. The patient was subsequently referred to Hematology/Oncology. After further labs, positron emission tomography scan, and bone marrow biopsy, the diagnosis of IgG lambda multiple myeloma was confirmed and the patient was initiated on chemotherapy with seven cycles of bortezomib, lenalidomide and dexamethasone (VRD).

He returned to Lipid Clinic after approximately two months of chemotherapy. In the interim, no changes were made to lipid lowering therapy. Most recent labs after reduction in paraproteins in response to chemotherapy demonstrated further improvement of his lipid panel: LDL-C 42 mg/dL, TC 106 mg/dL, high density lipoprotein cholesterol (HDL-C) 38 mg/dL, and triglycerides 131 mg/dL. Atorvastatin 80mg daily and ezetimibe 10mg daily were continued with a plan to discontinue ezetimibe at next visit if labs remained stable.

At his Lipid Clinic follow up visit six months later, the patient had completed induction chemotherapy (seven cycles of VRD) and remained on lenalidomide and

11/2016 11/2017 12/2017 2/2018

Total Cholesterol (mg/dL) 201 347 381 241

HDL-C (mg/dL) 39 34 35 34

Triglycerides (mg/dL) 146 304 335 256

LDL-C (mg/dL) 133 252 279 156

Alanine Aminotransferase 40 127

Table 1. Patient’s lab results

133

252

279

156

93

4228

LDL

(mg/

dL)

Baseline 12 mo later 2 wks later On Atorva80mg

Plus ezetimibe10mg

After 2 moinduction chemo

On maintenance chemo

Figure 1. Patient’s LDL cholesterol trends on medication therapy and during chemotherapy


dexamethasone maintenance therapy. Protein studies had normalized (Table 2) and patient’s lipid panel improved further: LDL-C 28 mg/dL, TC 90 mg/dL, HDL-C 44 mg/dL, and triglycerides 88 mg/dL. Ezetimibe was discontinued. See Figure 1 for a trend of the patient’s LDL-C cholesterol with medication therapy and during chemotherapy.

DiscussionAlthough patients with multiple myeloma typically present with a variety of systemic symptoms, elevated LDL is not known to be a common initial indicator of disease. Hyperlipidemic myeloma is a rare variation of multiple myeloma and little is known about its pathophysiology.

Misselwitz and colleagues published a case report and comprehensive review of 52 additional cases of hyperlipidemic myeloma. This report analyzed risk factors associated with hyperlipidemic multiple myeloma, as well as possible mechanisms for this rare presentation. They identified several commonalities in these patients as compared to multiple myeloma with a normal lipid panel. The majority of hyperlipidemic patients demonstrated IgA myeloma (53% vs. 21% with usual multiple myeloma) and these patients commonly present with cutaneous xanthomas (70%). Our patient presented with IgG lambda multiple myeloma and no cutaneous xanthomas. Of note, Misselwitz and colleagues reported that 42% of the hyperlipidemic cases included patients with IgG multiple myeloma, but when compared to 1,027 index cases of multiple myeloma, this incidence did not differ significantly from usual myeloma.(7) Additionally, it was noted that cholesterol levels were lower in IgG multiple myeloma than IgA.(5) For the majority of patients included within the case reports, the diagnosis of multiple myeloma preceded the diagnosis of hyperlipidemia, while in our patient the opposite occurred.

Misselwitz and colleagues also noted “a striking correlation between paraprotein and lipid concentrations in their case, with improvement in lipids with successful anti-myeloma chemotherapy. Our patient demonstrated a similar response, with only modest improvement with a combination of maximum dose atorvastatin and ezetimibe. However, after seven cycles of VRD and normalization of monoclonal proteins, he achieved an additional 65% LDL-C reduction.

Many of the cases presented in the literature conducted further testing of hyperlipidemic multiple myeloma patients’ blood to determine potential mechanisms of this phenomenon. Physical binding of paraprotein to lipoprotein occurred in 24/32 cases tested. In another analysis of six patients, all samples demonstrated an extended half-life for lipoproteins. More detailed testing is not readily available at our institution, so the patient was unable to undergo further analysis.

Although multiple myeloma is not a common cause of hyperlipidemia, it is

important to remain mindful that this could be a possibility with several different presentations, as seen in the literature and with this patient, and may require further workup in order to diagnose and treat this underlying cause. Our patient did achieve a moderate reduction in his lipids with standard medical therapy, with further subsequent improvement after treatment of his previously undiagnosed multiple myeloma. n

Disclosure statement: Dr. Rabatin has no financial disclosures to report. Dr. Bartsch has no financial disclosures to report. Dr. Baddour has no financial disclosures to report. Dr. Mehta has no financial disclosures to report.


Baseline 2 months after chemotherapy initiation

9 months after chemotherapy initiation

Serum Kappa Free Light ChainsReference Range: 3.9 - 26.0 mg/L

15.7 25.2 15.4

Serum Lambda Free Light ChainsReference Range: 6.4 - 22.1 mg/L

4,536.1 (H) 60.4 (H) 15.2

Serum Kappa/Lambda RatioLatest Ref Range: 0.51 - 1.72

0.00 (L) 0.42 (L) 1.01

IgG Reference Range: 600 - 1,560 mg/dL

2,089 (H) 749 701

IgA Reference Range: 90 - 410 mg/dL

122 108 164

IgM Reference Range: 30 - 360 mg/dL

21 (L) 20 (L) < 20 (L)

Serum Monoclonal ProteinLatest Ref Range: 0 mg/dL

1,462.8 (H) 18.3 (H) NONE DETECTED

Serum Beta 2 Microglobulin Latest Ref Range: 0.60 - 2.11 mg/L

6.3 (H) 2.1

Table 2. Patient’s protein studies at baseline and during chemotherapy


Chapter Update: The MWLA Three-Year Plan

The Midwest Lipid Association Chapter started the fall with our co-sponsored Clinic Lipid Update in Minneapolis in September. It was great to see many familiar NLA member colleagues as well as new attendees.

As part of the MWLA’s goals for this year, we are finalizing a three-year strategic plan. An important step was to create a mission statement.

The mission of the Midwest Lipid Association is to support the National Lipid Association in growing the field of lipidology.

Mission statements give each organization a foundation to build upon while maintaining focus. We hope ours will help guide our path forward for years to come. In serving our members, the MWLA’s

three-year strategies and measurable goals are to:

1. Grow and maintain clear communication pathways

2. Develop educational and research opportunities that will enhance the field of lipidology

3. Engage and support members through opportunities for personal and career growth

As Chapter leaders, we hope to offer clear communication to our members through the traditional publications such as the LipidSpin and our quarterly e-newsletter, but also build a toolkit of resources for future leaders to create smooth handoffs during times of leadership transition.

Regarding educational and research opportunities for our members, we plan to contribute to the NLA’s virtual lipid club in 2020 as well as build our lipid community through both local in-person and regional virtual meetings. The Chicago area has an active lipid interest group that meets regularly and is serving as a best practice for our discussions. We realize other regional chapters of the NLA have

their own best practices, and we continue to gather information on how to best reach and grow our membership. The MWLA is also evaluating options for reaching more members and nonmembers with ideas ranging from podcasts to webinars to the Project ECHO model (University of New Mexico) of provider support and education.

Finally, we want to engage and support our members to grow personally and professionally. We are creating a database of members with specific skillsets and interests. If you are a MWLA member and are interested in future career development, including speaking, writing, research and/or leadership opportunities, please reach out to myself or any of our chapter leaders.

