CMHC - Cardiometabolic Chronicle VOL. 2 Q1 - MARCH 2019

March 2019, VOL.2 Q1

Special Article Collection

ADDRESSING ASCVD RISK: Treatment of Blood Cholesterol and Beyond • The Challenge of HFpEF: Diagnostic and Treatment Advances • The Role of Real-World Data in the Management of T2DM • Which Nutritional Plan is Appropriate for the Cardiometabolic Patient • Expert Spotlight - Keith C. Ferdinand, MD, FACC, FAHA • The Patient Perspective - When Doctors Use Words That Hurt

LETTER FROM THE EDITOR Welcome to the third issue of Cardiometabolic Chronicle. As this publication continues to move forward, we strive to deliver content that remains relevant to clinical practices, and treating cardiometabolic patients. In staying current with the constantly emerging studies, therapies, and approaches in cardiometabolic medicine, CMHC brings together recognized experts across multidisciplinary fields to help readers better navigate a rapidly changing landscape, and focus on what is most effective in treating patients.

Several expert perspectives are represented in our newly developed section: Clinical Conversations. Pam Taub, MD discusses the impact of pregnancy on both immediate and long-term cardiometabolic health, a topic that will be further explored at the Women’s Health Summit: Navigating Female Cardiometabolic Care at the upcoming CMHC West event in Phoenix. In a conversation between Robert F. Kushner, MD and our co-chair Robert H. Eckel, MD, the clinicians explore the practical management of obesity, with hands-on clinical strategies to implement into practice. Lastly, Deepak Bhatt, MD and our co-chair Christie M. Ballantyne, MD discuss important clinical updates that will be part of the agenda at CMHC West.

Xiaoming Jia, MD explores the prevention and management of atherosclerotic cardiovascular disease (ASCVD) in two featured articles—both of which survey not only the management of elevated cholesterol in light of recently published guidelines, but also the role of other factors: such as triglycerides, inflammation, and Lp(a) in addressing residual ASCVD risk. In an article from our partner Endocrine Today, blood pressure (BP) control in patients with diabetes is analyzed, and key opinion leaders discuss appropriate BP targets and management strategies. Another featured article focuses on the challenge of diagnosing and treating heart failure with preserved ejection fraction (HFpEF), evaluating current and emerging therapies, and the strong association of HFpEF with metabolic syndrome. Additional articles introduce the topic of nutrition and its key role in cardiometabolic health; despite the critical importance of nutrition, clinicians rarely discuss its impact with their patents—primarily stemming from a lack of formal education, and controversies surrounding which plans are most appropriate. Lastly, an article assesses the ever-increasing role of real-world studies, coupled with their advantages and potential pitfalls, in the management of type 2 diabetes.

This issue’s Expert Spotlight features Keith C. Ferdinand, MD, a member of CMHC’s Senior Planning Committee, and an internationally recognized cardiologist. Dr. Ferdinand has dedicated his career to improving patient care— specifically in racial and ethnic minorities—and his interview illuminates aspects of his remarkable professional journey. The Patient Perspective features the story of heart disease patient, women’s health advocate, and author, Carolyn Thomas, as she outlines how commonly used medical jargon can significantly impact patients’ well-being.

Table of contents Featured Articles • Treatment of Blood Cholesterol for Atherosclerotic Cardiovascular Disease Risk Reduction – An Evolving Landscape

• Addressing Residual Atherosclerotic Cardiovascular Risk • For BP management in diabetes, debate continues on optimal definition, targets

3-6 6-8 9-11

• The Role of Real-World Data in The Management of T2DM

12-13

• Which Nutritional Plan Is Appropriate for the Cardiometabolic Patient?

14-15

• The Challenge of HFpEF: Diagnostic and Treatment Advances

16-18

Clinical Conversations • Cardiometabolic Risk Factors in Women

19

• The Practical Management of Obesity

20

• Looking ahead to 2019 CMHC West

21-22

Important 2018 Clinical Trials in Cardiometabolic Medicine

24-28

Patient perspective

When Doctors Use Words That Hurt

29-30

We hope that you enjoy this issue, and appreciate your support.

Expert spotlight

Shpetim Karandrea, PhD Editorial Director

Editorial Director:

Shpetim Karandrea, Ph.D.

Executive Director:

Amanda Jamrogiewicz, CHCP

Publisher: Cardiometabolic Health Congress, 1801 N. Military Trail, Ste 200, Boca Raton, FL 33431 Editorial board:

Neha Agarwal, Ph.D. Sarenka Smith Jessica Schumacher

Marketing and Creative Director:

Elizabeth Wheeler

Advertising & Custom Communications:

Kathleen Powell

Art Director:

Jose Wong

Dr. Keith Ferdinand

31

Disclaimer: Cardiometabolic Chronicle is published by Cardiometabolic Health Congress.

The ideas and opinions expressed in Cardiometabolic Chronicle do not necessarily reflect those of Cardiometabolic Health Congress, its faculty, or its affiliates. The mention of any company, product, service, or therapy in this publication should not be construed as an endorsement of any kind. The information contained in this publication is provided solely for educational purposes. It is the responsibility of the treating physician or other healthcare provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any product or therapy.

Cardiometabolic Chronicle, Cardiometabolic Health Congress, its faculty, and its affiliates assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

Treatment of Blood Cholesterol for Atherosclerotic Cardiovascular Disease Risk Reduction – An Evolving Landscape

By Xiaoming Jia, MD

Introduction Serum cholesterol carried in low density lipoproteins (LDL-C) has been shown to be atherogenic, and likely to have a causal relationship for the development of atherosclerotic cardiovascular disease (ASCVD).1-3 Meanwhile, multiple large randomized clinical trials involving statins, as well as newer non-statin agents— ezetimibe and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors—have demonstrated that lowering LDL-C is associated with reduction in ASCVD events.4-7 As new evidence becomes available, our approach towards the reduction of serum cholesterol has continued to evolve.

The recently released 2018 Cholesterol Guidelines have re-established the importance of targeting serum cholesterol levels: a concept that was de-emphasized since the publication of the 2013 Cholesterol Guidelines.8,9 As providers adapt their clinical practices, it is important to understand the nuances of the latest evidence and guidelines.

Below, we review important updates of the current prevention guidelines, treatment strategies that are available, as well as future therapies under development.

Return of Cholesterol Targets in the 2018 Guidelines

There were several important changes to the 2018 Cholesterol Guidelines compared to the 2013 guidelines. While the 2013 guidelines stressed treatment of patients with high or moderate intensity statin therapy depending on ASCVD risk, there was a move away from explicit cholesterol level targets as in prior guidelines.9,10 Though the 2013 guidelines recommend routine monitoring of lipids in patients on LDL-C lowering therapy, some clinicians may have unintentionally misinterpreted the lack of target cholesterol levels as not needing lab monitoring.11 The 2018 guidelines have clarified this issue by re-establishing target cholesterol goals.

For secondary prevention patients, in particular those who are very high risk, the 2018 guidelines recommend the use of high-intensity statins to achieve a target of LDL-C goal of <70 mg/dL and non-HDL-C goal of <100 mg/dL. If these cholesterol goals are not achieved via maximally tolerated statins alone, the guidelines recommend initiation of ezetimibe followed by a PCSK9 inhibitor. Even in older adults (>75 years of age), the guidelines recommend considering the initiation of high-intensity statins and the continuation of high-intensity statins if the patient was already on therapy (class IIa recommendations). No specific LDL-C

cutoffs are recommended for patients being treated for primary prevention of ASCVD. However, the guidelines suggest the use of high-intensity statins with goal of ≥50% reduction in LDL-C in high risk patients with or without diabetes mellitus as estimated by the Pooled Cohort Equation (10-year risk of developing ASCVD event ≥20%). A goal of ≥30% reduction in LDL-C is recommended in intermediate risk patients with diabetes or those with other risk enhancers.8 Notably, both the 2013 and 2018 guidelines emphasize the need for routine monitoring of fasting lipids and appropriate safety labs. For patients being initiated on LDL-C lowering therapy or undergoing dose adjustment, this entails labs within 4-12 weeks. For patients on a stable regimen, the guidelines recommend routine lipid monitoring every 3-12 months. Previous studies have shown that a significant number of at-risk patients are not on statins, or not on appropriate doses of statins.12,13 Moreover, those who are on therapy may not be adherent to medications.14-16 Thus, to assess the efficacy, adherence, and safety of statins and other LDL-C lowering medications, it is important for clinicians to routinely monitor lipid and safety labs as well as discuss results with their patients. www.cardiometabolichealth.org

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Treatment of Blood Cholesterol for Atherosclerotic Cardiovascular Disease Risk Reduction – An Evolving Landscape LDL-C Lowering Therapies and Strategies Lifestyle modification with diet and exercise remains one of the most important interventions in treating dyslipidemia.

However, patients at higher risk for ASCVD events may require additional pharmacotherapy. Multiple large outcomes trials have demonstrated the efficacy of statins in not only lowering LDL-C, but more importantly, reducing major adverse cardiovascular events both in the primary and secondary prevention of ASCVD.4 Given both the strength of evidence and the costeffectiveness, statins remain the first-line treatment of patients with elevated LDL-C. However, some patients have adverse effects to statin therapy, while others do not respond fully. In these situations, providers should recognize the multiple possible approaches depending on the clinical background and patient/physician preference.

Statin-related side effects are not infrequent in clinical practice. Common side effects are musculoskeletal symptoms and/or elevation of hepatic aminotransferases.17,18 Muscular symptoms, which may range from mild (i.e. fatigue and aches) to severe (rhabdomyolysis), are the most frequent side effects leading to statin non-adherence and discontinuation.19 Potential risk factors for statin-induced myopathy include advanced age, high physical activity, drugs affecting statin metabolism, renal insufficiency, heavy alcohol consumption, and genetic predisposition.20 In patients who cannot tolerate their current statin regimen, strategies include either adjusting dosages, frequency, or type of statins with or without

the addition of non-statin agents versus transitioning to non-statin agents alone.

Given the well-studied cardioprotective benefits of statins, the thought is that patients will derive some benefits even with low doses of medication. Previous data suggest that statins, especially high intensity statins, significantly lower LDL-C, even when given at lower doses or in less frequent intervals. In a study involving 61 patients with history of myalgia, those initiated on either rosuvastatin 5mg or 10mg daily had reduction of LDL-C by 42% and 39% compared to baseline, respectively.21 Only one patient within the cohort discontinued statins due to recurrent myalgia after a 4-week period. Meanwhile, multiple studies assessing the efficacy of alternate-day statin regimens involving lower dose atorvastatin (10mg) or rosuvastatin (5-10mg) have shown significant reduction of LDL-C in the range of 20-30% compared to baseline with good tolerability.22-24 While reduced dosing or less frequent statin regimens may be acceptable alternative strategies in managing patients with hypercholesterolemia, clinicians should understand that there are no outcomes trials directly studying the efficacy of these alternative regimens on ASCVD event reduction. Therefore, these strategies should be pursued only in patients who cannot tolerate full-dose statin therapy.

Non-statin therapy such as bile acid–binding resins and niacin are older medications that lower LDL-C but have not been shown to improve outcomes when added to statins. However, in recent years, nonstatin therapies that have been shown to

lower LDL-C and reduce ASCVD events have become available. Ezetimibe is an oral medication that blocks cholesterol absorption by inhibiting the cholesterol transport protein Niemann–Pick C1–like 1 (NPC1L1) protein in the intestine.25 On the background of maximally tolerated statins, ezetimibe has been shown to further lower LDL-C by 23.4% compared to statin alone.26 As a monotherapy, ezetimibe was shown to reduce LDL-C by 18.6% in a previous meta-analysis.27 Most importantly, ezetimibe in the background of statin therapy was shown in the IMPROVE-IT trial to improve cardiovascular outcomes in high-risk, secondary prevention patients.5 Furthermore, as ezetimibe is currently a generic medication, it represents a cost-effective second-line agent in patients who require additional lowering of LDL-C. The second class of non-statin agents that has been shown to reduce cardiovascular events includes PCKS9 inhibitors. The two available and approved medications in this class are evolocumab and alirocumab: both fully human monoclonal antibodies (mABs). The FOURIER trial, a large study randomizing 27,564 high-risk patients on statins with a history of ASCVD to receive evolocumab or placebo, demonstrated LDL-C reduction of 59% in the treatment arm at 48 weeks.6 At a median follow-up of 2.2 years, evolocumab in combination with statin was shown to have a relative risk reduction (RRR) of 15% (absolute risk reduction [ARR] of 1.5%) in ASCVD events (primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) compared with the placebo group.

Meanwhile, the ODYSSEY Outcomes trial demonstrated the efficacy of alirocumab in the reduction of LDL-C (54.7%) as well as major cardiovascular events (RRR 15%; ARR 1.6%) in 18,924 patients with acute coronary syndrome at a median follow-up of 2.8 years.7 Though evolocumab and alirocumab are effective in the reduction of LDL-C and ASCVD events, these agents have high cost.

As such, current guidelines recommend the use of PCSK9 inhibitors in secondary prevention patients who are not at LDL-C target levels despite being on maximally tolerated statins and ezetimibe.8 PCSK9 inhibitors are also approved for use in special cases of primary prevention when serum cholesterol levels are extremely elevated (i.e. familial hypercholesterolemia).

