In obesity, growing CV risk burden demands cross-specialty collaboration, new solutions

The prevalence of obesity in the U.S. is rising at an alarming rate, as are its cardiovascular consequences. In an analysis of 10 large prospective cohorts with long-term follow-up published last year in JAMA Cardiology, researchers found that adults with obesity had a significantly increased lifetime risk for CV morbidity and mortality and typically had a shorter life span vs. those with a normal BMI, and higher BMI conferred the greatest risk for incident heart failure among CVD subtypes.

Experts further contend that the bodily stress of excess weight can unmask underlying genetic tendencies that increase CV risk, such as hypertension, dyslipidemia and type 2 diabetes, virtually guaranteeing that a person with obesity will experience some CV effect over his or her lifetime.

“Fundamentally, you are more likely to die — and more likely to die of CVD — if you are overweight or obese,” Steven E. Nissen, MD, MACC, chairman of the department of cardiovascular medicine at the Cleveland Clinic and professor of medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, told Endocrine Today. “The risk goes up with weight in a linear fashion, and it gets to be substantial when you get to high levels of obesity.”

Even among physically fit and so-called metabolically healthy people with obesity, CV risk is greater when compared with those without excess weight, according to Steven B. Heymsfield, MD, FTOS, professor in the department of metabolism and body composition at Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, and president-elect of The Obesity Society.

“Obesity’s effects have long timelines on them,” Heymsfield told Endocrine Today. “Being obese doesn’t literally kill you overnight. Some of these people have latent disease which will manifest at some point.”

Photo by Ted Griggs, media manager, Pennington Biomedical Research Center. Printed with permission.

The management of multiple metabolic diseases demands collaboration from obesity medicine specialists and cardiologists, according to experts, who must now work together to address a growing health epidemic.

“We [cardiologists] have to be involved in this, because we’re dealing with the CV consequences,” Nissen said. “I can take a patient who is obese, and I can treat their hypertension, their high triglycerides, their atrial fibrillation, their heart failure, but if I don’t treat the cause of those disorders, I’ve failed.”

Similarly, Nissen said, an obesity medicine specialist cannot simply focus on reducing excess weight.

“If you don’t also deal with the comorbidities, you also have an issue,” Nissen said. “It is a collaboration, because we each have a role to play in improving the health outcomes for these very needy and very difficult patients.”

How obesity drives risk

Obesity — particularly abdominal adiposity — is at the base of several “mechanisms of harm,” Nissen said, including glucose intolerance, hypertension, inflammation, increased triglycerides and low HDL cholesterol.

CV risk rises in part through what Nissen called CV “dysmetabolic syndrome,” a constellation of risk factors that include obesity, hypertension, dyslipidemia and insulin resistance. Type 2 diabetes, which is associated with increased BMI, further increases the risk for CVD.

“It is important that we understand that it is abdominal obesity that seems to be the disproportionate factor here,” Nissen said. “It’s not just body weight. It’s the distribution of fat in the abdomen.”

In a 2015 study published in The Journal of Clinical Endocrinology & Metabolism, researchers examined the associations of abdominal visceral adipose tissue and abdominal subcutaneous adipose tissue, assessed via ultrasound, with CV risk factors in a cohort of 1,412 Danish men and women with normal glucose tolerance, prediabetes or screen-detected diabetes. Independent of subcutaneous adipose tissue and overall obesity, visceral adipose tissue was associated with higher triglyceride and lower HDL cholesterol levels in both men and women, as well as higher total cholesterol levels in men. Subcutaneous adipose tissue was independently associated with higher total cholesterol and LDL cholesterol levels in both sexes, as well as higher triglyceride and lower HDL cholesterol levels in women.

“Regional fat distribution, rather than overall obesity, has been recognized as important to understanding the link between obesity and CVD,” the researchers wrote. “In particular, findings show that central abdominal obesity is a better predictor of CVD than overall obesity.”

CV mortality, longevity

The health hazards of obesity have long been recognized, but recent studies have spurred controversy about the specific relationship between overweight status and mortality, Sadiya S. Khan, MD, MSC, assistant professor of medicine and preventive medicine at Northwestern University School of Medicine, and colleagues wrote in the JAMA Cardiology study.

