The new weight loss drugs

Understanding the new weight loss drugs: ©Nito - stock.adobe.com

Clinical trials with newer glucose-lowering agents for diabetes, particularly the injectable glucagon-like peptide-1 (GLP-1) receptor agonists, found another benefit: Patients on these medications also lost weight — a lot of weight, independent of the glucose-lowering properties. The drugs began being used off-label for weight loss, even for patients without diabetes.

“This new generation of anti-obesity medications is revolutionary,” says Beverly Tchang, M.D., endocrinologist and certified obesity medicine physician at Weill Cornell Medicine in New York City. “As a clinician who has specialized in this field for years, it’s amazing to see this disease finally have a treatment.”

This was a big change from previous medications developed for weight loss. Remember fen-phen (fenfluramine-phentermine)? By 1997 it was withdrawn from the market after a high percentage of those taking the drug developed heart valve disease. More recent drugs such as orlistat (Alli), phentermine/topiramate (Qsymia) and naltrexone/bupropion (Contrave) have not shown the same impressive results as the GLP-1 receptor agonists.

But is all good? Michael Schwartz, M.D., endocrinologist and co-director of the University of Washington Diabetes Institute, says that “while the emergence of GLP-1 receptor agonists and related incretin mimetic drugs is transforming the management of obesity and type 2 diabetes, their use also poses significant challenges.”

In this article we will review the impact of the obesity epidemic and discuss the new medications — the benefits, the drawbacks and a look toward what the future may bring.

How do the GLP-1 receptor agonists work?

GLP-1 receptor agonists are incretin mimetics. Incretins are gut-derived peptide hormones that are secreted in response to food ingestion. They were initially developed for the treatment of diabetes as they stimulate pancreatic -cells to secrete insulin, thereby lowering serum glucose. The GLP-1 receptor agonists also stimulate hypothalamic neurons that induce satiety, a process that is called “gut-brain signaling,” according to a 2022 study in Circulation.

Of note, we are still learning more about these drugs. For example, are the cardiovascular benefits such as reduction in systolic blood pressure due to a property of the drug or explained by weight loss?

What have clinical trials shown?

Two studies sponsored by Novo Nordisk and published in The New England Journal of Medicine showed significant weight loss with semaglutide in patients with obesity but without diabetes. In the 2021 STEP 1 trial, participants on semaglutide lost 14.9% of their weight compared with 2.4% in the placebo group. In the 2023 STEP-HFpEF trial, those on semaglutide lost 13.3% of their weight compared with 2.6% in the placebo group after 52 weeks.

Findings from Eli Lilly’s phase 3 SURMOUNT-3 trial with tirzepatide, a combined GIP/GLP-1 receptor agonist, were published in 2023 in Nature Medicine. Patients with obesity or overweight with a co-morbidity but without diabetes were randomly assigned to tirzepatide or placebo after an intensive 12-week lifestyle intervention with weight reduction of 5% or more. Those on tirzepatide had a mean weight loss of 18.4% at 72 weeks compared with 2.5% with placebo.

Results from Eli Lilly’s phase 2 trial with retatrutide, a triple-hormone-receptor agonist (GIP/GLP-1 and glucagon receptor agonist), were published in The New England Journal of Medicine. Those on retatrutide had weight loss of 30% or more on the highest dose at 48 weeks. The safety and side-effect profile were similar to that observed with other GLP-1 receptor agonists. Retatrutide appears to be the most potent of the weight loss drugs.

Reduction in cardiovascular events

A pivotal new study was presented at the American Heart Association Scientific Sessions on November 11, 2023, and published in The New England Journal of Medicine. Novo Nordisk’s phase 3 SELECT study provides data showing reduction of atherosclerotic cardiovascular events with the GLP-1 agonists used specifically for weight loss in a non-diabetic population with known cardiovascular disease.

The study enrolled 17,604 patients with body mass index (BMI) of 27 or more who were randomly assigned to semaglutide or placebo and followed for five years. There was a 20% reduction in cardiovascular death, nonfatal myocardial infarction or nonfatal stroke with semaglutide compared with placebo (6.5% vs. 8.0%; p < .001).

Another study, Eli Lilly’s phase 3 SURMOUNT-MMO trial of tirzepatide, is underway. This study is investigating morbidity and mortality in adults with obesity and established cardiovascular disease or multiple risk factors but without diabetes.

At present there is no data regarding the primary prevention of cardiovascular events in patients without atherosclerotic cardiovascular disease.

How has obesity been treated to date?

