NASHVILLE – It’s all hands on deck to fight the obesity epidemic, according to a cardiologist who made a plea for collaboration at the opening session at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery. said , because when significant weight loss is achieved, “we can have an amazing effect on cardiovascular death, stroke, myocardial infarction, and these feared complications of obesity.”
From Dr. Nissen’s perspective, though, rates of death from cardiovascular disease have plateaued and are creeping up after decades of marked improvement.
“I am sorry to tell you that these rates are beginning to go up again – because of the obesity epidemic. That’s why we need to work together on this problem,” said Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic. “It has basically stopped progress on cardiovascular disease.”
Dr. Nissen drew from the broad literature intertwining obesity and cardiometabolic health to tell a story that went beyond weight loss to focus on outcomes.
For bariatric surgery, the evidence of reduction in cardiovascular risk is looking very good, said Dr. Nissen. “There are just huge changes in the metabolic risk factors. … Clearly we have evidence that if we get people to lose substantial weight, you can get people to normalize major metabolic risk factors.”
Recent data from a multisite, retrospective, matched cohort study of patients with diabetes and severe obesity show the promise of substantial weight loss in reducing risk. The study tracked 5,301 bariatric surgery patients and compared them with 14,934 “well-matched” control participants who did not have bariatric surgery but received usual care for diabetes, said Dr. Nissen.
During 7 years of follow-up, the bariatric surgery group had a hazard ratio for coronary events of 0.64 (95% confidence interval, 0.42-0.99; P less than .001). A post hoc analysis showed an HR of 0.34 for all-cause mortality among the bariatric surgery patients (95% CI, 0.15-0.74; P less than .001;).
“I’ve been practicing in this field for about 40 years,” said Dr. Nissen. “With statins, we get about 25% risk reduction … a 34% risk reduction is just a whopping big reduction.” Background risk was high among this population with diabetes, and this was a cohort study, not a randomized, controlled trial (RCT).
“We need RCTs,” he said. “I hope we can come together – all of us – and do a large, multicenter, global RCT on the effects of bariatric surgery on cardiovascular outcomes. But barring that, these are the best data we are going to have.”
But can these changes be achieved and sustained without surgery?
“Can diet or drug therapy favorably affect atherosclerotic cardiovascular outcomes? To me, this is the holy grail,” Dr. Nissen said.
A major cautionary note was sounded by a European Medicines Agency–mandated cardiovascular outcomes study of sibutramine, said Dr. Nissen. In clinical trials, patients taking sibutramine had seen modest weight loss, with increased HDL cholesterol and decreased triglycerides. However, blood pressure rose by 1-3 mm Hg, and heart rates also climbed by 4-5 beats per minute, changes consistent with sibutramine’s sympathomimetic effects, said Dr. Nissen. The EMA-mandated trial included over 10,000 patients and looked at a composite endpoint of major cardiovascular events, including death, MI, stroke, and resuscitated arrest. Patients were included if they were aged older than 55 years, had a body mass index of greater than 27 kg/m2, and had a history of cardiovascular disease or diabetes with an additional risk factor. Patients who had significant heart rate or blood pressure increases during the study run-in period were excluded.
In the end, patients taking sibutramine had an increased risk for the composite endpoint (11.4% vs. 10.0%; P = .02). The risk for nonfatal stroke and nonfatal MI was also significantly elevated for the sibutramine group ().
Phentermine is a pharmacologic relative of sibutramine, with similar effects on blood pressure and heart rate. Since it was approved prior to the current increased focus on real-world clinical outcomes in drug approvals, phentermine’s cardiovascular outcomes have never been studied by means of a RCT. “Nobody’s going to do this study unless we push for it, but it has to be done,” he said. “Although this drug reduces weight, there is considerable uncertainty whether it increases cardiovascular outcomes.”
Even looking at weight loss alone, pharmacologic treatments show marginal benefit over time, said Dr. Nissen, citing, as an example, recently published outcome data on lorcaserin. Over 40 months of treatment, there was a “complete absence of any benefit for lorcaserin,” compared with placebo, and participants saw an average weight loss of just 1.9 kg by the end of the study period, with no change in cardiovascular outcomes ().
To drive home the point, Dr. Nissen shared a slide entitled “Established Benefits of Weight Loss Drugs on Clinically Important Outcomes.” The slide’s text read, “This slide intentionally left blank.”
“It’s very hard for me to argue in favor of giving any of these drugs,” said Dr. Nissen. “In the absence of established outcome benefits, there are only risks and costs. I know this is not going to be popular with everyone in this audience, but I have to tell you what I really believe here: We have to do better.”
More broadly, “I think we have to demand outcome trials for obesity drugs,” said Dr. Nissen. He noted that such trials are underway for some glucagonlike peptide–1 agonists, “and I applaud them. ... I hope you will participate in those studies, because they are going to give us some answers.”
Calling for renewed efforts to improve the efficacy of lifestyle interventions, Dr. Nissen said, “What we have to do is try. .... You know as well as I that there are some outliers” who will achieve profound weight loss without surgery, and those patients are likely to reap big benefits in risk reduction.
“We’ve got a problem that affects tens of millions of people, and we’ve got to find a societal approach to this. But we share these patients; let’s work together on trying to make them better.”
Dr. Nissen did not report any relevant financial disclosures.