2020 will be a great year for the MWLA. We look forward to hosting the Annual Scientific Sessions in Chicago in June. Agenda planning is already well underway and it is shaping up to be an exciting program. We look forward to seeing you there! n


ANN LIEBESKIND, MD, FAAP, FNLA President, Midwest Lipid AssociationFaculty, Foundations of Lipidology CourseFounder, Mobile Health Team Lipids ClinicAdjunct Assistant Professor of Pediatrics, University of Wisconsin School of Medicine and Public HealthNeenah and Wauwatosa, WI




Specialty Corner: Lipid Metabolism and Cardiovascular Disease

in Patients with Renal Disease

KAVEH REZAEI BOOKANI, MDFellow

NorthShore University Health SystemChicago, IL

DAVID DAVIDSON, MD, FACC, FNLA Director, Lipid Clinic

NorthShore University Health System Clinical Instructor

University of ChicagoChicago, IL


MARLYS L. KOSCHINSKY, PhD, FNLA Scientific & Executive Director, Robarts Research Institute

Professor, Department of Physiology & PharmacologySchulich School of Medicine & Dentistry

London, ON

Reduced estimated glomerular filtration rate (GFR) and chronic kidney disease (CKD) are also independently associated with the risk of death and cardiovascular (CV) events in community.(3) When compared to the general population, patients with CKD have a distinct lipid profile which involves alterations in different lipoprotein classes and shows considerable variations depending on the stage of CKD.(4) Although very complex, the most important characteristics of this uremic lipid profile can be simplified as follows: 1) hypertriglyceridemia, 2) elevated remnant lipoproteins including chylomicron remnants and IDL, 3) reduced HDL and 4) increased highly atherogenic small dense LDL (sdLDL), lipoprotein(a) and apolipoprotein A-IV. Although elevated LDL-C levels are not typically seen in CKD patients, it has been reported in patients with nephrotic syndrome and patients

on peritoneal dialysis (PD).(4) Therefore, LDL-C levels are not a reliable predictor of CV risk in patients with advanced CKD. Moreover, in end-stage renal disease (ESRD), low cholesterol levels, probably reflecting chronic inflammation and malnutrition, have been paradoxically related to high mortality risk.(5)

Use of Statin Therapy in Renal DiseaseU.S. population studies suggest an optimal total cholesterol level in the general population is about 150 mg/dL (3.8 mmol/L), which corresponds to an LDL-C level of approximately 100 mg/dL (2.6 mmol/L). Randomized clinical trials (RCTs) of cholesterol-lowering drugs in high-risk patients confirm that LDL-C lowering results in reductions in atherosclerotic cardiovascular disease (ASCVD).(6) Statins, as the mainstay of LDL lowering therapy, have also been shown to be

beneficial in reduction of CV morbidity and mortality in CKD patients. In different RCTs, simvastatin (7,8) pravastatin (9), atorvastatin (10) and rosuvastatin (11) were associated with improvement of CV risk profile in CKD patients. Furthermore, when compared with lower dosage, a higher dosage of atorvastatin (10mg daily versus 80mg daily respectively) was associated with 32% reduction in the relative risk of major cardiovascular events in CKD patients. This effect was twice as




large in CKD patients when compared to the population without CKD. The Study of Heart and Renal Protection (SHARP) indicated that simvastatin/ezetimibe combination therapy reduces the risk of major atherosclerotic events (coronary death, MI, non-hemorrhagic stroke or any revascularization) compared with placebo in people with GFR < 60 mL/min per 1.73 m2 (GFR categories G3a–G5).(13) While in renal transplant patients treatment with fluvastatin was associated with better cardiovascular outcomes compared with placebo, however, renal graft survival and all-cause mortality were not influenced.(14,15)

In contrast, the result of lipid lowering strategies and statin therapy in ESRD and hemodialysis (HD) patients are not consistent. For example, when compared with untreated HD patients, the 4D Study (Die Deutsche Diabetes Dialyse Studie) and the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial both failed to demonstrate improvement in cardiovascular endpoints in the group of ESRD patients who were treated with atorvastatin or rosuvastatin respectively, despite the expected decreases in their LDL-C levels. Interestingly, there was a two-fold increase in fatal strokes in the atorvastatin treatment group in the 4D study.(16,17) It is worth noting that many cardiovascular events in dialysis patients were due to arrhythmia or non-ischemic cardiomyopathy. Additionally, the

atherosclerosis was so advanced in these patients they were unlikely to benefit from drug therapy.(18)

Guidelines RecommendationsIn their 2013 guidelines, the Kidney Disease Improving Global Outcomes (KDIGO) recommended that lipid profile should be evaluated in all adults with newly identified CKD, while follow-up measurements were not required for the majority of patients since therapy was not geared toward a specific cholesterol level. In adults aged 50 years or older with eGFR >60 or <60 mL/min per 1.73 m2 but not treated with chronic dialysis or kidney transplantation, treatment with a statin is recommended. In patients with eGFR>60, the addition of ezetimibe could be considered. In adults aged 18-49 years with CKD but not treated with chronic dialysis or kidney transplantation, statin treatment was found to be beneficial if the person had one or more of the following: 1) known coronary disease (myocardial infarction or coronary revascularization), 2) diabetes mellitus, 3) prior ischemic stroke, and 4) estimated 10-year incidence of coronary death or non-fatal myocardial infarction >10%. In contrast, lipid lowering therapy was not suggested in dialysis-dependent patients but continuation of these agents was recommended if these patients were already receiving statins or statin/ezetimibe combination at the time of dialysis initiation.(19)

The 2018 Multisociety Guidelines on Management of Blood Cholesterol recognized CKD (eGFR 15-59 mL/min/1.73 m2) as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD) and its presence in adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 5%-19.9% favored a risk discussion regarding initiation of moderate-intensity statin therapy as a primary prevention strategy. In patients with history of previous ASCVD, CKD was considered

as a high risk condition. Very high risk patients have multiple ASCVD events, or one ASCVD event and multiple high risk conditions, which warrant using an LDL-C threshold of 70 mg/dL. If patients remain above this treatment threshold despite maximally tolerated statin therapy, addition of nonstatins was recommended.(20)

In the 2019 European Society of Cardiology (ESC) guidelines, patients were categorized with eGFR of < 30 mL/min/1.73 m2 as very-high-risk for ASCVD while eGFR of 30-59 mL/min/1.73 m2 was considered high-risk for future events. Therefore, using risk estimation models in these patients was not required. For people at very high CV risk, whether in secondary prevention or (rarely) in primary prevention, LDL-C reduction of ≥50% from baseline and an LDL-C goal of < 55 mg/dL are recommended whereas an LDL-C goal < 70 mg/dL are recommended in high CV risk patients. Similar to the Multisociety guidelines, they did not recommend initiation of lipid lowering agents in patents on dialysis but supported continuations of these medications if patients were taking them before commencement of dialysis.(21) n

Disclosure Statement: Dr. Bookani has no financial disclosures to report. Dr. Davidson has received honoraria from Amgen, Sanofi, Regeneron, Akcea, and Esperion. Dr. Koschinsky has received honoraria from Pifzer, Amgen, Eli Lilly, and Ionis.


“LDL levels are not a reliable predictor of CV

risk in patients with advanced CKD.”


Women’s Health: Guidelines for Lipid-Lowering in Women – What Have we Learned?

