CMHC - Cardiometabolic Chronicle MARCH 2018

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LETTER FROM THE EDITOR We are excited to announce the inaugural issue of Cardiometabolic Chronicle, a literary publication designed to reach active healthcare professionals in cardiometabolic care. The journal will deliver the most current and relevant information in cardiometabolic health, and provide exclusive access to faculty spotlights, partner communications, and interviews with industry KOLs. This journal will additionally provide a point of access for our extensive educational offerings, including CME/ CE accredited activities. As our annual Congress approaches its 13th year, the Cardiometabolic Chronicle is one of our newest initiatives. In this first issue, we have included a series of featured articles that focus on various aspects of cardiometabolic health, including critical updates surrounding the status of cardiovascular outcome trials for antidiabetic drugs, and education regarding type 2 diabetes and heart failure management. We also present the most recently emerging advancements in the field of cardio-oncology, and the potential of precision medicine and technology to minimize adverse cardiovascular outcomes of cancer treatments. Our Pulse and Cardiometabolic News sections reflect the most current events and highlights in the field of cardiometabolic health. The Patient Perspective discusses the challenges of access to PCSK9 inhibitors told through a patient’s viewpoint. The Expert Spotlight section includes a conversation with Alan Chait, MD, a renowned physician and scientist, and the keynote presenter at our upcoming CMHC West event. The advances and the rapidly expanding nature of cardiometabolic health prompts an increasing need for continuing education. Through expert and patient perspectives, highlights of past CMHC meetings, and literature scans, we expect Cardiometabolic Chronicle to reflect the evolution of the field. We hope that you enjoy this first issue, and continue to be an integral part of our future. We thank you for your engagement, involvement, and continuous support.

Featured Articles • Cardio-Oncology in the Modern Era: Innovative Tools for a Complex Problem (by Alexis Karandrea, PhD)

• Cardiovascular Prevention: Is it Achievable in Patients with T2DM? (by Editorial Board)

• The Evolving Landscape of T2DM Management (by Editorial Board) • New Guidelines: Addressing Practical Challenges in Heart Failure Care (by Editorial Board) Expert Spotlight

Alan Chait, MD

• The Co-Occurrence of Diabetes & Heart Disease

• New Guidelines for High Blood Pressure

• Chronic Stress & Obesity: A New Perspective on “Comfort Food”

• Eating Your Way Out of a Heart Attack • Pick Up the Pace! Cardiometabolic News

Shpetim Karandrea, PhD

Executive Director:

Amanda Jamrogiewicz, CHCP

Art Director:

Jose Wong

Editorial Board: Marketing & Creative Director:

5-6 7-10 11-12 13 16 16-17 17 19 19

• FDA approves GLP-1 receptor agonist semaglutide for Type 2 Diabetes


• New ultra-fast-acting mealtime insulin is FDA approved


• FDA approves evolocumab to prevent cardiovascular events


• FDA approves the first short-acting “follow-on” insulin


Editorial Director:


Pulse (by Sarenka Smith)

• Transcatheter interatrial shunt device shows promise in HFpEF treatment

Shpetim Karandrea, PhD Editorial Director


• Study supports the role of inflammation in cardiovascular disease


• Gestational diabetes and long-term CVD risk


Erin Franceschini, M.S. Jessica Schumacher Sarenka Smith

• International consensus statement released on use of continuous glucose monitoring


• Normal LDL-C conveys a risk for subclinical atherosclerosis


Elizabeth Wheeler

• Non-cardiac disease morbidity and mortality is higher in HFpEF


Advertising & Custom Communications: Kathleen Powell Publisher:

Table of contents

Cardiometabolic Health Congress, 1801 N. Military Trail, Ste 200, Boca Raton, FL 33431

Patient Perspective (by Kari Roundy)

CALL FOR SUBMISSIONS Cardiometabolic Chronicle welcomes the submission of articles on the topic of cardiometabolic health and spanning a diverse range of content, including featured articles, opinions, clinical pearls, patient perspectives and more. For more detailed information, please contact the journal at



By Alexis Karandrea, PhD

in the Modern Era: Innovative Tools for a Complex Problem Abstract The field of cardio-oncology (or the adverse cardiovascular effects of cancer treatments) is evolving due to the emergence of multiple new cancer treatments, many of which can have implications on cardiovascular health. Most physicians are forced to simply react to cardiovascular damage due to cancer treatment, and the tools for preventative medicine in this setting are minimal. Awareness about cardio-oncology is crucial, and there is a need to identify potential intervention tools that enable clinicians to be at the forefront of care. Innovative approaches, such as personalized medicine, 3-D cardiac modeling, and machine learning can uncover mechanisms related to adverse cardiovascular events during cancer treatment and improve patient care. Cardio-oncology: a new approach Cardio-oncology is a growing field positioned to elaborate upon and treat cardiovascular side-effects resulting from cancer treatment. In a salient 2017 article by Mitchel Zoler for Frontline Medical, numerous physician perspectives highlight the increasing fervor and necessity of such a subspecialty.1 Indeed, the sheer volume of publications mentioning “cardio-oncology” grew from 60 in 2014 to a staggering 195 in 2017, only three years later (Figure 1). Adverse cardiovascular events arise from oncologic treatment regimens, most commonly those that involve anthracyclines, anti-HER2 compounds, and VEGF inhibitors. Interestingly, specific publication trends that mention cardiooncology in the context of these treatments (as indicated in the title or abstract) reveal a more gradual increase over the past 5 years. These preliminary results could reflect magnified overall awareness from the medical community of the importance of cardiooncology as new studies are published. The possibility for cardiotoxicity resulting from chemotherapy treatment is not a matter to be taken lightly, as dyssynchronous heart failure in general has been shown to have lasting effects on a cellular and molecular level. Kirk and Kass highlight cardiomyocytes from dyssynchronous hearts in a canine model showing sarcomere shortening and slower contraction.2 Correspondingly, calcium handling is altered, a finding echoed on a molecular level where decreased mRNA expression of phospholamban and sarcoplasmic reticular Ca2+ ATPase has been noted. Irregularities in these and other membrane channels can alter overall signaling in the organ, leading to a prolonged

Figure 1: The total number of articles that mention at any point ‘cardio-oncology’ is highlighted in the background in grey. The foreground shows the publication segmentation for those articles that mention ‘cardio-oncology’ at any point while indicating in either their title or abstract specifically those therapies shown including VEGF inhibitors (blue), anti-HER2 compounds (orange), and anthracyclines (green).


Cardio-Oncology in the modern era: innovative tools for a complex problem

The dearth of appearances ‘cardiooncology’ has made in the patent world sits in stark contrast to the recent spike in publication interest, potentially indicating that those gene-based diagnostic, imaging, and modeling tools common for conventional oncology or cardiology have yet to be widely tailored to this emerging subspecialty. Therefore, a similar 3-pronged approach utilizing information on genetic susceptibility, 3D modeling, and machine learning, may be especially useful in the mechanistic elaboration, and ultimately prediction and prevention, of these adverse cardiotoxic effects in chemotherapy patients. Continued awareness of cardio-oncology however, remains crucial, as this alongside collaborative projects between physicians and scientists will indelibly improve the quality of cancer care provided to patients of the future.

action potential duration characteristic of heart failure. Such aberrant signaling places unusual energetic demands on the heart, resulting in increased basal mitochondrial oxygen consumption.2 Cardiac complications like heart failure and cardiac-induced cardiomyopathy are a sizeable problem for the oncology community, as these events have been reported in 1%-5% of cancer survivors.3,4 As the NCI predicts the number of people living beyond a cancer diagnosis to reach nearly 19 million by 2024, this could equate to roughly 190,000-950,000 patients who may suffer from adverse cardiac events during chemotherapy.5 “I involve the cardiologist once there is evidence of damage,” Zoler quotes Dr. Swain, a professor of medicine at Georgetown University in Washington1; but in the burgeoning era of preventative medicine, it may be more costeffective in the long run to develop measures to protect against this cardiotoxicity on the front-end of a treatment regimen. Such is true for some personalized medicine projects, in which a diagnostic test for genetic-based responsiveness to a given drug may be favored by providers on the basis of long-term cost savings. In such a hypothetical scenario, drug A would only be prescribed to those patients who were the most likely to improve, while others would be placed on a different (and more likely efficacious) regimen B. In so doing, likely ‘nonresponsive’ patients to drug A would also be spared the side effects of an unsuccessful treatment. Here, genetic testing holds promising potential in the world of diagnostics to facilitate customized, and optimized treatment while minimizing patient risk. However digital approaches too, like the BlueStar app, are also gaining traction in the insurance marketplace as they’ve highlighted an average savings of $470 per diabetic patient per month as a result of those prophylactic choices it encourages in its user population. In some instances, the app’s artificial intelligence was even more accurate in predicting adverse events like hypoglycemia than the endocrinologist.6 To this end, what if it was possible to noninvasively model, monitor, and predict those cardiovascular changes that occur as a result of chemotherapy? Which technologies are positioned to be the most useful for this purpose, and what are their current states of development and applications? Genetic information has demonstrated increasing utility throughout the past decade, especially when examined against patient health records. Sheng, et al. highlights how one particular study found a rare kinase gene variant that was associated with osteoporosis; revealing the potential for exacerbation of this side effect should a patient be treated with kinase inhibitors. Authors continued to elaborate that analyses of genetic information may yield similar insights as to the potential genetic susceptibility for adverse cardiovascular effects resulting from


Alexis Karandrea, Ph.D., is a Technology Analyst with IDTechEx specializing in life science technologies. References: 1. Mitchel Zoler. Cardio-oncology booms but awareness lags. Frontline Medical. https:// September 21, 2017. Accessed January 18, 2018. 2. Kirk, Jonathan A., and David A. Kass. “Cellular and molecular aspects of dyssynchrony and resynchronization.” Heart failure clinics 13.1 (2017): 29-41.

chemotherapy, including heart failure, sudden cardiac death, and myocardial infarction.7 However, our predictive power is not limited alone to genetic information. Computational 3D modeling is another technique which may be of particular use for these endeavors. Drs. Auricchio and Prinzen have recently published their “3B perspective” standing for a “bench, bits, and beside” approach in which these digital methods may be used in conjunction with understanding gained from basic bench science and clinical studies to provide optimal CRT placement and pacing for patients. Here, these studies yield insight as to the heart’s fiber orientation, ion channel function, and contractility.8 The results of such interdisciplinary ventures are astounding, where both enhanced imaging techniques and overall computational power have allowed for the development of what Lopez-Perez, et al. accurately describes as “patient-specific 3D cardiac models”.9 In theory, one goal would be to incorporate such an analysis into a strategic pacemaker implantation process for each patient; however, there is no reason why such techniques could not be similarly applied towards monitoring those cardiac effects in chemotherapy patients. In fact, Ultrasound Medical Device Inc. based out of Ann Arbor, Michigan, has filed one of the only method patents in a cardio-oncology context, indicating the use of ultrasound image data loops to continuously monitor the heart of a patient.10

3. Cardinale, Daniela, et al. “Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.” Circulation 109.22 (2004): 2749-2754. 4. Felker, G. Michael, et al. “Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.” New England Journal of Medicine 342.15 (2000): 10771084. 5. National Cancer Institute. Cancer Statistics. understanding/statistics March 22, 2017. Accessed January 18, 2018. 6. Kowitt, Sarah D., et al. “Combining the High Tech with the Soft Touch: Population Health Management Using eHealth and Peer Support.” Population health management 20.1 (2017): 3-5. 7. Sheng, Calvin Chen, et al. “21st Century Cardio-Oncology: Identifying Cardiac Safety Signals in the Era of Personalized Medicine.” JACC: Basic to Translational Science 1.5 (2016): 386-398. 8. Auricchio, Angelo, and Frits W. Prinzen. “Enhancing Response in the Cardiac Resynchronization Therapy Patient: The 3B Perspective—Bench, Bits, and Bedside.” JACC: Clinical Electrophysiology 3.11 (2017): 12031219. 9. Lopez-Perez, Alejandro, Rafael Sebastian, and Jose M. Ferrero. “Three-dimensional cardiac computational modelling: methods, features and applications.” Biomedical engineering online 14.1 (2015): 35. 10. Hamilton, James, Eric J. Sieczka, and Eric T. Larson. “Method and system for acquiring and analyzing multiple image data loops.” U.S. Patent Application No. 13/796,126.