Khan and colleagues observed that adults with obesity had an increased risk for CV morbidity and mortality and typically had shorter lives compared with adults with normal BMI. Those with overweight also had an increased risk for developing CVD at a younger age.

“We knew that obesity was associated with an increased risk of developing CVD, coronary disease, heart failure and stroke, but there was a lot of controversy in the literature with relation to overall life span and mortality once people with obesity develop CVD,” Khan said. “This was especially important to us in the context of trying to distinguish between health span vs. life span. We wanted to clarify not only the effect of obesity on CV mortality, but overall health span and life span.”

The researchers analyzed data from 190,672 patients (74% women; mean age for men, 46 years; mean age for women, 59 years) from 10 prospective cohort studies who were free from clinical CVD at baseline. Patients from these studies had at least one examination that included weight and height measurements, at least 10 years of follow-up and surveillance and adjudication for all subtypes of CV events and non-CV death.

The researchers calculated lifetime and cumulative risk for CVD events and non-CVD death. Patients were categorized by sex, age and BMI. Data included 3.2 million person-years of follow-up conducted until 2015.

Compared with patients with normal BMI, men and women who were middle-aged and overweight (BMI, 25-29.9 kg/m²) had an HR for incident CVD of 1.21 (95% CI, 1.14-1.28) and 1.32 (95% CI, 1.24-1.4), respectively. In those with obesity (BMI, 30-39.9 kg/m²), men had an HR of 1.67 (95% CI, 1.55-1.79) and women had an HR of 1.85 (95% CI, 1.72-1.99). The highest competing HRs were seen in men (HR = 3.14; 95% CI, 2.48-3.97) and women (HR = 2.53; 95% CI, 2.2-2.91) with morbid obesity (BMI, 40 kg/m²).

Patients with higher BMI had the greatest HRs for incident heart failure among CVD subtypes.

“For the person with obesity who has not yet developed CVD, the message is very strong,” Khan said. “Losing weight or maintaining a healthy weight is the most important thing to prevent the onset of CVD. Everyone would agree with that. The difficult situation is when patients have CVD, we don’t have good clinical evidence to show that weight loss would improve CV outcomes. Our data help support that, in the absence of obesity, there is lower CV mortality.”

Challenging the ‘obesity paradox’

Several studies have suggested that obesity could be protective in some adults, whereas low BMI is sometimes associated with increased mortality risk. In a 2016 review paper published in ESC Heart Failure, researchers observed that, although the risk for developing heart failure was higher among people with obesity, there was also, intriguingly, a survival advantage for patients with overweight or obesity when compared with normal-weight or low-weight patients. The advantage existed irrespective of the type, etiology or stage of heart failure, according to researchers; however, patients with morbid obesity did not have the same survival advantage.

“The ‘obesity paradox’ is a situation in which people who are obese seem to ultimately have a better outcome when they develop heart failure,” Robert H. Eckel, MD, professor of medicine in the divisions of endocrinology, metabolism and diabetes and cardiology at the University of Colorado Denver Anschutz Medical Campus, told Endocrine Today. “While this may be true, a couple of factors need to be considered. When you look at these U-shaped curves, being lean may carry additional risks related to cardiac cachexia or other chronic disease states unrelated to heart failure.”

There are three key issues with study findings that promote the idea of an obesity paradox, Nissen said. Any findings are confounded by smoking, which is associated with low body weight but high CV risk. Additionally, the effects of obesity may not be apparent in shorter studies, and some individuals are very thin because they have other chronic diseases that result in relative cachexia.

“If you’re not obese to begin with, you are less likely to develop heart failure or coronary disease,” Heymsfield said. “Becoming obese to ‘protect’ yourself is kind of foolhardy.”

Weight-loss benefits, challenges

Weight loss tends to reduce cardiometabolic risk factors in people with obesity, but only very substantial weight reduction has been linked to reduced CV risk, Nissen said.

In the landmark Look AHEAD study, a long-term, intensive lifestyle intervention targeting weight loss in more than 5,100 adults with type 2 diabetes and overweight or obesity, weight loss was modest — an average of 4 kg during a median 9.6 years of follow-up. The participants, Nissen noted, did not experience a reduction in CV events, including nonfatal myocardial infarction and nonfatal stroke.