Lifestyle intervention combining diet and exercise is a foundational component of obesity management but poor adherence limits its effectiveness. Bariatric surgery is indicated for those with BMI of 40 kg/m2 or more and co-morbidities. Surgery has provided greater efficacy than lifestyle changes or pharmacological treatments although studies with the newer drugs suggest that results may be comparable.Procedures have improved over the years and many are now performed using minimally invasive techniques such as laparoscopy. However, the procedures are not without risks. These include complications within 30 days such as bowel obstruction and wound infection as well as longer-term including incisional hernial, dumping syndrome and nutritional and vitamin deficiencies.

Risks and side effects of GLP-1 receptor agonists

We still do not have a full understanding of how the drugs work and adverse effects, particularly in the long term.

The most common side effects noted in clinical trials are gastrointestinal complaints (nausea, vomiting, diarrhea). Risk of hypoglycemia is minimal unless used with other agents that cause hypoglycemia. Some patients report that they no longer have an appetite or enjoy food, which is good for weight loss but to some, a disturbing side effect.

What about long-term safety?

Chris Shibutani, M.D., MBA, managing director, global investment research and senior biopharmaceutical analyst and equity researcher for Goldman Sachs, points out that “long-term safety data is always a concern for new drugs. Who we include in the studies (premarket) is different than those that will actually be prescribed the drug in the real world.” For example, patients with more complex medical issues may use the drugs and it may take years to show side effects not seen in previous trials.

In the The Journal of Clinical Investigation, Schwartz writes about the “prospect of exposing patients to potent and continuous activation of two or more different hormone receptors, each distributed widely throughout the body, potentially for a period of many years. How confident should we be that such an approach will not have unanticipated consequences?”

Yet it is assuring that these medications are not new. “We have two decades of experience with the use of GLP-1 receptor agonists for diabetes treatment and in all these years there have been no surprises,” says Daniela Hurtado Andrade, M.D., Ph.D., from the division of endocrinology, diabetes and metabolism and precision medicine for obesity program at Mayo Clinic in Florida. “Data so far supports that this class of medications is safe in the long term.”

She acknowledges, however, that “these medications are becoming more potent and with that there is concern for more pronounced side effects that have not been seen with older-generation and less potent medications.”

Are there protocols for use?

Not yet. For example, determining an individual’s magnitude and rate of weight loss, if and when there will be a plateau and how to adjust dosing of the medications, both initially and in the long term.

Some doctors have devised their own protocols. For patients who achieved their goals, Hurtado Andrade, M.D. has been decreasing the doses of anti-obesity medications very slowly and keeping them on the lowest dose at which they are able to maintain weight loss.

“I have other patients who are taking the lowest dose of semaglutide every 10 to 14 days for months without weight regain. Other patients in whom I tried to decrease the dose of the medication started regaining the weight back almost immediately. The next few years will be critical to understand how to help people living with overweight and obesity maintain their weight in the long term.”

Another big question is: Will patients have to take the drugs for a lifetime?

In a study published in Diabetes, Obesity and Metabolism patients with obesity or overweight but not diabetes were randomly assigned to semaglutide or placebo. Participants on drug had a mean weight loss of 17.3% at week 68, but following withdrawal they regained 11.6% of the lost weight by week 120. Cardiometabolic improvements also reverted toward baseline for most variables.

But should obesity treatment be any different from treatment of other chronic diseases? “Though the prospect of chronic use is troubling to some, it may reflect the double standard applied to obesity,” says Andrew Kraftson, M.D., the director of the weight navigation program at the University of Michigan. “As a society, we have accepted that those with high blood pressure, high cholesterol, heart disease, and diabetes require lifelong treatment. As such, it should come as no surprise that those with obesity may also require long-term medication treatment.”

Challenges in prescribing

What about day-to-day challenges for doctors? Will all feel comfortable prescribing a diabetes drug for patients with and without diabetes? Will they feel pressured to prescribe the drugs, even without indication, say, for a patient who wants to take off that 10 or 15 lbs?

In addition, many clinics have staffing shortages. Who will assist with the logistical issues in prescribing and obtaining the drugs such as prior authorization, teaching patients how to inject the drug and handling calls about injection-site reactions and other side effects?

A major hurdle: third party coverage

Lack of third-party coverage will continue, at least in the near term.

According to GoodRx, the drug pricing website, the cost of Wegovy is $1,378 for a month’s supply. However, the net cost of the drug — what health insurers and patients actually pay — may be less than the list price though still expensive. Wegovy, for instance, has a patient savings program posted on its website. For Zepbound, those with commercial insurance but no coverage may be eligible to pay $550 for a one-month prescription.