CARDIOVASCULAR PREVENTION: Is it Achievable in Patients with T2DM? By Editorial Board

Abstract The association between cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) is well accepted, but somehow, still poorly understood. This comes at a time that diabetes affects 29.1 million people in the United States (most of them type 2 diabetics), and 92.1 million people have some form of cardiovascular disease.1,2 Patients with T2DM have several comorbidities that are highly associated with cardiovascular risk, such as hypertension, being overweight or obese, and high lipid levels. It is not surprising that death from CVD is 70% higher in adults with diabetes, and many of these patients have decreased life expectancy, mostly due to premature cardiovascular death.1 Additionally, the question of cardiovascular safety of anti-diabetic drugs has contributed to the complexity that clinicians face in managing T2DM. Following the U.S. Food and Drug Administration’s (FDA) mandate that all new anti-diabetic drugs introduced since 2008 have to be evaluated for their long-term cardiovascular safety in T2DM patients, many cardiovascular outcome trials (CVOTs) of these drugs have been completed or are ongoing. In addition to safety, these trials have explored the possibility of longterm cardiovascular protection, however many questions still remain unanswered for clinicians in developing appropriate treatments for T2DM patients with CVD. This article will review and summarize the results from the major CVOT trials in antidiabetic drugs and their potential implications in optimizing clinical care in this patient population. Why the need for CVOTs in T2DM? It all started when rosiglitazone, the insulinsensitizer drug, was shown to be linked to increased rates of myocardial infarction (MI) in patients with T2DM in a large-scale metaanalysis.3 That evidence prompted the FDA to add prescribing restrictions on the drug, a restriction which has since been lifted.4 Given that many type 2 diabetics were taking rosiglitazone to improve insulin resistance

and glucose homeostasis, the concern was immediate: are we treating T2DM but also at the same time increasing the risk of cardiovascular complications? What about the cardiovascular safety of other antidiabetic medications? This huge knowledge gap led to the FDA’s decision in 2008 to require the assessment of CV safety before approval of glucose-lowering medications. Since the rosiglitazone controversy, many CVOTs in high-risk T2DM patients have been completed or are currently ongoing. Initially, the diabetes medical community was hoping for the best, but expecting the worst. Understandably, when results from early CVOTs showed that some anti-diabetic drugs were safe in high-risk T2DM patients, it was a great sign of relief. Results from the three CVOTs evaluating dipeptidyl peptidase-4 (DDP-4) inhibitors, SAVORTIMI (saxaglipitin), EXAMINE (aloglipitin), and TECOS (saxaglipitin, aloglipitin, and sitaglipitin), reported that they did not affect the rate of a major adverse cardiac event (MACE), measured by the composite score of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal ischemic stroke.5,6,7 Furthermore, most of the T2DM patients in these trials were at high-risk for cardiovascular complications and had preexisting heart disease.5,6,7 The ELIXA trial, demonstrated the cardiovascular safety of glucagon-like peptide 1 (GLP-1) receptor agonist (RA) lixisenatide in T2DM patients with a recent acute coronary event, as no effect on a 4-point MACE (composite of CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina) was reported.8 These results were a major step forward in the care for patients with T2DM and with CVD, and paved the way for additional studies that would reveal some very exciting outcomes. The next wave: glucose-lowering and improved cardiovascular safety Among the sodium-glucose cotransporter 2 (SGLT-2) inhibitors, the Empagliflozin Reducing Excess Glucose (EMPA-REG)

OUTCOME trial demonstrated superiority in reducing MACE.9 Patients receiving the drug had a 14% reduction in the primary composite outcome of death from CV causes, non-fatal MI, or non-fatal stroke than those receiving placebo, which was driven by the significant reduction in death from CV causes. There was no significant difference in the key secondary outcome, the risk of hospitalization for unstable angina. However, researchers did see a 38% reduction in CV mortality, a 32% reduction in all-cause mortality, and a 35% reduction in hospitalizations for heart failure compared to placebo.9 These benefits were unprecedented and had not been observed with any antidiabetic drugs to date. The positive results of the CVOT for empagliflozin led the FDA to approve empagliflozin for the new indication to reduce the risk of CV death in adult patients with T2DM and CV disease in December 2016. Furthermore, the CANVAS and CANVAS-R trials showed that another SGLT-2 inhibitor, canagliflozin, lowered the risk of cardiovascular events as evaluated by a 3P-MACE in T2DM patients, but did not show significant decreases in CV death, nonfatal MI, or nonfatal stroke when evaluated separately.10 Because of these promising results, CVOTs with two other SGLT-2 inhibitors, dapagliflozin (DECLARETIMI) and ertugliflozin (VERTIS-CV) are currently ongoing, with results expected in 201911. In addition to lixisenatide, CVOTs with other GLP-1 RAs were recently concluded and showed very different results. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial found a 13% reduction in the primary 3P-MACE composite outcome in T2DM patients treated with liraglutide compared to those receiving placebo, as well as a 22% reduction in CV death and a 15% reduction in all-cause death.12 The SUSTAIN-6 trial with semaglutide showed a robust reduction in 3P-MACE, but no reduction in CV death,


Cardiovascular Prevention: Is it Achievable in Patients with T2DM?

all-cause death, or hospitalizations due to heart failure.13 However, the EXSCEL trial, which evaluated the cardiovascular safety of GLP-1 RA exenatide, did not report improved cardiovascular outcomes as measured by the composite 3P-MACE, or cardiovascular and all-cause mortality, but confirmed the non-inferiority of this agent compared to placebo.14 Furthermore, two more GLP-1 RAs, dulaglutide (REWIND) and albiglutide (HARMONY) are currently being evaluated in clinical trials, with results anticipated later this year. The results from the concluded CVOTs have provided evidence about the non-inferiority of cardiovascular safety of most anti-diabetic drugs, suggesting that at least there is no increased risk of adverse cardiovascular events in high-risk T2DM patients. Results with some agents, particularly empagliflozin, canagliflozin, liraglutide, and semaglutide show that they decrease the likelihood of adverse cardiovascular events in T2DM patients with established CVD, however, it is unclear whether they can be used for primary prevention of CVD in type 2 diabetics. Results from ongoing CVOTs will provide additional information on the utility of these agents for primary CVD prevention, and to discern whether beneficial effects on cardiovascular health represent a class effect, since different outcomes have been reported even in drugs within the same class. A look ahead Based on the evidence from the LEADER, EMPA-REG, and CANVAS trials, the American Diabetes Association, in their newly released 2018 Standards of Medical Care in Diabetes, has incorporated the use of empagliflozin, canagliflozin, and liraglutide in T2DM patients with established cardiovascular disease.15 Since semaglutide was only approved by the FDA in December of 2017, it did not make it to this list, but may be added in future recommendations due to the positive results of the SUSTAIN-6 trial. Results from the CVOT trials have provided

strong evidence about the CV benefits and the lack of CV risk for many antidiabetic drugs. The hope is that these drugs will revolutionize patient care and lead to overall improved quality of life by making CVD prevention a near-reality in T2DM. As we all know, T2DM is a complex and chronic disease, and patients have many diverse comorbidities, including hypertension, obesity, dyslipidemia, and chronic kidney disease (CKD), which all impact the selection of antihyperglycemic therapies. Thus, a “one-size-fits-all” approach to treatment is insufficient, and there is an ever-growing need for individualized therapies that are specific to each patient. A multi-faceted approach to T2DM treatment should incorporate lifestyle modifications and the appropriate pharmacological therapies to meet glycemic targets. With the plethora of pharmacological agents now available, it is easy to get confused about which treatment plan is better for every individual patient. In addition, clinicians must consider psychosocial issues in all aspects of care, taking into account the patient’s emotional well-being and needs15. Although there is no shortcut to the complex clinical decisions that need to be made in T2DM care, some of the strategies can include: • Staying current with new and emerging advancements in the field • Reviewing updated standards of care, clinical practice guidelines and recommendations • Improving patient communication • Individualizing therapy for each patient The success of recent CVOTs has given clinicians more tools at their disposal, however, awareness about the efficacy and safety of these new agents is crucial in optimizing management plans for T2DM patients at high-risk for cardiovascular events. Strategies that can improve the currently poor cardiovascular outcomes in T2DM patients are around the corner. The combination of existing and newer therapies that lower the risk


29.1 million people in the United States

92.1 million

people have some form of CARDIOVASCULAR DISEASE 6

of cardiovascular complications while maintaining glycemic control provide an exciting opportunity for clinicians. However, more research is needed to understand the mechanisms responsible for these protective cardiovascular outcomes in order to determine whether these benefits are classor even drug-specific, and if they can be used in T2DM patients without established CVD.16 References:

1. Centers for Disease Control and Prevention. 2014 National Diabetes Statistics Report. statistics/2014StatisticsReport.html. Accessed January 12, 2018. 2. American Heart Association and American Stroke Association. Heart Disease and Stroke Statistics 2017 At-a-Glance. https:// uploads/2017/06/Heart-Disease-and-StrokeStatistics-2017-ucm_491265.pdf. Accessed January 12, 2018. 3. Nissen, Steven E., and Kathy Wolski. “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.” N Engl j Med 2007.356 (2007): 24572471. 4. Food and Drug Administration. FDA drug safety communication: FDA eliminates the risk evaluation and mitigation strategy (REMS) for rosiglitazone-containing diabetes medicines. ucm476466.htm. Accessed January 12, 2018. 5. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326. 6. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335. 7. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015. 373:232-242. 8. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373:2247-2257. 9. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. 10. Neal, Bruce, et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” New England Journal of Medicine (2017). 11. Schnell, Oliver, et al. “Updates on cardiovascular outcome trials in diabetes.” Cardiovascular diabetology 16.1 (2017): 128. 12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016a;375:311-322. 13. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016b;375:1834-1844. 14. Holman, Rury R., et al. “Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.” New England Journal of Medicine 377.13 (2017): 1228-1239. 15. American Diabetes Association. “9. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2018.” Diabetes care 41.Suppl 1 (2018): S86. 16. Kaul, Sanjay. “Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: a review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials.” Diabetes care 40.7 (2017): 821-831.

