Obesity Management Targets Complex Disease via New Drugs, Better Awareness

Despite significant medical advances in the U.S. on numerous fronts, obesity management seems stalled by many clinicians’ reliance on a regimen of “diet and exercise” alone to treat as well as prevent. Obesity medicine specialists cite the increasing availability of safe and effective anti-obesity medications on the market — with dozens more in the pipeline — to allow for a multipronged treatment approach, but they point out that physicians seldom prescribe such drugs, and insurers often balk at paying for them.

This is partly because individuals with obesity, an increasingly prevalent, serious and costly disease, continue to confront the societal bias that “lifestyle choices” are to blame, experts say. It is also because obesity is a complex disease to treat, not merely a matter of gauging body mass index (BMI), they explain, and unless treated effectively, it may become the pathway to a wide array of chronic conditions including heart disease, stroke, type 2 diabetes, asthma and some types of cancer, as well as disability and premature death.

Adding to the sense of urgency is what one obesity medicine expert describes as the “collision” between the obesity epidemic — including its disproportionate impact on Black and Hispanic populations and the steady rise in childhood obesity — and the raging COVID-19 pandemic, in which people with obesity are prone to higher risk of severe illness.

A forecast released in July predicts that the global obesity treatment market, including pharmacotherapy and bariatric surgeries, will top $27 billion in 2028.

Still, clinicians who are experts in the obesity field and on the front lines of patient care cite daunting practical challenges to keep pace with scientific advances in treatment options.

“I always say, imagine going with your loved one to a cancer doctor, and the doctor says, ‘We have first-line, second-line and third-line treatments,…so we’ll start here because it’s the least costly but also the least effective’ — and diet and exercise are the least effective,” says Catherine Welford Varney, D.O., a UVA Health family medicine physician who specializes in obesity medicine and is board-certified in both fields.

On average, an individual can expect to lose 5% to 10% of body weight with diet and exercise, Varney says, and even that is “unsustainable” because willpower is no match in fighting survival instincts. “So that’s where the medications come in,” she says. “Diet and exercise absolutely have to be part of it, but drugs change the physiology, change hormonal signals and suppress primitive signals like hunger.”

According to David Steinberg, Pharm.D., director of pharmacy insights at Scripta Insights, a data analytics company that helps health plans, self-insured employers and third-party administrators figure out plan design and PBM contracting, an important new trend focuses on the use of already FDA-approved, effective diabetes medications for weight loss. “First, Victoza rebranded and was released as Saxenda, and now Ozempic has been approved as Wegovy. The same drug but at a higher dose creates this new indication,” he says.

“I think obesity can be addressed by a multipronged approach by physicians, addressing underlying conditions,” Steinberg says. “Obesity really should be treated as a serious medical condition. It should be treated with urgency and seriousness, and these medications offer that approach.”

Adds Beverly Tchang, M.D., an endocrinologist and obesity medicine specialist at Weill Cornell Medicine’s Comprehensive Weight Control Center, “our approach is to absolutely treat obesity as a medical disease, just like diabetes, high blood pressure,…and this is where the field is headed.”

“For a very long time, we’ve been looking at obesity as a lifestyle choice, classically defined by weight and BMI, but it’s really a dysregulation of our energy state,” she says. “So some individuals never feel hungry; some individuals never feel full.” The crux, as she explains it, is that “you can’t change a medical disease just by changing your lifestyle,” and patients going to Weill Cornell’s clinic “are looking for another level, and for us this is pharmacotherapy.”

Medicare Coverage Is Lacking

Currently Medicare does not cover anti-obesity medications, though federal lawmakers continue trying to effect change. The bipartisan Treat and Reduce Obesity Act (S. 596) in the Senate and a House companion bill, first introduced in 2012 and reintroduced this year, would require Medicare to provide this type of drug coverage; the legislation also would broaden the types of clinicians able to get paid for behavioral counseling for obesity.

