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 CV consequences, a result of greater consumption of high-calorie foods, decreases in regular physical activity and increases in psychosocial stresses, especially in disadvantaged populations. In an analysis of 10 large prospective cohorts with long-term follow-up published recently in JAMA Cardiology, researchers found that adults with obesity had significantly increased lifetime risk for CV morbidity and mortality and typically had a shorter life span compared with those with a normal BMI. In addition, elevated BMI conferred the greatest risk for incident HF among CVD subtypes.

“For the person with obesity who has not yet developed CVD, the message is very strong: Losing weight or maintaining a healthy weight is the most important thing to prevent the onset of CVD,” Sadiya S. Khan, MD, MSc, assistant professor of medicine and preventive medicine at Northwestern University Feinberg School of Medicine, and an author of the aforementioned JAMA Cardiology study, said in an interview.

Moreover, the bodily stress of excess weight can unmask underlying genetic tendencies that raise CV risk, such as hypertension, dyslipidemia and type 2 diabetes, virtually guaranteeing that a person with obesity will experience some CV effect, including atrial fibrillation and HF, 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,” Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart & Vascular Institute, and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said in an interview. “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 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 immediate past president of The Obesity Society.

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

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

“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.”

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.

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

In one study, subcutaneous adipose tissue was independently associated with higher total cholesterol and LDL levels in both sexes, as well as higher triglyceride and lower HDL levels in women.

Abdominal adiposity has been associated with CVD and diabetes, but it is important to note that this type of adiposity can be subcutaneous or visceral, Ian J. Neeland, MD, FAHA, assistant professor of medicine and Dedman Family Scholar in Clinical Care at UT Southwestern Medical Center in Dallas and Cardiology Today Next Gen Innovator, said in an interview.

“It’s the visceral fat which is the bad actor and more closely linked to many risk factors of cardiovascular disease and, at the same time, the peripheral fat — the fat near the hips and buttocks — may be protective against risk factors of cardiovascular disease,” he said.

However, excess fat of any type appears to confer CV consequences, some experts said.

“Regardless of where the fat is centrally located or distributed more evenly, increase in obesity appears to be a risk factor for cardiovascular-associated conditions including hypertension, diabetes, atrial fibrillation and maybe one of the environmental factors increasing the rates of heart failure that are now being experienced in the United States,” Keith C. Ferdinand, MD, FACC, FAHA, FNLA, professor of medicine at Tulane University School of Medicine and Cardiology Today Editorial Board Member, said in an interview.

CV mortality, longevity

The health hazards of obesity have long been recognized, but recent studies spurred controversy about the specific relationship between overweight status and mortality, Khan and colleagues noted in the JAMA Cardiology study.

The researchers 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 in an interview. “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.”

Khan and colleagues 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 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.

Compared with participants 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), the HR was 1.67 (95% CI, 1.55-1.79) for men and the HR was 1.85 (95% CI, 1.72-1.99) for women. 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).

Participants with higher BMI had the greatest HRs for incident HF among CVD subtypes.

While the message is clear when it comes to weight and CVD prevention among those who do not yet have heart disease, “the difficult situation is when patients have CVD, we don’t have good clinical evidence to show that weight loss would improve CV outcomes,” Khan told Cardiology Today. “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 paper published in ESC Heart Failure, researchers observed that, although the risk for developing HF 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 HF, according to researchers; however, patients with morbid obesity did not have the same survival advantage.

“It may be that in some patients especially with HF [with reduced ejection fraction], which is advanced, there’s a deleterious body weight loss which suggests lower cardiac output associated with a loss of muscle mass,” Ferdinand said. “Nevertheless, in patients who have significant obesity and develop either HF [with preserved EF] or HFrEF, it would be reasonable to attempt slow, consistent and healthy weight loss in order to unload the ventricle and increase the patient’s exercise tolerance and sense of well-being.”

Some experts say that how weight is managed in patients depends on their condition.

“I never tell people you should gain weight unless you’re underweight for those situations,” Neeland said. “For example, if someone comes in who has MI and maybe their BMI is 31 kg/m², it’s reasonable to start an exercise program, a diet program and to lose a little bit of weight. If someone has, say, a large acute myocardial infarction and now has an EF of 20%, I don’t necessarily think they should try to drop their weight all the way down below normal because those people are at risk for this catabolic state. I say don’t gain weight, but at the same time, lose weight in a targeted, appropriate manner.”

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 MI 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, the struggle lies in managing two competing components to weight reduction: losing excess weight and maintaining the weight loss, Robert H. Eckel, MD, emeritus professor of medicine in the divisions of cardiology and endocrinology, diabetes and metabolism, emeritus professor of physiology and biophysics and Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Anschutz Medical Campus and past president of the American Heart Association, said in an interview.