The Evolving Landscape of Type 2 Diabetes Mellitus Management By Editorial Board

Abstract Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia and insulin resistance. It affects approximately 28 million people in the United States (US).1 The prevalence of diabetes has almost doubled in the last two decades and it costs the US economy $245 billion annually; with most costs attributed to T2DM.1 Furthermore, about 7.2 million people with diabetes are not diagnosed, and an estimated 84.1 million people have prediabetes.2 Maintaining glycemic control is crucial in the long-term management of T2DM and to decrease the risk of major complications, and its importance is widely recognized in the clinical practice guidelines.3 However, even with the plethora of therapies currently approved for the management of T2DM, glycemic control remains suboptimal.4 Maintaining target HbA1c within the normal range remains elusive in many type 2 diabetics. Beyond HbA1c targets, patients with type 2 diabetes should also monitor glycemic variability, which has been associated with long-term T2DM complications such as cardiovascular disease.5 New literature supports the view that while managing chronic hyperglycemia is important, closely monitoring glycemic variability (such as dangerous postprandial glucose spikes or hypoglycemia) is equally as relevant. Although many pharmacotherapies are available for treatment, spanning from the traditional (such as metformin, sulfonylureas, basal insulin, thiazolidinediones) to newer agents (dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium glucose cotransporter 2

(SGLT-2) inhibitor, glucagon-like peptide-1 receptor agonist (GLP-1RA), new insulins), there are still several major barriers to optimizing T2DM care: • Personalization of treatment remains a challenge for clinicians • Low patient adherence to treatment • Clinical inertia • Lack of clinician education about newer antidiabetic agents Insulin therapy and clinical inertia The main pathophysiology that has gotten the most attention in the treatment of T2DM is insulin resistance, or the decreased action of insulin in target tissues (primarily liver, skeletal muscle, and adipose tissue), leading to chronic hyperglycemia. In pre-diabetes and T2DM, initially there is an increased production of insulin from the pancreatic beta-cells to compensate for this insulin resistance. This “overproduction” ultimately leads to beta-cell death and decreased insulin secretion; meaning that most type 2 diabetics will need exogenous insulin administration at some point during their lifetime.6 Thus, defining T2DM as “non-insulin dependent diabetes mellitus” was not entirely accurate, and now is widely recognized and accepted that both insulin resistance and inadequate insulin secretion are major pathophysiologies of T2DM. The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) guidelines recommend early intensification of therapies targeting beta-cell preservation,

initiating dual therapy with anti-hyperglycemic agents in untreated type 2 diabetes patients having A1cs ranging from 7.6-9%. However, initiation of insulin is often delayed by at least 5 years, despite the patient’s need for glycemic control.7 Most clinicians and patients prefer to choose dual or even triple oral therapy before selecting injectable basal insulin to reach the patient’s individualized glycemic target, and its initiation in T2DM is often delayed.4,8,9 Physicians’ barriers to initiation of insulin therapy include concerns about potential adverse effects (eg., increased hypoglycemia and weight gain) and practical concerns (eg., patient anxiety about insulin, perceived adherence issues, difficulties in training patients to administer insulin).4 In an international survey and a clinical practice review, primary care physicians (PCPs) and diabetes specialists reported that insulin initiation was prevented by lack of:4,10 • Time required to train patients • Clear guidelines and definitions • Support, as represented by Certified Diabetes Educators • Experience in taking a proactive role in insulin initiation • Coordination of care between PCPs and endocrinologists • Motivation Intensification has traditionally been achieved by adding short-acting insulin to cover post-prandial glucose (PPG) excursions that are not targeted by basal insulin. Intensive insulin regimens often result in a higher


Cardiovascular Prevention: Is it Achievable in Patients with T2DM?

risk of hypoglycemia and weight gain, which can contribute to a greater cardiometabolic burden on patients.4 Recently, newer, ultrafast-acting mealtime insulins have been approved, which allow for greater flexibility in managing PPG control.11 An alternative is to intensify therapy by adding a short-acting GLP-1RA rather than prandial insulin. This provides complementary actions, lowering both post-prandial glucose and fasting plasma glucose, and improves glycemic control with no increased hypoglycemia or weight gain.12 Recent studies have demonstrated that the combination of a GLP-1 RA with a basal insulin results in better glycemic control than adding multiple mealtime insulins.13 Due to this evidence, the basal insulin/GLP-1 RA combination has been incorporated as a possible treatment option by both ADA/EASD and AACE/ ACE.9,14 In addition, two agents that contain a fixed-ratio combination of basal insulin and GLP-1 RA delivered as a single daily injection are FDA approved (glargine U-100/ lixisenatide and degludec/liraglutide).15,16 These fixed-ratio combinations combine the clinical advantages associated with basal insulin and GLP-1RA therapy while limiting the primary side effects of each individual agent.15,16 Given the benefits of a convenient, once-daily schedule, improved glycemia and weight control, and no increase in the incidence of hypoglycemia, early initiation of single dose GLP-1 RA/insulin combination therapy is an emerging treatment option for a spectrum of patients with T2DM. This includes those patients not controlled using metformin alone, metformin combined with another oral agent, or basal insulin.15,16 Navigating treatment algorithms Current guidelines as put forth by the American Diabetes Association/European Association for the Study of Diabetes (ADA/ EASD) statement, and the consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) on the Comprehensive Type 2 Diabetes Management Algorithm, recommend an individualized approach that takes into account age, comorbidities, and hypoglycemia risk, as well as the patient’s access to resources and support systems.13,14 Because overly aggressive control in older patients with more advanced disease may not show significant benefits, current guidelines emphasize an individualized approach to treatment, taking into account the adverse effects of glucose-lowering medications, as well as the patient’s age and health status. In certain patients, the goal of 7.0% may need an upward adjustment, such as in those with longer diabetes duration, co-morbidities, shorter life expectancy, or advanced complications including nephropathy and severe hypoglycemia. Data from the National Health and Nutrition Examination Survey (NHANES) and the Veterans Administration found that diabetes


is over-treated and over-intensified in those over 65 years, increasing the risk of severe hypoglycemia and hospitalization.17,18 Indeed, a large randomized trial of patients with an average age of 62 years showed that intensive treatment to target HbA1c levels < 6.0% resulted in increased mortality and no reduction in major cardiovascular events.19 Both the ADA and American Geriatric Society recommend that glycemic targets in the elderly need to be individualized based on their functional and cognitive status and life expectancy, with a focus on minimizing the complications of hypoglycemia as well as hyperglycemia and maximizing day-to-day functionality.20 While metformin is considered the first-line of pharmacotherapy, the rapid increase in the number of new therapies makes the choice of a second and third T2DM medication more difficult. Clinicians need to understand the comparative evidence of newer treatment choices to help guide clinical decision making.21 Metformin remains the initial drug of choice because of its antihyperglycemic efficacy, low risk of hypoglycemia, modest weight loss, low cost, and possible benefits on cardiovascular outcomes. In addition to reducing cardiovascular risk, patients should also be advised to stop smoking and adopt healthy lifestyle habits, and, if indicated, be prescribed antihypertensive therapy, statins, and antiplatelet therapy. If the initial HbA1c target is not reached after three months, one of six treatment options should be considered: a sulfonylurea, thiazolidinedione (TZD), DPP-4 inhibitor, SGLT-2 inhibitor, GLP-1RA, or basal insulin. If, after another three months of dual therapy, HbA1c targets are still not reached, a third drug may be added. At that point, the addition of a third oral agent may enhance treatment efficacy, but the third drug will likely be less efficacious than if it were given as first-line or second-line therapy.14 Unfortunately, most clinicians and patients prefer to continue with oral agents before deciding to add an injectable basal insulin or GLP-1RA to reach the glycemic target.8 Although sulfonylureas and TZDs have been routinely used in T2DM, they are associated with hypoglycemia and weight gain. DDP-4 inhibitors, on the other hand, are weight neutral and have a low risk of hypoglycemia. A new class of medications, the gliflozins (SGLT-2 inhibitors), have shown efficacy in the treatment of type 2 diabetes with positive clinical outcomes of significant decrease in HbA1c and weight, without significant increases in hypoglycemia.22 This is an especially attractive profile since hypoglycemia and excessive weight gain are a major barrier to intensive glycemic control for many patients with T2DM. The mechanism of action for this class of agents is inhibition of the sodium-glucose transport protein (SGLT-1 or SGLT-2), located in the proximal convoluted tubule of the kidney, which increases glucose excretion and thereby improves glycemic control in those

with diabetes.22 In 2013-2014, the FDA approved three oral SGLT-2 inhibitor agents to be used as monotherapy or in combination with other anti-hyperglycemic drugs to manage T2DM: empagliflozin, canagliflozin, and dapagliflozin.22 Ertugliflozin was FDA approved in December of 2017 and sotagliflozin (a dual SGLT1 and SGLT2 inhibitor) is in phase 3 trials.22 Another new class of agents, the GLP-1 RAs, potentiate the effects of endogenous GLP1, an incretin hormone that is secreted following a meal bolus. Effects of GLP-1 RA include stimulation of insulin secretion and inhibition of glucagon release when hyperglycemia is present, delay of gastric emptying, reduction of food intake with associated weight loss, and reduction of fasting and postprandial glucose.23 Five subcutaneous injectable formulations are available (lixisenatide, liraglutide, exenatide, dulaglutide, albiglutide) with variable dosing, efficacy, and tolerability.23 Three GLP-1 RAs formulations (exenatide, albiglutide, dulaglutide) are available for once-weekly dosing.23 Semaglutide as a once-weekly injection was approved at the end of 2017, and a novel oral formulation, is in the later stages of the FDA approval process.23 In addition to their glucose-lowering effects, results from recent cardiovascular outcome trials (CVOTs) have indicated that two SGLT2 inhibitors (canagliflozin and empagliflozin) and two GLP-1 RAs (liraglutide and semaglutide) may be beneficial in decreasing cardiovascular risk in patients with T2DM and heart disease.24 Clinical practice guidelines and algorithms from ADA/EASD and AACE/ACE reflect the latest evidence-based data, incorporating the latest agents, results from CVOTs, emphasizing the need for individualizing treatment therapies, and focusing on patient-centered care.13,14 However, these guidelines have differences in their specific