“All this energy, all this effort, and they only got 4 kg of weight loss over 10 years.” he said. “The trial failed not because weight loss is not good. It’s because they didn’t get much weight loss. This was a strategy that just didn’t work out.”

For most adults with obesity, Eckel said, the struggle lies in managing two competing components to weight reduction: losing excess weight and maintaining the weight loss.

“From an energy balance perspective, these are two different agendas,” Eckel said. “We try to modify food intake as the primary intervention initially. Many guidelines suggest 5% weight loss, though changes in blood pressure or LDL cholesterol are less likely with 5%. But 10% weight loss will modify most of the cardiometabolic risk factors.”

Pharmacotherapy hurdles, CV safety

Lifestyle modification is often insufficient for weight loss for people with severe obesity; however, pharmacotherapy is still not a generally accepted treatment strategy, according to survey data presented at ObesityWeek 2018. Additionally, some weight-loss medications have been associated with CV safety signals.

In August, researchers at the European Society of Cardiology Congress presented findings from CAMELLIA-TIMI 61, a CV outcomes trial that demonstrated that the weight-loss drug lorcaserin (Belviq, Eisai) facilitated sustained weight loss in patients with overweight or obesity without a higher rate of major adverse CV events vs. similar patients assigned to placebo.

Still, weight loss in the treated group was modest — a between-group difference of –1.9 kg at 40 months.

For patients who are good candidates, Eckel said he will sometimes recommend the generic appetite suppressant phentermine, as it is affordable and he has seen patients have success with the therapy.

“I found that people who eat because they are hungry are good phentermine responders, and people who eat due to stress response do not [respond],” Eckel said. “I’m not a big obesity pharmacotherapist, but if the person has no hypertension and they take the drug in the prescribed manner, then, ultimately, the person that eats when they are hungry can experience a benefit that is sustained for years.”

Nissen, who has expressed skepticism about the established benefits of any weight-loss drugs on clinically important outcomes, said caution with phentermine is warranted. The drug, he said, has effects on BP and heart rate similar to the appetite suppressant sibutramine, which was withdrawn from the market in 2010 after the FDA determined observed CV risks outweighed the marginal weight-loss benefits. Lorcaserin, Nissen said, demonstrated a “complete absence of any benefit,” although CV safety was established in the CAMELLIA-TIMI 61 study.

“In the absence of established outcome benefits, there are only risks and costs,” Nissen said of pharmacotherapy.

Surgical intervention

More substantial weight loss can favorably affect atherosclerotic CV outcomes.

In a retrospective analysis of more than 20,000 patients, published in October in JAMA, researchers found that adults with obesity and type 2 diabetes who underwent bariatric surgery were half as likely to experience macrovascular complications over 4 years, including acute MI or stroke, compared with similar patients receiving usual care.

The researchers found that bariatric surgery was associated with a lower composite incidence of macrovascular events at 5 years (2.1% vs. 4.3%), for an HR of 0.6 (95% CI, 0.42-0.86). Additionally, bariatric surgery was associated with lower incidence of coronary artery disease (HR = 0.64; 95% CI, 0.42-0.99). The between-group difference in cerebrovascular events, however, did not rise to significance (0.7% vs. 1.7%), according to the researchers.

In a national database analysis presented at ObesityWeek 2018, Ali Aminian, MD, FACS, FASMBS, associate professor of surgery at the Cleveland Clinic, and colleagues observed that adults with obesity who underwent bariatric surgery and later developed heart failure were nearly 50% less likely to die of heart failure in the hospital vs. similar patients who did not have prior bariatric surgery. In an analysis of patients with heart failure who did and did not undergo prior bariatric surgery, the researchers found that bariatric surgery was associated with reduced length of stay for hospitalization for heart failure.

“Surgery is a powerful tool — it is very safe and effective, and it can improve all of the comorbid conditions associated with the obesity,” Aminian told Endocrine Today. “It can significantly improve insulin resistance, diabetes, elevated cholesterol, elevated triglycerides and hypertension — all risk factors for CVD. By modifying those risk factors, we would expect that CV risk decreases significantly, and there are data to support that.”