The 2003 Medicare Prescription Drug, Improvement and Modernization Act prohibits Medicare from covering the cost of treatments for obesity. Medicaid offers coverage in some states but with restrictions, prior authorization and limited formulary. Some select Medigap and Medicare Advantage plans may provdde coverage. Many private insurers do not cover GLP-1 drugs prescribed for weight loss only.

In some instances, coverage is being scaled back. North Carolina is planning to stop paying for these drugs for state employees as of
April 1, 2024, due to high cost.

Will we see a change?

The drug companies are working on clinical trials to show how their drugs favorably impact diabetes and cardiovascular disease in order to expand Food and Drug Administration (FDA) indications and insurance coverage.

But the path to Medicare and Medicaid reimbursement is complex. Shibutani points out that the “Treat and Reduce Obesity Act of 2023 is being reintroduced after many past attempts to have this sent to Congress and passed as legislation.” This bill would expand Medicare coverage to include treatment of obesity. However, the process is long and involves calendar dynamics for sessions of Congress, timing relative to election cycle and competing interests.

On the positive side, with so many pharmaceuticals having or developing these medications, competition will influence prices. “We must remember that these medications will eventually become generic,” says Hurtado Andrade.

Another favorable move is that the Congressional Budget (CBO) has asked for research on factors that affect the use of anti-obesity medications and overall impact on health care spending. The CBO then provides Congress with information that can affect legislation on the cost of medications.

In the meantime, lack of reimbursement and, more recently, a drug shortage due to demand (Wegovy has been on the FDA’s drug shortage list since March 2022) have led to workarounds to obtain the drugs.

One way is to prescribe off-label where diabetes is listed as the diagnosis despite the patient not having diabetes. Another way is compounding, where the pharmacist mixes components to replicate the medication. Compounding is allowed when a drug is in short supply and meets requirements in the Federal Food, Drug, and Cosmetic Act. Risks include substitution of some components and possible contamination when mixing the drug with saline and using this from the vial instead of the injectable pen.

Concerns have also been raised about direct marketing. Eli Lilly, makers of Zepbound, have set up a direct-to-consumer online platform where people can obtain a prescription for their drug. An independent telehealth group pairs a health care provider to a prospective patient where relevant information (such as body weight and medical history) are reviewed and medication prescribed. Another telehealth company, Ro, has launched an aggressive marketing campaign to offer online prescription of obesity drugs.

A boon for pharma

Novo Nordisk has been focused on diabetes. However, company scientists realized its medications, particularly the GLP-1 receptor agonist liraglutide, were associated with weight loss. In 2014, it received FDA approval to market liraglutide for weight loss and in 2021 FDA approval for another GLP-1 drug, semaglutide. So began a boon for pharma.

Eli Lilly’s Zepbound received FDA approval on November 8, 2023, with Priority Review and Fast Track designation based on the phase 3 SURMOUNT-1 and -2 trials. With the 20% lower list price and greater efficacy, along with the current shortage of Wegovy, Eli Lilly’s drug may gain a significant portion of the obesity market.

Companies are pushing forward. Eli Lilly is working on an oral GLP-1 receptor agonist. Novo Nordisk hopes to leverage findings from the SELECT trial showing reduction in cardiovascular events and has already filed paperwork with the FDA to update Wegovy’s label. Other companies, such as Amgen Inc. and Pfizer, are expediting their drug pipelines.

MarketWatch, operated by Dow Jones & Co., feels that there is “unprecedented potential for the overall obesity market in the U.S. and beyond” and forecast that the drugs will reach peak global sales of $100 billion by 2035.

What the future may bring

Obesity and weight-loss drugs are here to stay and the obesity epidemic is not abating. But did we get a bit ahead of ourselves in terms of expectations?

Reimbursement will likely remain a challenge, at least in the near future. Will there be any surprise adverse effects with many more people being treated? Should they be used for those who are overweight, but not obese, to lose 10 to 15 pounds? What becomes of endorsing and facilitating lifestyle modification?

There are hopeful signs, however. Public health officials realize the importance and urgency for treating obesity including enacting legislation that widens Medicare and Medicaid reimbursement. Research showing added benefits, such as reduction in cardiovascular and cardiometabolic disease, may widen FDA indications and influence third-party coverage. Competition among pharmaceutical companies will produce more drugs and promote reduction in prices. We will eventually see brand formulations becoming generic.

“Stay tuned,” Shibutani says. “It is going to be a journey.”