recommendations for monotherapy and step-wise therapy, as well as use different levels of HbA1c for recommendation of treatment initiation,13,14 which can add to the challenges clinicians face in optimizing care. Implementing the latest evidencebased therapies and guidelines is crucial in T2DM management; however, clinicians should consider patient characteristics, co-morbidities, and the efficacy and safety of anti-diabetic drugs. An update on continuous glucose monitoring (CGM) Measuring HbA1c has been the method of choice to assess glucose control; however, this method does not reflect potential glucose excursions leading to hypoglycemia or postprandial hyperglycemia, which increase the risk of long-term complications.5 Self-monitoring of blood glucose (SMBG), although beneficial in glycemic control, is associated with low patient adherence. The limitations of HbA1c measurement for glycemic control were recognized in the latest American Diabetes Association (ADA) standards of care for diabetes.13 Continuous glucose monitoring (CGM) technology can circumvent some of these issues in T2DM management by providing near real-time glucose concentrations derived from interstitial fluid (Danne 2017; Petrie 2017; Riddle 2017).5,25,26 Clinical trials have supported the role of CGM in improving HbA1c and decreasing potentially dangerous glycemic excursions in diabetic patients.27-30 The emergence of CGM has given clinicians more options in individualizing T2DM management; however, several factors have contributed to the relatively low implementation of such devices in clinical practice.5,25,26 The landscape for CGM technology is rapidly changing with the continual development of new devices, tools, and applications; thus,

clinicians may have trouble navigating this evolving field. Education about existing guidelines and recommendations along with how clinicians can incorporate newest CGM technologies into their practice may help improve management of patients with T2DM. To date, a few position statements and guidelines have been put together by different professional societies to aid clinicians in incorporating CGM technologies in diabetes management.31-33 However, lack of consensus in the use of available CGM remains a challenge. In 2017, a group of experts in CGM technologies including physicians, researchers, and patients formulated new recommendations aimed to improve the utility of CGM; “International Consensus on Use of Continuous Glucose Monitoring.”5 The panel reviewed and made recommendations about the accuracy, data reporting, and utility of CGM systems. It called for usage of CGM technologies that have an acceptable level of accuracy and for standardization of key CGM metrics to assess glycemic control in order to optimize clinical decision-making.5 Furthermore, the panel reviewed different aspects of glycemic control that can be aided by CGM technologies, such as risk of hypoglycemia, glycemic variability, and HbA1c levels.5 Although the evidence regarding the use of CGM in T1DM patients is more robust, such evidence remains incomplete for T2DM. While it was initially believed that glucose measurements derived from interstitial fluid (measured by CGM sensors) were not as reliable as capillary blood glucose (using standard of care), recent studies have reported otherwise. A study evaluating the use of CGM in patients with T1DM reported an increased time in target glucose range when insulin administration decisions were based on CGM as opposed to SMBG34. Moreover, CGM technologies have been demonstrated to be reliable when used with automated insulin delivery (AID) systems.25 CGM can be a more reliable tool in detecting glycemic variability, as demonstrated by a recent study comparing CGM to SBGM in patients with T1DM or T2DM.35 Data from several studies support the use of CGM to determine glucose variability in T2DM patients.36-38 These studies have provided evidence about the utility of CGM technologies in managing T2DM; however, there is still a need for larger randomized clinical trials (RCTs) to evaluate CGM technologies in this setting.25 Furthermore, evaluating the utility of CGM devices is complicated by the different treatment regimens for T2DM patients, as well as the lack of standardization of outcome parameters for glycemic control and glucose variability.25 CGM technologies have the potential to individualize treatment and care in T2DM, such as for patients at high risk for hypoglycemia, on insulin therapy, or with chronic kidney disease.5 Conclusion Management of type 2 diabetes mellitus is

constantly evolving, not only because there are new therapies and technologies available to clinicians, but also due to the ever-changing treatment goals and the re-definition of glycemic control. While it is important to recognize the new advancements in T2DM care, clinicians must take into account the efficacy and safety of each new approach and tailor treatment to accommodate the specific patient needs and characteristics. References

1) American Diabetes Association. Statistics about diabetes. Last reviewed July 19, 2017. Accessed January 2, 2018. 2) Centers for Disease Control and Prevention. “National diabetes statistics report, 2017.” Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services (2017). 3) American Diabetes Association. “Standards of Medical Care in Diabetes—2018.” Diabetes care 41.Supplement 1 (2018): S13-S27. 4) Khunti, Kamlesh, et al. “Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: a systematic review.” Diabetes, Obesity and Metabolism (2017). 5) Danne, Thomas, et al. “International consensus on use of continuous glucose monitoring.” Diabetes care 40.12 (2017): 1631-1640. 6) Halban, Philippe A., et al. “β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.” The Journal of Clinical Endocrinology & Metabolism 99.6 (2014): 1983-1992. 7) Rubino, A., et al. “Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with type 2 diabetes: a population-based analysis in the UK.” Diabetic Medicine 24.12 (2007): 14121418. 8) Rosenstock, Julio, et al. “Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial.” Diabetes Care 39.11 (2016): 2026-2035. 9) Inzucchi, Silvio E., et al. “Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.” Diabetes care 38.1 (2015): 140-149. 10) Cuddihy, Robert M., Athena Philis-Tsimikas, and A. Nazeri. “Type 2 Diabetes Care and Insulin Intensification.” The Diabetes Educator 37.1 (2011): 111-123. 11) Muchmore, Douglas B. “The Need for Faster Insulin: Problem Solved?.” Journal of Diabetes Science and Technology 11.1 (2017): 157-159. 12) Eng, Conrad, et al. “Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and metaanalysis.” The Lancet 384.9961 (2015): 22282234. 13) American Diabetes Association. “1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes—2018.” Diabetes Care 41.Supplement 1 (2018): S7-S12. 14) 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–2017 executive summary.” Endocrine Practice 23.2 (2017): 207-238.


Cardiovascular Prevention: Is it Achievable in Patients with T2DM?

15) Vedtofte, Louise, Filip K. Knop, and Tina Vilsbøll. “Efficacy and safety of fixed-ratio combination of insulin degludec and liraglutide (IDegLira) for the treatment of type 2 diabetes.” Expert Opinion on Drug Safety 16.3 (2017): 387-396. 16) Scott, Lesley J. “Insulin Glargine/Lixisenatide: A Review in Type 2 Diabetes.” Drugs 77.12 (2017): 1353-1362. 17) Lipska, Kasia J., et al. “Potential overtreatment of diabetes mellitus in older adults with tight glycemic control.” JAMA internal medicine 175.3 (2015): 356-362. 18) Thorpe, Carolyn T., et al. “Tight glycemic control and use of hypoglycemic medications in older veterans with type 2 diabetes and comorbid dementia.” Diabetes Care 38.4 (2015): 588-595. 19) Action to Control Cardiovascular Risk in Diabetes Study Group. “Effects of intensive glucose lowering in type 2 diabetes.” N Engl j Med 2008.358 (2008): 2545-2559. 20) Migdal, Alexandra, et al. “Update on diabetes in the elderly and in nursing home residents.” Journal of the American Medical Directors Association 12.9 (2011): 627-632. 21) Kuhn, Alexander, et al. “Intensifying Treatment Beyond Monotherapy in Type 2 Diabetes Mellitus: Where Do Newer Therapies Fit?.” Current cardiology reports 19.3 (2017): 25. 22) Mosley, Juan F., et al. “Sodium-glucose linked transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: a drug class overview.” Pharmacy and Therapeutics 40.7 (2015): 451. 23) Singh, Sonal, et al. “Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis.” Diabetes, Obesity and Metabolism 19.2 (2017): 228-238.

24) Schnell, Oliver, et al. “Updates on cardiovascular outcome trials in diabetes.” Cardiovascular diabetology 16.1 (2017): 128. 25) Petrie, John R., et al. “Improving the clinical value and utility of CGM systems: issues and recommendations.” Diabetologia60.12 (2017): 2319-2328. 26) Riddle, Matthew C., Hertzel C. Gerstein, and William T. Cefalu. “Maturation of CGM and Glycemic Measurements Beyond HbA1c—A Turning Point in Research and Clinical Decisions.” Diabetes care 40.12 (2017): 16111613. 27) Beck, Roy W., et al. “Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections: a randomized trial.” Annals of internal medicine 167.6 (2017): 365-374. 28) Ehrhardt, Nicole M., et al. “The effect of real-time continuous glucose monitoring on glycemic control in patients with type 2 diabetes mellitus.” Journal of Diabetes Science and Technology 5.3 (2011): 668-675. 29) Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. “Continuous glucose monitoring and intensive treatment of type 1 diabetes.” N Engl J Med2008.359 (2008): 1464-1476. 30) Vigersky, Robert, and Maneesh Shrivastav. “Role of continuous glucose monitoring for type 2 in diabetes management and research.” Journal of Diabetes and its Complications 31.1 (2017): 280-287. 31) Bailey, Timothy S., et al. “American Association of Clinical Endocrinologists and American College of Endocrinology 2016 outpatient glucose monitoring consensus statement.” Endocrine Practice 22.2 (2016): 231-261. 32) Klonoff, David C., et al. “Continuous glucose

monitoring: an endocrine society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 96.10 (2011): 2968-2979. 33) Peters, Anne L., et al. “Diabetes technology— continuous subcutaneous insulin infusion therapy and continuous glucose monitoring in adults: an endocrine society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 101.11 (2016): 3922-3937. 34) Aleppo, Grazia, et al. “REPLACE-BG: a randomized trial comparing continuous glucose monitoring with and without routine blood glucose monitoring in adults with wellcontrolled type 1 diabetes.” Diabetes Care 40.4 (2017): 538-545. 35) Mangrola, Devna, et al. “Self-blood glucose monitoring underestimates hyperglycemia and hypoglycemia as compared to continuous glucose monitoring in type 1 and type 2 diabetes.” Endocrine Practice (2017). 36) FLAT-SUGAR Trial Investigators. “Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk.” Diabetes Care39.6 (2016): 973-981. 37) Bajaj, Harpreet S., et al. “Lowest glucose variability and hypoglycemia are observed with the combination of a GLP-1 receptor agonist and basal insulin (VARIATION Study).” Diabetes care 40.2 (2017): 194-200. 38) Haak, Thomas, et al. “Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulintreated type 2 diabetes: a multicenter, openlabel randomized controlled trial.” Diabetes Therapy 8.1 (2017): 55-73.