A CMS spokesperson explains that the agency has excluded all drugs used for weight loss from basic Medicare Part D coverage since the program began in 2006, regardless of their use for obese individuals. “By statute, certain drugs — specifically, those that may be excluded by Medicaid under section 1927(d)(2) of the Social Security Act — are excluded from basic coverage under Medicare Part D,” he says. “This includes ‘agents when used for anorexia, weight loss, and weight gain.’”

Part D sponsors may cover excluded weight loss drugs that would otherwise meet the definition of a Part D drug as supplemental benefits under enhanced coverage, the CMS spokesperson says. However, he says, “to the extent they’re being used for an excluded indication like weight loss, Medicare Part D plans will be unable to cover potential GLP-1 [i.e., glucagon-like peptide-1]-based drugs under the basic benefit.”

He further notes that policy changes within the basic Part D coverage with respect to certain drugs take place by statutory requirement, and CMS does not comment on petitions that the agency has received for policy changes and/or any potential policy changes.

By contrast, states generally have broadened coverage for bariatric surgery and nutritional counseling, spurred on by the Affordable Care Act, and premium surcharges for being obese are prohibited in most insurance policies in all 50 states, including those sold through state-based ACA exchanges. Varney notes that some of the best coverage for bariatric surgery and anti-obesity medications comes from the states, including Virginia, and is available for state employees and Medicaid plan enrollees alike.

However, private commercial health insurers typically put coverage for obesity treatment, including pharmacotherapy, in policy riders at an additional premium cost, experts note.

Interventions May Fuel Savings

Nationwide, the Centers for Disease Control and Prevention (CDC) reports that 42.4% of adults in the U.S. were obese in 2017-18, up from 30.5% in 1999-2000; in all, roughly seven in 10 Americans are either overweight or obese.

Obesity medicine experts cite a 2018 study by The George Washington University’s Milken Institute School of Public Health that put annual health care costs related to the prevalence of obesity in the U.S. at $150 billion. They also point to research findings underscoring the benefits of taking action, including a 2019 study published in the Journal of Medical Economics that concludes anti-obesity interventions, including pharmacotherapy, could generate savings of $20 billion to $23 billion to Medicare over 10 years.

More recently, a study published in March 2021 in the Journal of Managed Care + Specialty Pharmacy (JMCP) put the annual aggregate national cost figure for obesity at $260.6 billion. Researchers found that the effects of obesity raised U.S. medical care costs “substantially” for every category of expenditure from outpatient care to inpatient care and prescription drugs, and for public health insurance programs and private health insurers alike.

The study appearing in JMCP had input from Novo Nordisk, manufacturer of the two most recently FDA-approved anti-obesity drugs on the market: Wegovy (semaglutide), an injectable product approved in June 2021 as the first new drug treatment for chronic weight management since Saxenda (liraglutide), also an injectable, was approved in December 2014.

By all accounts, demand is outpacing Novo Nordisk’s supply of Wegovy, which the FDA approved for adults who are obese or overweight and have at least one weight-related condition such as hypertension, type 2 diabetes or high cholesterol.

Wegovy is basically a higher dose (2.4 mg) of Ozempic (semaglutide), a diabetes drug that is administered by injection once weekly; it works by imitating a hormone, GLP-1, that targets areas of the brain regulating appetite and food intake. Saxenda (liraglutide), also part of the class of diabetes drugs known as GLP-1 agonists, is injected daily; it got the FDA’s go-ahead in December 2020 to expand into use for children ages 12 and older.

Novo Nordisk spokesperson Michael Bachner tells AIS Health, a division of MMIT, that “we’ve never seen weight loss outside of surgery like this [i.e., Wegovy] — upwards of 20% in clinical trials.” Since there is no recognition of anti-obesity medications by the federal government, “our focus is on private insurance…and trying to get obesity recognized by Congress as a disease.” He adds that “three major” PBMs, which he did not name, have agreed to cover Wegovy to date.

Previously, semaglutide was approved under the brand names Rybelsus (oral) and Ozempic (a lower-dose injection) to treat type 2 diabetes. GLP-1, a naturally occurring hormone in the body, acts on the brain to regulate appetite and food intake, and patients with obesity have lower levels of GLP-1 at baseline, Varney says.

