Cover Story | By Debra L. Beck

It’s a reality: the busier doctors get, the harder it is to see what’s right in front of them. Consider those frustrating, perplexing comorbidities like depression and diabetes: many physicians don’t recognize depression (or its significance) and expect diabetes to have already been treated by someone else. And obesity? Well, it’s almost impossible to treat anyway, right? But these conditions not only increase risk in heart patients (no matter what you’ve heard), they are, in fact, worthy of greater consideration and attention.

In this cover story, CardioSource WorldNews addresses each of these elephants in the waiting room – depression, diabetes, and obesity—looking at what’s new and why they should not be ignored.

Surprise: Your Patient Is Depressed

Depression is an independent risk factor for cardiovascular disease (CVD) but, importantly, it also complicates treatment and prognosis. We have new data (and some old data that bear repeating) to encourage more engagement with an issue many clinicians are reluctant or feel unprepared to address.

The prospective cohort Heart and Soul Study originally showed in 1,024 patients with stable coronary heart disease (CHD) that depressive symptoms were associated with a higher rate of CV events. One problem: the association was largely explained by poor health behaviors.¹ However, only now have the Heart and Soul investigators parsed the association between depression and lifestyle behaviors.² In an analysis just published online ahead of print, Nancy L. Sin, PhD, at the Center for Healthy Aging, The Pennsylvania State University, University Park, PA, and colleagues indicated that the directionality of the data was stronger for depressive symptoms as a predictor of subsequent health behavior change.

She and her colleagues wrote, “Given the importance of psychosocial factors for determining CVD risk and mortality, these findings suggest that depressive symptoms may serve as critical targets in efforts to improve health behaviors among patients with CHD.”

The benefits of screening all adults for depression were emphasized in a new U.S. Preventive Services Task Force (USPSTF) recommendation statement supporting screening (in primary care) of all adults 18 years or older.³ One caveat: “Screening (should) be implemented with adequate systems in place,” meaning either having the systems and clinical staff in place to conduct the screening and then treat or a system of referral for treatment as needed. While this critical step should be handled at the primary care level, it remains overlooked more often than not, probably for the lack of those “systems.”

There is a rationale for ignoring this particular elephant in your office: it’s really not your job. Yet studies abound in the cardiovascular literature linking psychological symptoms such as anxiety and depression to cardiovascular risk. About 20% of patients hospitalized for acute coronary syndrome (ACS) meet diagnostic criteria for major depression, with even more showing subclinical levels of depression. Numerous reports show a robust association between depression and increased CV morbidity and mortality. Moreover, adherence to therapy is hard enough under ideal circumstances; throw in depression and you can expect far from ideal results.

Granted, the heterogeneous nature of the studies has made it difficult to formally elevate depression to the status of a risk factor for adverse medical outcomes in ACS patients. Nevertheless, a recent scientific statement from the American Heart Association⁴ concluded that “the preponderance of evidence supports the conclusion that depression after ACS is a risk factor for all-cause and cardiac mortality, as well as for composite outcomes including mortality or nonfatal cardiac events. As such, depression should be elevated to the level of a risk factor for poor prognosis after ACS by the AHA and other health organizations.”

The Dance of Depression and Inflammation

It may not be news that inflammation is linked to diabetes and obesity, but did you know it’s also connected to depression? So does that mean we can lower cardiovascular risk by treating depression? Since it is unknown which came first, there are major efforts underway targeting inflammation in the CIRT and CANTOS trials (see the sidebar “Inflammation: The Uniting Force”) It’s encouraging because there is some good evidence that treating inflammation may indeed attenuate both depression and cardiovascular risk.

