Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC

Obesity is a serious and life-threatening disease and it is good to have more tools in the tool kit that we can offer our high-risk patients. The GLP-1 receptor agonists and dual agonists, like tirzepatide, are game changers to help our patients. Despite lifestyle modification, which is always the foundation of any treatment plan, obesity is far more complicated than “calories in, calories out.” The brain regulates the body’s weight “set point,” and many of our patients are unable to get to a healthy weight to achieve their cardiometabolic health goals with lifestyle alone.

Obesity is strongly associated with serious CV complications — not only atherosclerotic CVD, but also heart failure, atrial fibrillation, sleep apnea and mortality. Data from LOOK AHEAD trial demonstrated that significant weight loss of 10% or more with lifestyle alone was associated with a significant reduction in major adverse CV events. We have seen similar data with weight loss after bariatric surgery and the use of GLP-1 receptor agonists. Topline results from the SELECT trial, which enrolled high-risk patients with overweight and obesity with established CVD, show semaglutide 2.4 mg reduced the risk for major adverse CV events by 20%. That is a large and meaningful reduction in risk. I suspect we will see similar results with tirzepatide; those trials are ongoing. For high-risk patients who have a lot of downstream CV risk factors related to overweight and obesity status, if you can address obesity, you can reduce CV events.

Dual agonists like tirzepatide are more potent in reducing weight with a similar side effect profile to the GLP-1 receptor agonists. This is important. The disease of obesity has not received the same level of attention as other chronic serious diseases. This is very stigmatizing. We do not say hypertension, for example, is a “lifestyle disease.” We treat it for CV risk reduction. We must also treat obesity for CV risk reduction because effective treatments now exist.

Katherine H. Saunders, MD, DABOM

The approval of tirzepatide for obesity is a tremendous milestone in the history of obesity medicine. Only a decade ago, naltrexone SR/bupropion SR (Contrave, Currax Pharmaceuticals), liraglutide (Saxenda, Novo Nordisk) and phentermine/topiramate (Qsymia, Vivus) were approved, and we were thrilled to have several anti-obesity medications associated with clinically significant weight loss. Compared with the best lifestyle interventions, which produce 3% to 5% total body weight loss, each of these new agents enabled our patients to achieve 5% to 10% total body weight loss on average.

In 2022, the approval of semaglutide (Wegovy, Novo Nordisk) was a game changer — 15% total body weight loss with a single medication. This degree of weight loss basically obliterates risk for developing type 2 diabetes. The bar was raised dramatically. Now with the approval of tirzepatide, which was associated with 26% total body weight loss in the SURMOUNT-4 trial, the landscape of obesity care has changed forever.

While the Zepbound news is incredibly exciting, effective treatment of the complex, heterogenous, chronic disease of obesity goes beyond two highly effective medications. We need to prescribe these agents as part of comprehensive, individualized, empathetic and long-term medical obesity care. Too many clinicians are dabbling in obesity medicine by simply writing a prescription without educating or supporting their patients. This is one of the reasons for semaglutide side effect hype. We must prescribe to carefully selected patients and set them up for success with personalized weight management plans addressing all factors contributing to weight gain and all barriers preventing weight loss.

Prescribing tirzepatide is a responsibility that can’t be taken lightly. It’s so powerful that we must teach patients to adjust eating behavior to minimize side effects. We also need to inform patients to identify early warning signs long before serious adverse events occur.

Inappropriate management can lead to severe side effects, a complete lack of appetite, vitamin deficiencies or too much weight loss. Patients are sometimes reluctant to disclose their gastrointestinal symptoms or extremely low caloric intake when they’re thrilled to be losing weight. Many of our patients simply cannot handle or do not require dose escalation according to manufacturer’s guidelines. We need to take the time to ask the right questions, and we shouldn’t increase the dose if a patient has side effects or zero appetite.

Tirzepatide is generally well tolerated when dose titration protocols are tailored. We have an unprecedented opportunity to help our patients. Let’s do this responsibly.