SASHA DE JESUS, MDInternal Medicine

Lenox Hill Hospital New York, NY

MERLE MYERSON, MD, EdD, FACC, FNLADirector, Preventive Cardiology & Lipid Clinic

Division of CardiologyBassett Medical Center

Cooperstown, NY


EUGENIA GIANOS, MD, FACC, FASE, FNLA System Director, Cardiovascular Prevention

Northwell HealthDirector, Women’s Heart Health

Lenox Hill Hospital New York, NY


Cardiovascular disease (CVD) remains the leading cause of death for women in the United States.(1) Unique factors affecting a woman’s health contribute significantly to CVD risk, but historically were not always represented in major guidelines. Some of these factors include hormonal changes, the presence of gender-specific risk factors and comorbidities more frequently seen in women (e.g. rheumatoid arthritis and systemic lupus erythematosus). Although women typically present with heart disease later in life, they have a longer life expectancy, leaving a greater lifetime risk for CVD.(1) This provides a great opportunity for prevention if risk is recognized early with the correct risk algorithms and preventive measures specific to the different phases of a woman’s lifetime. In this review, we intend to highlight the recent 2018 ACC/AHA Multisociety Guideline on the

Management of Blood Cholesterol(2) related to women in comparison to other prior guidelines. Risk StratificationThe 2018 ACC/AHA Multisociety Guideline, along with the National Lipid Association (NLA) 2015 Recommendations for Patient-Centered Management of Dyslipidemia (Part 2)(1) and professional organizations acknowledge the Pooled Cohort Equations (PCE) as the main tool for estimating a 10-year risk in U.S. adults ages 40 to 79. A limitation of the PCE is that it is not validated in adults > age 79, which is particularly important for risk stratification in women, considering their life expectancy is longer than men’s by approximately 5 years.(3)

To individualize risk, especially for those at borderline or intermediate risk (risk score

of 5%-19.9%), “risk-enhancing factors” can be used to further guide decisions.(2) Risk-enhancing factors specific to women include premature menopause (before age 40), complications of pregnancy (hypertension, preeclampsia, gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries) and chronic inflammatory conditions such as systemic lupus erythematosus or rheumatoid arthritis that disproportionately affect women.




The use of a coronary artery calcium (CAC) score can guide statin therapy in the intermediate risk group (score of ≥7.5%-19.9%) and in select borderline risk cases (score of 5%-7.5%) in which treatment remains unclear after consideration of enhancing factors. A patient with a CAC of zero has a low 10-year risk for ASCVD and statin therapy can be withheld, except for those who are current smokers, those with diabetes, those with a strong family history of ASCVD and those with inflammatory conditions such as HIV. As a result, it can potentially downgrade treatment in a patient for whom older age is amongst the few risk factors. A CAC score of ≥100 Agatston units or ≥75th percentile is used to guide statin therapy, because those patients will have a 10-year risk score of ≥ 7.5%.(2)

The NLA 2015 Recommendations recognize the challenges in ASCVD risk assessment, with some experts recommending calculation of a patient’s risk by multiple algorithms.(1) This is supported by prior analyses of calibration and discrimination through large registries showing widely varying underestimation

and overestimation of risk with different risk algorithms. They also emphasize the risk conferred by pregnancy-associated disorders to a woman’s ASCVD risk but add another woman-specific condition to the list: polycystic ovarian syndrome (PCOS). (Table 1) Women with PCOS have an increased risk for metabolic syndrome, diabetes mellitus and pregnancy complications. This risk is acknowledged by the American Association of Endocrinologists (AACE)(4), though the 2018 ACC/AHA Multisociety guidelines do not include PCOS as a risk-enhancer. Although PCOS is not discussed in the 2018 ACC/AHA Multisociety Guideline, most PCOS patients would be captured by the diagnosis of metabolic syndrome. The exact cardiovascular (CV) event risk conveyed by PCOS remains unclear based on current data.

The 2017 AACE recommendation for risk assessment tools include the Reynolds Risk Score and the Framingham Risk Assessment Tool.(4) The AACE guidelines also lists high-density lipoprotein cholesterol (HDL-C) of < 50mg/dL as a marginal risk factor for ASCVD and as

an established independent risk factor for ASCVD when it is < 40mg/dL in women. Another independent risk factor is an elevated fasting and/or postprandial triglyceride (TG).

Statin Therapy in WomenBased on a large meta-analysis of data from primary prevention randomized controlled clinical trials (RCTs), the NLA concluded that women and men with comparable ASCVD risk experience similar reductions in events and all-cause mortality when treated with statin therapy, particularly when adjusted for age and comorbidities.(1) They therefore recommend treating women without established ASCVD based on ASCVD risk assessment, with the intensity of the lipid-lowering therapy matching their risk, much is as done with men. For those with known ASCVD, statin therapy is indicated regardless of gender and regardless of an untreated low-density lipoprotein cholesterol (LDL-C) level. Statin therapy in women also is supported by the AACE and the 2018 ACC/AHA Multisociety Guidelines, similar to recommendations for men who are at risk for ASCVD. However, pregnancy and lactation warrant separate considerations that are discussed later in this review.

Non-Statin Lipid-Lowering AgentsThere are very few sex-specific recommendations with respect to the use of non-statin therapies in any of the lipid guidelines, mainly because sub-analyses of the larger trials for differences in women tend to be underpowered. The few sex-specific recommendations include the AACE recommendation for the use of niacin in high- and intermediate-risk women when there is low HDL or elevated non-HDL.(4) This is added before and after LDL-C goal is reached in those at high and intermediate risk, respectively. Based on recent negative trials in which niacin was added to statin therapy,(9,10) the other societies do not list specific

Childbearing age

Statin (pluscontraception)

Pregnancy

Menopause

Throughout LifeEncourage exercise and lifestyle modi�cations

Chronicin�ammatoryconditions

Lactation

StatinColesevelamLDL apheresisLifestyle modi�cations+ omega-3-fatty acidsand/or feno�brate orgem�brozil for high TG

✘

StatinsColesevelamCholestyramine resinEzetimibeFeno�brate

Lifestylemodi�cations.+/- Statins

StatinHRT (unless forsymptom control)

✘

Figure 1. Optimizing Risk over the Course of a Woman’s Lifetime.


recommendations for niacin based on sex. There also is an NLA recommendation for the use of bile acid sequestrants during pregnancy in the setting of severe hypercholesterolemia (see below).

Adverse Effects of Therapy in WomenThe NLA promotes awareness of the different factors that can contribute to adverse effects of statin therapy in women, such as difference in age, comorbidities, BMI, body fat, muscle mass and polypharmacy, leaving them potentially more susceptible to elevated glucose levels and myalgias with statin treatment.(1)

PregnancyThe 2018 AHA/ACC Multisociety Guideline recommend that women of childbearing age who are on statin therapy and are sexually active should use a reliable form of contraception and, if they become pregnant while on statin, statin use should be stopped as soon as the pregnancy is discovered. If pregnancy is planned, statin therapy is recommended to be stopped one to two months before pregnancy is attempted and not restarted until after pregnancy and breastfeeding

are completed. The physiologic effects of pregnancy lead to steady elevations in all lipid parameters, which peak by the third trimester, most notably in triglycerides even in women without underlying lipid disorders. Because of this effect, those with genetic lipid disorders should consider consulting a lipid expert before starting the pregnancy for optimization of lifestyle and disease.(2)

Also, it is worth mentioning that the Food and Drug Administration (FDA) has replaced the ABCDX system of the FDA Pregnancy and Lactation Labeling Rule (PLLR) that requires narrative text to describe risk information, clinical considerations and background data for the drug.(11)

The NLA specifically recommends the use of colesevelam (the only bile acid sequestrant that is categorized as Class B by the former FDA classification) for the treatment of severe dyslipidemias during pregnancy, especially those with familial hypercholesterolemia (FH).(1) Other bile acid sequestrants that can be considered during pregnancy are cholestyramine

resin and colestipol, though they are Class C.(12) The NLA also suggests consideration of LDL apheresis in cases in which LDL-C is markedly elevated. The efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not been determined during pregnancy, therefore, there is no guideline recommendation for their use. However, there are ongoing registries to track the safety of statin use during pregnancy.(13) Ezetimibe has been associated with adverse fetal effects in animal studies, and it is not recommended in pregnancy.(12)

With respect to TG, very high levels (≥500 mg/dL) may be treated with diet and lifestyle modifications, with the addition of omega-3-fatty acids and/or fenofibrate or gemfibrozil early in the second trimester but with the understanding that these are Class C medications(1) with limited pregnancy-related data and fibric acid derivatives are associated with adverse fetal effects in animal studies. If omega-3 supplementation is to be considered, prescription medications should be used based on the inconsistent amount of eicosapentaenoic acid (EPA) and

CONDITION ASSOCIATION WITH HEART DISEASE

Premature Menopause This is hypothesized to be detrimental to heart disease because of the lack of cardiovascular protection conferred by endogenous estrogens, which leads to stiffer blood vessels and alterations in lipoproteins. During this process, the renin-angiotensin-aldosterone system is noted to be activated, with subsequent endothelial and immune dysfunction and inflammation, processes that are associated with obesity, diabetes and hypertension.(5)

Polycystic Ovarian Syndrome There is a cascade of hormonal changes occurring as a result of this condition that are associated with metabolic dysfunction, such as hyperandrogenism, insulin resistance, dyslipidemia and inflammatory state.(6) The exact CV risk conveyed by PCOS is unclear based on mixed data.