Depression and inflammation are intimately entwined, with each feeding and fueling the other. In a recent overview on the topic in the American Journal of Psychiatry, Janice K. Kiecolt-Glaser, PhD, and colleagues showed how heightened inflammation plays a key role in depression’s pathogenesis, although they added that inflammation is “neither necessary nor sufficient to induce or sustain depression.”⁵ But, depression does increase inflammation: depressed patients show increased proinflammatory cytokine levels, including interleukin-6, tumor necrosis factor-alpha, and C-reactive protein (CRP). And in the case of mindfulness meditation, somewhat of a hot topic these days in psychology, a study in press (Biological Psychiatry) demonstrates that its broad impact on health may be due to reduced inflammation (specifically, lower levels of interleukin-6).

This inflammation is not universal; only about one-third of depressed patients (compared to the majority of nondepressed controls) actually have elevated inflammatory biomarkers. However, for these patients, it does not seem to be just an incidental finding: Kiecolt-Glaser et al. report that response to antidepressant medication appears to be poorer in patients with major depression who have heightened plasma inflammatory markers.

Dr. Kiecolt-Glaser is director of the Ohio State Institute for Behavioral Medicine Research and the S. Robert Davis Chair of Medicine in The Ohio State University College of Medicine. One of her research areas of expertise is the impact of social behavior on physiology. She refers to a “bidirectional loop, in which depression facilitates inflammatory responses and inflammation promotes depression.” Inflammatory mediators—for example, cytokine therapies used to treat some cancers and chronic viral infections—actually seem to provoke the onset of major depression in up to 45% of patients. Conversely, treatments that lower depression, including those designed to alter the gut microbiota, which has been shown to contribute to obesity, inflammation, and mood, among other things, can reduce symptoms of depression. Ditto for omega-3 fatty acids and exercise, both known to decrease inflammation.

She and her colleagues wrote, “Inflammation is not ubiquitous among people with depression, but when the two conditions co-occur, treating inflammation in tandem with depression can enhance recovery and reduce the risk of recurrence.” It goes without saying (but they said it anyway): effective treatment of depression and inflammation will have an impact, too, on the myriad disorders and systemic diseases all characterized by heightened inflammation, “including CVD diabetes, metabolic syndrome, rheumatoid arthritis, asthma, multiple sclerosis, chronic pain, and psoriasis.”

Diabetes: Risk Multiplier

We’ve known since the last century of the strong association between glycemia and macrovascular and microvascular complications of type 2 diabetes mellitus (T2DM). Mark A. Creager, MD, FACC, a professor of medicine at Harvard, and colleagues have published on the epidemiology, pathophysiology, and management of diabetes and atherosclerosis.⁶ The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes diabetics to atherosclerosis. T2DM markedly increases the risk of myocardial infarction (MI), stroke, amputation, and death.

That’s all pretty broadly known among the cardiovascular community. But in the last couple years, some confusion has set in. It stands to reason that tight glucose control should reduce risk and including glycemic measures in algorithms used to calculate risk of CVD might improve their predictive ability. Indeed, guidelines on risk assessment conclude that measurement of glycoslated hemoglobin or HbA1c levels may be reasonable in asymptomatic adults without a diagnosis of diabetes. Makes sense…until you look at the data. It turns out that HbA1c is not associated with clinically meaningful improvement in assessment of CVD risk. That was a big surprise when the results were first reported of an analysis of data from almost 300,000 people without known diabetes and CVD at baseline indicates.⁷

There seems to be a glucose paradox: while fasting blood sugar and HbA1c predict future macro- and microvascular events, tight glucose control definitely reduces microvascular events but does not impact macrovascular effects. That’s quite different from blood pressure control and the use of statins for lipid lowering, both of which reduce macrovascular events. So, does a place for tight glucose control exist? Probably.

Dr. Creager and colleagues note that, despite this paradox, diabetes is most certainly a risk multiplier in atherosclerosis. It increases both the risk of developing atherosclerosis and the incidence of complications of atherosclerosis, and is associated with poorer outcomes from these events.

They added that health care professionals enjoy the benefit of a wide variety of clinical trial data supporting specific treatments and targets for patients with diabetes. These include:

Lipid-lowering therapy with statins, medication for blood pressure control, and antiplatelet therapy in patients with increased cardiovascular risk scores.