Heymsfield said bariatric surgery is a “very reasonable option” for those with severe obesity and type 2 diabetes, but these patients make up only about 10% of adults with excess weight.

“The other 90% have two options: behavioral and lifestyle changes, or medical therapy plus lifestyle modification,” Heymsfield said.

Bariatric surgery, Heymsfield acknowledged, is associated with reduced risk for all-cause and CV mortality in obesity.

“Those are facts, and they are accurate,” Heymsfield said. “But dismissing behavioral management belies the idea — and very clear evidence — that if you engage in what we call an intensive behavioral program, you can lose weight, keep it off for a long time and have clinical benefits.”

Patient education

With any weight-loss intervention, there will always be outliers — the person with obesity who can lose significant weight participating in an intervention and gain a substantial CV benefit — but outliers are not representative of the millions of people who struggle with excess weight, Nissen said.

“We have to figure out how to do lifestyle [intervention] better, we need to understand the drugs better,” Nissen said. “We have a problem that affects tens of millions of people, and we have to find a societal approach to this.”

Eckel said it is important to explain to patients that weight maintenance will involve permanent changes, not a temporary diet.

“You have to educate the patient,” Eckel said. “The behavioral and biologic drive for weight regain is still there after you lose the weight. How many of us have lost 5 lb, 10 lb? Weight is regulated where we max out at. To get someone to achieve 10% to 15% weight loss and then maintain that, you have to modify your day-to-day behavior.”

Heymsfield said there is clear evidence that patients who engage in an intensive behavioral program, typically meaning frequent meetings for 6 months, along with continued follow-up with a professional, does translate to clinical benefits and sustained weight loss.

“It’s only now that that level of treatment is fanning out to communities as a whole,” Heymsfield said. “For example, there are physician nutrition specialists who are being trained to administer that program. There are centers of excellence that offer this, and it is even now at some YMCAs. It is slow, but it is coming. The problem is the recidivism rate is not trivial, and the magnitude of weight loss is, on average, not very large, usually 5% to 8%.”

The long-term answer to obesity, Heymsfield said, is going to come from prevention strategies.

“It involves changing the environment, changing the foods and incentivizing health,” Heymsfield said. “Those are the real solutions, and they’re going to take a long time.” – by Regina Schaffer

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• References:
• Aleassa EM, et al. A-105. Presented at: ObesityWeek 2018; Nov. 11-15, 2018; Nashville, Tenn.
• Bhaskaran K, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/s2213-8587(18)30288-2.
• Bohula EA, et al. N Eng J Med. 2018;doi:10.1056/NEJMoa1808721.
• Fisher DP, et al. JAMA. 2018;doi:10.1001/jama.2018.14619.
• Khan SS, et al. JAMA Cardiol. 2018;doi:10.1001/jamacardio.2018.0022.
• Nagarajan V, et al. ESC Heart Fail. 2016;doi:10.1002/ehf2.12120.

• For more information:
• Ali Aminian, MD, FACS, FASMBS, can be reached at the Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195; email: aminiaa@ccf.org.
• Robert H. Eckel, MD, can be reached at the Cardiac and Vascular Center-Anschutz, 12605 E. 16th Ave., Third Floor, Aurora, CO 80045; email: robert.eckel@ucdenver.edu.
• Steven B. Heymsfield, MD, FTOS, can be reached at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808; email: steven.heymsfield@pbrc.edu.
• Sadiya S. Khan, MD, MS, can be reached at Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, 680 N. Lake Shore Drive, 14-002, Chicago, IL 60611; email: s-khan-1@northwestern.edu.
• Steven E. Nissen, MD, MACC, can be reached at the Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195; email: nissens@ccf.org.

Disclosures: Eckel reports he serves on advisory boards for Kowa and Sanofi/Regeneron. Heymsfield reports he serves on an advisory board for Medifast. Nissen reports he has conducted clinical trials supported by AbbVie, Amgen, AstraZeneca, Eli Lilly, Esperion, Ethicon Endosurgery, Novartis, Orexigen, Pfizer, Resverlogix, Takeda and The Medicines Company. Aminian and Khan report no relevant financial disclosures.