Preterm Delivery This association is believed to be due in part to the development of postpartum chronic hypertension, hypercholesterolemia, type II diabetes mellitus, and changes in body mass index.(7) Systemic inflammation and oxidative stress, which are well-known promoters for atherogenesis, also are present in the leading cause of pre-term delivery – preeclampsia – and intrauterine growth retardation.(8)

Table 1. Cardiovascular Risk Factors Specific to Women


docosahexaenoic acid (DHA) noted in over-the-counter supplements and the fact that the supplement market is not well regulated.(14) MenopauseBoth the NLA and the AACE note the atherogenic lipid profile seen in menopause secondary to the hormonal changes.(1,4) Hence, it is possible that women with abnormal risk factors will have them worsen during menopause. Based on the AACE data review, emphasis is placed on the relevance of statin therapy for postmenopausal LDL-C reduction.(4) With the use of risk calculators factoring in age, this risk is likely to be appreciated.

Hormone Replacement Therapy and Heart DiseaseBoth the NLA and the AACE agree that hormone replacement therapy (HRT) should be used to control menopause-related issues that interfere with a woman’s quality of life but should not be given for primary or secondary prevention of CVD, based on data suggesting an increased risk with treatment in those with elevated baseline risk.(15) As studies have shown, higher levels of total cholesterol and TG have been noticed in postmenopausal women, likely because of lower estrogen hormone levels.(16) HRT formulations have been associated with improvement in the lipid profile (increase in HDL-C and decrease in LDL-C and TG)

(17). However, as previously stated, the use of HRT for CVD risk reduction is not recommended based on guidelines and should only be considered with an individual risk/benefit assessment depending on the patient’s age at the onset of menopause and her individual cardiovascular risk profile. Hormone replacement therapy is not discussed in the 2018 ACC/AHA Multisociety Guideline as a choice of therapy for CV risk reduction.

Chronic Inflammatory ConditionsIn the AHA/ACC guideline, chronic inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus and psoriasis are conditions considered to

Table 2. Comparison of Various Lipid-Lowering Guidelines for Women.

2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol

2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease

National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2

Recommended tool for CVD risk assessment in women

- Pooled Cohort Equation- Individual risk based on risk-

enhancing factors and women’s specific risk factors

- Coronary Artery Calcium Score

- Reynolds Risk Score- Framingham Risk Score - Individual risk assessment

based on women’s specific risk factors, including HDL levels

- Framingham Risk Score - Pooled Cohort Equation- Reynolds Risk Score- Individual risk assessment based on

women’s specific risk factors

Recommendation on Statin therapy

Recommended Recommended Recommended

Pregnancy - Patients on statin who are sexually active should use a reliable method of contraception.

- Discontinue statin 1 to 2 months prior to attempting pregnancy.

- Should pregnancy occur while patient is on statin, it should be discontinued as soon as pregnancy is discovered.

Not discussed - Similar suggestions as the AHA/ACC.- For patients with familial

hypercholesterolemia (FH), bile sequestrant agent colesevelam (category B) is recommended, as well as LDL apheresis.

- For hypertriglyceridemia, diet and lifestyle modifications are suggested, as well as omega-3-fatty acids and/or fenofibrate or gemfibrozil early in the second trimester (class C medications).


enhance risk for CVD.(2) If, after a trial of 3 to 6 months of lifestyle modifications, a patient with one of these conditions has an ASCVD risk estimate of ≥5% over 10 years, initiating a moderate-intensity statin would be reasonable, with important implications in women who are disproportionately affected by these conditions. The increased risk of ASCVD in women with these conditions also is noted in the AACE guidelines, with the addition of ankylosing spondylitis.(4)

Recognizing and Optimizing Risk over the Course of a Woman’s LifetimeRecognizing the potential for recognition and optimization of risk over the course of a woman’s lifetime, the authors make the following suggestions:

• Encourage a heart-healthy diet and exercise habits starting in childhood, with special attention to the observation that girls tend to be less physically active than boys(18) and experience eating disorders more commonly than boys.(19) Establishing these habits early may impact health years later.

• In child-bearing years, consider treating high-risk women (i.e., familial hypercholesterolemia) who may wish to become pregnant in the future even more aggressively during their “non-pregnancy years,” knowing that they may be off medications entirely for several series of attempts to become pregnant over the years. It has been shown that the years of exposure to elevated lipid levels greatly influences risk; therefore, aggressive treatment with statins as first-line agents in conjunction with lifestyle in high-risk women is imperative. Be certain that the patient understands the risks and has a good method in place to safely avoid pregnancy during these times.

• Consider sex-specific risk factors as well

as exposure to radiation, chemotherapy or hormone suppressive drugs that are increasingly prevalent with rates of invasive breast cancer in women reaching 1/8 in the U.S. (about 12%) over the course of a women’s lifetime.(20) Increased CVD prevalence in the breast cancer survivor population is likely partly because of therapies for breast cancer but also from overlapping risk factors between breast cancer and heart disease, such as – but not limited to – family history, race, obesity, tobacco use and age, making it imperative for clinicians to recognize these risk factors for both primary and secondary prevention of each disease.(21)

• Sex-specific questionnaires embedded in the patient intake can assure that these risk factors are recognized.

• Focus on menopause as a time for reassessment of CV risk based on changes in the cardiometabolic profile associated with hormonal change.

• Always use shared decision-making for arriving at an optimal treatment plan.

Conclusion Optimal risk stratification and lipid

lowering in women with or at risk for established CVD is a key mechanism for physicians to improve cardiovascular risk in women. The 2018 ACC/AHA Multisociety Guideline, which reflect even more recent data, provide significant guidance specific to women, building even further on established guidelines in this field. Although the guidelines from different societies may differ slightly in their recommendations for women, the larger message is making more clinicians who care for these patients familiar with them to impact a larger at-risk population. Partnerships with obstetrics and gynecology practices can aid in assuring that this becomes part of routine care for the female patient.(22) n

Editor’s Note: This Women’s Health article is being re-published due to a photo error in the preceding issue. We thank Dr. De Jesus for her hard work and contribution to our publication.

Disclosure statement: Dr. De Jesus has no financial disclosures to report. Dr. Myerson has received honoraria from Kowa and Medicure. Dr. Gianos has received honoraria from Regeneron.


“Optimal risk stratification and lipid

lowering in women with or at risk for

established CVD is a key mechanism for

physicians to improve cardiovascular risk in

women.”


Backspin: New Cholesterol Guidelines: Coronary Artery Calcium Scores a Win

MICHAEL AYERS, MD Fellow-in-Training, Post-Graduate Year 5Cardiovascular Medicine, University of Pennsylvania Philadelphia, PA

DOUGLAS JACOBY, MD, FNLA Director, Penn Cardiology Penn Preventative Care Medical Director, Penn Presbyterian Heart and Vascular Pavilion Associate Professor of Clinical MedicinePhiladelphia, PA


In October of 2018, the American College of Cardiology (ACC) and the American Heart Association (AHA), in collaboration with the National Lipid Association and other organizations, published evidence-based guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD).(1) Along with the guidelines, there was a Special Report summarizing the rationale and evidence base for the current quantitative risk assessment tools.(2) These newest iterations strengthen recommendations on lifestyle modifications, provide low-density lipoprotein cholesterol (LDL-C) thresholds for non-statin therapies (such as proprotein convertase subtilisin-kexin type 9 inhibitors) in high-risk and very high-risk groups and lists “risk-enhancing” comorbidities to help personalize treatment decisions in

borderline (10-year ASCVD risk of 5-7.5%) and intermediate (10-year ASCVD risk of > 7.5-20%) risk groups. Notably, the guidelines formalize the use of coronary artery calcium scoring (CAC) as a decision tool for the intermediate 10-year risk group. Given the decades of data supporting CAC as a reliable means of improving risk assessment scores for cardiovascular outcomes,(3) the thoughtful inclusion of CAC in the guidelines merits commendation.