Hyperglycemia should be treated to a target glycosylated hemoglobin of 7%, with therapy that includes an agent that improves insulin sensitivity, such as metformin.

Optimal medical treatment, including risk factor modification, antiplatelet therapy, and antianginal medications remains the preferred approach for most patients with diabetes and stable CAD.

What about aggressive glucose-lowering therapy? When you parse the data, this approach continues to demonstrate benefits in some individuals. At ACC.15, Dr. Creager said aggressive glucose lowering is particularly warranted in younger, leaner patients with a shorter duration of T2DM, lower baseline HbA1c levels, and without evident CAD.

While tight glycemic control improves macrovascular events, caution is warranted in older patients and those with established CVD or multiple comorbidities. He also emphasized that aggressive early treatment of T2DM may impact CV events due to a legacy, or memory, effect which may take many years to become evident.

“A Heart Med Masquerading as a Diabetes Med”

At a scientific meeting, a presenter will commonly enjoy polite applause upon reaching the end of his or her presentation. But it’s not often the findings of a new trial are met with a gasp followed immediately by a standing ovation. When it happens, it’s a good guess the findings might be “game changing.”

Enter the EMPA-REG OUTCOME trial.

“It’s the first rigorously designed, positive clinical outcomes trial using any clinical outcome endpoint in the field of diabetes, type 1 or type 2,” said Darren K. McGuire, MD, MHSc, FACC, in an interview with CardioSource WorldNews. “It is absolutely a game-changing result.”

Dr. McGuire is the Dallas Heart Ball Chair for Research on Heart Disease in Women at UT-Southwestern Medical Center in Dallas, and an expert in large-scale clinical trial design and execution. He is the co-editor of Diabetes in Cardiovascular Disease: A Companion to Braunwald’s Heart Disease (1st edition, 2015) and disclosed that he consults with several pharmaceutical companies on their diabetes programs.

With nearly 1 in 10 U.S. adults suffering from type 2 diabetes, it’s no wonder the EMPA-REG OUTCOME trial results engendered excitement from diabetologists. The results were initially presented at the 2105 European Association for the Study of Diabetes meeting in September with the main findings presented for a cardio-centric audience at the 2015 AHA Scientific Sessions 2 months later in Orlando.⁸

The trial enrolled patients with T2DM and established CVD at high risk for CV events and assigned to either empagliflozin 10 or 25 mg (Jardiance, Boehringer Ingelheim) or placebo. A total of 7,020 patients from 42 countries and 590 sites participated.

Here’s why cardiologists should be interested in this drug: over a median of 3.1 years, empagliflozin (pooled data from the doses studied) was superior to placebo for the primary composite outcome of CV death, nonfatal MI, or nonfatal stroke (10.5% vs. 12.1%; hazard ratio [HR]: 0.86; p = 0.04), with the difference driven primarily by a 38% relative risk reduction (RRR) in CV death (p < 0.0001). No significant differences were seen in nonfatal MI or nonfatal stroke.

Empagliflozin also reduced the composite of heart failure (HF) hospitalization and CV death (HR: 0.66; p < 0.001), with similar benefit seen with both doses. All-cause hospitalization was reduced by 11% with empagliflozin (HR: 0.89; p < 0.05).

Further investigation of HF outcomes in EMPA-REG were published in January 2016 and showed that the drug improved HF outcomes both in those patients with and without baseline HF.⁹

“We now have a drug that’s labeled as a drug for diabetes that actually prevents hospitalization for heart failure and cardiovascular and all-cause mortality, but none of us believe (that) has anything to do with blood glucose control, so it’s kind of difficult to call this a diabetes drug,” said Dr. McGuire. “It looks more like it’s a cardiovascular drug that has a side effect of lowering blood glucose.” 

It Works, Use it!

As for Dr. McGuire, he started prescribing empagliflozin to his T2DM patients the day after he saw the EMPA-REG findings. “Despite my diabetes interest, I have never managed blood glucose as a clinician, but after EMAP-REG OUTCOME, it is the first time in my career where I have a drug that lowers blood glucose and has cardiovascular risk benefit so I use it not for the glucose benefit but for the cardiovascular risk benefit.”