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New Guidelines: Addressing Practical Challenges in Heart Failure Care By Editorial Board

Abstract Statistics indicate that approximately 6.5 million people in the United States are diagnosed with heart failure (HF), an uptick from 5.7 million in only a few years— leading to a multitude of risk factors often associated with cardiometabolic syndrome.1 These factors include—but are not limited to—obesity, increased blood pressure, a predisposition towards diabetes, abnormal cholesterol levels, and hypercoagulability. In turn, the aforementioned risk factors lead to significantly increased mortality, primarily due to heart attack, stroke, congestive HF, and chronic kidney disease. As the global obesity epidemic continues to plague the population, there will be an inevitable increase in the epidemiology of HF. As a result, new guidelines reflecting the latest evidence-based treatment strategies and recommendations have recently been released to aid clinicians in optimizing HF care. The big picture The prevalence of HF is currently estimated at 6 million people in the United States, and is projected to increase by 46% and affect more than 8 million by 2030.1 Heart failure has enormous monetary impacts on the economy; each patient’s hospitalization cost is $23,077, and annual costs for HF patients will likely exceed $31 billion dollars.1 Moreover, studies confirm that almost a quarter of all HF patients are readmitted to the hospital within 30 days of discharge; nearly half are hospitalized 4 or more times, and these patients are also often cognitively impaired— furthering the risks of hospitalization and readmission.1,2 Further data indicates that 11% of HF patients die within 30 days of

hospital discharge, and about 50% die within 5 years of diagnosis.1 The fact that hospital readmission rates for HF are extremely high has become an increasingly serious public health issue, even monitored by the Centers for Medicare & Medicaid Services as part of an initiative to lessen readmission rates and impacts.3 The two most common subsets of HF are patients with reduced ejection fraction (HFrEF), and patients with preserved ejection fraction (HFpEF). Among patients

The prevalence of HF is currently estimated at 6.5 million people in the US

diagnosed with HF, around 50% have HFpEF, a condition that has become both more prevalent and challenging to diagnose.4 Although there are distinctive myocardial structural and primary functional derangements in HFrEF, clinical presentations and prognosis are similar to HFpEF.4 Diagnosing the correct subset of HF is perhaps further complicated by the lack of agreement about classification of left ventricular ejection fraction (LVEF). Reduced ejection fraction is variably classified (as ≤35%, <40%, and ≤40%), and the same goes for preserved ejection fraction (classified as >40%, >45%, >50% and ≥55%); and new studies suggest that there is even a new phenotype defined as heart failure with midrange ejection fraction (40-49%).4 This adds to the complexity of HF management, since patients with HFrEF respond well to established pharmacotherapies, but the same is not true for patients with HFpEF.4 Due to the high prevalence of HF in the US and coexisting conditions, such as diabetes, chronic respiratory conditions, renal dysfunction, or peripheral vascular disease, HF patients are often managed and treated by health care providers from multiple disciplines, including primary care physicians, internists, family medicine physicians, cardiologists, and endocrinologists. Due to the rapidly increasing prevalence of HF, coupled with its economic burden and strong correlation to cardiometabolic syndrome, it is critical for clinicians to stay current surrounding guidelines, newly emerging pharmacotherapies, and coordination of care strategies that collectively enhance and optimize patient outcomes.


New guidelines: addressing practical challenges in heart failure care


New guidelines Due to new evidence and treatment protocols, the “2013 ACCF/AHA Guideline for the Management of Heart Failure” was updated in 2017 through a partnership between the Heart Failure Society of America, the American College of Cardiology, and the American Heart Association. The update represented the second of a two-stage publication with the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for heart Failure, and includes revisions to sections concerning biomarkers, the introduction of new therapies for HFrEF, updates on HFpEF, newly updated data surrounding critical comorbidities including sleep apnea and anemia, and further insights into the potential prevention of HF.5,6,7 More recently, in order to complement and supplement the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACC/AHA Guideline for the Management of Heart Failure, the American College of Cardiology has released new guidelines that address new medical therapies, prevention protocols, and relevant comorbidities—while outlining management of HFrEF with specific considerations for certain groups.8

of aldosterone receptor antagonists should be considered. Additionally, for patients with New York Heart Association (NYHA) class II and III HF accompanied by comorbid iron deficiency anemia, the use of intravenous iron replacement could ultimately prove successful.6

The 2017 update suggested the use of natriuretic peptide biomarker-based screening, followed by team-based care including a cardiovascular specialist. The optimization of guideline-directed management and therapy (GDMT) was found to be effective in preventing not only the development of Left Ventricular (LV) dysfunction—both systolic and diastolic—but also the onset of new HF.6 Other findings confirmed that for the pharmacologic treatment of Stage C HFpEF, the application

therapies, and ways in which to manage both the cost and complexity of HF.8 The newly revised guidelines also discuss the integration of palliative care, and transition to hospice care, among patients with HF.8 In addition, these guidelines address specific population cohorts at higher risk for HF (such as the elderly, the frail, and African Americans) and patients with common comorbidities, including cardiometabolic risk factors. One of the hallmark traits of this new document is its direct application of

The 2017 update further emphasized goals and recommendations for the management of blood pressure, for patients at risk of HF development, and those with both stage C HFrEF with hypertension and HFpEF with hypertension. The focused update also incorporated new data regarding patients with NYHA class II-IV HF, and the potential of sleep disordered breathing or excessive daytime sleepiness. The verbiage emphasized the importance of diagnosing obstructive versus central sleep apnea, coupled with new data that further highlighted HF prevention, management of hypertension, and the treatment of other common comorbid conditions.6 The most recent document outlined ten specific areas of interest to HF clinicians, including how to address challenges of care coordination, improve adherence to

HF guidelines to the clinic, due to the clinical practice gaps that clinicians face in the prevention, diagnosis, and treatment of HF.8 Conclusion As new therapies and diagnostics for HF become available, guidelines for the management of the disease continue to evolve, with the goal of bridging the clinical practice gaps and complexities of HF care. An increasing realization surrounding the critical comorbidities also allows clinicians to better address HF, and evolving updated guidelines and documents continue to address the critical reality and need for prevention. With specifically outlined clinical practice gaps and recommendations for improvement, the updated guidelines are an added tool for the healthcare professionals to more effectively treat the global epidemic of heart failure. However, as the experts conclude, “no guideline, pathway, or algorithm should supersede clinical judgement”, and clinicians should choose the appropriate therapies based on patient preferences and clinical presentation.8 References

1. Benjamin, Emelia J., et al. “Heart disease and stroke statistics—2017 update: a report from the American Heart Association.” Circulation 135.10 (2017): e146-e603. 2. Wong CY, Chaudhry SI, Desai MM, et al. Trends in comorbidity, disability, and polypharmacy in heart failure. Am J Med. 2011;124(2):136. 3. Fonarow, Gregg C., Marvin A. Konstam, and Clyde W. Yancy. “The Hospital Readmission Reduction Program Is Associated With Fewer Readmissions, More Deaths: Time to Reconsider.” (2017): 1931-1934. 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 journal37.27 (2016): 2129-2200. 5. Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-e239. 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 cardiac failure 23.8 (2017): 628-651. 7. Yancy, Clyde W., et al. “2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an 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 Cardiac Failure 22.9 (2016): 659-669. 8. Yancy, Clyde W., et al. “2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction.” Journal of the American College of Cardiology (2017): 24465.


Alan Chait, MD Dr. Chait is a renowned physician and scientist in the cardiometabolic field. He has received funding from the NIH and other research programs, and has authored numerous publications and both basic and clinical research articles in international peer-reviewed journals. His research focuses on lipoproteinproteoglycan interactions, the role of diabetes in the pathogenesis of macrovascular disease, and the links between obesity, inflammation, insulin resistance, and atherosclerosis. At 2018 CMHC West, Dr. Chait will present the keynote address, titled: “Obesity and Inflammation: What have we learned from animal models?”. What inspired you to become a physician? I grew up in South Africa and we went straight from high school to medical school, as was the custom there. I was 17 years old at the time, and I wasn’t sure what I was getting myself into. My father was a physician, so going to medical school seemed like something I wanted to do and a good idea at the time. Who has had the greatest influence on your career? I’ve been fortunate to have great mentors along the way. Two stand out. When I finished medical school and my internship in South Africa, I moved to London, where I got interested in internal medicine and wanted to do research, but only had a vague idea of what research entailed. During my time at Hammersmith Hospital in London, I was very fortunate to meet Professor Barry Lewis, an excellent mentor who had a major influence in my life. He introduced me to research, got me excited about the importance of it, and about lipid research. After being in London for 7 years, I came to the University of Washington to gain additional research experience. Here I met my second mentor, Dr. Edwin L. Bierman, who further fostered my excitement about lipid research, and I am honored to be the recipient of an Endowed Professorship in his name. I must thank these two outstanding mentors for getting me started in a career that has been very enjoyable.

Edwin L. Bierman Professor of Medicine Division of Metabolism, Endocrinology, and Nutrition at University of Washington at Seattle

What has been the greatest challenge during your professional career? The greatest challenge for all of us involved in research is the difficulty in getting funding. Most of us are spending an inordinate amount of time on grant preparation, leaving less time to do the meaningful research that will lead to the advancement of therapies. In addition, because of the insecurity of funding, which has worsened over the years, convincing brilliant young scientists and investigators to stay in biomedical research is another challenge that we face. During my career, I’ve had the great pleasure and honor to work with some excellent young investigators, and it would be a disservice to the field if we are deprived of such talent in the future.

What area of research in cardiometabolic health interests you most now and why? A major interest of mine is to explore how inflammation affects cardiovascular disease, and particularly the relationship between obesity and inflammation. It’s an evolution of my thinking over the years. I started by thinking mainly about lipid metabolism, then got into mechanisms of atherosclerosis, the role of proteoglycans in atherosclerosis and inflammation, which evolved into adipose tissue inflammation and how it relates to atherosclerosis. The interesting thing is that my research has now come full cycle, since we now found that proteoglycans also are produced in adipose tissue. We currently are exploring how they affect adipose tissue inflammation and some of the downstream consequences such as insulin resistance and cardiovascular disease. What do you think is going to be the next big thing in your field in the next decade? Of interest is the role that inflammation plays in cardiovascular disease, particularly in the context of obesity. Just this past year, there was a proof of concept study showing that an anti-inflammatory agent had an independent effect in reducing cardiovascular disease outcomes. Although treating patients with this specific anti-inflammatory agent for cardiovascular prevention is not practical, this study lays the groundwork to explore how reducing inflammation per se can impact cardiometabolic health in obese patients. Another fascinating topic that I believe we will hear more of in the future is how the gut microbiome can impact obesity.