In preventative cardiology, we treat patients based on their risk, such that higher risk patients receive more aggressive interventions. In patients with known clinical atherosclerotic disease, diabetes or genetic dyslipidemias, the risk is high enough to qualify for pharmacotherapy (i.e., statins) and non-statins are considered when LDL-C is above treatment thresholds. On the other hand, care for primary prevention adults without severe hypercholesterolemia and diabetes is more nuanced and starts with assessment of patient preference in a thoughtful clinician-patient discussion. We rely first on risk calculators. By their very nature, quantitative 10-year risk

assessment scores are based on large-scale population studies. These tools define a distribution of risk for a given patient based upon several broad characteristics (age, sex, race, blood pressure, total/low density and high density lipoprotein cholesterol, presence of diabetes, smoking and antihypertensive medication status and use of statins and/or aspirin). For patients at high risk due to their calculated scores or presence of enhancing risk factors, statin therapy is favored. In the borderline and intermediate groups, the distribution of risk becomes much more clinically relevant. CAC measurements have proven superior to serum biomarkers and traditional risk factors for refining risk of ASCVD.(4) Adding CAC measurements to risk assessment tools improves both the precision and accuracy of risk assessment by personalizing the decision-making to an individual’s personal burden of disease. Subclinical atherosclerosis imaging reflects a lifetime of known and unknown risk factors. CAC scoring may reclassify an individual into a higher or lower risk stratum,(5) clarifying the role of statin therapy.

The group specifically mentioned in the




guidelines as most likely to benefit from CAC scoring is intermediate risk patients between 40 and 75 years of age in whom the decision to treat is uncertain. For intermediate risk patients with CAC score of > 100 Agatston Units (AU) or > 75th percentile for age/sex/race/ethnicity, event rates occur in a range where statin therapy clearly exceeds potential for harm, resulting in the so-called “up-risking” of these patients. CAC scores between 1 to 99 AU and < 75th percentile for age/sex/race/ethnicity result in only modest risk reclassification rates. While the guidelines favor treatment on patients over age 55 years old in this category, we (DJ and MA) believe this is too limiting since in adults less than 55 years of age, any non-zero score carries significant ten-year and lifetime cardiac risk.(6)

Intermediate risk patients with a CAC score of 0 AU appear to have 10-year event rates < 5%, suggesting drug therapy would likely be of limited value.(7) As the guidelines point out, clinicians should not down-risk patients who are persistent cigarette smokers, have diabetes mellitus, have a strong family history of ASCVD, nor those with chronic inflammatory conditions whose CAC of zero does not rule out risk from noncalcified plaque.(1) Overall, we appreciate the effort from the guideline committee to correctly risk stratify intermediate risk patients, but we typically recommend CAC for the purpose of down-risking only if the patient is actively trying to avoid medications or if there is a history of significant statin intolerance. Given the favorable risk:benefit profile of statins,(8) we believe the greatest benefit of CAC is to up-risk patients so that they might receive protection from statin initiation. The guidelines highlight that if a decision is made not to treat with a statin, repeating CAC at five to ten years could be considered. Conversion from a CAC of zero to greater than zero is non-linear. Careful surveillance is prudent, since as

many as 25% percent of zero CAC scores will convert to non-zero scores by 4 years.(9) Our recommendation is to rescreen non-treated patients every five years, the earlier portion of the range suggested by the guidelines.

While CAC scoring may reclassify some subgroups of patients with borderline ASCVD risk scores, the data is less robust than for those with intermediate risk.(3) For borderline risk patients, the new guidelines suggest screening for risk-enhancing factors prior to considering CAC scoring. By selecting the borderline risk patients with risk-enhancers, the hope is that this approach is more likely to identify patients in whom a CAC score may “up-risk” the patient. Two other groups mentioned as possibly benefiting from CAC included low risk women (10-year risk of ASCVD < 5%) with a strong family history of premature ASCVD and patients less than 45 years of age with significant and sustained risk factors through young adulthood but low or borderline 10-year risk.(2,6,10) Particularly in these two younger cohorts, a CAC score of > 0 AU was associated with ASCVD event rates in the range of statin benefit.(6)

While we agree with the consideration of borderline, and some low risk, populations, for CAC scores, we wish this suggestion was stronger and more widely applied. The group most likely not to be prescribed a statin despite probable benefit from

therapy are members of the low 10-year risk group with non-zero CAC scores. A study by Nasir et al found that 21% of patients with only one traditional risk factor had non-zero coronary calcium scores and four percent of the low 10-year risk cohort had CAC scores > 100 AU.(5) Adults younger than 50 years old with any CAC, even with very low CAC scores, are at 3 to 5-fold increase risk for cardiovascular events compared to similar cohorts with CAC scores of 0.(11) Given the prevalence of non-zero scores in the low 10-year risk group, guidelines should encourage clinicians to screen for risk-enhancers in all patients. If any are found, especially a family history of heart disease, the guidelines should encourage consideration of CAC scoring to avoid missing patients in whom treatment is warranted. While the prevalence of non-zero scores will be lower in this group, the area in which we can provide the most benefit to a patient is to identify cardiovascular risk that the patient did not realize he or she had, and thus intervene and lower lifetime risk with intensive lifestyle modification and proven pharmacologic therapies that are safe and effective. As with previous versions of the guidelines, a large emphasis is placed on 10-year risk for clinical decision making. As the obesity epidemic has more impact on younger generations, it will become more important to consider not just 10-year but lifetime risk. At least half of the US adult population has a 10-year risk of ASCVD < 10% with a lifetime risk of ASCVD > 39%.(12) As such, the guidelines note that simultaneous assessment of 10-year and lifetime risk is “reasonable” for decision making. While shared decision making is admirable, having clear guideline recommendations for disparate 10-year and lifetime risk scores will help alleviate some of the strain on a primary care system that is already stretched quite thin. In this area,

“CAC is a reliable means of improving

risk assessment scores for cardiovascular

outcomes. ”


subclinical atherosclerosis imaging may be useful as well.

When considering younger populations and lifetime risk, CAC is less useful due to the decreased prevalence of coronary artery calcification below age 40. In these patients, we advocate for use of carotid intimal media thickness (CIMT) testing. While CAC has greater prognostic power, and CIMT ultrasonography is controversial, CIMT can provide valuable guidance in appropriate younger populations, female populations, and populations with unique risk factors such as previous neck radiation therapy.(13) CIMT is briefly mentioned in the current guidelines as a “weaker predictor of overall ASCVD events compared with the CAC score.” CIMT may be more useful in younger populations where many of the patients with high lifetime risk may have zero or near-zero CAC scores.(14) CAC and CIMT may be complementary as predictive tools, with the soft plaque visualized on a carotid ultrasound potentially complementing the calcified plaque detected by CAC. CIMT may also have more ability to predict cerebrovascular events.(13) Given the large benefit realized by preventing premature ASCVD at a young age, CIMT is reasonable when assessing risk in young patients with low or borderline 10-year risk scores but with risk-enhancers or high lifetime risk.