In its third-quarter 2021 earnings report, released Nov. 3, Novo Nordisk said that initial demand for Wegovy in the U.S. had “significantly exceeded” the Danish pharmaceutical company’s expectations, which it said underscores the “high unmet need” for people living with obesity.

W. Timothy Garvey, M.D., a professor in the department of medicine at the University of Alabama at Birmingham and director of UAB’s Diabetes Research Center, says the undersupply of Wegovy and issues related to coverage of anti-obesity medications are creating “a real bottleneck right now.”

Garvey, too, explains that patients with obesity need medications as part of their treatment plans, but they are not included in standard coverage, “and employers often have the same bias and don’t understand what obesity is doing to their workforce.”

A top researcher involved in numerous clinical trials of anti-obesity medications, Garvey explains that Wegovy’s higher dosage gives it “twice the efficacy compared to previous medications” — and this makes it “a gamechanger.” He says the amount of weight loss that it engenders “can ameliorate a range of obesity complications, like pre-diabetes, diabetes, NASH [i.e., nonalcoholic steatohepatitis, a fatty liver disease] and cardiovascular risk factors,…and [we should] treat obesity like we treat other chronic diseases.”

Garvey, lead author of clinical practice guidelines for the medical care of patients with obesity, issued by the American Association of Clinical Endocrinology in 2016, describes obesity as “a complex disease to treat” because of environmental factors, a “heavy genetic component” and psychological overlay. He says he hopes the availability of new anti-obesity medications, “with the benefits so clear,” will cause clinicians and health systems to “take notice and start coverage.”

He anticipates that the comprehensive obesity care guidelines will be updated in 2022 to keep up with advances. “Previously, there was not much to update, but there is the need for it now due to semaglutides,” Garvey says. In the meantime, he anticipates that Wegovy, as “a new drug with this potency,” will stimulate the engagement of patients and create an informed health care system to produce the best outcomes. “I’m talking about a ‘complications-centric’ approach — not just losing weight but losing enough to improve health,” he says.

Also in 2016, The Endocrine Society released its own guidelines on the pharmacological management of chronic obesity. Its guidelines suggest choosing alternative medications that are weight-losing or weight-neutral in managing other medical conditions such as depression and chronic inflammatory diseases. But Garvey says that while there is “a little more recognition of weight-gaining medications now” by clinicians, he would not characterize it as “a groundswell.”

Pharmacotherapy Isn’t Straightforward

Garvey, asked about the idea of anti-obesity pharmacotherapy being tailored to specific populations, replies, “my personal feeling is we’re a long way away from precision medicine here. With obesity, we have nothing like those biomarkers [used to target cancer therapy],” and while there is a genetic predisposition, it’s difficult to focus on a particular pathway.

He notes that researchers looking into the higher dosage of semaglutide “tried to find any characteristic of who’d lose more or less weight, but we could find nothing” — and 15% or so of patients didn’t lose more than 5% of their body weight.

This necessitates a broad approach to obesity treatment, using medications currently on the market and looking toward drugs still to come. “I think the pipeline is very promising,” he says, noting UAB continues to be involved in clinical trials of novel anti-obesity and diabetes pharmacotherapies.

According to Varney, who is assistant professor in the department of family medicine at the University of Virginia School of Medicine, current weight-loss medications include:

  • Several appetite suppressants, first approved for short-term use in the 1960s — phentermine, phendimetrazine, diethylpropion and benzphetamine — with monthly out-of-pocket costs of $20 to $30;
  • GlaxoSmithKline plc’s Alli (orlistat), which has monthly OOP costs of about $30 to $60, but is “rarely used given terrible GI [i.e., gastrointestinal] side effects”;
  • Nalpropion Pharmaceuticals LLC’s Contrave (naltrexone and bupropion) at $150 to $250 per month OOP;
  • Vivus LLC’s Qsymia (phentermine and topiramate) at about $200 per month OOP;
  • Saxenda, which runs between $600 and $1,300 per month OOP; and
  • Wegovy at about $1,100 per month OOP.