How do you see the role of the physicianscientist in patient care? I believe that physician-scientists play a tremendously important role in patient care, because they are used to a scientific thought process rather than an empirical approach to treatment. Due to their unique training, they have an understanding of both basic and clinical aspects of the specific disease states they treat, which allows for a more comprehensive approach to management. What do you consider your greatest achievement? I can’t pinpoint a specific achievement. Most of us in science make incremental discoveries that together with the contributions of other scientists help us in trying to understand the big picture. I hope I’ve made a number of such discoveries that have aided to our understanding of the biology and treatment of disease. What are your hobbies outside of practicing medicine? I’ve been doing photography since my teenage years. I use the camera as my tool to create abstract photography that looks more like painting, and have also exhibited my work. It’s a great way to take a break from research and medicine. I have enjoyed boating around the Seattle area, as well as skiing. I also like to read and listen to music. What is your motto or philosophy? In my career, I’ve had the privilege of being at a university where I’ve had the opportunity to do research, see patients, teach, and establish relationships with friends and colleagues all over the world. All these components make life as a physician-scientist exciting. If one week you’re not getting the results you want in the lab, that same week you’re in the clinic and having success with your patient, or getting satisfaction from teaching, and it all balances out.


WHO IS CMHC? As a rapidly expanding global epidemic surrounds cardiometabolic disease, clinicians are increasingly faced with an imminent threat, and a pressing need for the most current clinical education and research. With heart disease as the primary cause of death in the United States, there is an urgency to not only combat cardiovascular disease, but also assist patients while improving inadequacies in cardiovascular care.

Continuing its tradition of delivering the latest research and findings surrounding cardiometabolic care, the Cardiometabolic Health Congress (CMHC) represents a diverse educational platform that allows frontline clinicians to stay current with evolving science and innovations. Our team at CMHC is consistently dedicated to sparking ingenuity and fostering collaborations at both our live conferences and digital forums, as we provide unique programming and a synergistic learning environment to healthcare professionals from across the globe. Due to recent estimates that indicate over one third of the nation’s population has at least one cardiometabolic risk factor, CMHC offers a convenient and accessible opportunity for clinicians to network, engage, and internalize the latest developments in cardiometabolic health and care.

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topics such as: 2 covering • Obesity and Lifestyle Medicine

Come listen to world renowned experts • Dyslipidemia and Atherosclerosis • Heart Failure and Hypertension • Diabetes Management






Learn new protocols and techniques to immediately change your practice



Our CMHC Pulse blog is a biweekly online publication, with posts that highlight current events and contemporary findings in cardiometabolic health. Based on the most recent clinical studies and information, Pulse delivers its readers summaries of the newest available data in heart health, with accompanying graphics and visuals.

By Sarenka Smith

The co-occurrence of diabetes & heart disease DIABETES AFFECTS

29.1 million

people in the United States, including

8.1 million

people who remain undiagnosed children and young adults with diabetes THE CO-OCCURRENCE mellitus have a fivefold increased risk of

The number of people living with diabetes has tripled since 2000, leading to enormous financial ramifications: the global cost of the disease is $673 billion each year.1 The latest estimates from the International Diabetes Federation indicate that one in 11 adults worldwide have diabetes1; most have type 2 diabetes, which is strongly linked to obesity and lifestyle factors. There is a strong link between type 2 diabetes and cardiovascular disease, as people with diabetes are more than twice as likely to develop cardiovascular disease and have lower life expectancy.

all-cause mortality, and a sevenfold increased of Diabetes & Heart Disease risk of sudden cardiac death, compared with

According to a study presented at the American Heart Association’s Scientific Sessions in 2017, data indicates that

New guidelines for high blood pressure

At the conclusion of 2017, the American Heart Association (AHA) and the American College of Cardiology (ACC) published new evidence-based guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults.1 The new guidelines are the first comprehensive set since 2003 and have lowered the definition of high blood pressure from 140/90mmHg to


age-matched individuals without diabetes.2 The findings highlight the critical need for continuous cardiovascular risk monitoring and management in young people with DM.

Less than half of those diagnosed with diabetes are aware that the diseases places them at a much higher risk for cardiovascular disease complications; the lack of awareness prevents addressing risks and improving health, often leading to preventable deaths. Ken Thorpe, Chairman of the Partnership to Fight Chronic

130/80mmHg to account for complications that can occur at lower numbers as well as allow the initiation of earlier treatment. According to a joint statement issued in 2017 by the American Heart Association and the American College of Cardiology, nearly half of all adult Americans will be considered to have high blood pressure under new guidelines.1 “The numbers are scary,” said Dr. Robert M.

Disease, urges education and the power of prevention. “We must do better to diagnose, treat, and prevent chronic conditions like diabetes and cardiovascular diseases, and one of the first and most important actions we can take is to raise awareness among patients, providers, and policymakers of the alarming co-existence of these two debilitating conditions, and what can be done to avoid them in the first place.” The total number of people with diabetes worldwide is now 415 million, and is expected to reach 642 million by 2040 if current trends continue.1 Coupled with the increasing numbers of cardiovascular disease, the combination of these two conditions can be deadly. This link is recognized by most professional medical societies and reflected in current clinical practice guidelines, which call for assessing cardiovascular risk factors in all patients with diabetes. References:

1. Herman, William H. “The Global Burden of Diabetes: An Overview.” Diabetes Mellitus in Developing Countries and Underserved Communities. Springer International Publishing, 2017. 1-5. 2. Svane, Jesper, et al. “Young Persons With Diabetes Have a 7-Fold Increased Risk of Sudden Cardiac Death Compared to Persons Without Diabetes: A Nationwide Cohort Study in Denmark.” American Heart Association. Circulation (2017): A20507-A20507.

Carey, professor of medicine at the University of Virginia and co-chair of the committee that formulated the new guidelines. The nation’s leading heart experts state that tens of millions more Americans will now meet criteria for the condition of high blood pressure. The number of adults with high blood pressure, or hypertension, will rise to


Chronic stress & obesity: a new perspective on “comfort food”

The biological connection between stress and obesity has long been suspected: during times of high anxiety and stress, people often crave ‘comfort foods,’ which are high in fat or sugar. Researchers have now found that specific hormones may play a significant role in this process: stress has been linked to biochemical changes that can trigger cravings, which lead to overeating, and ultimately result in obesity. Specific biochemical reactions help explain this correlation: when we reach for fattening foods during stressful times, it is often an attempt to self-mediate—carbohydrates raise the body’s serotonin levels, the body’s ‘feel-good’ chemical. Researchers have also discovered that chronic stress can cause the body to release excess cortisol, a hormone critical in managing fat storage and energy use. Cortisol is known to increase appetite,

103 million from 72 million under the previous standards—meaning that 46% of US adults will be considered hypertensive. Carey states that the reformulation stems from the recognition that blood pressure considered ‘normal’ in the past—or ‘pre-hypertensive’—actually placed patients at significant risk for heart disease and death and disability, as medical evidence confirms that people with high blood pressure in the 130-139 range carry a doubled risk of heart attack, stroke, and heart and kidney failure. “The risk hasn’t changed. What’s changed is our recognition of the risk.” Nevertheless, the report’s authors predict that few of those who fall into the new hypertensive category will require medication. Rather, the hope is that many with early stages of the condition will address it through lifestyle changes, including weight loss, diet improvements, increased physical activity, less alcohol and sodium consumption, and lowered stress. “An important cornerstone of

and may encourage cravings for sugary and fatty foods. More recent studies suggest that our bodies process food differently when under stress. One study found that lab mice, when fed a diet high in fat and sugar, gained significant amounts of body fat when placed under stressful conditions.1 Conversely, mice fed a normal diet did not gain as much weight—despite being placed under stressful conditions. Researchers linked this phenomenon to the molecule neuropeptide Y, which is released from nerve cells during stress and encourages fat accumulation. Diets high in fat and sugar appear to further accelerate the release of neuropeptide Y.1 As physicians better understand the factors behind weight gain, they may be better equipped to help address the global obesity epidemic. Yet the most insidious aspect of the link between stress and obesity is that it is often self-reinforcing. When people are stressed and make unhealthy choices, they often gain weight, which only serves to further exacerbate stress. While stress is an

inevitable part of life, it does not necessarily need to lead to weight gain. By keeping portion size in mind, not allowing yourself to become too hungry, eating healthy snacks, and becoming more mindful about nutrition, we can avoid gaining weight when times are tough. The interesting interaction between food intake, obesity and neural pathways will be explored during our upcoming CMHC West Conference that will be held in Las Vegas from May 4-5, 2018. Our upcoming agenda features a session titled “Benefits of Physical Activity and Exercise on Cardiovascular and Mental Health,” delivered by Jason R. Tregellas, Ph.D., that review the link between food intake and neural pathways which can lead to dentification of novel therapeutic targets for obesity prevention. Reference:

1. Reichmann, Florian, and Peter Holzer. “Neuropeptide Y: a stressful review.” Neuropeptides 55 (2016): 99-109.



these new guidelines is a strong emphasis on lifestyle changes as the first line of therapy. There is an opportunity to reduce risk without necessarily imposing medications,” said Richard Chazal, the immediate past president of the American College of Cardiology. High blood pressure is one of the leading cause of death, and the second-leading cause of preventable death in the United States, after cigarette smoking.2 Hypertension is often a precursor for cardiovascular disease, strokes, severe kidney disease, and other disorders that kill millions annually.2 Thomas R. Frieden, the former director of the US Centers for Disease Control and Prevention who now runs a global health initiative that focuses on heart disease and stroke, has called hypertension “the world’s most under-addressed preventable health problem.” The new blood pressure guidelines have the potential to change the standard of care for hypertensive and cardiometabolic patients,

but have also stirred a lot of debate in the medical community. At the 2018 CMHC West conference in Las Vegas, Matthew R. Weir, MD, Professor of Medicine and Division Head of Nephrology at the University of Maryland School of Medicine, will provide an overview of the new 2017 AHA/ACC blood pressure guidelines, including changes from previous guidelines and recommendations. This session will be followed by a challenging patient case that will take into consideration the new guidelines when determining a treatment plan for a patient with hypertension and other comorbidities including type 2 diabetes mellitus and chronic kidney disease. References:

1. American College of Cardiology. http:// November 13, 2017. Accessed January 5, 2018. 2. Centers for Disease Control and Prevention. High Blood Pressure. bloodpressure/. November 13, 2017. Accessed January 5, 2018.


ADVANCING PERSONALIZED HEART HEALTH. TRANSFORMATIVE INSIGHTS TO ENHANCE YOUR PRACTICE. SpectraCell’s CardioMetabolic analysis goes beyond standard cholesterol screening to help define risk for atherosclerotic cardiovascular disease (ASCVD), progression toward Type 2 Diabetes, and inflammation conditions that typically precede heart attacks, stroke, and diabetes. CardioMetabolic Profile: ▪ CardioMetabolic and Type 2 Diabetes risk assessments ▪ Lipoprotein Particle Profile® Plus - measures lipoprotein size and density; cardiovascular risk stratification; and also includes triglyceride and traditional cholesterol screening ▪ OmegaCheck® - measures the ratio of omega-6 to omega-3 fatty acids in one’s blood Our science-based and innovative technologies assist you in the delivery of personalized treatment and disease prevention solutions that support an effective patient-centered approach to wellness.