Most insurance companies do not cover CAC testing, which is explicitly mentioned in the current guidelines. Given the new emphasis from these preeminent cardiology societies on CAC in medical decision-making, there may be renewed pressure on insurers to cover these tests. The guidelines also address two other pragmatics issues brought up by CAC scores. Firstly, the radiation of a CAC score is small at 1 millisievert, roughly 1/3 of the amount of background radiation absorbed in a year.(15) Secondly, discovery of incidentalomas can be minimized by

narrowly windowing around the heart.(1)

CAC is a reliable means of improving risk assessment scores for cardiovascular outcomes.(3) Including this powerful subclinical atherosclerosis imaging modality in the latest guidelines should improve the cardiovascular health of millions of Americans, particularly those with intermediate 10-year risk scores or borderline 10-year risk scores but with risk-enhancers. Overall, we agree with the committee’s interpretation of CAC scores. We do hope that providers use CAC scores more broadly in the lower risk and borderline risk patients with risk enhancers to up-risk appropriate patients into a statin treatment group, thereby avoiding missed opportunities to lower risk in patients before they develop cardiovascular events. We also hope that patients with non-zero scores receive treatment with statin therapy, and that patients with zero scores not on statin therapy receive surveillance scan at approximately 5-year intervals to justify remaining off treatment. Hopefully more data continues to become available leading to further refinement in future guidelines. n

Editor’s Note: This article is being re-published due to a photo error in the preceding issue. We thank Dr. Ayers

for his hard work and contribution to our publication.

Disclosure Statement: Dr. Jacoby received honoraria from Regeneron, AstraZeneca, and Quest. Dr. Ayers has no financial disclosures to report.



Guest Editorial: Postprandial Dysmetabolism: Understanding the Impact of

Elevated Postprandial Glucose and Triglycerides with the Potential to Prevent or Intervene Early

KEVIN C. MAKI, PhD, CLS, FACN, FNLADepartment of Applied Health Science

School of Public HealthIndiana University

Bloomington, INMidwest Biomedical Research

Addison, IL

In 2019, the Centers for Disease Control and Prevention reported that prevalence for both obesity and overweight have continued to rise over the last eight years and are at an all-time high for adults and adolescents.(1) Approximately two-thirds of US adults are either obese (31%) or overweight (35%). Approximately one-third of US adolescents in grades 9-12 are obese (15%) or overweight (16%). Obesity in childhood and young adulthood is a predictor of weight difficulties in middle age and beyond. This pandemic is largely driven by poor diet quality and physical inactivity, although genetic predisposition and other lifestyle factors also play important roles.(2) Latency between eating occasions has declined in the US, leading to a nearly continuous

postprandial state, except overnight while sleeping.

Overweight and obesity are associated with insulin resistance and chronic inflammation. Eventually, these may lead to pancreatic beta-cell dysfunction, producing impaired glucose tolerance and type II diabetes mellitus (T2D). Expanded adipose stores and insulin resistance result in chronically elevated circulating levels of free fatty acids. When the liver is exposed to these high levels of free fatty acids, it has only three options: (1) increase hepatic lipid oxidation, (2) increase production of larger, triglyceride (TG)-enriched very-low-density lipoprotein particles or (3) increase ectopic deposition of TG. Because hepatic lipid oxidation

can only be increased to a modest extent, the excess of free fatty acids resulting from increased adiposity are generally converted to TG and thus contribute to enhanced risks for fasting and postprandial hypertriglyceridemia and fatty liver (non-alcoholic fatty liver disease and non-alcoholic steatohepatitis).

The term postprandial dysmetabolism was coined by O’Keefe and Bell in

MARY R. DICKLIN, PhDMidwest Biomedical Research

Addison, IL

MAYA BALAKRISHNAN, MDSection of Gastroenterology & Hepatology

Baylor College of Medicine Houston, TX

DAVID R. NEFF, DOPast President, Midwest Lipid Association

Michigan State UniversityCollege of Osteopathic Medicine

Associate Clinical ProfessorDepartment of Family & Community

MedicineIngham Regional Medical Center

Lansing, MI




2007 to describe the combination of hypertriglyceridemia, hyperglycemia and hyperinsulinemia that often accompanies overweight, obesity and other insulin resistant conditions such as T2D and polycystic ovarian syndrome.(3) A growing body of literature has developed that, taken together, supports the view that postprandial dysmetabolism contributes to the pathophysiology of cardiometabolic diseases, including atherosclerotic cardiovascular disease (ASCVD), microvascular diseases (retinopathy, neuropathy and nephropathy) and fatty liver.(4-8)

The main pathophysiologic mechanisms for the development of tissue damage with postprandial dysmetabolism are excessive glucose levels leading to the production of advanced glycation end products, and excessive TG-rich lipoproteins (from both the gut and the liver). These contribute, through a number of mechanisms, to pro-oxidative and inflammatory states, as well as increased coagulation and reduced fibrinolysis. Excess post-meal nutrients overburden electron transport, exceeding the metabolic capacity of muscle and adipose tissue mitochondria, and thus, result in increased production of reactive oxygen species. Remnants of TG-rich lipoproteins of both hepatic and intestinal origin enter the subendothelial space where they undergo oxidative and other types of modification, triggering uptake by macrophages and activation of inflammatory mechanisms. While both elevated levels of low-density-lipoprotein cholesterol (LDL-C) and TG-rich lipoprotein cholesterol are associated with higher levels of circulating inflammatory markers, such as high-sensitivity C-reactive protein, the relationship is roughly 5- to 6-fold stronger for the latter.(9)

Some obese individuals do not develop chronic inflammation and oxidative stress. It has been hypothesized that a ‘second

hit’ or ‘multiple hits’ are necessary to induce these disturbances.(10) Along with chronic hyperglycemia and hypertriglyceridemia, other factors such as smoking (and other inhaled pollutants), chronic alcohol consumption and disturbances in gut microbiota also play important roles.(11) Genetic variants that influence body fat distribution and the production of pro-inflammatory cytokines in response to expansion of adipose stores also likely contribute to interindividual variation in the degree of metabolic disturbance associated with a given level of adiposity.

Implications of Postprandial DysmetabolismTesting for postprandial hyperglycemia is well standardized.(12) However, measuring postprandial lipids is not. In their original article, O’Keefe and Bell reported using a standard glucose load (75-g) mixed with 700-kcal/m2 whipping cream as a mixed glucose-fat tolerance test.(3) Other protocols have been used for research, but not in the clinical setting due to lack of normative data and practical challenges associated with administration of tests that take several hours to complete.

The conventional methods for the detection of postprandial hyperglycemia are the 75-g oral glucose tolerance test and self-monitoring of glucose through finger sticks or continuous glucose monitoring. Glycated hemoglobin provides an integrated measure of the average blood glucose level over a period of several weeks, thus it incorporates fasting and postprandial exposure.(12) An emerging technology for the evaluation of postprandial glucose levels is the measurement of plasma 1,5-anhydroglucitol (1,5-AG). Glycemic control has long been known to be important for maintaining health of the microvasculature. Evidence also exists for

a role of TG management in prevention of microvascular complications. Results from the Fenofibrate and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) studies showed reduced microvascular complications in T2D patients treated with fenofibrate, which lowers fasting and postprandial TG concentrations.(13)

Although limited data are available to assess the independent predictive value of postprandial lipemia, the results to date suggest that it is likely that some individuals show discordance, i.e., higher levels of postprandial lipemia than would be suggested by fasting levels of TG and TG-rich lipoproteins.(14,15) Surrogate measures now available include apolipoprotein (apo)B-48 levels and remnant-like lipoprotein (RLP) cholesterol and TG concentrations. A study in 10 male, normolipidemic subjects showed that postprandial levels of apoB-48, TG, RLP-C and RLP-TG significantly increased after the intake of a high-fat meal; however, there was no postprandial increase in apoB-100 or LDL-C levels.(16)

In human carotid and femoral endarterectomy samples, the quantity of apoB-48 proteins was similar to that of apoB-100 proteins, and the apoB-48/apoB-100 ratio was much higher than predicted based on the relative plasma concentration (< 1% of the apoB in fasting samples is apB-48).(17) These results support the Zilversmit hypothesis, first proposed in the 1970s, emphasizing the roles of chylomicron particles and postprandial lipemia in the promotion of atherosclerosis.(18) Fasting apoB-48 levels correlate significantly with the incremental area under the curve of TG after the intake of a high-fat meal.(19) Additional data are needed to determine whether such information can be used clinically to identify those with increased


cardiometabolic risk due to postprandial dysmetabolism, and, further, whether interventions to address postprandial dysmetabolism will enhance risk reduction.