Is Lower LDL-C Better?

With the advent of new LDL-C lowering medications, it is feasible to achieve very low levels of LDL-C. The mean LDL-C level achieved when ezetimibe was added to statin therapy was 54mg/dl in IMPROVE-IT.5 In the FOURIER trial, the median LDL-C achieved at 48 weeks was 30mg/dL, while in the ODYSSEY OUTCOMES trial, the mean LDL-C level at 12 months was 48mg/dL.6,7 Data from these large outcome trials suggest

4

www.cardiometabolichealth.org

Treatment of Blood Cholesterol for Atherosclerotic Cardiovascular Disease Risk Reduction – An Evolving Landscape that treating LDL-C to levels well below guideline-recommended goals to ranges of 30-50mg/dL may continue to confer additional cardioprotective benefits. However, the safety of reaching and maintaining such low levels of LDL-C has become an increasingly important topic of discussion.

Cholesterol is essential to basic cellular membrane integrity, and plays an essential role in adrenocortical and hepatobiliary function.28 Earlier observational studies and some findings from clinical trials have raised concerns that low serum cholesterol levels were associated with disruption in production of steroid based hormones and absorption of fat-soluble vitamins, in addition to increased rates of adverse events. For instance, previous findings of a U-shape relationship in total mortality with respect to total cholesterol levels link low ranges of total cholesterol with higher rates of non-cardiovascular deaths.29 Some previous studies on statins have reported association between treatment to low LDL-C levels and increased risk of cancers, and hemorrhagic strokes.30,31 Post-hoc analysis from the JUPITER trial also found association between low LDL-C (<30mg/dL) with diabetes with some subsequent metaanalysis also showing increased association with higher intensity statin regimens with diabetes.32,33 Some evidence of cognitive decline was also observed in earlier studies involving treatment with PCSK9 inhibitors.34 With respect to cancers and hemorrhagic strokes, new data—especially from more recent, larger outcomes trials—do not appear to support association between treatment lowered LDL-C thresholds with adverse events. Randomized control data including meta-analysis from the Cholesterol Treatment Trialists’ (CTT) Collaboration did not find significant differences in cancer incidence, mortality, or any non-vascular mortality in statin compared with control groups.4 Furthermore, longitudinal safety data from IMPROVE-IT, FOURIER and ODDYSSEY OUTCOMES trials did not show any significant differences in major adverse events including incidence of diabetes, hemorrhagic strokes, neurocognitive decline or cancers.5-7,35,36 There were also no differences in levels of fat soluble vitamins and steroid hormone levels detected between the treatment and control arms. In pooled analysis of trials involving alirocumab, very low achieved levels of LDL-C were associated with more cataracts.36 With regards to diabetes, it is unclear whether the association is with statins or with achieving very low LDL-C levels. Again, studies of ezetimibe and PCSK9 inhibitors did not demonstrate increased incidence of diabetes despite low LDL-C levels achieved, although the majority of patients included in FOURIER and ODDYSSEY OUTCOMES were also on high intensity statins at baseline. Taken as a whole, the benefit of

lowering LDL-C and reducing ASCVD risk, especially in high risk patient groups, likely outweighs the possibility for incident diabetes. Thus, treatment to LDL-C ranges of 30-50mg/dL likely confers a net benefit, from cardiovascular risk reduction. As such, the 2018 guideline recommends using clinical judgement regarding whether to de-intensify LDL-C lowering therapy in the setting of two repeat labs showing LDL-C levels <25mg/dL. Therapies on the Horizon Continuing research into new therapies targeting LDL-C have the potential to provide clinicians with additional tools in preventing ASCVD events. Two new agents in the developmental pipeline to note are inclisiran and bempedoic acid.

Inclisiran is a small interfering RNA (siRNA) molecule, administered as subcutaneous injections, against PCSK9.37 In a phase 2 trial, inclisiran was shown to significantly reduce PCKS9 and LDL-C levels in a dose-dependent manner, with effects on lipid profile persisting over 6 months even after single dose.38 The long half-life of inclisiran has the potential to allow for drug administration every several months, which may improve ease of use as well as adherence compared to current PCSK9 mAb agents, which requires either once or twice per month administration. However, the pharmacodynamics features can also lead to longer duration of side effects, should they develop. The most common adverse effects observed were musculoskeletal pain, headache, nasopharyngeal symptoms, dizziness, fatigue, hypertension and diarrhea.

Serious adverse events were not significantly different between treatment and placebo groups in previous trials (Ray NEJM 2017).

Several phase 3 clinical trials (ORION-9, 10, 11) (ClinicalTrials.gov Identifier: NCT03397121; ClinicalTrials.gov Identifier: NCT03399370; ClinicalTrials.gov Identifier: NCT03400800), including a cardiovascular outcomes trial (ORION-4) (ClinicalTrials.gov Identifier: NCT03705234) are underway.

Bempedoic acid, on the other hand, is an oral agent that targets the adenosine triphosphate (ATP) citrate lyase (ACL): an enzyme within the cholesterol synthesis pathway upstream of HMG-CoA reductase. Several clinical trials have shown safety and efficacy of bempedoic acid in patients with elevated LDL-C. Bempedoic acid was shown to reduce LDL-C in a dose dependent fashion up to 26.6% in hypercholesterolemia patients with or without elevated triglycerides.39 In a study of patients with hypercholesterolemia and diabetes, the group on bempedoic acid had a significant reduction of LDL-C by 39% and non-high-density-lipoprotein cholesterol (nonHDL-C) by 31.4% compared to placebo.40 Meanwhile, the combination bempedoic acid with ezetimibe was shown in the phase 3 CLEAR-Tranquility trial to reduce LDL-C by 28.5% when compared with ezetimibe alone, which may represent a beneficial therapeutic

option for patients who cannot tolerate statin therapy.41 Several ongoing phase 3 clinical trials involving bempedoic acid include an outcome trial: CLEAR Outcomes (ClinicalTrials.gov Identifier: NCT02993406).

Conclusion Although LDL-C and non-HDL-C are well-established risk factors for ASCVD, nuances in treatment of serum cholesterol have continued to evolve. Growing evidence suggests that treatment of LDL-C and nonHDL-C to lower targets may confer additional ASCVD risk reduction, especially in high risk patients. And while statins remain the first line therapy for LDL-C reduction, ezetimibe and PCSK9 inhibitors provide additional, evidence-based options when additional therapies are needed to achieve cholesterol targets, or when patients have significant statin-associated side effects. Moreover, newer therapies are in development that will further expand the horizon for LDL-C treatment.

Xiaoming Jia, MD is a Lipid and Atherosclerosis Fellow at the Baylor College of Medicine in Houston, TX

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16. Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA, Choudhry NK. Gender and racial disparities in adherence to statin therapy: a metaanalysis. Am Heart J. 2013;165(5):665-78, 78 e1.

17. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6(4):390-9.

18. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al. Statin-associated muscle symptoms: impact on statin therapyEuropean Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-22.

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22. Keles T, Akar Bayram N, Kayhan T, Canbay A, Sahin D, Durmaz T, et al. The comparison of the effects of standard 20 mg atorvastatin daily and 20 mg atorvastatin every other day on serum LDLcholesterol and high sensitive C-reactive protein levels. Anadolu Kardiyol Derg. 2008;8(6):407-12.

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32. Everett BM, Mora S, Glynn RJ, MacFadyen J, Ridker PM. Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER). Am J Cardiol. 2014;114(11):1682-9.

33. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderatedose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556-64.

34. Khan AR, Bavishi C, Riaz H, Farid TA, Khan S, Atlas M, et al. Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase SubtilisinKexin Type 9 Inhibitors. Circ Cardiovasc Qual Outcomes. 2017;10(1).

35. Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):196271.

36. Robinson JG, Rosenson RS, Farnier M, Chaudhari U, Sasiela WJ, Merlet L, et al. Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data From Randomized Trials.

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37. Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017;376(1):41-51.

38. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

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39. Ballantyne CM, Davidson MH, Macdougall DE, Bays HE, Dicarlo LA, Rosenberg NL, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebocontrolled, parallel-group trial. J Am Coll Cardiol.

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40. Gutierrez MJ, Rosenberg NL, Macdougall DE, Hanselman JC, Margulies JR, Strange P, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoproteincholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol.

2014;34(3):676-83.

41. Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statinintolerant patients with hypercholesterolemia: A randomized, placebo-controlled study.

Atherosclerosis. 2018;277:195-203.

Addressing Residual Atherosclerotic Cardiovascular Risk

By Xiaoming Jia, MD

Introduction Atherosclerotic cardiovascular disease (ASCVD) remains a major cause of mortality worldwide. To address this significant public health issue, prevention and treatment of ASCVD continues to be an area of intense research. Over the last few decades, our understanding of the mechanism of atherosclerosis has undergone several paradigm shifts, evolving from a simplistic model of cholesterol deposition to a complex system that encompasses interactions between dyslipidemia, inflammation, metabolic disturbances, endothelial dysfunction, and other yet-to-bediscovered risks. Therefore, while lowering LDL cholesterol (LDL-C) remains central in the prevention and treatment of ASCVD, the enhanced perspective has yielded further opportunities to improve risk assessmentâ&#x20AC;&#x201D; while providing additional therapeutic targets against ASCVD beyond control of LDL-C. Below, we outline the roles of triglyceride rich lipoproteins, lipoprotein (a), and inflammation as contributors of residual ASCVD risk outside of LDL-C, and provide insight into the current status and future potential for clinical application.

Triglycerides Elevated triglycerides, along with low HDL-C, insulin resistance, and dysglycemia constitute a pattern of metabolic dysfunction associated with increased risk for cardiovascular disease. Triglycerides are primarily carried in chylomicrons, very low-density lipoprotein particles (VLDL), and their remnant particles while in circulation. Current epidemiologic and Mendelian randomization studies support elevated levels of these triglyceride-rich lipoproteins (TRLs) as a likely causal risk factor for ASCVD.1-5 Experimental data have shown that while larger particles are not atherogenic, smaller remnant particles readily penetrate into the arterial intima and promote atherosclerosis.2,6,7 Indirectly, TRL remnants are thought to drive accelerated atherogenesis by promoting endothelial dysfunction and activating pro-inflammatory pathways.8,9 Whether it is the triglycerides or remnant cholesterol carried in TRLs that represent the culprit for atherogenesis remains a nuanced subject of continued research.

Present evidence suggests that remnant cholesterol is associated with increased ASCVD risk,10,11 though some data suggest that TGs may also play a role.2,12 As such, elevated TGs should be recognized as a marker of ASCVD when risk stratifying patients. In the 2018 Cholesterol Guidelines,

elevated TGs >175mg/dL represents a risk-enhancing factor to determine need for statin therapy.13 Earlier outcomes trial data investigating TG lowering therapies including fibrates, niacin, and omega-3 fatty acids when used with statin therapy have largely been unsuccessful in showing significant reduction in risk for ASCVD events. However, recent outcome trials on higher dosing of purified omega-3 eicosapentaenoic acid (EPA), icosapent ethyl, was associated with significant reduction in ASCVD events when compared with placebo.14,15 Moreover, several novel therapies targeting steps in pathways in TRL metabolism are being developed, including agents against apoCIII and ANGPTL3.16,17 These new therapies represent potential tools for targeting residual risk from TRLs in the prevention and treatment of ASCVD. Lp(a) Like TRLs, Lp(a) has been shown to be a causal risk factor for ASCVD in both epidemiological and Mendelian randomization studies.18,19 Lp(a) is a cholesterol-rich lipoprotein with a similar structure and lipid content to that of LDL.20 However, Lp(a) also contains apo(a), a lipoprotein containing variable length kringle motifs resembling those found in plasminogen. The unique molecular structure of Lp(a) is thought to contribute to both atherogenic as well as thrombogenic risks. Specifically in patients with a history of premature ASCVD, those without significant traditional risk factors, or in the setting of strong family history of premature ASCVD, testing for Lp(a) may be considered.

With improved qualities of assays, testing for Lp(a) has been increasingly adopted into clinical practice, and elevated Lp(a) is recognized as a risk enhancing factor for initiation of statin therapy. It should be noted, however, that statins have not been shown to significantly affect Lp(a) levels, and the purpose of statin therapy in cases of elevated Lp(a) is to optimize risk via lowering of LDL-C.21 Of the currently available therapies, niacin and PCSK9 inhibitors are known to reduce Lp(a) levels. However, post-hoc analysis of randomized clinical trials do not demonstrate strong evidence to indicate that reduction of Lp(a) with these medications is associated with reduction in events, and no major outcomes trials directly assessing efficacy in patients with elevated Lp(a) using these medications have been performed.22,23 More recently, development of the novel antisense oligonucleotides against apo(a) may provide a potential therapeutic option of targeting Lp(a) in the future. Phase 2 data have shown mean Lp(a) reduction of between 66.8%-71.6% compared to placebo, though outcome trials investigating how the dramatic reduction in Lp(a) will translate to reduction in ASCVD risk will be warranted.24 Inflammation With the understanding that atherosclerosis has evolved far beyond cholesterol deposition into the arterial wall, inflammation has emerged as an important component of atherogenesis. Increased expression of adhesion molecules occurs around atheroma and promote localization of monocyte and T-cells and penetration of immune cells into the arterial wall. Once in the intima, these immune cells express various cytokines and chemokines that begin a cascade of local inflammatory response. Present evidence from both animal and human models support important roles of immune cells and mediators in plaque progression and rupture.25 From a clinical perspective, high sensitivity C reactive protein (hs-CRP) has been validated in epidemiological studies as a biomarker of ASCVD risk.26-28 An hs-CRP level greater or equal to 2mg/L is considered an ASCVD risk enhancer in the current cholesterol treatment guidelines.13 Though hs-CRP may vary significantly with acute inflammatory processes such as infections, providers should recognize that chronic conditions such as metabolic syndrome, diabetes, and obesity all represent pro-inflammatory disease states.