He lets his patients’ primary care physicians know he has prescribed an SLGT2 inhibitor, but doesn’t delay starting the medication. “It’s a simple prescription, there is no dose titration and very little risk of hypoglycemia. The two doses in the trial looked identical, so I use 10 mg daily and don’t think there is any use for 25 mg.” His bigger concern is affordability, since empagliflozin costs about $300 monthly.

“Some physicians are still going to wait and my question is what are you waiting for? Do you think there’s going to be another trial? No way, we’ve got a winner here. The trial was robust and well conducted; the results were significant and heart failure and CV death signals were extremely robust.”

Most of the glucose filtered by the kidneys is reclaimed in the proximal tubules and sodium glucose cotransporter-2 (SGLT2) is responsible for about 90% of this reabsorption. A selective inhibitor of SGLT2, empagliflozin reduces this reabsorption and increases urinary glucose excretion. It is this “glucosuria” that is responsible for the most common known issue of SGLT2 inhibitors: genital infections.

Other than glucosuria and an increased risk of subsequent genital infection, particularly in women, the only red flags so far raised about the gliflozins class of drugs is a potential for volume depletion-related adverse events and a concern that they may increase the risk of diabetic ketoacidosis (DKA).

In a warning released in May 2015, the U.S. Food and Drug Administration (FDA) said that patients should be aware of the symptoms of DKA (“difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness”) and seek medical attention immediately if they occur. The tricky part for these patients hinges on the fact that they don’t feel well but because their blood glucose stays in a normal range, they don’t seek attention.

“We have to learn to recognize this known complication of diabetes and be ready to find it when a well-treated type 2 diabetic comes in feeling poorly, maybe a bit of abdominal discomfort, and their blood sugar might be 160, but their bicarbonate is 16 and they are actually breathing a little bit Kussmaulian, so that’s the circumstance when we check the urine and maybe the blood for ketones,” said Raymond Townsend, MD, PhD, University of Pennsylvania, Philadelphia, PA, in an on-camera interview with CSWN.

Empagliflozin is actually the third SGLT2 inhibitor to receive FDA approval, preceded by canagliflozin (Invokana, Janssen Pharmaceuticals) and dapagliflozin (Farxiga, AstraZeneca/BMS). All three are undergoing rigorous testing of their CV outcomes (Table 1) as is a fourth in class agent, ertugliflozin (Merck Sharp & Dome Corp/Pfizer), not yet FDA approved. Although it’s unclear if the findings from EMPA-REG OUTCOME represent a class effect, there is promising evidence from a recent meta-analysis.¹⁰

By the way, there are nine FDA-approved classes of pharmacotherapy for T2DM (Table 2). Trying to ascertain cardiac risk of these has proven challenging. In the case of the glitizones, for example, for several years the FDA released a number of advisories, which were subsequently removed. A 2014 meta-analysis found no suggestion of CV harm (or benefit) with the gliptins.¹²

Obesity: The Weight of the World

You may have noticed: no CVD risk prediction score includes body weight. General obesity is not an independent risk factor and does not improve CVD risk prediction in women or men. In support of this perhaps surprising point: CVD mortality has continued to fall despite a robust obesity epidemic in which 74% of men and 64% of women are now overweight/obese, and obesity reduction trials have failed to reduce CVD. So, is obesity another elephant or a red herring?

In the last year, investigators have reported on the potential role of obesity in atrial fibrillation, which—it is fair to say—has reached epidemic proportions, too. At the end of 2015, the Journal of the American College of Cardiology published a review of emerging data on the importance of weight loss and cardiovascular exercise in the prevention and management of AF.¹³ The authors noted, “Currently, the body of evidence is enough to strongly recommend weight loss for both prevention and management of AF.” (Obesity joins the list of modifiable risk factors for AF, listed in Table 3.)

