Cardiovascular (CV) disease is the leading cause of death in the western world. It affects nearly 6.6 million people over the age of 18 in the United States, with an additional three million new cases expected by 2030, a 25% increase from 2010 (1). Heart failure is a complex cardiovascular clinical syndrome with a progressive decline in the clinical course leading to death in 50% of cases within about five years – a statistic that hasn’t changed much in the last several decades. The rate of disease progression is dependent both on the primary pathology and the activity of the compensatory processes, the most important of these being neural, endocrine, renal and morphological. Most of these chronic compensatory processes, such as activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, are believed to be harmful, although the increase in natriuretic peptides is believed to be a beneficial compensatory response.
And thus, modifying these compensatory mechanisms has been the cornerstone of heart failure medical therapy and drug development. The first-line heart failure treatment is renin–angiotensin–aldosterone system (RAAS) inhibition, and more particularly, angiotensin-converting enzyme-inhibition, as the first class of therapeutic agents able to conclusively show a reduction in mortality and heart failure hospitalizations. This was followed by beta blockade, which had fallen out of favor decades ago because of an increase in dyspnea seen in patients with acute heart failure. With a better understanding of the neurohormonal mechanisms, beta blockade has since become a foundational heart failure therapy. Inhibition of beta receptors initially leads to a decrease in contractility (which is why beta blockade is initiated slowly and carefully once heart failure has stabilized). Long term, beta receptor inhibition leads to an improvement in myocardial contractility and reduction in cardiac events.
After Two Decades, A New Agent Emerges
However, there have been about two or more decades between beta blockade and the next agent that conclusively reduces mortality and heart failure hospitalizations. That agent is the unique compound—sacubitril/valsartan (2). Mineralocorticoid Receptor Antagonists, eplerenone and spironolactone, have indeed demonstrated benefit in event reduction, yet there was never much physician uptake in the U.S. although it is being used more in Europe (3-4). The lack of prescriber use in the U.S. most likely is due to the side effect profile with excess hyperkalemia abounding.
There was also the more recent ivabradine, approved for use in the U.S. shortly before sacubitril/valsartan. While this agent can play a role in patients with heart failure and elevated heart rate, it has not been shown to reduce mortality but instead to only reduce heart failure hospitalizations (5). Thus it is looked at as niche heart failure therapy rather than as first-, second-, third-line, or an alternative to first-line therapy like sacubitril/valsartan.
With the advent of sacubitril/valsartan and ivabradine, a resurgence of interest in heart failure therapies has taken hold again. But the future of heart failure treatment will not be as simple as in the past. We can no longer look to a solution as simple as inhibiting negative compensatory mechanisms or enhancing beneficial compensatory mechanisms. We must take it a step further in order to generate agents that can still reduce events in the face of current standard of care.
HF Drug Development: Today’s Drug Candidates Examine Off-Target Effects
Some of today’s drug development candidates for heart failure are examining off-target effects not traditionally assessed when evaluating patients for treatment. For instance, the pleiotropic effects of agents in the past, such as lipid agents, led to the unfortunately failed concept that statins could be used for more than lipid-lowering.
More recently, dipeptidyl peptidase 4 inhibitors, also known as DPP-4 inhibitors or gliptins, are a class of oral hypoglycemic agents such as saxagliptin and alogliptin, currently in use to treat diabetes. However, recent cardiovascular outcomes studies of these two agents failed to show benefit and instead showed a small but statistically significant increase in death and heart failure hospitalization (6-7). This ultimately led to warnings and precautions labeling that addressed this increased risk, particularly in patients with a prior history of heart failure or kidney impairment.
Yet, the basic physiology of these agents is to modulate the activity of several cardioactive factors, including neuropeptide Y and, more importantly, stromal cell derived factor-1 (SDF-1), which has been shown to affect stem cell homing, decrease myocardial apoptosis, increase myocyte survival leading to cardiac repair in animal studies of acute myocardial infarction and heart failure (8). This would support the notion that cardiovascular effects, whether positive or negative, may not be a class-specific phenomenon of DPP-4 inhibitors. Indeed, a large, population-based study with data from the FDA-funded mini Sentinel program failed to find an increase in heart failure hospitalizations relative to other diabetic agents, contradicting the SAVOR and EXAMINE trials (6-7). Further research into understanding the cardiovascular effects of this diabetic drug will represent major progress that could dramatically influence the management of the cardiovascular disease.