More importantly, therapies that reduce inflammation have been shown to reduce www.cardiometabolichealth.org

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Addressing Residual Atherosclerotic Cardiovascular Risk

risk for future ASCVD events. Analysis of patient data from the JUPITER trial showed that patients with achieved hsCRP < 2mg/L had reduction in ASCVD risk, in addition to reduction in LDL-C: suggesting that hs-CRP may not only be a useful biomarker for risk assessment of ASCVD, but also one with utility in assessing efficacy of treatment.29 The concept of specifically targeting inflammation for reduction of ASCVD risk was demonstrated through the CANTOS trial. Results from CANTOS showed that treatment with canakinumab, a monoclonal antibody against interleukin-1β, at 150mg every 3 months was associated with significant reduction in ASCVD events when compared to placebo in patients with evidence of increased inflammation as characterized by elevated hs-CRP.30 Of note, the recent CIRT trial involving low dose methotrexate did not show significance in ASCVD event reduction in high risk patients, although methotrexate did not induce significant changes in any of the pre-specified inflammatory biomarkers measured—and the overall mean hs-CRP were much lower in CIRT compared to CANTOS.31 Taken together, data from CANTOS and CIRT suggest that the role of inflammation in progression of atherosclerotic disease is likely mediated through specific pathways: i.e. those involving IL-1β. Improved understanding of these pathways has the potential to yield further targets for therapy.

Conclusion Atherosclerosis involves the convergence of multiple pathologic processes including dyslipidemia, endothelial dysfunction, inflammation, and other likely still unknown contributors. While hypercholesterolemia is an important, modifiable risk factor of ASCVD, residual risk may be present after optimization of LDL-C levels. Hypertriglyceridemia, Lp(a), and inflammation are important risk factors for ASCVD, and have been incorporated in guidelines for use in risk assessment.

Moreover, these risk factors are becoming increasingly recognized as targets for therapy in the prevention and treatment of ASCVD. Xiaoming Jia, MD is a Lipid and Atherosclerosis Fellow at the Baylor College of Medicine in Houston, TX References 1. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115(4):4508.

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2. Lawler PR, Akinkuolie AO, Chu AY, Shah SH, Kraus WE, Craig D, et al. Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol. J Am Heart Assoc.

2017;6(7).

3. Triglyceride Coronary Disease Genetics C, Emerging Risk Factors C, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375(9726):1634-9.

4. Jorgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjaerg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013;34(24):1826-33.

5. Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22-31.

6. Nordestgaard BG, Stender S, Kjeldsen K. Reduced atherogenesis in cholesterol-fed diabetic rabbits.

Giant lipoproteins do not enter the arterial wall.

Arteriosclerosis. 1988;8(4):421-8.

7. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32(11):1345-61.

8. Alipour A, van Oostrom AJ, Izraeljan A, Verseyden C, Collins JM, Frayn KN, et al. Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28(4):792-7.

9. Ting HJ, Stice JP, Schaff UY, Hui DY, Rutledge JC, Knowlton AA, et al. Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha.

Circ Res. 2007;100(3):381-90.

10. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61(4):427-36.

11. Jepsen AM, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased Remnant Cholesterol Explains Part of Residual Risk of All-Cause Mortality in 5414 Patients with Ischemic Heart Disease. Clin Chem. 2016;62(4):593-604.

12. Saeed A, Feofanova EV, Yu B, Sun W, Virani SS, Nambi V, et al. Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease. J Am Coll Cardiol.

2018;72(2):156-69.

13. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, 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. J Am Coll Cardiol. 2018.

14. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.

N Engl J Med. 2019;380(1):11-22.

15. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet.

2007;369(9567):1090-8.

16. Gaudet D, Alexander VJ, Baker BF, Brisson D,

Tremblay K, Singleton W, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373(5):438-47.

17. Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222-32.

18. Emerging Risk Factors C, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-23.

19. Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol. 2014;64(9):851-60.

20. Banach M. Lipoprotein (a)-We Know So Much Yet Still Have Much to Learn. J Am Heart Assoc.

2016;5(4).

21. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129(6):635-42.

22. Ooi EM, Watts GF, Chan DC, Pang J, Tenneti VS, Hamilton SJ, et al. Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2015;35(12):2686-93.

23. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, et al. Lipoprotein(a), PCSK9 Inhibition and Cardiovascular Risk: Insights from the FOURIER Trial. Circulation. 2018.

24. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet.

2016;388(10057):2239-53.

25. Vaccarezza M, Balla C, Rizzo P. Atherosclerosis as an inflammatory disease: Doubts? No more. Int J Cardiol Heart Vasc. 2018;19:1-2.

26. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14):973-9.

27. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.

N Engl J Med. 2000;342(12):836-43.

28. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557-65.

29. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet.

2009;373(9670):1175-82.

30. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31.

31. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

N Engl J Med. 2018.

For BP management in diabetes,

debate continues on optimal definition, targets

By Endocrine Today

In November of 2017, a revised guideline from the American Heart Association, the American College of Cardiology and nine other societies redefined hypertension as blood pressure greater than 130 mm Hg/80 mm Hg. The updated guideline, which lowered the threshold for hypertension from 140 mm Hg/90 mm Hg and also eliminated the category of pre-hypertension, created a new diagnosis for millions of Americans virtually overnight. For adults with diabetes, however, a debate continues regarding the optimal BP threshold and treatment target.

In September 2017, a guideline issued by the American Diabetes Association included the more relaxed BP goal of less than 140 mm Hg/90 mm Hg for most people with diabetes and emphasized the need to individualize specific BP targets for each patient. The dueling American Heart Association (AHA) and ADA guidelines have been a source of debate since they were published. At professional meetings, clinicians continue to offer differing opinions on whether a mantra of “the lower, the better” or a more nuanced BP goal for some patients with diabetes is the right strategy.

“This is a timely topic and there has been a great deal of discussion and controversy among physicians,” Helena W. Rodbard, MD, FACP, MACE, medical director of Endocrine and Metabolic Consultants in Rockville, Maryland, and a past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology, told Endocrine Today.

“People with diabetes have an increased risk for cardiovascular events. We must not be narrowly glucocentric and address exclusively glycemic control. We must also address blood pressure and lipids in conjunction with glycemic control.” Different trials have demonstrated potential CV risk and benefit — depending on diabetes status — when treating to a systolic BP target less than 120 mm Hg, further complicating the debate, according to experts. “I am partial to the AHA/[American College of Cardiology] goal of 130/80 mm Hg,” Rodbard said. “The guidelines do recommend individualization.

That’s true for glycemic control, and it’s true for blood pressure. We must use our clinical judgment, which takes priority over anything else. Some people advocate higher numbers.

Lower is better, as long as it can be achieved safely.”

In an editorial published on April 2018 in JAMA, George L. Bakris, MD, FAHA, professor of medicine and director of the Comprehensive Hypertension Center at University of Chicago Medicine and Endocrine Today Editorial Board Member, and colleagues defended the higher ADA recommendation, noting that available evidence suggests that BP targets lower than 140 mm Hg/90 mm Hg yield CV benefits for some populations, but also increase risk for adverse events. The ADA recommendation, the researchers argued, distinguishes BP thresholds used to diagnose hypertension from those used as treatment targets, similar to ADA recommendations for HbA1c thresholds. “If you look at the totality of the data that exists, 100% of it defends a blood pressure of < 140/90 mm Hg for people with diabetes, and for that matter, people without diabetes,” Bakris told Endocrine Today. “That is irrefutable, defendable and there should be no question about that. The real issue is, what are we doing arguing about 10 mm Hg lower? The old edict was, ‘Let’s get people as low as you can go.’ We know that’s wrong. So, where are we?”

A looming debate Before the updated 2017 position statement, the ADA recommended treating to a systolic BP target of less than 130 mm Hg, but that goal was relaxed after findings from the ACCORD-BP trial demonstrated an increased risk for adverse events in adults with advanced type 2 diabetes treated to a target of less than 120 mm Hg vs. those treated to a target of less than 140 mm Hg. In ACCORD-BP, researchers observed no between-group differences for the primary composite CV outcome, which included myocardial infarction, stroke and CV death (HR = 0.88; 95% CI, 0.73-1.06), as well as an increased risk for adverse events in the intensive BP group, including elevations in serum creatinine and electrolyte abnormalities.

“This is a timely topic and there has been a great deal of discussion and controversy among physicians.”

–Helena W. Rodbard, MD, FACP, MACE

More recently, the SPRINT trial demonstrated that intensive control to a systolic BP of less than 120 mm Hg resulted in CV benefit in high-risk patients with hypertension — but without diabetes — vs. routine BP control to less than 140 mm Hg. In a recent post-hoc analysis of ACCORD patients meeting SPRINT criteria (hypertension and at least one risk factor for CVD), researchers observed a benefit for the

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For BP management in diabetes, debate continues on optimal definition, targets

“People with diabetes have an increased risk for cardiovascular events.”

–Helena W. Rodbard, MD, FACP, MACE

more intensive BP group; however, patients in both SPRINT and ACCORD had a greater than 15% 10-year CV risk. “So, it becomes somewhat controversial as to whether we can apply those [SPRINT] results to people with diabetes, when in the ACCORD study it didn’t work,” Vivian A. Fonseca, MD, assistant dean for clinical research at Tulane University School of Medicine, told Endocrine Today. “We need to look at it in the context of in whom these trials were done. The ACCORD study population had much more advanced cardiovascular disease, where it may have been too late to change the natural course of the disease.”

In the 2018 consensus statement issued by the AACE and the American College of Endocrinology (ACE), the authors recommend that BP control be individualized, but that a target of less than 130 mm Hg/80 mm Hg is appropriate for most patients. “Less stringent goals may be considered for frail patients with complicated comorbidities or those who have adverse medication effects, while a more intensive goal (eg, < 120/80 mm Hg) should be considered for some patients if this target can be reached safely without adverse effects from medication,” Endocrine Today Chief Medical Editor Alan J. Garber, MD, PhD, MACE, professor in the departments of medicine, biochemistry and molecular biology, and molecular and cellular biology at Baylor College of Medicine in Houston, and colleagues wrote in the consensus statement.

The lack of a randomized controlled clinical trial in patients with diabetes that is designed to assess targets for BP control with

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outcomes such as CV events and mortality have contributed to the confusion concerning an optimal target, according to W. Timothy Garvey, MD, FACE, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham. “When you get a situation like that, you’re going to have disagreement because everyone has to put the available data, the existing clinical trials, together and try to come up with the best judgment on how to interpret the totality of the data,” said Garvey, also a co-author of the AACE/ ACE consensus statement. “I’m in favor of the AACE and AHA/[American College of Cardiology] recommendations, which I think are in fairly good agreement, and that is to try to control blood pressure to 130/80 mm Hg or below in patients with diabetes, and even try to achieve 120/80 mm Hg if it can be safely achieved in patients with very high degrees of risk.”

Lower targets, increased risk In adults with type 2 diabetes and comorbid hypertension without CVD, evidence has suggested that achieving a target systolic BP less than 130 mm Hg was not associated with a reduction in CV risk vs. similar patients treated to a systolic BP between 130 mm Hg and 140 mm Hg. In an analysis published online in April in Diabetes Care, Eric Wan Yuk Fai, a doctoral student in the department of family medicine and primary care at the University of Hong Kong, and colleagues analyzed data from 28,014 adults managed in general outpatient clinics of the Hong Kong Hospital Authority with type 2 diabetes and hypertension (systolic BP 130 mm Hg) and without a prior history of

CVD, recruited between 2009 and 2011.

Participants were stratified into three achieved systolic BP groups: less than 120 mm Hg (n = 2,079; mean age, 67 years), less than 130 mm Hg (n = 10,851; mean age, 66 years) and less than 140 mm Hg (n = 15,084; mean age, 67 years). Participants were followed from baseline (date when patients first had an increase in antihypertensive drugs prescribed) to the date of CVD event, all-cause mortality or November 2015.

The primary outcome was a CVD event, and secondary outcomes included incident coronary heart disease, heart failure, stroke and all-cause mortality. Researchers used Cox proportional hazards regression to estimate the effect of different systolic BP groups on the incidence of CVD events.