Excessive postprandial lipemia and glycemia are both known to induce oxidative stress, thus lowering nitric oxide availability and triggering transient endothelial dysfunction.(20,21) The degree of endothelial dysfunction after a high-fat meal correlates strongly with postprandial elevations in TG, apoB-48 (reflecting the number of chylomicron particles) and glucose.(19) Postprandial endothelial dysfunction is associated with increases in release of pro-inflammatory cytokines and expression of adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1). These processes stimulate infiltration of monocytes into the subendothelial space, where they can differentiate into macrophages.

Thus, there is a strong theoretical basis for the view that normalizing postprandial levels of TG-rich lipoproteins and glycemia might reduce risk for atherothrombosis. Recently published results from studies of interventions that have these effects provide indirect support for this hypothesis, including studies showing reduced major adverse cardiac event (MACE) risk with glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter 2 inhibitors and icosapent ethyl.(22,23) The Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial (REDUCE-IT) showed a 25% reduction in MACE risk with 4 g/d of icosapent ethyl compared with placebo in statin-treated patients at high- and very-high ASCVD risk. Changes in LDL-C and non-high-density lipoprotein cholesterol with icosapent ethyl appear unlikely to explain more than approximately one-third of the risk

reduction.(23) Icosapent ethyl has been shown to reduce fasting and postprandial levels of TG as well as biomarkers of inflammation and indicators of monocyte activation.(24,25) Additional research appears warranted to further investigate the potential contribution of improved postprandial metabolism as a partial explanation for the benefits associated with icosapent ethyl, as well as other therapies.

Treating Postprandial DysmetabolismThe current primary treatment approach for postprandial dysmetabolism is lifestyle therapies, including weight loss (5-10% of body weight) if overweight or obese, smoking cessation and physical activity, incorporating both aerobic (≥150 min of moderate intensity activity) and resistance exercise.(7,26) In addition to weight loss, dietary intervention should include a diet low in saturated fat, cholesterol and added sugars, as well as moderation or abstinence from alcohol consumption.(7)

Antiglycemic and lipid-lowering medications generally improve both fasting and postprandial levels of glucose and TG-rich lipoproteins. Additional research is needed to determine whether emerging biomarkers of postprandial dysmetabolism can be utilized clinically to identify subsets with greater likelihood of improved cardiometabolic outcomes with specific types of interventions. For example, those with well-controlled LDL-C and fasting TG in the normal or slightly elevated range, but with an elevated level of apoB-48 (suggesting postprandial lipemia) might experience greater risk reduction with omega-3 fatty acid or fibrate therapy compared with intensification of LDL-C reduction. Like metabolic syndrome, levels of apoB-48, RLP-C, RLP-TG, and 1,5-AG may also be useful for identifying individuals to target for intensification of lifestyle intervention through referral to behavioral programs

and/or prescription of weight loss medications. At present, these remain hypotheses that will need to be tested in clinical trials.

ConclusionsPostprandial dysmetabolism is characterized by elevated levels of plasma glucose and TG after meals. A strong theoretical basis exists for the view that postprandial dysmetabolism may contribute to risks for atherothrombosis and microvascular damage, affecting numerous tissues. Overweight, obesity and insulin resistance appear to be key factors driving the development of postprandial dysmetabolism. The primary goal of preventive efforts is to avoid overweight and obesity and to treat these early to prevent downstream consequences. Lifestyle therapies are critically important and drug therapies for control of lipids and glycemia will generally improve both fasting and postprandial levels. Additional research is needed to establish normative data for biomarkers of postprandial dysmetabolism and assess their clinical utility. Individuals with discordance between fasting and postprandial levels of glucose and TG, i.e., normal or mildly elevated fasting levels, but with exaggerated postprandial responses, may represent a group with increased and modifiable risk for adverse micro- and macrovascular outcomes. Further validation of biomarkers for postprandial dysmetabolism may provide useful clinical tools to guide risk stratification and treatment selection. n

Disclosure statement: Dr. Maki received honoraria from Acasti, Akcea, Amgen, AstraZeneca, Corvidia, Matinas Biopharma, Pharmavite, LLC, Sanofi/Regeneron, Kellog, and General Mills. Dr. Dicklin received honoraria from Acasti, Akcea, Amgen, AstraZeneca, Corvidia, Matinas Biopharma, Pharmavite, LLC, Sanofi/Regeneron, Kellog, and General Mills. Dr. Balakrishnan received honoraria from Intercept, Gilead, and Ebix Reviews.Dr. Neff has no financial disclosures to report.



Clinical Feature1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic

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2. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global Epidemiology of Non-Alcoholic Fatty Liver Disease–Meta-Analytic Assessment of Prevalence, Incidence and Outcomes. Hepatology (Baltimore, Md). 2015:n/a-n/a.

3. Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014;59(6):2188-95.

4. Black D, Brockbank S, Cruwys S, Goldenstein K, Hein P, Humphries B. The future R&D landscape in non-alcoholic steatohepatitis (NASH). Drug Discov Today. 2019 Feb;24(2):560-566. doi: 10.1016/j.drudis.2018.09.020. Epub 2018 Oct 3.

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16. Thiagarajan P, Aithal GP. Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges. J Clin Exp Hepatol. 2019 Jul-Aug;9(4):515-521. doi: 10.1016/j.jceh.2019.03.002. Epub 2019 Mar 13.

17. Vizuete J, Camero A, Malakouti M, Garapati K, Gutierrez J. Perspectives on Nonalcoholic Fatty Liver Disease: An Overview of Present and Future Therapies. J Clin Transl Hepatol. 2017 Mar 28;5(1):67-75. doi: 10.14218/JCTH.2016.00061. Epub 2017 Mar 20.

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EBM Tools for Practice

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Lipid Luminations 1. Zinman B, Wanner C, Lachin JM, et. al. Empagliflozin, Cardiovascular

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2. Neal B, Vlado Perkovic V, Mahaffey, KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57.

3. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249–59.

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M. Alterations of lipid metabolism in chronic nephropathies: mechanisms, diagnosis and treatment. Kidney Blood Press Res. 2010;33:100–110.

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Women’s Health1. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid

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18. Telford RM, Telford RD, Olive LS, et al. Why are girls less physically active than boys? Findings from the LOOK longitudinal study. PLoS One. 2016;11:e0150041 10.1371/journal.pone.0150041.

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Backspin1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/

AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2018.

2. Lloyd-Jones DM, Braun LT, Ndumele CE, et al. Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology. Journal of the American College of Cardiology. 2018.

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Chronic Disease Prevention and Health Promotion, Division of

Nutrition, Physical Activity, and Obesity. Data, Trend and Maps [online]. [accessed Nov 05, 2019]. URL: https://www.cdc.gov/nccdphp/dnpao/data-trends-maps/index.html.

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16. Matsuda D, Sakai N, Sugimoto T, et al. Fasting serum apolipoproteinB-48 can be a marker of postprandial hyperlipidemia. J Atheroscler Thromb. 2011;18:1062-70.

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19. Masuda D, Yamashita S. Postprandial hyperlipidemia and remnant lipoproteins. J Atheroscler Thromb. 2017;24:95-109.

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22. Scheen AJ. Cardiovascular outcome studies in type 2 diabetes: comparison between GLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract. 2018;143:88-100.

23. 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;In press. Currently available at https://www.lipid.org/nla/nla-scientific-statement-use-icosapent-ethyl-statin-treated-patients-elevated-triglycerides-and.