In a study of more than 8,000 people followed for almost a decade, Vermond et al. identified obesity as a significant risk factor for incident AF, with a 45% increased risk for every 5 kg/m² increase in body mass index.¹⁴ Animal studies suggest that obesity directly contributes to the AF substrate by altering atrial electrical and structural remodeling. Obesity also could increase the risk of AF by its association with other risk factors, including epicardial fat, which has been identified as a risk factor for the increased prevalence and severity of AF, perhaps because it is metabolically active and produces inflammatory cytokines.

Similarly, patients with obstructive sleep apnea (OSA) have roughly a 4-fold increased risk of developing AF.¹⁵ It is not yet clear whether OSA is a causal risk factor or part of a larger risk profile, but the finding that continuous positive pressure ventilation reduces the recurrence rates of AF in these patients suggests a possible pathogenic role.

In an accompanying commentary to the Vermond study, Kowey and Robinson found a ray of hope in the midst of the obesity and AF epidemics.¹⁶ Studies have demonstrated that physician-led weight loss programs can significantly reduce the number of AF episodes, as well as the symptom burden and severity in obese patients with AF. They wrote, “Such studies indicate that the medical community will likely need to take a much more active role in facilitating risk factor modification to slow the rising incidence of AF globally.”

It’s not just an issue of weight: Cardiorespiratory fitness predicts arrhythmia recurrence in obese individuals with symptomatic AF and improving cardiorespiratory fitness augments the beneficial effects of weight loss.¹⁷ The CARDIO-FIT study, as it’s called, showed a significant dose-response relationship between baseline cardiorespiratory fitness with a 20% reduction in the risk of AF recurrence for each MET increase in baseline cardiorespiratory fitness (Figure). Moreover, a METs gain in cardiorespiratory fitness ≥ 2 on top of weight loss (< 10%) was associated with 2-fold greater freedom from AF over a 5-year period (32% AF freedom without rhythm control vs. 13% who achieved an increase in METs < 2). Still, patients probably don’t need to overdo it: other evidence suggests a curvilinear relationship between AF and exercise intensity, with diminishing benefit or even risk with the most intense exercise. AF incidence was 28% lower in the Cardiovascular Health Study with moderate-intensity physical activity, but those exercising at the highest intensity had a risk of AF not significantly different from the no-exercise group.

In their review in JACC, Miller et al concluded that for AF prevention and management, use weight loss through light-to-moderate exercise (not high-intensity exercise) and appropriate management of modifiable risk factors.

Well, where does all this leave us? For understandable reasons, cardiologists tend to ignore depression and expect diabetics to be already treated. As for obesity, it is so obvious, why bring it up? Patients are probably sick of hearing about it. Yet, given the growing body of evidence supporting an increased role for comprehensive cardiac risk factor modification, here are three ‘elephants’ who need more attention. Don’t assume “it’s covered” by someone else. Jerry Garcia got to the heart of the matter years ago when he said, “Somebody has to do something, and it’s just pathetic that it has to be us.”

References:

1. Whooley MA, de Jonge P, Vittinghoff E, et al. JAMA. 2008;300:2379-88.
2. Sin NL, Kumar AD, Gehi AK, et al. Ann Behav Med. 2016 Jan 27. [Epub ahead of print]
3. Siu AL, Bibbins-Domingo K, Grossman DC, et al. JAMA. 2016;315:380-7.
4. Lichtman JH, Froelicher ES, Blumenthal JA, et al. Circulation. 2014;129:1350-69.
5. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Am J Psychiatry. 2015;172:1075-91.
6. Beckman JA, Creager MA, Libby P. JAMA. 2002;287:2570-2581.
7. Di Angelantonio E, Gao P, Khan H, et al. JAMA. 2014;311:1225-33.
8. Zinman B, Wanner C, Lachin JM, Fitchett D, et al. N Engl J Med. 2015;373:2117-28.
9. Fitchett D, Zinman B, Wanner C, et al. Eur Heart J. 2016 Jan 26. [Epub ahead of print]
10. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.
11. Lathief S, Inzucchi SE. Trends Cardiovasc Med. 2016;26:165-79.
12. Wu S, Hopper I, Skiba M, Krum H. Cardiovasc Ther. 2014;32:147-58.
13. Miller JD, Aronis KN, Chrispin J, et al. J Am Coll Cardiol. 2015;66:2899-906.
14. Vermond RA, Geelhoed B, Verweij N, et al. J Am Coll Cardiol. 2015;66:1000-7.
15. Andrade J, Khairy P, Dobrev D, Nattel S, et al. Circ Res. 2014;114:1453-68.
16. Kowey PR, Robinson VM. J Am Coll Cardiol. 2015;66:1008-10.
17. Pathak RK, Elliott A, Middeldorp ME, et al. J Am Coll Cardiol. 2015;66:985-96.