Using patients who achieved a systolic BP target of 140 mm Hg as the reference group, those who achieved a target systolic BP less than 120 mm Hg saw a marked increase in the incidence of CVD (HR = 1.67; 95% CI, 1.46-1.9); no difference in likelihood was seen in those who achieved a target systolic BP less than 130 mm Hg. Results persisted after stratifying by CVD subtype. Achieving systolic BP targets of less than 120 mm Hg and less than 130 mm Hg was associated with an increase in all-cause mortality, with HRs of 2.28 and 1.19, respectively (P = .003), when compared with patients treated to the systolic target of less than 140 mm Hg. Differing findings associated with patient comorbidities and risk factors illustrate the need for individualized treatment, with goal decided on by the patient and clinician together, according to George

For BP management in diabetes, debate continues on optimal definition, targets Grunberger, MD, FACP, FACE, chairman of the Grunberger Diabetes Institute in Bloomfield Hills, Michigan. The differing BP targets, he said, have the same underlying goal. “It’s one thing to say, the higher the worse, and, theoretically, the lower the better, when you talk about glucose, HbA1c, LDL cholesterol and blood pressure,” Grunberger told Endocrine Today. “But if you have a sick individual with established atherosclerosis, for example, and you force that blood pressure down, will you actually be able to achieve immortality? That’s the dilemma with all these trials.”

“People sometimes view these guidelines as edicts from god,” Bakris said. “The reality is these are put together by people. It’s not just about the numbers. It’s about the patients and the process.” But a lower BP target also reflects a reality that many patients simply will not reach it, Rodbard said. “Different people are partial to one set of studies over another,” Rodbard said. “The reality is that most people don’t really achieve the goal of 130/80 mm Hg, just like most people don’t have an HbA1c of less than 7%.”

Rodbard said it is important to remember the motivation that comes with a lower BP target, for both clinicians and patients. “A certain goal doesn’t mean we achieve that level,” Rodbard said. “If we start aiming for 140/90 mm Hg, people are going to be walking around at even higher [BP] levels.

If you aim for 130/80 mm Hg, maybe the patient will achieve, say, 135/85 mm Hg, or somewhere in between.”

Management strategies In position statements from AACE and ADA and the AHA/American College of Cardiology guideline, recommendations for the treatment of confirmed hypertension in people with diabetes are similar: angiotensinconverting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) and thiazide diuretics are favored choices for first-line treatment. The selection of therapies should be based on factors such as presence of albuminuria, CVD, heart failure and patient race. For many patients with diabetes and comorbid hypertension, combination therapy with multiple agents is needed to reach a defined target. The AACE algorithm, for example, recommends that patients with BP 150 mm Hg/100 mm Hg or higher start immediately on combination therapy, including an ACE inhibitor or ARB, and one of the other agents.

“If the person comes in with BP 160/90 or above, you have to settle on at least two agents,” Garvey said. “It takes multiple agents to control substantially elevated BP in these patients. The only caveat is some of these patients might be overweight or obese, and weight-loss therapy can improve all the CV risk factors. So, weight loss is also a good option that’s been shown to lower BP while reducing the need for antihypertensives in

some studies.” Garvey said other therapy choices include one of the new vasodilatory beta-blockers, such as carvedilol, which has been shown to have fewer adverse metabolic effects vs. older beta-blockers.

Bakris noted that an ACE inhibitor or ARB does not have to be the first-line choice in the setting of diabetes without kidney disease, defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 or at least 300 mg albuminuria per day. “If you do not have kidney disease — microalbuminuria, which is not kidney disease, by the way — and an eGFR above 60, then I don’t care what you use,” Bakris said. “You can use a diuretic, a [renin-angiotensin-aldosterone system] blocker, a CCB, any of those are fine to get the blood pressure down. That’s what the ACC says, and that’s what [the ADA] says.

“The old edict of ‘You have diabetes, boom, you’re on an ACE inhibitor’ is gone,” Bakris said. “There is no evidence to support that rationale, but that doesn’t mean you shouldn’t do it.”

Increasing patient burden For people with diabetes and hypertension, the biggest challenge in reaching an intensive BP goal is the need to take multiple antihypertensive medications, Rodbard said.

“Medication adherence and persistence are major concerns, particularly for people with chronic diseases, such as diabetes and hypertension,” Rodbard said. “As a clinician, I try to simplify the therapeutic regimen as much as possible, minimizing the number of drugs while maintaining efficacy.”

To help decrease medication burden when managing hypertension in the setting of diabetes, Rodbard said clinicians should prescribe therapies with complementary modes of action and opt for drugs that have prolonged effect. In studies that aimed to achieve intensive BP control, the average number of agents used was 3.8, Grunberger said, adding that clinicians sometimes forget that it may take three or four agents to reach a BP target.

“That gets back to the original issue: What are you, as a clinician, going to ask patients to do, knowing that they are not going to feel any better?” Grunberger said. “No one ever comes to me saying, ‘My blood pressure hurts’ or ‘My cholesterol is really bothering me.’ And then I’m going to put them on 12 drugs that will certainly cause them financial strain no matter what insurance plan they have and, probably, one or more side effects, and they won’t feel any better. Then people are surprised that 60% of people are not still taking their medications at 1 year, and this is for life.”

Grunberger emphasized the importance of presenting patients with treatment options.

Not every patient, he said, will want to take on the burden of intensive BP control, and it is important to discuss that idea up front.

“These days, I can bring anyone’s blood pressure, cholesterol or glucose down to any level I want, theoretically,” Grunberger said.

“You have to look at a completely different issue: Will the patient with a specific blood pressure live a longer, happier life? We don’t have the answer for that.”

It is also important to consider other changes to improve other risk factors, Garvey said. “When we talk about blood pressure, it’s important that we engage in total risk factor improvement,” Garvey said.

“If we pay attention to glycemia, lipids and blood pressure all together, we can improve outcomes over and above paying attention to any one of those factors alone. So, blood pressure, yes, but, we must look at it in the context of the overall risk burden.”

This article was originally published in Endocrine Today and is reprinted with permission. For more content and information, visit Healio.com/Endocrinology

References: de Boer, Ian H., George Bakris, and Christopher P. Cannon. “Individualizing Blood Pressure Targets for People With Diabetes and Hypertension: Comparing the ADA and the ACC/AHA Recommendations.”

JAMA 319.13 (2018): 1319-1320.

De Boer, Ian H., et al. “Diabetes and hypertension: a position statement by the American Diabetes Association.” Diabetes Care 40.9 (2017): 1273-1284.

Garber, Alan J., et al. “Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm–2018 executive summary.” Endocrine Practice 24.1 (2018): 91-120.

Wan, Eric Yuk Fai, et al. “Effect of Achieved Systolic Blood Pressure on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus: A PopulationBased Retrospective Cohort Study.” Diabetes Care (2018): dc172443.

Whelton, Paul K., et al. “2017 ACC/AHA/AAPA/ ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology 71.19 (2018): e127-e248.

Disclosures: Bakris reports he is a principal investigator for studies for Bayer, a steering committee member for trials sponsored by Janssen and Vascular Dynamics and a consultant for Merck, Relypsa and Vascular Dynamics. Fonseca reports receiving contracted research payments (paid to institution) from Abbott, Asahi, Eli Lilly, Endo Barrier, Gilead Sciences and Novo Nordisk; receiving consultant fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Pamlab, Sanofi-Aventis and Takeda; and serving on speakers bureaus for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Pamlab, Sanofi-Aventis, Takeda. Garvey reports he is a consultant for the American Medical Group Association, Merck and Novo Nordisk. Rodbard reports she has received grant support and consultant fees from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk and Sanofi.

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The Role of Real-World Data in The Management of T2DM

The Role of RealWorld Data in The Management of T2DM

By Shpetim Karandrea, PhD

More than 30.3 million individuals, or 9.4% of the US population, have diabetes -- with type 2 diabetes mellitus (T2DM) accounting for 90-95% of total diabetes cases.1 T2DM is associated with multiple comorbidities, including cardiovascular disease (CVD), hypertension, obesity, dyslipidemia and kidney disease, which increase its morbidity and mortality and complicate treatment decisions.2 Death from CV disease (CVD) is 70% higher in adults with diabetes compared to those without diabetes, and patients with diabetes have a decreased life expectancy, mostly due to premature CV death.3 The recent and continuously emerging results from cardiovascular outcomes trials (CVOTs) with the newer antihyperglycemic drugs have shown not only cardiovascular safety, but also CV benefits in addition to non-CV (renal, blood pressure, weight loss) beneficial effects, and are poised to change the clinical management of T2DM and its comorbidities.3 As such, guidelines to individualize T2DM therapy based on patientsâ&#x20AC;&#x2122; comorbidities have already changed according to the results from these landmark randomized clinical trials (RCTs).4 However, while RCTs are the gold-standard for evaluating the safety and efficacy of new pharmacotherapies, including for T2DM, the exclusion of many patient populations due to strict criteria in RCTs can sometimes mean that the population studied does not fully represent the patients seen in everyday practice.5 Real-world studies, which use evidence and information from large electronic health and insurance claims databases, may help bridge the gap between randomized trials and actual clinical practice by providing real-world insights to patient care.5 As such, clinicians need to be aware of the role, as well as strengths and limitations of real-world evidence in optimizing care for patients with T2DM. The role of real-world evidence Real-world studies can be either retrospective or prospective, as well as observational or interventional (called prospective pragmatic studies).5 Retrospective real-world studies can include data from several sources (such as those from electronic health recordsâ&#x20AC;&#x201D;EHRs, patient registries and claims databases) and can inform or complement the results of RCTs in the real-world setting, as well as a retrospective external control arms for RCTs.5 In addition, large prospective trials with a randomized design that evaluate the efficacy and safety of a therapy in a diverse and heterogenous patient population that is closer to what is seen in clinical practice, are an increasing source or real-world evidence.5,6

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One of the main differences between RCTs and real-world studies is that RCTs are usually conducted in very select patient populations, dictated by the strict inclusion and exclusion criteria determined by the investigators.5,6 However, due to these stricter criteria, RCTs may lack generalizability, and real-world evidence has the potential to more efficiently provide additional answers www.cardiometabolichealth.org

The Role of Real-World Data in The Management of T2DM

that inform outcomes, quality, efficacy and patient care and to fill in the gaps that remain unanswered from RCTs.5 In this setting, real-world studies can provide valuable information on how drugs perform within specific subgroups and patient populations that are often excluded from RCTs and to assess long-term efficacy and safety.2 However, real-world studies can have several limitations, including being subject to additional bias and confounding factors, which can reduce their internal validity.5,6 As such, clinicians need to be aware of the different types of real-world evidence, their advantages and potential pitfalls when it comes to using or interpreting them when making clinical decisions that influence patient care.5 Real-world evidence in the treatment of T2DM In the treatment of diabetes, real-world studies can demonstrate the efficacy and safety of pharmacotherapies that considers adherence to treatment and the frequency of side effects in less controlled settings.7,8 In fact, several real-world studies have provided key insights that have informed T2D treatment decisions and contributed to the development of clinical practice guidelines.5 A prime example is the UK Diabetes Study which confirmed the importance of glycemic control in the prevention of microvascular and macrovascular complications of T2DM in a real-world population.9 Results from recent CVOTs with the newer antihyperglycemic agents, such as GLP-1 RAs and SGLT-2 inhibitors, have shown cardiovascular benefits in addition to their antihyperglycemic effects, thus providing clinicians with additional options to treat the complex patients with T2DM and CVD.3 To date, GLP-1 RAs liraglutide, semaglutide, dulaglutide, and albiglutide have been shown to significantly reduce the risk of 3P-MACE (combined outcome of CV death, nonfatal MI, or nonfatal stroke), while lixisenatide and exenatide demonstrated CV safety in patients with T2DM.3 In turn, SGLT-2 inhibitor empagliflozin demonstrated a significant reduction in 3P-MACE, as well as in the individual components of CV death, all-cause death, and hospitalization for heart failure in the EMPA-REG OUTCOME RCT; while another SGLT-2 inhibitor, canagliflozin, also showed a significant reduction in 3P-MACE and hospitalizations for heart failure in the CANVAS RCT.3 Most recently, the SGLT-2 inhibitor dapagliflozin was shown to reduce the risk of the co-primary endpoint of CV death and hospitalizations for HF in the DECLARE-TIMI 58 RCT.10 These data have been practice-changing, and results from additional large real-world studies have supported and expanded upon the data derived from these RCT trials in patients with T2DM and CVD. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) real-world study, which included more than 300,000 T2DM

patients both with (13%) and without (87%) established CVD, demonstrated a significant reduction in hospitalization for HF with three SGLT-2 inhibitors (canagliflozin, empagliflozin, dapagliflozin).11 In addition, the OBSERVE-4D study, which used 4 large US claims databases, demonstrated that canagliflozin and other SGLT-2 inhibitors reduced the incidence of heart failure hospitalizations in patients with T2DM, with or without established CVD.12 The results of these real-world studies served to not only corroborate the class effects seen in RCTs for SGLT-2 inhibitors, but also to suggest that these benefits might extend even to T2DM patients with a lower risk of CVD (no established CVD), which were excluded from the RCTs.2,11,12 In addition, real-world studies with SGLT-2 inhibitors have helped to address some of the safety concerns that have emerged from RCTs, particularly the observed increased risk of lower extremity amputations. For example, the OBSERVE4D study showed no increased risk of belowknee extremity (BLKE) amputations with SGLT-2 inhibitors in patients with T2DM compared to other antihyperglycemic agents (including GLP-1 RAs, DPP-4 inhibitors, thiazolidinediones, sulfonylureas, and insulin).12

Conclusion Real-world studies can complement, confirm, or even expand the information from RCTs, thus playing an important role in determining the overall efficacy and safety of T2DM pharmacotherapies, aiding clinicians in their decision-making and improving patient outcomes. Since real-world studies can be more inclusive than RCTs and represent patient profiles similar to what clinicians encounter in everyday practice, their role in the individualization of T2DM therapy is crucial to inform treatment decisions even in the CVOT era. However, due to the less rigorous nature of real-world studies, there are several potential limitations with realworld evidence, and clinicians need to be aware of the overall role, as well as strengths and limitations of these studies in assessing T2DM treatments.