“I’d say the cheaper generics are always used more than the expensive ones. So [clinicians] tend to turn to phentermine because it’s so cheap,…but it’s always the case where people would do better with Wegovy than phentermine.” She describes insurance plans’ coverage as “either a ‘yes’ or a ‘no’ — they cover all anti-obesity medications or none of them.”

A spokesperson for AHIP, asked for clarification, did not get back to AIS Health by press time.

Varney notes that phentermine is part of combination drug Qsymia’s makeup, but the newer drug is approved for long-term use while the older drug is not due to what she describes as “unfounded worries” by the FDA that people would become addicted to appetite suppressants. She says their longer-term use hasn’t been fully evaluated because pharma manufacturers would have to undergo a lengthy, expensive process to seek any change to what amounts to cheap medications.

This leads to misunderstandings on the part of prescribing physicians, Varney says, noting she gets “asked every day” about nutrition and obesity management by doctors who spent only a fraction of medical school studying such subjects.

Among obesity medicine specialists, she explains, “the medications still get prescribed. We just do it off label. We’re choosing other medications instead of theirs [i.e., the costlier drugs not covered].” For example, she says, a lot of obesity medicine specialists will prescribe bupropion and naltrexone separately, off label, if Contrave, the combination drug using both, isn’t covered. Or topiramate and phentermine are prescribed separately, off label, if Qsymia isn’t available.

“But it is done safely and within the scope of standard care among obesity specialists,” she says. “They’re not going rogue.”

Tchang says the drugs used most often for patients at Weill Cornell’s weight loss center, partly because of insurance coverage, “are mostly off-label, older drugs — mixes and matches of medications. We’re using Ozempic too, A lot is born out of necessity…when we’re dealing with a disease that no one recognizes as a disease.”

“We use Ozempic all the time,” Tchang says. “We started doing this way before Wegovy came out.…For some individuals, we can get higher doses of Ozempic, like model doses of Wegovy.”

As for Wegovy, which has faced supply issues as well as cost and coverage issues since its market entry in June, Varney says, “either we don’t have the option for patients and choose something like metformin instead but not for weight loss. We choose to treat diabetes and not obesity.”

“So if the patient has diabetes, I choose Ozempic,” which comes in 0.5 mg or 1 mg doses, Varney explains. “So patients only get partial benefit — 2.4 mg. [i.e., Wegovy’s strength] is the best dose for weight loss vs. a 1 mg maximum dose with Ozempic.”

Steinberg, the pharmacist, says his firm took a careful look but did not find a clinically meaningful difference between the two strengths of semaglutide. He agrees that doctors know that the diabetic drug Ozempic is covered under insurance while the 2.4 mg. Wegovy is not and act accordingly when they feel that their patients with obesity, often also having diabetes, will benefit.

“Because Saxenda and Wegovy are prior auth[orization], step therapy or excluded completely from the formulary,” Steinberg says, “they’re going to Ozempic, which can’t be excluded from the formulary because it’s a diabetes medication. So we’re seeing more of a pickup in Ozempic due to Saxenda and Wegovy being denied.”

Varney says she sees about 240 patients per month, and only about 20% of them, or 48 individuals, have coverage for anti-obesity medications. But 100% of her patients with obesity (using the term “obese patients” “marginalizes” people, she asserts) have other chronic conditions. “Obesity is implicated in 236 other diseases,” she says. “Anything from depression to chronic pain and 13 different cancers.”

She notes that the UVA health care system has a clinic for patients at high risk of pancreatic cancer, “and one of the things we’re trying to do is get a formal weight-loss program for them.”

Varney describes Wegovy as an “amazing” anti-obesity medication. She says not only does the drug cause the most weight loss in patients, but weight loss of 14% to 17%, on average, has been shown to be sustained for up to 104 weeks. Moreover, at least 50% of individuals taking it lose at least 15% of their body weight, with 40% of patients losing 20% or more of body weight, and compliance isn’t an issue since it’s a once-a-week shot.

In short, she describes Novo Nordisk’s Wegovy as “a better product” than its Saxenda, which requires daily injections for less weight loss.