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PULSE BLOGS | Continued

Eating your way out of a heart attack

According to the CDC, each year approximately 790,000 Americans have a heart attack1—a statistic that can be mitigated by lifestyle interventions. “Heart disease needs urgent intervention. And that intervention, it is increasingly getting clear, has to be a lifestyle and diet makeover,” says Kenneth Thorpe, chairman at Partnership to Fight Chronic Disease (PFCD). Studies have noted a marked increase in the number of young patients suffering from heart attacks. A recent article2 discussed a 29-year-old professional who suffered a heart attack, yet had no prior family history of cardiovascular disease. However, the patient’s lifestyle included heavy smoking, insufficient exercise, and overweightness. In 2011, the same patient suffered a second heart attack, and a third two years later. At only 45 years old, he underwent a heart transplant. Subsequent to his surgery, his life has transitioned to one in which he exercises daily, engages in minimal drinking and smoking, consumes less sodium, and continuously checks his lipid profile. A study published in the Journal of The American Medical Association in March of 2017 indicates that a large percentage of deaths due to cardiovascular disease and diabetes are linked to poor diet.3 According to the findings, 10 foods/nutrients associated with cardiometabolic diseases are fruits, vegetables, nuts/seeds, whole grains, unprocessed red meats, processed meats (refined oils, hydrogenated fats, etc.), sugar-sweetened beverages (SSBs), polyunsaturated fats (PUFA), seafood omega-3 fats and sodium.3 Moreover, excess sodium intake had strong correlations to the highest proportion of heart disease: associated in 9.5% of deaths. Extensive data has previously demonstrated that high-salt diets significantly increase blood pressure, and the risk of heart disease.3 Research has also revealed that daily consumption of over 13.7 grams of salt leads to two times higher risk of heart

failure, compared to those who consume less than 6.8 grams each day. “The World Health Organization recommends a maximum of 5g per day,” says Dr. Sundeep Mishra, Professor of Cardiology at All India Institute of Medical Sciences. The majority of the population ingests more than 10 times the amount of salt needed to meet sodium requirements. However, not all fats are detrimental to diet and lifestyle: “Saturated and trans fats increase blood cholesterol and heart attack rates. PUFA (polyunsaturated fatty acids) and monounsaturated (MUFA) fats lower the risk of heart attacks,” according to Dr. Simmi Manocha of the Asian Institute of Medical Sciences, Faridabad. Omega-3 fatty acids are a type of PUFA that are highly beneficial for cardiovascular health. According to a study at Tufts University, both plant-based and seafood-based omega-3 lower the risk of fatal heart attacks by approximately 10%. The researchers also found that fish, walnuts, and flaxseed oil are the best sources of omega-3. Other dietary patterns that impacted heart health were low intake of nuts and seeds (8.5%), high intake of processed meats (8.2%) and low fruit and vegetable intake (7.6 and 7.5%, respectively). The overarching conclusion of the aforementioned studies is that diet is critical in terms of preventing and treating heart disease.3 A poor diet can not only lead to weight gain, but also an elevated risk of heart attack: up to 25%. Despite healthy blood pressure, blood sugar, and cholesterol levels, being overweight or obese increases the risk of coronary heart disease by up to 28%, compared to those with a healthy body weight, according to a study published in the European Heart Journal.4 References:

1. Benjamin, Emelia J., et al. “Heart disease and stroke statistics—2017 update: a report from the American Heart Association.” Circulation 135.10 (2017): e146-e603. 2. LiveMint. Are you eating your way to a heart attack? Science/6UgERyTXiXXdSAgJomm6kL/Areyou-eating-your-way-to-a-heart-attack.html. September 26, 2017. Accessed October 13, 2017 3. Micha, Renata, et al. “Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States.” Jama 317.9 (2017): 912-924 4. Lassale, Camille, et al. “Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis.” European heart journal(2017).

Pick up the pace!

Heart disease is often a result of high blood pressure, obesity and high cholesterol among other factors, and is the leading cause of death in the US, causing about 610,000 deaths annually. Furthermore, the reported estimated annual costs of heart disease in the U.S. is a staggering $200 billion.1 According to a new study, healthy adults who are slow walkers are twice as likely to die from heart disease as those of us who walk at a more brisk pace.2 “This suggests that habitual walking pace is an independent predictor of heart-related death,” lead author Professor Tom Yates said. Researchers from the University of Leicester followed 420,727 people over a period of six years to assess death rates. Those who were slow walkers were found to be between 1.8 and 2.4 times more likely to die of heart disease – which is the world’s biggest killer – during the timeframe.2 The researchers took into account risk factors including smoking, BMI and diet, but found that the conclusion still applied to both men and women. However, it was actually adults with the lowest BMIs who were found to have the highest risk from walking slowly. The study’s authors believe that walking pace is an indicator of overall health and fitness as it’s strongly linked to exercise tolerance. “Self-reported walking pace could be used to identify individuals who have low physical fitness and high mortality risk,” said Professor Yates. The researchers also looked into whether walking pace could be linked to cancer, but no connection was found. This is not the first study to link heart disease and walking pace though – research from 2009 concluded that walking slowly is “strongly associated” with an increased risk of dying from cardiovascular disease, including heart disease and stroke.3 References:

1. Benjamin, Emelia J., et al. “Heart disease and stroke statistics—2017 update: a report from the American Heart Association.” Circulation 135.10 (2017): e146-e603. 2. Yates, Thomas, et al. “Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality: a UK Biobank observational study.” European heart journal 38.43 (2017): 3232-3240. 3. Dumurgier, Julien, et al. “Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study.” Bmj 339 (2009): b4460.


CARDIOMETABOLIC NEWS FDA approves GLP-1 receptor agonist semaglutide for Type 2 Diabetes TAKE-HOME MESSAGE • The FDA has approved semaglutide as a complementary supplement with diet and exercise for individuals with type 2 diabetes. Following an October 2017 advisory panel endorsement, semaglutide-a long-acting glucagon-like peptide-1 receptor agonist--is the seventh approved and available GLP-1 receptor agonist. In a tested study with its competitors, semaglutide reduced hemoglobin A1c by 1.5-1.8 percentage points, performing well above its competitors’ capabilities. The evaluation of semaglutide was performed in several phase 3a clinical studies involving more than 8000 adults with type 2 diabetes. • In these trials, semaglutide was also associated with a 4.5 to 6.4 kg weight loss compared to placebo. Reference: da_docs/label/2017/209637lbl.pdf

New ultra-fast-acting mealtime insulin is FDA approved

TAKE-HOME MESSAGE • The FDA has approved the usage and application of the PCSK9 inhibitor evolocumab to prevent myocardial infarction, stroke and coronary revascularization in individuals with previously established cardiovascular disease. Originally approved in 2015 as a supplement to diet and statin therapy, evolocumab indicated efficacy in lowering LDL-cholesterol levels. Based on results from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) outcomes trial--which involved over 27,000 participants with atherosclerotic CVD-evolocumab was effective in decreasing major cardiovascular events, and also significantly lowered LDL-cholesterol levels. • The results from the FOURIER trial show that aggressive lowering of LDL-cholesterol levels is associated with lower risk of adverse CVD events and provide additional treatment options for high-risk patients. Reference: da_docs/label/2017/125522s014lbl.pdf

TAKE-HOME MESSAGE • As the ultimate goal of insulin therapy is to mimic physiologically normal insulin secretion in order to control both fasting plasma glucose and postprandial glucose (PPG) in patients, newer insulin analogues have demonstrated high efficacy in glycemic control. These insulin options include rapid-acting prandial insulin and ultra-rapid-acting inhaled insulin, both of which maintain optimal glycemic control with minimal side effects, such as weight gain and hypoglycemia. Recently, the FDA specifically approved an ultrarapid-acting insulin aspart called Fiasp®, which can act within 4 minutes injection to normalize glucose levels, allowing for better postprandial glucose control. In a phase 3 trial, ultra-fast acting insulin aspart significantly improved mean 2-hour PPG levels compared to basal-only insulin, however this effect was associated with an increase in hypoglycemia.

FDA approves the first shortacting “follow-on” insulin

• The approval of this ultra-fast-acting insulin gives patients more flexibility by allowing them to inject insulin closer to a meal, thus potentially improving adherence rates and dangerous glucose excursions.

• This is the second overall “follow-on” insulin approved in the US after the longacting Basaglar (insulin glargine) was approved in December 2015.



FDA approves evolocumab to prevent cardiovascular events

TAKE-HOME MESSAGE • The FDA recently approved Admelog (insulin lispro), the first short-acting insulin approved as a “follow-on” product. Admelog is a shortacting insulin designed to improve blood sugar levels in adults with type 2 diabetes, and pediatric patients above the age of 3 with type 1 diabetes. Originally approved through an abbreviated approval pathway--the 505(b) (2) pathway--these new drug applications are intended to reduce overall drug development costs, so that patients can access effective products at lower price points. This pathway relies on FDA’s findings and approvals regarding previously approved drugs and their safety and efficacy, or clinic literature that supports the safety and efficacy of the proposed product.