References: 1. Centers for Disease Control and Prevention. 2017 National Diabetes Statistics Report. https://www. cdc.gov/diabetes/data/statistics/statistics-report. html. Accessed January 23, 2019.

2. Baptist, Gallwitz. “The Cardiovascular Benefits Associated with the Use of Sodium-Glucose Cotransporter 2 Inhibitors–Real-World Data.”

European Endocrinology 14.1 (2018): 17.

3. Das, Sandeep R., et al. “2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.” Journal of the American College of Cardiology 72.24 (2018): 3200-3223.

4. Davies, Melanie J., et al. “Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).” Diabetologia 61.12 (2018): 2461-2498.

5. Blonde, Lawrence, et al. “Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician.” Advances in therapy (2018): 1-12.

6. Sherman, Rachel E., et al. “Real-world evidence— what is it and what can it tell us.” N Engl J Med 375.23 (2016): 2293-2297.

7. Carls, Ginger S., et al. “Understanding the gap between efficacy in randomized controlled trials and effectiveness in real-world use of GLP-1RA and DPP4 therapies in patients with type 2 diabetes.” Diabetes Care (2017): dc162725.

8. Edelman, Steven V., and William H. Polonsky. “Type 2 diabetes in the real world: the elusive nature of glycemic control.” Diabetes Care 40.11 (2017): 1425-1432.

9. Stratton, Irene M., et al. “Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.” Bmj321.7258 (2000): 405-412.

10. Wiviott, Stephen D., et al. “Dapagliflozin and cardiovascular outcomes in type 2 diabetes.” New England Journal of Medicine (2018).

11. Kosiborod, Mikhail, et al. “Lower Risk of Heart Failure and Death in Patients Initiated on SodiumGlucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering DrugsClinical Perspective: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors).”

Circulation136.3 (2017): 249-259.

12. Ryan, Patrick B., et al. “Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D).”

Diabetes, Obesity and Metabolism 20.11 (2018): 2585-2597.

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Which Nutritional Plan Is Appropriate for the Cardiometabolic Patient?

Which Nutritional Plan Is Appropriate for the Cardiometabolic Patient?

By Shpetim Karandrea, PhD

The ever-increasing presence of cardiometabolic risk continues to be a major challenge for health care providers in the United States.

Current estimates suggest approximately 23% - 38% of all U.S. adults have metabolic syndrome, a constellation of cardiometabolic risk factors, including excessive abdominal obesity, insulin resistance, type 2 diabetes, inflammation, dyslipidemia, and hypertension.1 Patients with multiple cardiometabolic risk factors have twice the likelihood of developing and dying from cardiovascular disease and more than seven times the risk of developing diabetes compared to those with no cardiometabolic risk factors.2 Cardiovascular disease already affects approximately 92.1 million U.S. adults (> 1 in 3) and is the leading cause of U.S. deaths; however, this CVD burden is expected to increase.3 It is important that clinicians address this excessive cardiometabolic risk. Urgent solutions to slow the growing epidemic of cardiometabolic disease are needed. A poor diet is a major contributor in exacerbating the impacts of the cardiometabolic disease; as well as a leading contributor to morbidity and mortality worldwide.4,5 The importance of proper nutrition for cardiometabolic health is paramount and emphasized in several clinical practice guidelines.6-8 However, defining proper nutrition for cardiometabolic disease is challenging and can be very controversial.5,9 Clinicians may not be aware of appropriate healthy eating patterns or the evidence for different dietary approaches on cardiometabolic health outcomes; this is more apparent by the fact that many clinicians do not receive

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adequate training on nutrition and are less likely to address nutrition as a topic during a clinical visit.4 Thus, there is a need for additional education on the benefits of proper nutritional plans and their central role in addressing cardiometabolic risk.

Challenges Ahead • Lack of clinician training on nutrition – Several studies have shown that most physician and other healthcare professionals receive limited education on nutrition as part of their formal clinical training.10 Just 25% of medical schools in the United States offer a dedicated nutrition course and few medical schools achieve the 30 hours of nutrition education recommended by the National Academy of Sciences.11 Furthermore, lack of nutrition persists even after formal training, as studies have shown that most clinicians that specialize in cardiometabolic care do not keep up to date with continuing education in nutrition.4 • Low levels of nutritional counseling in everyday practice – Unsurprisingly, the deficiencies in nutrition training lead to low levels of nutrition counseling provided to patients .4,5,10,11 Clinicians often do not feel confident in their abilities to counsel their patients about nutrition, and many do not have adequate knowledge about dietary patterns, and the role of several major food groups on cardiometabolic health.4,10,11 As a result, only 12% of clinical visits include counseling about diet, and even in highrisk patients with cardiovascular disease,

diabetes, or dyslipidemia, only 1 in 5 receive nutritional counseling.10 • Macronutrient composition controversies – Although most guidelines and evidence agree on healthful eating patterns, the macronutrient composition of optimal diets for managing and controlling cardiometabolic disease has long been a subject of controversy.5 As such, clinicians need to be aware of the evidence behind dietary approaches, including plant-based, Mediterranean, and DASH diets on cardiometabolic disease management.

Addressing the Gaps • The role of certain foods in perpetuating cardiometabolic disease – Several guidelines have extensively addressed that certain foods, including those with added sugar, saturated fat, and salt, or with high cholesterol should be limited.9 There is extensive evidence demonstrating that excess dietary saturated fat, sodium, cholesterol, and sugar can contribute to the development of cardiometabolic disease or increase the morbidity and mortality of those with existing cardiometabolic disease, including the increased incidence of type 2 diabetes, coronary heart disease, cardiovascular death.9,12 However, even in this area, there are several controversies,9,12 and clinicians would benefit from expert perspectives on the role of nutrients and dietary patterns on cardiometabolic risk factors.

Which Nutritional Plan Is Appropriate for the Cardiometabolic Patient?

• Promote healthful eating patterns – Most clinical practice guidelines agree that clinicians should promote healthful eating patterns that focus on overall cardiovascular health.5,6,12 Some of these patterns include, but are not limited to:

o Focus on achieving and maintaining a healthy body weight in order to improve or achieve glycemic, blood pressure, and lipid targets

o Promote patterns of food intake that are high in vegetables, fruits, whole grains, legumes, nuts, and dairy

o Avoid the intake of highly processed foods

o Focus on nutrient-dense foods with less focus on specific nutrients • Uncovering the evidence behind plant-based diets and other diets on cardiometabolic health o Plant-based diets – A plant-based diet refers to eating habits that avoid the consumption of most or all animal products and support the high consumption of fruits, vegetables, legumes, seeds, grains, and nuts.13 Plant-based diets have been shown to decrease the incidence of type 2 diabetes, as well as significantly improve quality of life and management of several important outcomes (hyperglycemia, weight, total and LDL cholesterol, triglycerides) in patients with type 2 diabetes.14 In addition, plant-based diets have been shown to decrease the risk for heart failure, coronary heart disease, and hypertension.15 o The Mediterranean and DASH diets – Other dietary approaches that are generally recommended in the cardiometabolic disease treatment guidelines are the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) approaches.6,8 The Mediterranean diet is based on the abundant consumption of olive oil, fruit, nuts, vegetables, and cereals; a moderate intake of fish and poultry; a low intake of dairy products, red meat, processed meats, and sweets; and wine in moderation, consumed with meals.16 The Mediterranean diet has been shown to prevent several cardiovascular adverse events (myocardial infarction, stroke, or cardiovascular death) as shown by the recently published PREDIMED trial.16 Most importantly, in this study, participants had either type 2 diabetes mellitus or at least three of the following cardiometabolic risk factors (smoking, hypertension, elevated low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease).16 The DASH diet, rich in fruits, vegetables, whole grains and low in fat, has been shown to lead to better blood pressure, improve lipid

risk factors, and help in adequate weight management in individuals with cardiometabolic disease.17,18 Conclusion The increasing prevalence of cardiometabolic disease calls for comprehensive approaches in order to adequately manage cardiometabolic risk factors and improve immediate and long-term patient outcomes. Nutrition is a critical aspect of proper cardiometabolic care, however, clinicians often do not adequately address nutrition with their patients.

Given the lack of formal and continuing educational training that clinicians receive on nutrition, many are not well equipped to address the importance of proper nutrition, which can exacerbate the morbidity and mortality of cardiometabolic disease. Furthermore, there are many controversies as to what optimal nutritional plans should consist of, leaving clinicians more puzzled about how to approach this topic in clinical practice.

Thus, it imperative that clinicians receive additional education on the benefits of nutrition and comprehensive nutritional approaches aimed at better managing patients with cardiometabolic risk or cardiometabolic disease.

At 2019 CMHC West, the topic of nutrition in cardiometabolic health will be addressed by a series of talks titled: The Great Debate: Which Nutritional Plan is Best for Your Patient? In these talks, expert faculty Alice H. Lichtenstein, DSc, Director and Senior Scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Andrew M. Freeman, MD, Director of Cardiovascular Prevention and Wellness at National Jewish Health, and Kim A. Williams, Sr., MD, Chief of Cardiology at Rush University Medical Center, will review the common elements of healthful eating patterns, the relationship between nutrients and cardiometabolic

risk, and the effect of plant-based diets on cardiometabolic disease. The talks will be moderated by Ken Fujioka, MD, Director of Center for Weight Management and of the Nutrition and Metabolic Research Center at Scripps Clinic.

References: 1. Centers for Disease Control and Prevention.

“Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988–2012.”

Preventing Chronic Disease. https://www. cdc. gov/ pcd 2017/16_0287a (2016).

2. Kaur, Jaspinder. “A comprehensive review on metabolic syndrome.” Cardiology Research and Practice 2014 (2014).

3. Benjamin, Emelia J., et al. “Heart disease and stroke statistics—2018 update: a report from the American Heart Association.” Circulation 137.12 (2018): e67-e492.

4. Aggarwal, Monica, et al. “The deficit of nutrition education of physicians.” The American Journal of Medicine 131.4 (2018): 339-345.

5. Forouhi, Nita G., et al. “Dietary and nutritional approaches for prevention and management of type 2 diabetes.” BMJ 361 (2018): k2234.

6. American Diabetes Association. “5. Lifestyle Management: Standards of Medical Care in Diabetes—2019.” Diabetes Care 42.Supplement 1 (2019): S46-S60.

7. Flack, John M., David Calhoun, and Ernesto L. Schiffrin. “The New ACC/AHA Hypertension Guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults.” (2017): 133-135.

8. Grundy, Scott M., 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.” Journal of the American College of Cardiology (2018): 25709.

9. Bowen, Kate J., et al. “Nutrition and Cardiovascular Disease—an Update.” Current Atherosclerosis Reports 20.2 (2018): 8.

10. Kahan, Scott, and JoAnn E. Manson. “Nutrition counseling in clinical practice: how clinicians can do better.” JAMA 318.12 (2017): 1101-1102.

11. Adams, Kelly M., Martin Kohlmeier, and Steven H. Zeisel. “Nutrition education in US medical schools: latest update of a national survey.” Academic Medicine: Journal of the Association of American Medical Colleges 85.9 (2010): 1537.

12. Freeman, Andrew M., et al. “A clinician’s guide for trending cardiovascular nutrition controversies: part II.” Journal of the American College of Cardiology 72.5 (2018): 553-568.

13. McMacken, Michelle, and Sapana Shah. “A plantbased diet for the prevention and treatment of type 2 diabetes.” Journal of Geriatric Cardiology: JGC 14.5 (2017): 342.

14. Toumpanakis, Anastasios, Triece Turnbull, and Isaura Alba-Barba. “Effectiveness of plant-based diets in promoting well-being in the management of type 2 diabetes: a systematic review.” BMJ Open Diabetes Research and Care 6.1 (2018): e000534.

15. Satija, Ambika, and Frank B. Hu. “Plant-based diets and cardiovascular health.” Trends in Cardiovascular Medicine (2018).

16. Estruch, Ramón, et al. “Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts.”

New England Journal of Medicine (2018).

17. Appel, Lawrence J., et al. “A clinical trial of the effects of dietary patterns on blood pressure.” New England Journal of Medicine 336.16 (1997): 11171124.

18. Soltani, Sepideh, et al. “The effect of dietary approaches to stop hypertension (DASH) diet on weight and body composition in adults: a systematic review and meta-analysis of randomized controlled clinical trials.” Obesity Reviews 17.5 (2016): 442-454.