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“Fat Not Always the Devil”

The obesity paradox gets a lot of coverage in the consumer press, partly because counterintuitive findings play nicely in headlines, but also because the world loves to hear that being overweight might not be so bad. Every month sees a new batch of headlines either promoting this paradox or chipping away at the validity of the idea that some extra weight might actually be protective.

To better understand how the obesity paradox should be handled in the clinical setting and to get an update on this hot topic, CSWN spoke with Carl “Chip” J. Lavie, MD, one of the first researchers to identify the obesity paradox (in a 2003 article on body composition and prognosis in chronic heart failure).¹

Dr. Lavie is the medical director of Cardiac Rehabilitation and Prevention and the director of the Stress Testing Laboratory at Ochsner Health System in New Orleans, LA. He is also the author of the 2014 book The Obesity Paradox, lauded as a clear, research-based analysis of body fat and the function it plays in human health.

In the literature, the body of data on the topic continues to grow. While some of these data clearly conflict, in aggregate they confirm the obesity paradox. In a recently published meta-analysis of 89 studies and 1.3 million coronary heart disease patients, researchers found a clear J-shaped relationship between mortality and body mass index (BMI) in patients with coronary artery disease.²

Interestingly, the long-term benefit of obesity disappeared after 5 years of follow-up, indicating, according to Dr. Lavie and colleagues in an accompanying editorial, that “weight loss still appears to be advantageous,” particularly when combined with increased physical activity and improved cardiorespiratory fitness.³

And while BMI has oft been criticized—most recently in a “Short Communication” in the International Journal of Obesity⁴ that received a lot of press coverage—because it “misclassifies” certain individuals, Dr. Lavie and colleagues noted that the obesity paradox has also been demonstrated using percent body fat and waist circumference/central obesity.

Q&A with Carl “Chip” Lavie, MD:

What is the main message you want to send about the obesity paradox?

Fat is not always the devil. The bottom line is that people carrying excess weight can still be healthy and have very good survival, especially if they have a decent level of fitness. Fitness is more important than fatness for predicting long-term cardiovascular and overall survival.

Are there some patients you might tell to lose weight and others you’ll advise to improve cardiorespiratory fitness?

Everyone with low fitness would benefit from a higher level of fitness. This is especially true for the overweight and mildly obese, who have a very good prognosis if they have a decent fitness. Not many severely obese people have good fitness and prevention, and treatment of severe obesity is extremely important.

What’s your best advice for overweight and obese patients?

For the overweight and mildly obese, keeping decent levels of fitness and preventing additional weight gain with regular physical activity and exercise is the most important goal. Purposeful weight loss is probably beneficial as well, especially allowing for less need for medications, less hospitalizations, and lower risk of heart failure. There is some evidence suggesting that purposeful weight loss may even reduce cardiac events and mortality, although this is based on relatively small amounts of data. The strongest data support maintaining a good fitness and avoiding moderate and severe degrees of obesity.

Keywords: CardioSource WorldNews, Comorbidity, Depression, Depressive Disorder, Diabetes Mellitus, Obesity, Risk

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