Richard E. Pratley, MD

Tirzepatide is clearly the most effective medical treatment for obesity and seems relatively well tolerated based upon our clinical experiences and in patients with type 2 diabetes. What this means for patients with obesity is there are now a lot more options besides oral medications, which have limited efficacy, and the other extreme of bariatric surgery. People can have significant weight loss up to 22% on average with tirzepatide, and there were people who lost way more than that. What I think this will do is open up the possibilities for obesity treatment to a much broader audience.

It's interesting that Eli Lilly are pricing Zepbound well below Wegovy. We understand that health care insurers are not going to continue that ever-increasing cycle. They see such a huge potential market for this medication that the insurance companies are very worried that they're going to go broke if they pay for this for everybody. How do we figure out how to get the medication to the right people at a cost that doesn’t break the system? Now, this current cost is probably not that ideal cost, but it’s a step in the right direction.

Though research suggests that the benefits of cognitive behavioral or lifestyle medicine on top of these medications are minimal because these medications are so powerful, there's still a role for lifestyle education and improvement for a couple of reasons. One is that we've ingrained in people over time that lifestyle change is important, and there's an expectation from our patients that they should be doing it. The actual execution of it is harder, but I think it needs to be part of the offer.

Secondly, if you don't pay attention to lifestyle intervention, you won't get the maximum benefit from these medications, and people need to be on the complete journey when they're on these medications. They need to be thinking about what they eat and their activity levels. On the one hand, when you lose a lot of weight, you can improve your functional abilities. If you don't take advantage of losing the weight, getting out there and doing more physical activity, it's not going to be as impactful.

I think we'll find that people lose weight on these medications, but they won't necessarily want to stay on them forever. If they haven't changed their lifestyle and haven't adopted new exercise habits, their chances of rebound weight gain are much higher. For those reasons, lifestyle remains a cornerstone of our therapy and our recommendations.

I think this is just the beginning of what we will see in this space. We're still waiting to see the ancillary benefits that we've seen with semaglutide in terms of cardiovascular outcomes, potential kidney outcomes and maybe outcomes on other obesity-related diseases. I expect that we'll see a drumbeat of new evidence in that area that will meaningfully change the long-term complications of obesity for the people that are able to access this class of medication.

Steven B. Heymsfield, MD, FTOS

The approval of tirzepatide adds another choice for effective weight management. It’s good to have more medications available as not every patient responds equally to the same drug.

In the past, our treatments were not particularly effective or well-tolerated in terms of the pharmacological management. We had behavior and exercise interventions, but that treatment never fully entered the primary care world.

Primary care doctors will be prescribing these drugs and I have concerns about that. The most obvious one is the cost of these drugs are substantial. Eventually, the cost will come down as more drugs enter the market and we get a better sense of their effectiveness. The other issue is that we’re treating an environmentally caused disease. You have to have the genetic makeup to have obesity, but on the other hand, we have an environment that’s playing on those genes. We’re creating a problem through our environment and then finding a very effective, but expensive way of treating it. At some point, we have to think hard about how our world is built around us and whether or not it can be modified to reduce the risk for obesity separately from using a drug.

One thing that’s been discussed a lot is how safe these drugs are. Both semaglutide and tirzepatide are already in use at lower doses. When you use a drug in hundreds of thousands or even millions of people and you use them for a long period of time, you begin to see rare side effects. What we have to be mindful of is that we’re going to see rare side effects, and to an extent, they’re going to make people a little more cautious. Most adverse events are mechanism-related and they’re largely gastrointestinal events. My own experience is that most people are willing to tolerate those effects. We get surprisingly good retention because people are losing weight and they’re saying, “I don’t mind a little nausea, vomiting or diarrhea.”

No one is more surprised than me with how effective and well-tolerated these drugs are. Everyone I know who I work with in this field thinks this is one of the big game changers. Assuming that nothing brings it down, tirzepatide is transformational and the implications are enormous.