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The Challenge of HFpEF: Diagnostic and Treatment Advances

The Challenge of HFpEF: Diagnostic and Treatment Advances

Introduction Among patients with heart failure (HF), about 50% have a preserved ejection fraction (HFpEF) and the prevalence of this condition has increased over time.1 Prognosis and treatment of HFpEF is complicated by diagnostic challenges and complicated pathophysiologies.1 Compared to HF patients with reduced ejection fraction (HFrEF), HFpEF patients are generally older, more often female, and have increased metabolic comorbidities such as obesity, hypertension, and type 2 diabetes mellitus.2 These metabolic comorbidities are associated with an increased risk of developing HFpEF, making the increase in metabolic syndrome in the recent decades particularly concerning. Studies have shown that non-cardiovascular deaths are greater in patients with HFpEF, particularly due to increased comorbidities.1 Furthermore, current pharmacological therapies that have been successful in reducing morbidity and mortality in HFrEF patients are ineffective in patients with HFpEF.1 The lack of specific therapies for HFpEF have contributed to the increased prevalence and poor prognosis of the disease, and along with complicated diagnosis and pathophysiologies, contribute to the challenges that clinicians face in managing HFpEF. Diagnosing HFpEF is challenging In the HFpEF subtype of HF, left ventricular ejection fraction (LVEF) is preserved (>40%), while in the HFrEF subtype it is severely impaired (â&#x2030;¤40%), as the definitions suggest.3 However, a preserved EF does not mean

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a normal cardiac output. If in HFrEF the decreased cardiac output can be more easily explained by the decreased LVEF, in HFpEF this is more challenging due to complex pathophysiologies.1 HFpEF is primarily characterized by impairments in ventricular diastolic function, which includes delayed relaxation, impaired left ventricle filling, increased stiffness, and increased intracardial pressures.1 The fundamental pathophysiologies leading to HFpEF are not clear, although left ventricular remodeling, endothelial inflammation, oxidative stress, atrial fibrillation, and aging have been associated with the risk of developing HFpEF.1 Symptoms are often indistinguishable with HFrEF. This is particularly true for the early stages of HFpEF, where a normal ejection fraction and lack of additional symptoms can contribute to the condition going undetected.4 One of the few symptoms that can be present in early stages is exercise dyspnea due to fluid accumulation in the lungs, common in patients with HF. However, properly evaluating reduced exercise capacity is challenging in older and obese patients which makes up most of the HFpEF patient population. Diagnosis of HFpEF becomes more complex when considering the lack of consensus when defining EF cut-off criteria and the fact that such diagnosis must be based on excluding other common symptoms associated with heart failure.3 Current guidelines identify several criteria for diagnosing HFpEF, which include the presence of symptoms or signs of HF,

preserved LVEF, elevated levels of natriuretic peptides, and evidence of structural heart disease or diastolic dysfunction.4 After determining the presence of HF, LVEF is evaluated by electrocardiography, followed by more detailed tests to determine structural heart disease, such as left ventricular hypertrophy, left atrial enlargement, and pulmonary hypertension.4 Symptoms of diastolic dysfunction (elevated LV filling pressure) can be evaluated by both noninvasive (Doppler echocardiography) and invasive methods (LV end-diastolic pressure or pulmonary capillary wedge pressure).4 However, in some patients, elevated LV filling pressure is normal at rest and only apparent during exercise, and exercise hemodynamic testing may need to be performed to confirm diagnosis.4 Recently, other diagnostic scores, such as the H2FPEF score, which is based on simple clinical characteristics and echocardiography, have been proposed to estimate the presence of HFpEF in patients with unexplained exertional dyspnea.5 Natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have emerged as important biomarkers to aid clinicians in HF diagnosis.6 According to the latest 2017 ACC/AHA/HFSA focused HF guideline update, measurement of natriuretic peptides can aid in preventing HF in highrisk patients and in diagnosing patients presenting with unexplained dyspnea.6 In addition to NPs, several other biomarkers such as markers of fibrosis (galectin-3 and ST2), inflammation, oxidative stress, vascular dysfunction have been evaluated in

The Challenge of HFpEF: Diagnostic and Treatment Advances

clinical trials.6 However, the adoption of such biomarkers in clinical practice is pending evaluation in larger RCTs.6 Current Treatments and Gaps in HFpEF care While the prognosis of HFrEF has improved and overall prevalence of HFrEF has decreased over the years, the opposite has been reported for HFpEF. A recent study evaluating the epidemiology and trends in HF in patients from the Framingham Heart Study spanning three decades show that the frequency of HFpEF increased from 41% in the 1985-1994 decade to 56.17% in the 2005-2014 decade with no improvement in HFpEF-related cardiovascular mortality.2 While successful pharmacotherapies have been established for HFrEF, patients with HFpEF do not successfully respond to these therapies, underlining the differences in pathophysiologies and potential causes between these conditions.

Current recommended treatments for HFpEF focus on managing the coexisting conditions, primarily hypertension, control of heart rate in patients with atrial fibrillation, and coronary vascularization in patients with CAD.6 The use of diuretics to reduce volume overload is one of the few therapies clinicians can currently use, however this poses risks for patients with impaired renal function.3 The updated 2017 ACC/AHA/ HFSA guidelines for management of heart failure support the use of ACE inhibitors, angiotensin receptor blockers (ARBs) and angiotensin receptor neprilysin inhibitors (ARNis) for the management of hypertension, but do not recommend the use of nitrates and other antihypertensive agents in the HFpEF setting.6 Ample evidence exists for the lack of effectiveness of ACEi, ARBs, beta-blockers, and mineralocorticoid receptor antagonists in reducing mortality in HFpEF, a view reflected in the current guidelines.3,4,6 Several potential therapies have been tried in HFpEF with limited or no success.

The use of phosphodiesterase-5 (PDE-5) inhibitors to improve cardiac relaxation and diastolic performance in HFpEF was evaluated in the RELAX-HF trial but failed to improve exercise capacity and other secondary end points.6 A more recent study evaluating the effects of PDE-5 inhibitor sildenafil in HFpEF patients with pulmonary hypertension reported similar results.7 As a consequence, current guidelines do not recommend the use of PDE-5 inhibitors to improve oxygen consumption or exercise tolerance in HFpEF.6 Spironolactone, an aldosterone antagonist, has been shown to reduce cardiac fibrosis, hypertrophy, diastolic dysfunction and improve cardiac remodeling in HFpEF patients.6 A larger multi-national RCT (TOPCAT) that evaluated the effects of spironolactone on combined primary outcomes of cardiovascular mortality, aborted cardiac arrest, or hospitalization in HFpEF patients did not show significant improvements in this primary endpoint.6

However, because spironolactone improved HF hospitalizations in this trial, its use in a subset of HFpEF patients is now recommended in the 2017 ACC/AHA/HFSA guidelines.6 A recent trial (INDIE-HFpEF) evaluating inhaled inorganic nitrite in HFpEF patients reported no improvement in exercise capacity or clinical status in patients receiving the treatment, and similar results have been reported with nitrates.6,8 Current guidelines have been updated to reflect the results of the latest clinical trials, however there is still uncertainty about current therapies. To address any knowledge and competence gaps in this area, an overview of the safety and efficacy of available therapies for HFpEF will be presented.

Looking ahead Due to the need to develop specific therapies for HFpEF, several new targets and agents are currently being explored in clinical trials.

An elevated heart rate (HR) is associated with increased mortality in patients with HF, including HFpEF and reducing heart rate might be a potential treatment target.

Ivabradine reduces HR by inhibiting sinoatrial node If current and it was shown to improve cardiac fibrosis, vascular stiffness, systolic and diastolic dysfunction in animal models of HFpEF, however results from clinical studies have been conflicting.9 A recent proof of concept trial, EDIFY, reported that HR reduction with ivabradine did not improve cardiac function in HFpEF patients.10 Preventing the degradation of biologically active natriuretic peptides and inhibiting vasoconstriction are potential approaches to targeting the underlying pathophysiological mechanisms of HFpEF. This is the idea behind using a combined ARB and neprilypsin inhibitor (sacubitril/valsartan) to improve NP degradation and cardiac function. In the phase II PARAMOUNT trial, this combination proved effective in reducing the levels of NT-proBNP after 12 weeks in HFpEF patients.11 Furthermore, sacubitril/valsartan reduced left atrial volume and dimension after 36 weeks, suggesting that it can lower left ventricular filling pressure in HFpEF patients.11 Due to these promising results, a larger trial, PARAGONHF, is currently evaluating the effects of this combined approach compared to valsartan alone in reduction of cardiovascular mortality in HFpEF patients, and results are expected in 2019.12 Other approaches that target potential pathophysiologies in HFpEF are currently being used. Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin and other SGLT-2 inhibitors has been shown to reduce HF hospitalizations in patients with type 2 diabetes, although many mechanisms have been linked to these effects.13 Due to these results, a current phase III study to evaluate the safety and efficacy of empagliflozin in

HFpEF patients is ongoing (EMPERORPreserved, NCT03057951, ClinicalTrials. gov). Targeting the NO-cGMP-PK signaling cascade by activating soluble guanylate cyclase (sGC) to increase cGMP production could be beneficial in HFpEF patients; the downregulation of this pathway is associated with increased oxidative stress, inflammation, and endothelial dysfunction, and contributes to HFpEF pathophysiology.1 Vericiguat, a direct sGC stimulator, was recently evaluated in the phase II SOCRATES-PRESERVED study in HFpEF patients .14 In this trial, vericiguat did not reduce NT-proBNP levels or left atrial volume after 12 weeks, but a subsequent analysis showed that improvements in health-related quality of life, physical limitations, NYHA class, and signs and symptoms of congestion with vericiguat compared to placebo.14 A phase II study to evaluate the effects of this agent on improving the quality of life in patients with HFpEF is ongoing (NCT03547583, ClinicalTrials.gov). Praliciguat (IW-1973), a novel sGC simulator that enhances NO signaling, is currently being evaluated in a phase II study about its potential effects on exercise capacity as well as overall safety in HFpEF patients (CAPACITY-HFpEF, ClinicalTrials.gov NCT03254485). Recently praliciguat was granted a Fast Track Designation by the FDA for the treatment of HFpEF. In addition to pharmacotherapies, a new approach using an interatrial shunt device (IASD) has been shown to lower pulmonary capillary wedge pressure (PCWP) during exercise in HFpEF patients in small nonrandomized studies.15 These results were confirmed in the phase II randomized study REDUCE LAP-HF I15 and an additional phase II (REDUCE LAP-HF II) study to look at the effects of this device on cardiovascular mortality in HFpEF patients is ongoing (NCT03088033, ClinicalTrials. gov). Recently, a 1-year follow-up of the REDUCE LAP-HF I study was published, demonstrating that IASD treatment was safe during this follow-up period compared to sham-control.16 Conclusion The prevalence of HFpEF has increased in the recent years and it remains a major health problem with significant financial impacts to the US economy.

The complicated pathophysiology of the condition, the inadequacy of current treatments, and the lack of specific FDAapproved therapies are major barriers that clinicians face in optimizing treatment.

Furthermore, the presence of important metabolic comorbidities and the generally older age of the HFpEF patient population exacerbate this problem. However, advancements in disease pathophysiology, diagnostic tools, current and emerging treatment options may give clinicians additional tools to improve the outcomes of the disease; including morbidity, mortality, and quality of life. www.cardiometabolichealth.org

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The Challenge of HFpEF: Diagnostic and Treatment Advances

References: 1. Lam, Carolyn SP, et al. “Heart failure with preserved ejection fraction: from mechanisms to therapies.”

European Heart Journal (2018).

2. Vasan, Ramachandran S., et al. “Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades.” JACC: Cardiovascular Imaging (2017).

3. Yancy, Clyde W., et al. “2013 ACCF/AHA guideline for the management of heart failure.” Circulation (2013): CIR-0b013e31829e8776.

4. Ponikowski, Piotr, et al. “2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.” European Heart Journal 37.27 (2016): 2129-2200.

5. Reddy, Yogesh NV, et al. “A Simple, EvidenceBased Approach to Help Guide Diagnosis of Heart Failure with Preserved Ejection Fraction.”

Circulation (2018): CIRCULATIONAHA-118.

6. Yancy, Clyde W., et al. “2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of

America.” Journal of the American College of Cardiology 70.6 (2017): 776-803.

7. Liu, Licette CY, et al. “Effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing and health-related quality of life measures in heart failure patients with preserved ejection fraction and pulmonary hypertension.” European Journal of Heart Failure 19.1 (2017): 116-125.

8. Parikh, Kishan S., et al. “Heart Failure With Preserved Ejection Fraction Expert Panel Report: Current Controversies and Implications for Clinical Trials.” JACC: Heart Failure 6.8 (2018): 619-632.

9. Ashrafian, Houman, et al. “The effect of selective heart rate slowing in heart failure with preserved ejection fraction.” Circulation (2015): CIRCULATIONAHA-115.

10. Komajda, Michel, et al. “Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebocontrolled trial.” European Journal of Heart Failure (2017).