Reference: PressAnnouncements/ucm588466.htm

Transcatheter interatrial shunt device shows promise in HFpEF treatment TAKE-HOME MESSAGE • In non-randomized, open-label studies, findings showed that a transcatheter interatrial shunt device (IASD) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and increased quality of life combined with greater exercise capacity in patients diagnosed with heart failure and mid-range or preserved ejection fraction (determined as EF ≥ 40%). Results from a recently-concluded phase 2 randomized trial, REDUCE LAP-HF, confirmed the beneficial effects of mechanically creating an atrial shunt in patients with Heart Failure with Preserved Ejection Fraction (HFpEF). Data concluded IASD treatment reduced PCWP during exercise among patients with HF and EF ≥ 40%, which can potentially lead to improved clinical outcomes. • Results from this study showed that IASD can have beneficial clinical effects in the treatment of Heart Failure with Preserved Ejection Fraction (HFpEF), a condition that is challenging due to the lack of specific therapies that reduce morbidity and mortality. Reference: pubmed/29142012

Study supports the role of inflammation in cardiovascular disease TAKE-HOME MESSAGE • A sub-study conducted through the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), further confirms evidence surrounding the independent role that inflammation plays in cardiovascular disease. The report, presented recently at an American Heart Association meeting and published in The Lancet, may dictate a new targeted approach to CVD treatment. The report indicates that patients with acute coronary syndrome (ACS) who demonstrated a significant drop in high sensitivity C-reactive protein (hsCRP) after a single dose of canakinumab (llaris)--a monoclonal antibody that targets IL-1ß--exhibited a significantly greater benefit than patients without a large reduction in hsCRP. The primary results of the larger CANTOS trial earlier this year revealed a significant benefit to the drug in ACS, and served as

initial clinical proof of inflammation’s role in CVD. • Results from this sub-study suggest that anti-inflammatory agent canakinumab can be beneficial in preventing adverse cardiovascular events and provide options in personalizing treatment of cardiovascular disease. Reference:

Study shows that lifestyle factors play a role in the association between gestational diabetes and longterm cardiovascular risk TAKE-HOME MESSAGE • A recent report in JAMA Internal Medicine has investigated the proposed link between gestational diabetes and long-term risk for development of cardiovascular disease (CVD). Previous studies have found a positive association between gestational diabetes and CVD later in life. As a result, in 2011, the American Heart Association added gestational diabetes mellitus (GDM) to cardiovascular risk assessment in women. The Nurse’ Health Study II (NHS II), which followed a large cohort of U.S. women with at least one pregnancy and no CVD at baseline for more than 20 years, reported that women with a history of GDM had a 43% increased risk of cardiovascular events compared to non-GDM women. However, this association was not significant when adjusting for additional factors, such as weight gain and lifestyle choices. • Although women with prior gestational diabetes are at an increased risk of experiencing major CVD events later in life, this large prospective study showed that adhering to a healthy lifestyle may mitigate some of these risks. Reference: pubmed/29049820

International consensus statement released on use of continuous glucose monitoring TAKE-HOME MESSAGE • One of the most critical aspects of diabetes management is maintaining glycemic control. In February 2017, the Advanced

Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of clinicians, expert researchers, and individuals diagnosed with diabetes in order to address issues stemming from the use of continuous glucose monitoring (CGM). While the traditional method for assessing glycemic control has been measurement of glycated hemoglobin (HbA1c), it presents certain intrinsic limitations. Continuous glucose monitoring, from either real-time use or intermittently viewed, provides the means to move beyond the HbA1c measurement--yet standardized metrics and clear criteria are lacking, and many research questions surrounding CGM must still be assessed and analyzed. • The consensus statement, published in Diabetes Care in December 2017, supports the use of CGM in addition to HbA1c for patients with type 1 diabetes, and in patients with type 2 diabetes on intensive insulin therapy who are not achieving glucose targets. The consensus also recommends the definition of key metrics to optimize CGM use based on several criteria.

Non-cardiac disease morbidity and mortality is higher in HFpEF TAKE-HOME MESSAGE • Data indicates that patients with heart failure generally present with several co-morbidities, which ultimately contribute to the risk of both adverse cardiovascular (CV) and non-cardiovascular outcomes. In a study that assessed the contribution of these disease burdens to CV outcomes among patients with heart failure, findings confirm that the relative contribution of cardiac and non-cardiac disease burdens differed depending on left ventricular ejection fraction (LVEF). The study’s authors suggest that the high risk of events attributable to non-cardiac disease burden may explain why medication designed to modify cardiac risk is more effective in heart failure patients with reduced ejection fraction (HFrEF), and not those with preserved ejection fraction.


• This study supports prior data showing increased mortality from non-cardiac causes in HFpEF compared to HFrEF, which confirms the different clinical characteristics of these two conditions.

Normal LDL-C conveys a risk for subclinical atherosclerosis

Reference: pubmed/29193462

TAKE-HOME MESSAGE • Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerosis. Although specific target levels of LDL-C are not currently defined, most guidelines focus on the LDL-C lowering for atherosclerosis prevention for patients with cardiovascular risk factors (CVRFs). A prospective observational cohort study has detected subclinical atherosclerosis among middle-aged adults who lacked standard CVRFs, including diabetes and high LDL cholesterol. Authors report that plaque or coronary artery calcification was observed in 49.7% of CVRF-free participants. LDL-C was also found to have independent correlations with atherosclerosis in a separate cohort study, further representing the relationship between LDL-C and atherosclerosis. • The findings confirm that what many consider to be ‘normal’ cholesterol levels are likely already creating atherosclerosis; and emphasizes the need for further LDL-C lowering to optimize risk reduction. Reference: pubmed/29241485

CALL FOR SUBMISSIONS Cardiometabolic Chronicle welcomes the submission of articles on the topic of cardiometabolic health and spanning a diverse range of content, including featured articles, opinions, clinical pearls, patient perspectives and more. For more detailed information, please contact the journal at


Familial chylomicronemia syndrome (FCS) is a hereditary enzymatic deficiency characterized by the buildup of chylomicrons (chylomicronemia), which leads to severe hypertriglyceridemia, a hallmark of the disease.1 Chylomicronemia also brings increased risk of morbidity and mortality, including episodes of abdominal pain and the threat of unpredictable and potentially fatal acute pancreatitis.2,3


1 2 3

SEVERE, REFRACTORY HYPERTRIGLYCERIDEMIA6,7 • Fasting triglycerides >880 mg/dL (10 mmol/L) • Minimally or not responsive to standard therapies

CLINICAL HISTORY1,2 • Acute pancreatitis and/or abdominal pain (may be recurrent or chronic), without other explainable causes

ABSENCE OF SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA 8,9 • Excess alcohol intake, uncontrolled diabetes, certain medications, or other medical conditions

FCS Visit for comprehensive FCS education and resources. Sign up to affirm your commitment to fighting rare lipid disorders and Akcea will make a donation to Global Genes®. Proposed diagnostic criteria.


References: 1. Brahm et al. Nat Rev Endocrinol. 2015;11:352-362. 2. Brunzell et al. The Metabolic and Molecular Bases of Inherited Disease. 2001:2789-2816. 3. Stroes et al. Atheroscler Suppl. 2017;23:1-7. 4. Jacqueline. Accessed January 24, 2018. 5. Davidson et al. Expert Rev Cardiovasc Ther. 2017;15(5):415-423. 6. Tremblay et al. Front Genet. 2014;5:90. 7. Reiner et al. Eur Heart J. 2011;32(14):1769-1818. 8. Miller et al. Circulation. 2011;123(20):2292-2333. 9. Berglund et al. J Clin Endocrinol Metab. 2012;97(9):2969-2989.

© 2018. Akcea Therapeutics, Inc. All rights reserved. FCS-00310 01/2018

DIABETES by numbers Prevalence of diabetes


Costs of diabetes

Other statistics

Total costs

7 th



23 million diagnosed 7.2 million undiagnosed

Diabetes by Age


Direct $176 billion/year Indirect

(reduced productivity)

(4.6 million)

45-64 (14.3 million)


$69 billion/year

Average medical expense for diabetics



(12 million)

($7,900 of this attributed directly to diabetes)

Age-Adjusted Prevalence of Diagnosed Diabetes Among US Adults



Medical expenses


Hospitalizations & ED

Overweight and Obesity Physical Inactivity High Blood Pressure High Cholesterol

People with diabetes are at higher risk for developing serious complications (compared to non-diabetics)


hospitalizations associated with diabetes

Kidney Disease


(2-4X more likely)

ED visits associated with diabetes

(28X more likely)


<4.5% 4.5% - 5.9% 6.0% - 7.4% 7.5% - 8.9%



7.5% - 8.9%


Risk factors for diabetes

(2-4X more likely)

6.0% - 7.4%



than non-diabetics

4.5% - 5.9%


leading cause of death




(25X more likely)

Heart Disease Amputations



CVD by numbers Prevalence of CVD disease


CVD costs

$316.1 million

million total

(direct and indirect)

Out of this

Projected costs



million are estimated to be ≼60 years of age

million in direct costs by 2030

CVD prevalence by age and sex

billion indirect costs by 2030

20-39 = 13.5%



40-59 = 41.4% (M), 39.4% (F)

60-79 = 69.6% (M), 68.6% (F)

≼80 = 84.4% (M), 86.5% (F)

Heart Failure


High Blood Pressure


Arterial Disease

3.2% Other

(percent of population that has CVD)

(M), 11.5% (F)

Breakdown of deaths attributable to CVD

CVD causes

30.8% of all deaths

(leading cause of death)

801,000 deaths

(1 every 3 deaths in the US)


Americans die of CVD each day

17.6% Powerful statistics


American dies of CVD every



(1 every 40 seconds)


CMHC Education Resource Center


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Health insurers going to extremes to deny medically necessary drugs By Kari Roundy

As President Trump and Congressional leaders continue to negotiate health care reform, increased access to prescribed health care treatments must become a top priority. If elected officials truly wish to expand access to health care, and do more than score easy political points, they must prevent insurers from denying patients the medications they are prescribed. As one of the 23 million Americans diagnosed with cardiovascular disease, I have been adversely impacted and frustrated by my insurers’ attempts to reject the treatment plan designed my doctors. Following years of failed treatments and

ineffective medications, my cardiologist suggested a new, but more expensive medication known as a PCSK9 inhibitor. While I began taking a sample, my doctor contacted my insurer to get the necessary approval. My health insurer denied my claim on three separate occasions, delaying my treatment for at least six months. My cardiologist warned me this could be a long road due to the higher cost, but I never imagined cost-savings would supersede my health. I began to wonder if I would get approved before a heart attack. My story is not unique. Many Florida residents are struggling with denials for access to critical medications. In my case, we were first told the insurer wouldn’t approve the new medication at all. Following the next appeal, the insurer claimed they would only approve statin therapy first, a medication I’ve been on that has not worked. The insurer, who has never examined me, argued the new medication “wasn’t medically necessary,” contrary to my doctor’s prescription. After six months of denials, my insurer finally approved the medication for the limited time of three months. Soon thereafter, I received a letter stating that they would no longer honor my policy in 2017. I continued to pay my premiums, but given the half year I spent appealing to obtain a vital medication, my insurers did not honor their end of the bargain.

Like many Floridians, I have been paying an exorbitant amount for my insurance and pay out of pocket for most doctors and expenses. But I counted on health insurance for my medication and they did all in their power to ensure that I didn’t receive it rather than insuring my health. My insurer contributed to the stress of managing a chronic disease that puts me at risk for a heart attack. While there is a legitimate need to verify prescriptions, insurers put cost-saving strategies ahead of the medical expertise earned through years of school and experience by physicians and other health care providers. Their power to deny medications is unethical. They have no grasp of a patient’s personal history, yet they are willing to take our lives into their hands. Our lawmakers must take notice of this situation and halt health insurance abuses through any new health care bill. Unless insurers are willing to examine each patient, taking full responsibility for their care, they should not have the right to override a doctor’s decision and potentially jeopardize patients’ health. Kari Roundy is a patient advocate for the Global Healthy Living Foundation’s 50-State Network in Florida. This patient perspective was adapted from The Doctor-Patient Rights Project (https://doctorpatientrightsproject. org/ourstories/kari-roundy/).



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