In discussing Wegovy’s market entry with investors in June, a Novo Nordisk executive acknowledged there would be “a risk of some cannibalization” between its two drugs for chronic weight-loss management in the short term, but the company planned to focus on starting new patients on Wegovy rather than switching patients who were currently benefiting from Saxenda.

Is Wegovy a ‘Gamechanger’?

Varney says she always gets labs when a new patient comes in for obesity management, then she discusses “meals, movement, medication and mind” with them. But “you absolutely have to personalize care.…So I can look at those labs, family and medical history and say what diet might work best, like lower carbs,” for that individual and so on.

“Is Wegovy a gamechanger? No, it’s not,” she says. “Because it’s not accessible. If it were accessible to all, it would be.…It’s an amazing medication because it’s changing physiology — a hormone tells the brain, ‘I’m satisfied.’…So we’re fixing the physiology rather than putting a Band-Aid on things.”

“If insurance companies want to look like they’re doing the right thing, this [i.e., coverage of anti-obesity drugs] is one of the things they can do,” Varney adds. “They can create access for patients.” She says employers sponsoring health plans would see a huge return on investment in terms of a healthier, more productive workforce.

Tchang, an assistant professor of clinical medicine at Weill Cornell Medicine, describes semaglutide 2.4 mg as “an incredibly effective medication that is recognized as safe.” Wegovy has demonstrated two-year weight control efficacy, which is not unique, she says, but the percentage of individuals who respond to the medication by losing 5% of their body weight and maintaining the loss over two years has risen to as high as 80%, compared with 20% previously.

Moreover, obesity is always talked about as a “heterogeneous disease,” she says, and targeting treatments is full of uncertainties, “so it’s great to have medication with broad application.”

Anti-Obesity Drug Pipeline is Robust

Currently, there are more than 80 anti-obesity drugs in the pipeline, says Steinberg, “and each one is looking at this in a different way.”

Garvey and others note the search for promising anti-obesity medications has encountered complications along the way. Wyeth LLC withdrew its popular drug combination known as fen-phen (fenfluramine and phentermine) from the market in 1997 due to dangerous cardiovascular side effects that led to a 1999 class action settlement.

In 2010, says Garvey, the FDA recommended against the continued prescribing and use of Abbott Laboratories’ Meridia (sibutramine) because of potential cardiovascular risks to patients, and the manufacturer voluntarily withdraw the product from the U.S. market. And in 2020, the agency requested the withdrawal of Eisai Inc.’s anti-obesity drug Belviq/Belviq XR (lorcaserin) from the market, citing potential cancer risks that outweighed any benefits, he says, “so there’s that kind of baggage these drugs have to carry.”

As far as the drug pipeline, Garvey says Eli Lilly & Co.’s tirzepatide, an investigational dual gastric inhibitory polypeptide (GIP) and GLP-1 receptor agonist that has shown some promise in clinical trials over the past couple of years in lowering A1C and body weight in people with type 2 diabetes, “seems furthest along.” He adds that another principle moving forward is combining drugs to reach different pathways, which he expects to be used in anti-obesity drug development over time.

Of interest to Evercore ISI, an investment banking advisory firm that “tracks the obesity space from afar,” as one of its analysts puts it, is Altimmune, Inc.’s ALT-801, an investigational GLP-1/glucagon dual receptor agonist being studied in Australia for its weight loss potential. The company announced positive interim data in June, saying study participants achieved weight loss of 5.4% after six weeks of once-weekly treatment, surpassing the 2% treatment target.

Evercore describes itself as cautiously optimistic but notes the ALT-801 program is “still at an early stage with a lot of uncertainties.”

Tchang notes that one medication in clinical trials targets fat loss, not weight loss, and muscle buildup. “So, I think the future will be the treatment goal of not weight loss, but fixing metabolism…and [reducing] fat mass.”

Contact Varney at cwv9v@hscmail.mcc.virginia.edu, Garvey at garveyt@uab.edu, Steinberg at david@scriptainsights.com, Bachner at mzyb@novonordisk.com and Tchang at bgt9001@med.Cornell.edu.

By Judy Packer-Tursman

© 2024 MMIT
Freelance Reporter

Freelance Reporter Freelance Reporter

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