“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. Additionally, some weight-loss medications have been associated with CV safety signals.

Previous data from the CAMELLIA-TIMI 61 CV outcomes trial 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 a placebo. Still, weight loss in the treated group was modest — a between-group difference of –1.9 kg at 40 months.

More recently, data have emerged on the potential benefits of antihyperglycemic agents including SGLT2 inhibitors and GLP-1 agonists. In the DAPA-HF trial presented in September at the European Society of Cardiology and published in The New England Journal of Medicine, patients with HFrEF who were assigned dapagliflozin (Farxiga, AstraZeneca) lost more weight from baseline to 8 months compared with those assigned placebo (0.88 kg vs. 0.1 kg).

Weight loss with SGLT2 inhibitors may be related to glucose excretion, which can contribute to a loss of approximately 300 calories per day, experts told Cardiology Today.

“The reason this becomes important for the cardiologist is because one of the benefits of these agents, despite their antihyperglycemic effects, is that the SGLT2 inhibitors assist with weight loss, so using these agents may be a consideration for the cardiologist for both their cardiovascular protection and their potential benefit for assistance with achieving proper weight,” Ferdinand said.

Although data are not as robust for GLP-1 agonists with regard to protection against HF or renal disease, these medications have been shown to protect against major adverse CV events in patients with atherosclerotic CVD, experts said.

Surgical intervention

More substantial weight loss can favorably affect atherosclerotic CV outcomes.

In a study published in JAMA in September, researchers assessed data from 13,722 patients with diabetes and obesity who underwent bariatric surgery compared with matched controls. At 8 years, the primary endpoint of extended major adverse CV events including coronary artery events, all-cause mortality, HF, cerebrovascular events, AF and nephropathy occurred in 30.8% of patients who underwent bariatric surgery (95% CI, 27.6-34) vs. 47.7% who did not (95% CI, 46.1-49.2; absolute 8-year risk difference = 16.9%; 95% CI, 13.1-20.4; adjusted HR = 0.61; 95% CI, 0.55-0.69).

“That suggests that cardiologists will need to evaluate their patients who may be appropriate candidates for bariatric surgery and not simply for cosmetic weight loss, but for the potential benefits including a wide range of major cardiovascular adverse events,” Ferdinand said.

Ferdinand suggested utilizing bariatric surgery in patients with extreme obesity, defined as a BMI of 40 kg/m² or greater, and even patients with a BMI of 35 kg/m² to 39.9 kg/m².

Despite the proven benefits of bariatric surgery in patients with obesity, many clinicians believe that lifestyle alterations should be attempted before moving forward with that option.

“Making sure lifestyle changes, diet, physical activity are important regardless of your weight is important, but certainly as someone starts to gain weight, it comes at a greater importance,” Neeland said. “If those changes fail to improve your weight or your health, and certainly once you develop risk factors in the obese range, then those secondary strategies are necessary.”

Education, prevention key

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.

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 ultimately 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.”

Beyond this, the role of the cardiologist needs to go beyond treating intermediate risk factors, such as hypertension and diabetes, and move to addressing the upstream cause of obesity, which is a long-term strategy to improve health, Neeland said.

“Just treating the intermediate factors as we’re doing now with medications, for example, and not really trying to tackle obesity is only a short-term strategy,” he added. “It’s really going to be doomed to fail, and the only way to improve health is to treat obesity itself.” – by Regina Schaffer and Darlene Dobkowski

• References:
• Aminian A, et al. JAMA. 2019;doi:10.1001/jama.2019.14231.
• Bhaskaran K, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/s2213-8587(18)30288-2.
• Bohula EA, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1808721.
• Khan SS, et al. JAMA Cardiol. 2018;doi:10.1001/jamacardio.2018.0022.
• McMurray JJV, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911303.
• Nagarajan V, et al. ESC Heart Fail. 2016;doi:10.1002/ehf2.12120.

• For more information:
• Robert H. Eckel, MD, can be reached at robert.eckel@ucdenver.edu.
• Keith C. Ferdinand, MD, FACC, FAHA, FNLA, can be reached at kferdina@tulane.edu.
• Steven B. Heymsfield, MD, FTOS, can be reached at steven.heymsfield@pbrc.edu; Twitter: @heymsfield.
• Sadiya S. Khan, MD, MS, can be reached at s-khan-1@northwestern.edu.
• Ian J. Neeland, MD, FAHA, can be reached at ian.neeland@utsouthwestern.edu.
• Steven E. Nissen, MD, MACC, can be reached at 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. Ferdinand, Khan and Neeland report no relevant financial disclosures.