24. Dai Perrard XY, Lian Z, Bobotas G, et al. Effects of n-3 fatty acid treatment on monocyte phenotypes in humans with hypertriglyceridemia. J Clin Lipidol. 2017;11:1361-1371.

25. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22.

26. Correa CS, Teixeira BC, Bittencourt A, et al. Postprandial lipemia and cardiovascular diseases: the beneficial role of strength exercise. 2014;13:123-130.

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Shared Decision Making (SDM) is a collaborative process enabling both patients and providers to make healthcare decisions together. It takes into account both medical information and patient preferences.

The SHARED approach was created to help facilitate the SDM process, which can help improve patient outcomes, rates of self-management, satisfaction with care, and lower healthcare costs.

...AND WHAT DO I DO ABOUT IT?

Seek Your Patient’s ParticipationSHelp Your Patient Explore and Compare Treatment OptionsHAssess Your Patient’s Values and PreferencesAReach a Decision With Your PatientREvaluate Your Patient’s DecisionEDecide Which Local Resources Will Effectively Support the Patient and How To ConnectD

Why do I need to take a statin?

What are the side effects of statins?

How would I know if I can’t tolerate taking them?

How long do we try this out?

I’ve heard that statins might not be

the best option.

What are some of my other treatment options?

Taking a statin is one of the most effective ways to lower your risk of cholesterol build up in your arteries

(atherosclerosis). It’s a silent disease that usually develops without any symptoms; and could lead to a

heart attack or stroke.

Statins are the most widely prescribed class of medications in the United

States. Statins reduce the risk of heart attack, stroke and

death in a wide range of patients.

You can benefit from statin therapy to lower your risk. Do you want to retry a low dose

of the statin you have? Or, try another statin at a low dose

once or twice a week? There are seven statins we can try.

Your Care Team includes myself,

a nurse practitioner, registered dietician,and a pharmacist.

We can help.

Although many patients have symptoms during statin therapy, serious side effects related to statins are very uncommon in

clinical trials. Most patients with symptoms during statin therapy can switch to a lower

dose or a different statin.

Take the statin until our next visit.Call me if you have problems before then

and we can decide what to try next.

What resources are available to help me?

* Note. Adapted from “The SHARE Approach,” by the Agency for Healthcare Research and Quality, Content last reviewed August 2018. Retrieved from http://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/index.html

National Forum's Value & Access Initiative is made possible through support from Amgen (Founding Sponsor), Sanofi & Regeneron, the FH Foundation, Mended Hearts, Partnership to Improve Patient Care, and Preventive Cardiovascular Nurses Association.

What is Statin Intolerance?

Seek Your Patient’s Participation

Shared Decision Making for Statin Intolerance

• Taking a statin is one of the most effective ways tolower your risk of atherosclerosis (cholesterol buildup in your arteries).

• Atherosclerosis is a silent disease that usuallydevelops without any symptoms, until there is ablood clot, causing a heart attack or stroke.

• At least 1 in 3 people over their lifetime willexperience a heart attack or stroke that will causedeath or damage to the heart or brain.

• Statins are generally well-tolerated; and reduceall-cause mortality by 10% per 39 mg/dL reductionin LDL "bad" Cholesterol (LDL-C).

• The potential benefits of taking statins outweigh thepotential risks for most people.

What do you need to know about taking statins?• Statins have been studied in clinical trials in 200,000+

people over 30 years and have been shown to be safeand effective in preventing cardiovascular disease.

• Statins are recommended if you have:○ Atherosclerotic cardiovascular disease (ASCVD)○ LDL levels of > 190 mg/dL○ Type 2 diabetes○ An estimated 10-year risk of ASCVD > 7.5% and

are between 40-75 years old

• Rates of muscle, liver and cognitive adverse eventsare similar in statin and placebo groups, and in high- versus moderate-intensity statins.

• Rates of serious myopathy/rhabdomyolysis, orhemorrhagic stroke are about 1/10,000 patients peryear in randomized controlled trials (RCTs).

• In RCTs, the majority of patients reporting intoleranceto two or more statins can tolerate 20 mg ofatorvastatin.

• There are other treatment options that we candiscuss, including: bile acid sequestrants, niacin,ezetimibe, PCSK9 inhibitors, fibrates, and viscousfiber (found in oat bran, legumes, & psyllium).

• Also, swapping mono- or polyunsaturated fats fortrans fats or saturated fats could be beneficial.

• While they help and are important factors for yourcardiovascular disease, diet and lifestyle changesalone don't result in as much LDL-C lowering asthey do in combination with a statin.

• There are seven statins available. Usually you canfind one that provides the best results for you.

Why Is Taking A Statin Important?

Statin intolerance is real, but uncommon.

Below are some side effects that you might feel:

• Muscle aches in the legs, trunk, or shoulders and upper arms

• Muscle weakness

• And uncommonly, other symptoms

Stopping and retrying statins, under medical supervision, can help determine if symptoms are related to treatment. If you experience rhabdomyolysis symptoms (severe muscle pain or weakness, or dark/decreased urination), a very rare side effect, stop your statin and call me right away.

There is a small increased risk for diabetes with statins in people who have other risk factors for diabetes. The benefit of statins for reducing atherosclerosis, heart attack and stroke risk outweighs the small increase in risk of diabetes. Regular physical activity and weight control also reduce the risk of diabetes.

S

Help Your Patient Explore and Compare Treatment OptionsH

Assess Your Patient’s Values and PreferencesA


Let's take a look at the treatment options that are

best for you.

Shared Decision Making for Statin Intolerance

R

E

D

Reach a Decision With Your Patient

Date: _______________ For the next _____ months

Heart-Healthy Diet goals: _________________________________________________________________________________

Exercise goals: ____________________________________________________________________________________________

Other risk factor goals: ____________________________________________________________________________________

___________________________________________________________________________________________________________

Medication: _______________ Medication: ______________ Medication: ______________ Dose Frequency Dose Frequency Dose Frequency

Lab test: _____ months Next appointment: _____ months

My Treatment Plan

What are the benefits of taking a statin for you?

• ______________________________________________________________________________________________________________________________________________________________________________________________________________

What might get in the way of achieving your goals and what can we do about that?

• ______________________________________________________________________________________________________________________________________________________________________________________________________________

Connect with the Cardiovascular Care Team

• Primary Care Physician: __________________________________________

• Nurse Practitioner: _______________________________________________

• Registered Dietician: ______________________________________________

• Genetic Counselor: _________________________________________________________________

• Pharmacist: _________________________________________________________________________

• Other Specialist Referrals: Pediatric Specialist, Cardiologist_________________________________________________

• Health Insurance Plan: ____________________________________________________________________________________

Evaluate Your Patient’s Decision

Decide Which Local Resources Will Effectively Support Your Patient and How To Connect

This is how I connect with my Cardiovascular

Care Team.


*References Guyton JR, Bays HE, Grundy SM, Jacobson TA, “An assessment by the Statin Intolerance Panel: 2014 update” Journal of Clinical Lipidology. March 2014. http://dx.doiorg/10.1016/j.jacl.2014.03.002

Grundy SM, Stone NJ, Bailey AL, et. al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018; DOI: 10.1161/CIR.0000000000000625

Stone NJ, Robinson JG, Lichtenstein AH, et. al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129:S1-S45. doi.org/10.1161/01.cir.0000437738.63853.7a

The symptoms that I’m experiencing while taking my statin(s) include:

Muscle aches in my legs, trunk, shoulders, or upper arms

Muscle weakness

Other: ___________________________

On a scale from 1 to 10, with 1 being hardly noticeable, to 10 entirely negatively impacting my daily routine, I rate my symptoms as a __________.

Are these symptoms tolerable? Y | N

Is my ability to exercise limited by these symptoms? Y | N

It is recommended that you aim to maintain statin treatment in some form. However, the decision of whether to continue taking the statin is up to the patient.

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