11. Solomon, Scott D., et al. “The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 doubleblind randomised controlled trial.” The Lancet 380.9851 (2012): 1387-1395.

12. Solomon, Scott D., et al. “Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial.” JACC: Heart Failure 5.7

(2017): 471-482.

13. Das, Sandeep R., et al. “2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.” Journal of the American College of Cardiology 72.24 (2018): 3200-3223.

14. Filippatos, Gerasimos, et al. “Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction (SOCRATESPRESERVED) study.” European Journal of Heart Failure 19.6 (2017): 782-791.

15. Feldman, Ted, et al. “Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]) A Phase 2, Randomized, Sham-Controlled Trial.” Circulation 137.4 (2018): 364-375.

16. Shah, Sanjiv J., et al. “One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial.” JAMA Cardiology (2018).

CLINICAL CONVERSATIONS Cardiometabolic Risk Factors in Women Part of the CMHC’s 13th Annual Congress was the very successful Women’s Health Summit: Cardiometabolic Health Across the Lifespan, which focused on the unique challenges faced by women in cardiometabolic health. As we look forward to the CMHC West Women’s Heath Summit: Navigating Female Cardiometabolic Care, Pam Taub, MD, Associate Professor of Medicine and Director of Cardiovascular Rehabilitation and Wellness Center at University of California in San Diego, shared some clinical pearls on the immediate and long-term impacts of pregnancy on cardiometabolic health: “I think that women’s health is important for all providers that take care of patients.

About 80% of women have a pregnancy in their lifetime, and it is very relevant in taking care of these women that we understand the changes that happen during pregnancy and how they impact long-term cardiovascular health. For instance, women that develop gestational diabetes have a much higher incidence of developing type 2 diabetes later in life. Women that do not have gestational diabetes have only a 2% risk of developing type 2 diabetes later in life, whether this risk is 19% in women with gestational diabetes at a 9-year follow-up.

In our practice, we often come into contact with women in their 50s or 60s, and at that time pregnancy is such a remote event for them and is not even on their radar in terms of a potential health issue that needs to be addressed with their provider. But is important to educate women, that things that occurred in their pregnancy, such as gestational diabetes, have a long-term impact on cardiometabolic health. One of the goals of the Women’s Health Summit was to raise awareness among providers about these conditions, so that they can ask women when getting a history about them. The reason that is important to do that is because it really changes your management. For instance, if you have a woman that has gestational diabetes, she needs to be screened every three years for type 2 diabetes. If her numbers come back as slightly elevated, or borderline HbA1c, then it is important to be more aggressive about lifestyle and pharmacological management strategies. Recognizing the impact of pregnancy-related conditions on long-term health is very important.

One of the other topics that we discussed was polycystic ovarian syndrome (PCOS), which is associated with insulin resistance. PCOS is important to keep in mind when a woman gets pregnant, because pregnant women with PCOS often develop gestational diabetes; about 10% of women with gestational diabetes have PCOS. These are patients that we want to screen very early in their pregnancy for elevated blood sugars, because that also changes how we manage both maternal and fetal health in terms of screening and close monitoring.”

References: • Feig, Denice S., et al. “Risk of development of diabetes mellitus after diagnosis of gestational diabetes.” Canadian Medical Association Journal 179.3 (2008): 229-234.

• Lo, Joan C., et al. “Risk of type 2 diabetes mellitus following gestational diabetes pregnancy in women with polycystic ovary syndrome.” Journal of diabetes research 2017 (2017).

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Obesity

The Practical Management of

CLINICAL CONVERSATIONS At the 2018 Cardiometabolic Health Congress 13th Annual Congress, Robert F. Kushner, MD, Professor of Medicine at Northwestern University School of Medicine in Chicago, IL, shared some of his practical approaches about the management of obesity in everyday practice, in a conversation with one of our co-chairs, Robert H. Eckel, MD: Dr. Robert H. Eckel: When we think of the increasingly closing Venn diagram between metabolic diseases and cardiovascular disease, obesity and obesity-related comorbidities is a big part of this.

Dr. Robert F. Kushner: Obesity is foundational to all of the cardiometabolic problems, most notably type 2 diabetes, cardiovascular disease, and hypertension.

When it comes to obesity, I think that the physician needs to be part of the solution and not continue to be part of the problem.

We know that metabolic risk is a problem and the medications to use, but one of the biggest challenges is how to change a patient’s behavior to deal with cardiometabolic risk factors and with weight loss. So, the question is, what can you do in a practical office visit to assess the patient in an adequate and comprehensive way, but also make the link between assessment and treatment, or referral if needed?

Dr. Robert H. Eckel: One of the scenarios that is common in my practice is the obese patient with a lot of comorbidities that relate to cardiovascular disease risk. Do I treat the risks first before the weight reduction or should I focus more on the weight reduction first? How does that get individualized?

Dr. Robert F. Kushner: You have to treat both. It is perhaps a false dichotomy to favor one over the other. When I see a patient with obesity and cardiometabolic risk, my focus is to get the risk reduction in place. This can be specifically by treating the type 2 diabetes, hypertension, hypercholesterolemia, but at the same time, educating the patient about the need to improve the weight and overall health.

A lot of these decisions are not prioritized in a specific order; for example, when I’m treating diabetes, I’m also treating obesity.

We now of course have medications that do both, but when I help patients with weight loss or calorie reduction, it is really treating both problems and I don’t have to make that choice between diabetes and obesity.

Dr. Robert H. Eckel: Over your years of experience, can you find some tips on the ability to assess a patient in terms of their readiness to lose weight and ultimately distinguish between the successful weight losers versus those who may not.

Dr. Robert F. Kushner: Unfortunately, we can’t predict who is going to be successful

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and who will not, but what we do use is motivational interviewing. We talk about how important is it for you to improve your diet, get physically active, and loose weight in a scale of 0-10. We also then follow up by asking how confident is the patient in making these changes. Sometimes you get a gap between these two assessments, and that is a conversation starter. So, if someone says that it is important for me to get my weight under control (it is an 8), but the patient is not that confident, as a practitioner you don’t need all the answers, but rather to pay close attention to the questions a patient asks. The practitioner should be thinking about how they can help bring up the patient’s confidence, and in most times the patient will tell you. Often patients tell you they need more education on what to eat, more family support, or find time to exercise. They’re giving you a starting point on how to focus the conversation.

Dr. Robert H. Eckel: I think most physicians are frustrated in the clinical setting in that they feel they don’t have enough time. If I’m seeing a patient with obesity only, with very little other risks, that in itself is a 20-30-minute conversation beyond the usual history and physical examination. What can you recommend to physicians in practice about approaching the topic of obesity?

Dr. Robert F. Kushner: Obesity care is a team sport, you do not have to have all the answers yourself. At the very least I would recommend is that you need to assess obesity, advise weight management, treat comorbid conditions, and refer if you do not have the time yourself. If you want to have more time, then you can start with some of the behavior change recommendations, strategies, and tactics, or refer to a dietician.

So, you just have to be part of the solution; if you don’t have the time yourself, think of the individuals around you who you can refer to.

Dr. Robert H. Eckel: In your opinion, what do you think makes CMHC different compared to other conferences in terms of its value going forward?

Dr. Robert F. Kushner: You have experts in the field, who know a lot about lipid, diabetes, hypertension management, cardiovascular disease and putting them all together.

Obesity is part of that picture and all of these factors are connected, more like the Venn diagram you mentioned. As someone comes to CMHC wanting to know more about diabetes and other risk factors, they are also learning about the role of obesity and how does that play in.

Reference: • Kushner, Robert F. “Providing Nutritional Care in the Office Practice: Teams, Tools, and Techniques.”

Medical Clinics100.6 (2016): 1157-1168.

CLINICAL CONVERSATIONS

Looking ahead to 2019 CMHC West

At our 2018 CMHC annual congress, our cochair, Christie M. Ballantyne, MD, sat down with Deepak L. Bhatt, MD, MPH, to have a very candid conversation about the upcoming 2019 CMHC West meeting in Phoenix and what clinicians can expect out of it.

Dr. Ballantyne: Deepak, let’s tell people what’s happening at CMHC West 2019 in Phoenix this May Dr. Bhatt: I’m really looking forward to the meeting, it is a great time to have a cardiometabolic meeting and there is going to be plenty of new information to discuss.

Dr. Ballantyne: Let’s talk about the area of obesity, nutrition, and diet. There are some encouraging data with metabolic surgery for severely obese patients, correct?

Dr. Bhatt: I’m very excited about bariatric surgery, and that may surprise people since I’m an interventional cardiologist. It has been an area that for many years I’ve thought is quite promising, but under-researched.

However, now have randomized clinical trials of modest size but very positive. We have large observational series that have been extremely favorable for bariatric surgery. I

think if we are careful in selecting the appropriate patients, bariatric surgery is an option, especially for patients that have both diabetes and obesity.

Dr. Ballantyne: One aspect of cardiometabolic health is no doubt treating the obese patient with cardiometabolic comorbidities, but we now also have data that lifestyle modifications in at-risk adolescent patients can impact the development of diabetes and cardiovascular disease later in life. This gets us to focus on the fundamental aspects of healthy nutrition and lifestyle, even at younger ages.

Dr. Bhatt: For people interested in prevention, the times have never been better. There is so much data now that intervening in the young, in adolescence, can make a huge difference in their future trajectory of health or illness. I think that there is a lot that we can do as individual clinicians, as well as a lot that we can also do on the population and public health level. These are topics that will be discussed at this meeting that will be very timely and very useful.

Dr. Ballantyne: We will also extensively cover the areas of lipid management, athero-

sclerosis, atherothrombosis, and there is a lot happening in these areas.

Dr. Bhatt: There is, and the timing of this meeting is fantastic because there is going to be a few approved drugs that weren’t approved a few months ago. There will be guidelines, such as the lipid guidelines, and data that are actionable and will influence clinical practice.

Dr. Ballantyne: We have waited a number of years for this, but now the new ACC/AHA lipid guidelines are out, as well as comprehensive prevention guidelines by ACC. We’ll also talk about the patients with hypertriglyceridemia, and atherothrombosis. In particular, the patient with peripheral artery disease (PAD) is hard to treat. What is going on in this area?

Dr. Bhatt: Absolutely, vascular medicine doctors are very excited about the recent approval of rivaroxaban for high-risk, but stable coronary artery disease (CAD) and/or PAD, based on the results of the COMPASS trial.

Both the CAD and PAD components are interesting, particularly the PAD part, since there is a lack of current medical therapies that reduce amputation risk in PAD patients.

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Looking ahead to 2019 CMHC West

Dr. Ballantyne: We will also have new data with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as well as some updates on lipoprotein (a).

Dr. Bhatt: Absolutely, and there was a relatively recent announcement about the drop of the list price of PCSK9 inhibitors, which puts them in the range of direct oral anticoagulants (DOACs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. I think what this means to our potential attendees, particularly if they haven’t really paid attention to PCSK9 inhibitors due to these previous concerns, is that the change can facilitate their practical use.

Dr. Ballantyne: Very true, I have noticed better approval rates for PCSK9 inhibitors in my practice, where we treat a lot of difficult and high-risk patients. Moving on to hypertension and heart failure; hypertension has been relatively quiet in terms of new updates, but there a lot of new information in heart failure (HF) has come out, particularly in its relation to metabolic risk factors.

Dr. Bhatt: Heart failure with respect to hypertension, as well as in the patient with diabetes is being recognized as a major problem, and a very under-recognized and under-treated one. A lot of the diabetes cardiovascular outcomes trials (CVOTs) have really unearthed HF as a major complication of diabetes, both HF with preserved (HFpEF) or reduced (HFrEF) ejection fraction. And now antihyperglycemic agents, mainly SGLT-2 inhibitors, seem to impact that risk pretty substantially.

Dr. Ballantyne: Also, more intensive blood pressure control is making a big impact, as shown in the SPRINT study. As a preventive cardiologist, the “low-hanging fruit” is prevention of HF, and I feel that we haven’t focused a lot on HF, but rather more on stroke and myocardial infarction (MI). However, the increase in the aging population, obesity, and diabetes, makes HF the emerging threat and that is something that everyone who comes to this meeting will be excited to hear about.

We just talked about what is driving HF, diabetes, and to me as a cardiologist the recent advances in diabetes treatment have been an eye opener. A lot has changed, right?

Dr. Bhatt: I think the diabetes CVOTs have made a huge impact on the field of cardiovascular medicine. Initially there was some skepticism whether these trials were necessary, but as it turns out, we have learned a lot about diabetes drugs, and have uncovered some side effects that we wouldn’t have been able to identify otherwise. Even more important, we have found that agents, like SGLT-2 inhibitors that impact HF, and in some cases, at least in higher-risk patients, can also lower mortality. The same process has also uncovered the beneficial effects of glucagon-like peptide 1 (GLP-1) receptor agonists on atherosclerosis by showing a reduction of ischemic events. With two new classes of drugs impacting cardiovascular outcomes in diabetes, it is a great time to be interested in cardiology and diabetes and their intersection. I think it has now gotten to a point that as a cardiologist, you need to not only be aware of these agents, but how to actually use them in your practice. As cardiologists, we no longer can offload the overall care of the diabetic patient to the primary care physician or to the endocrinologist only and need to take ownership of our patients’ overall health. And of course, if it is complex, we need to collaborate with endocrinologists and primary care physicians. But, it is an exciting time and there is a lot to learn.