The Role of Personalized Medicine in Cardiovascular Clinical Research and Drug Development
Personalized medicine is an approach that separates patients into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. This idea is a long-time coming, and early approaches are showing promise.
One great example of this is 123I-metaiodobenzylguanidine (123I-MIBG), a norepinephrine analogue that is taken up in cardiac sympathetic nerve endings. In heart failure, this uptake is decreased as myocardial norepinephrine stores are depleted. MIBG planar imaging can be used as a prognostic marker to assess for cardiovascular risk and prognosis. So a heart/mediastinum ratio >/= 1.6 has been shown to correlate with fewer cardiovascular events in patients with dilated cardiomyopathy (8). In 2013, the FDA approved MIBG for use, but how will it be used? An ideal solution would be to look at how heart failure patients could benefit from a low or high risk stratification. This is at the heart of personalized medicine, to find better uses for devices or drugs that are already in use. Another example is the prognostic and diagnostic marker NT-proBNP. This marker is being used more and more in heart failure research to both diagnose heart failure patients as well as stratify them into low and high risk. With sacubitril/valsartan as well as other newer agents not yet approved, this marker has become key to defining a higher risk patient population that could benefit better from medical therapy.
There also is the use of antisense oligonucleotides to modulate over-production of proteins by targeting the upstream mRNA. One of the first agents to be used in the cardiometabolic space is mipomerson, an antisense oligonucleotide designed to treat familial homozygous hypercholesterolemia. It prevents production of apoliprotein B-100, the main component of low density lipoprotein (LDL-cholesterol) (9). It targets hepatocytes and is a good first effort; unfortunately its most common risk of injection site reactions is enough to cause many to discontinue use of the drug. Additionally, it has the risk of serious liver damage and thus must be prescribed with a risk management plan monitored by the FDA. Future products should both target over-expression of disease-causing proteins, as well as more accurately target the hepatocyte, producing better efficacy with fewer side effects.
Looking Ahead to a Bright Future of Heart Failure Treatment
Finally, no discussion of future therapy would be complete without mentioning the promise of gene transfer for cardiovascular clinical research. Most recently, a study of adenylyl cyclase-6, a gene seen to successfully improve myocardial contractility when increased, has demonstrated successful transfection using an adenovirus in an intracoronary administration. The study, although in Phase 2, seems to foretell a potential for a one-time treatment of heart failure with few side effects and actual reverse remodeling of the heart (10). We will have to see what happens here; however, agents such as this, if successful, may someday completely change the way heart failure is treated.
In summary, rather than being at the end of our proverbial rope in treating heart failure and cardiovascular disease, we are hurtling forward into a bright future of novel heart failure treatment.
- Mozaffarian D, Benjamin EJ, Go AS, et al on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association [published online ahead of print December 16, 2015].Circulation.
- McMurray JJ,Packer M, Desai AS, et al. for the PARADIGM-HF investigators. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
- Pitt B, Zannad F, Remme WJ et al.for the Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709-717.
- Zannad F, McMurray JJV, Krum H, et al. for the EMPHASIS-HF Study Group. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011; 364:11-21.
- Swedberg K, Komadja M, Bohm M, et al. on behalf of the SHIFT investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet.2010;376:875-85.
- Scirica BM, Bhatt DL, Braunwald E et al. for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013;369:1317-26.
- White WB, M.D., Cannon CP, Heller SR, et al. forthe EXAMINE Investigators. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes N Engl J Med 2013; 369:1327-1335
- Jacobson AF,Senior R, Cerqueira MD, et al. for the ADMIRE-HF investigators. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212-21.
- Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients. Eur Heart J. 2012;33:1142-9.
- Hammond HK, Penny WF, Traverse JH et al. Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure. JAMA 2016;1:163-71.