Dr. Ballantyne: There is a lot going on, so we hope to see you in Phoenix and it will be a great meeting.

Dr. Bhatt: I agree.

References: • American Diabetes Association. “3. Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes—2019.” Diabetes Care 42.Supplement 1 (2019): S29-S33.

• Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017. S0140-6736(17):32409-1.

• Anand, Sonia S., et al. “Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease.” Journal of the American College of Cardiology 71.20 (2018): 2306-2315.

• Das, Sandeep R., et al. “2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.”

Journal of the American College of Cardiology 72.24 (2018): 3200-3223.

• Grundy, Scott M., 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.” Journal of the American College of Cardiology (2018): 25709.

• Pareek, Manan, et al. “Metabolic surgery: weight loss, diabetes, and beyond.” Journal of the American College of Cardiology 71.6 (2018): 670-687.

• Rosenson, Robert S., et al. “The evolving future of PCSK9 inhibitors.” Journal of the American College of Cardiology 72.3 (2018): 314-329.

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PAT I ENT PERSPE CTIVE

Consider hearing the scary diagnosis of “heart failure” tripping lightly from your doctor’s lips, as if it were no big deal. Can there be anything more terrifying and demoralizing than hearing that your heart is “failing”? The words don’t even accurately reflect this condition, which actually means that your heart is not pumping blood as well as it should. Why did doctors come up with this heart failure name, and what on earth were they thinking when they decided it would be a good idea to say these words out loud to real live patients? Is there a better piece of medical jargon they could use instead?

Using comparable terminology like “failing a treadmill stress test,” or “abnormal electrocardiogram,” or “sick sinus syndrome” are jarring when heard by the average, freshly-diagnosed, patient, according to cardiologist Dr. Bernard Lown, a Nobel Peace Prize recipient and author of The Lost Art of Healing. Words like these, he says, likely reflect physicians’ use of common clinical jargon without any real awareness of the damaging impact on patients. In a paper called, Words That Harm, Words That Heal, published in The Archives of Internal Medicine*, Dr. Lown and his colleagues explained: * “Consider the patient who has just had a heart attack: the first few hours of uncertainty in the coronary care unit are also an introduction to mortality, eliciting worry that every beep on the heart monitor might be the last. Then, at the height of the patient’s anxiety, the physician might come in and gravely announce: “You have the type of lesion we call a widow maker!”

Those are precisely the same words I heard while recuperating from a heart attack in the CCU (the hospital’s intensive care unit for cardiac patients.) In a more recent essay on The Lown Conversation, the enlightening and delightful blog that Dr. Lown co-writes with his granddaughter, Melanie Lown, he explained further:** “The doctor is part of our culture wherein doom forecasting is within the social marrow. Even the daily weather is often reported with anxiety-provoking rhetoric.

“To be heard, one learns the need to be strident, equally true for weather predictions as for medical prognostications. The end result is that doctors justify their ill-doing by their well-meaning.

By Carolyn Thomas

“Unfortunately many doctors are poor communicators. It begins with medical school. The curriculum is weighted heavily with science while the art of medicine is given short shrift. As a result, medical students focus on the disease, rather than on the whole patient. Little time or effort is devoted to honing skills in interpersonal relations or cultivating the art of caring. www.cardiometabolichealth.org

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“The effect is that doctors don’t listen, trust is undermined, and patients are less likely to follow medical advice.

“Projecting a grim scenario also achieves the important objective of gaining the patient’s compliance without the need for reasoned and time-consuming explanations.

“In our health care system today there is constant pressure to minimize time with patients. The less time a doctor spends with a patient, the more profitable the encounter.

Instilling anxiety makes for a customer ready to buy – namely, to undergo any test or procedure.”

Instilling anxiety may do far more than make a patient pay attention to what the doctor is saying, in fact, it can do just the opposite. It can also intensify the emotional distress that so often accompanies a heart disease diagnosis. The Mayo Clinic reports that up to 65% of heart patients experience significant symptoms of depression, yet fewer than 10% are appropriately identified.

Dr. Lown believes that instilling anxiety by using alarmist language, like heart failure, is sometimes what a caring physician may do in order to convey a sense of urgency, thus hoping to ensure that his or her patient will comply with lifesaving recommendations.

Even in non-emergency situations, the physician may believe that these words are necessary to persuade the patient to accomplish what needs to be done to maintain health.

The internist Dr. Eric Cassell coined this observation:

“Sticks and stones may break your bones, but a word can kill you.”

As a heart attack survivor who has experience alarmist language, like “widow maker,” from a physician, I can tell you that whatever words follow those are likely lost in the roaring freight-train-rush going through the patient’s brain. When frightening words finally do sink in, their effect is far more demoralizing than motivational.

Dr. Lown cites real-life physician statements like the following: o “You have a time bomb in your chest” o “The next heartbeat may be your last” o “Your life is hanging by a thread” o “There is no choice. We have to operate.”

He also describes how these common examples, taken from the field of cardiology, illustrate how words – perhaps spoken with the best of intentions – can cause what’s known as iatrogenic harm (which is defined as a new medical issue that occurs as a result of the actions of a medical provider). He adds, “Unfortunately, medicine encourages ‘detached concern’ which devalues subjectivity, emotion, relationship, and solidarity.”

This leaves the question, what alternative words might physicians come up with to replace hurtful ones like “heart failure?” Dr. Lown suggests this:

“Heart failure is not a disease. It’s just a description of clinical syndromes. A heart failure prognosis is no longer what it used to be; much of the damage that occurs to the heart may be reversible and the symptoms controlled over decades. Perhaps a better term would be stiff muscle syndrome.”

Scottish physician, Dr. Trisha Elliott of Edinburgh, has her own favorite substituteterm for heart failure -- insuffisance cardiaque -- as she suggests on Twitter.

So please, docs, along with being more sensitive about using those hurtful (or simply unhelpful) words you may be using, let’s try to come up with a less scary alternative to the word “failure” for this particular cardiac diagnosis.

This story is printed with permission from the blog Heart Sisters, created and run by Carolyn Thomas (for more information, please visit https://myheartsisters.org/).

Carolyn is a patient and an advocate for women with heart disease, and in addition to her successful blog, she also recently authored the book, A Woman’s Guide to Living with Heart Disease ( Johns Hopkins University Press, 2017.)

References: * Bedell, Susanna E., et al. “Words that harm, words that heal.” Archives of Internal Medicine 164.13 (2004): 1365-1368. ** Lown, Bernard, and Melanie Lown. “The Roots of ‘Medical Bullying’.” The Lown Conversation, 21 Feb. 2013, https://thelownconversation. wordpress.com/2013/02/21/the-roots-of-medicalbullying/, accessed 26 Nov. 2018

MAY 3-5, 2019 Phoenix, AZ BACK BY POPULAR DEMAND: The Most Widely-Attended Session from the 13th Annual CMHC

SUNDAY, MAY 5 TH Pamela B. Morris, MD Expert on female cardiovascular risk & co-director of the Women’s Heart Care Program at the Medical University of South Carolina

• Outline clinical strategies to address cardiovascular concerns in breast cancer patients during treatment • Review evidence-based guidelines for prevention, screening, and treatment of cardiometabolic complications of PCOS and pregnancy • Evaluate postmenopausal hormone therapy in women from a cardiometabolic perspective • Address both psychological factors and medical disorders among women with diabetes • Identify primary and secondary CVD risk assessment, treatment, and prevention for women

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EXPE RT SPOTLIGHT

Keith C. Ferdinand,

MD, FACC, FAHA, FNLA, FASH Expert spotlight with Keith C. Ferdinand, MD, FACC, FAHA, FNLA, FASH, Professor of Medicine and Gerald S. Berenson Endowed Chair in Preventive Cardiology at the Tulane University School of Medicine and the Tulane Heart and Vascular Institute in New Orleans, Louisiana Dr. Ferdinand is a nationally and internationally recognized cardiologist, and has dedicated his career to improving patient care, particularly in racial and ethnic minorities. Dr. Ferdinand is past Chair of the National Forum for Heart Disease and Stroke Prevention and has served as Chief Science Officer and past chair of the Association of Black Cardiologists. He has also served as a board member of the American Society of Hypertension, the Southwest Lipid Association, the International Society of Hypertension in Blacks, and the National Heart, Lung, and Blood Institute (NHLBI) National High Blood Pressure Education Program(NHBPEP). As an investigator, Dr. Ferdinand has conducted numerous trials in the fields of cardiology, cardiovascular disease, lipids and cardiometabolic risk, especially in racial and ethnic minorities. Dr. Ferdinand’s participation in research has been published in several high-impact peerreviewed journals, including the New England Journal of Medicine, the Journal of the American College of Cardiology, Circulation, the Journal of Clinical Hypertension, the American Journal of Cardiovascular Drugs, Clinical Lipidology, Cardiorenal Medicine, and Hypertension.

What inspired you to become a physician?

My desire to become a physician was born out of my interest in helping my community.

I grew up in the Lower Ninth Ward in New Orleans, LA, which was an African-American community that has been subsequently devastated by hurricane Katrina in 2005. As a child, I was told to be the best I can be in terms of becoming a change agent for my community. As I matriculated through formal education, I became convinced that being a physician would be one of the best ways that I could contribute to the positive development of my neighborhood.

Who has had the greatest influence on your career?

I would first have to give respect to my parents, who put the energy and time into my education and into my sense of self, to allow me to develop the skills and the psychological fortitude to become a physician. I would also think I was influenced greatly by my

elementary school teachers and my general community, who supported me throughout my younger years. As a cardiologist, my two greatest influences were Charles Curry, MD, former Chief of Cardiology at Howard University in Washington, DC, and the late Gerald S. Berenson, MD, who was Chief of Cardiology at Louisiana State University in New Orleans, and I am honored to be recently appointed to the Gerald S. Berenson Endowed Chair in Preventive Cardiology by Tulane University in his name.

What area of research in cardiometabolic health interests you most now and why?

During my 30 years of experience in cardiovascular disease it became quite apparent that we were treating patients at the end-stage of high cardiovascular risk.

Especially in the African-American population and patients who are underserved, it became increasingly clear that high blood pressure was perhaps the most powerful overriding risk factor. As new drugs were being developed in the field of hypertension and new approaches to patients with high blood pressure, I was pleased to be a member of the NHBPEP, which promulgated the Joint National Committee reports, known as the JNC reports. As a practicing clinician, I became even more convinced that persons with glucose intolerance and diabetes have further increased risk. And merging my interests in hypertension, dyslipidemia, and diabetes, I think that treating the whole patient from a cardiometabolic point of view is increasingly important if we are going to curtail the recent slowing decline in cardiovascular mortality that we are now experiencing.

What do you think is going to be the next big thing in your field over the next decade?

Cardiologists have now entertained the possibility of becoming cardiometabolic specialists. There is some discussion of even developing a new cardiometabolic

subspecialty. Regardless, cardiologists no longer can just treat heart failure, stroke, and acute myocardial infarction without paying attention to the contribution of cardiometabolic risk factors underlying these conditions. The next big thing therefore will be breakthrough drugs that target not only blood pressure or glucose, but also decrease the burdens of cardiovascular disease. We are seeing the beginning of this with the recently-approved SGLT-2 inhibitors and GLP-1 receptor agonists, which have demonstrated not only that they control glucose, but also the ability to improve cardiovascular outcomes.

What has been the greatest challenge during your professional career?

The biggest challenge that I have seen is that even after participating in multiple clinical trials with newer medications for blood pressure, lipids, and glucose, is ensuring that these great therapies are equally applied to all patients, regardless of race, ethnicity, socioeconomic status, or geography. The truth is that in the United States today, all patients are not treated equally; those with means or with an identifiable source of medical insurance have better outcomes, better access, and increased longevity compared to underserved, sociallydisadvantaged persons, and persons without insurance.

What do you consider your greatest achievement?

As a member of the NHBPEP working with the NHLBI, I was able to help identify unique aspects of hypertension in Blacks, and to build on some of the landmark trials which confirmed the benefit or risk reduction, especially with the appropriate use of antihypertensive agents. It is now known that treating blood pressure is perhaps the most important first step to decrease cardiovascular death and disability in this population. We have a long way to go to diminish these disparities, and hopefully before my career has ended, we are able to eliminate disparities in cardiovascular outcomes based on race and ethnicity.

What are your hobbies outside of medicine?

Prior to becoming a physician, I was a pretty good artist. I did portraits and landscapes in acrylics and oil, and I am still able to sketch with a moderate degree of proficiency.

Unfortunately, medicine tends to take over a person’s time and talents, and hopefully I would be able to one day return to some of the promise I had as a young artist.

What is your motto or philosophy?

My guiding principle, both for medicine and life, is that the greatest thing we can do is help others. Dr. Martin Luther King said that “everybody can be great because everybody can serve.” I often tell my fellows, residents and students who are working with me, that we are simple human beings with simple tools, and our main purpose is to serve the patients, not our own sense of grandiose selfworth or financial gain. www.cardiometabolichealth.org

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