Show On June 4, 2021, the FDA announced the long-anticipated approval of Wegovy, an injectable medication taken once per week for weight management. Wegovy received significant media attention in the months preceding approval, with a New York Times article declaring it a "game changer," MedPage Today reporting its "unprecedented results," and the BBC announcing it could mark a "new era" in treating obesity. Ongoing media coverage continues to extol the efficacy of Wegovy as better than any other medication currently on the market for weight management. Such sensational headlines are commonplace in the media, so we must ask ourselves: is all the media attention truly warranted? What is Wegovy and how does it work?Wegovy is the brand name for the high-dose injectable peptide hormone molecule known as semaglutide, a medication that was previously approved by the FDA under the brand names Rybelsus (oral) and Ozempic (lower-dose injection) for the treatment of type 2 diabetes. Injectable semaglutide eliminates the strict guidelines for ingesting on an empty stomach required by oral semaglutide, while the higher-dose Wegovy allows for better crossing of the blood-brain barrier, which increases its weight-loss efficacy. Semaglutide is in a class of medications known as glucagon-like peptide-1 receptor agonists, or GLP-1 RAs. GLP-1 is a hormone naturally released in the gastrointestinal tract in response to nutrient intake. It has multiple effects, including increasing insulin release from the pancreas, slowing down stomach emptying, and targeting receptors in the brain that cause appetite reduction. This results in a sensation of satiety, or fullness, lasting much longer than possible with natural GLP-1 hormone levels. Who can take Wegovy?Wegovy, like all other prescription medications designated for the treatment of obesity, is approved for use in those with a body mass index (BMI) of 30 kg/m2 or greater, or those with a BMI of 27 kg/m2 with a weight-related medical condition such as high blood pressure, type 2 diabetes, or high cholesterol. What are the risks and benefits of Wegovy?Phase 3 clinical trials of Wegovy, dubbed the STEP (Semaglutide Treatment Effect in People with Obesity) trials, were conducted in a variety of clinical scenarios, each varying slightly in the study population and study design. The widely reported STEP 1 trial, the results of which were published in the New England Journal of Medicine, demonstrated an average of 14.9% body weight reduction after 68 weeks of therapy in those assigned to the medication group, versus only 2.4% weight loss in those assigned to the placebo group. The average weight loss seen with existing anti-obesity medications is typically about 5% to 9%, while those engaged in lifestyle and behavioral therapy alone are expected to lose only 3% to 5% of their body weight. The most common side effects of Wegovy are nausea, diarrhea, vomiting, and constipation. The medication also comes with a warning for risk of a specific tumor of the thyroid, and thus it is not recommended for those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (a genetic condition associated with endocrine tumors). It should be noted that tumors were only observed in animal studies, and not seen in the human trials. How long can you take Wegovy?Wegovy is one of six medications currently approved by the FDA for the long-term treatment of obesity. As such, it can be used for as long as it remains beneficial for weight loss and/or weight maintenance and is not causing intolerable side effects. The first GLP-1 RA medication to gain FDA approval was exenatide in 2005; since then, multiple GLP-1 RAs have been approved and undergone long-term trials demonstrating either non-inferiority or superiority, when compared to placebo for major adverse cardiovascular events such as heart attacks and stroke. The SELECT trial is the long-term cardiovascular outcomes trial for Wegovy that aims to assess its effects on heart disease and stroke in patients with overweight and obesity; it is currently ongoing and expected to be completed in September 2023. Anti-obesity medication management: An evolving landscapeWegovy is the latest in a line of medications, starting with phentermine in 1959, that have achieved FDA approval for the treatment of obesity. Currently there are 10 FDA-approved anti-obesity medications in the US: phentermine, diethylpropion, benzphetamine, phendimetrazine, orlistat, phentermine/topiramate ER (Qsymia), bupropion/naltrexone (Contrave), liraglutide (Saxenda), setmelanotide (Imcivree), and now semaglutide (Wegovy). Of note, setmelanotide is only approved for the treatment of obesity caused by specific, rare genetic conditions. Other medications such as metformin, zonisamide, and other GLP-1 RAs normally used for treating diabetes are often prescribed "off label" and at the discretion of the prescriber for the treatment of obesity. Medication treatment of obesity has been a tumultuous arena plagued by many instances of therapeutics being unable to demonstrate sufficient safety data to warrant FDA approval, such as rimonabant (Acomplia); or of adverse effects necessitating market withdrawal, such as lorcaserin (Belviq), sibutramine (Meridia), dexfenfluramine (Redux), fenfluramine (Pondimin), and the infamous combination medication fen-phen — a drug which, despite its extreme popularity in the 1990s, was never actually granted FDA approval. Unfortunately, the rocky anti-obesity medication landscape often leads to discomfort among clinicians in using the many safe and effective tools we currently have for treating obesity, or worse, hesitance to address obesity as a health concern at all. Paying for anti-obesity medicationsFor those who do prescribe anti-obesity pharmacotherapy, challenges arise with the exorbitant cost of some of the newer therapeutics, as well as refusal of many private and public insurers to cover anti-obesity medications. Sometimes patients or their advocates may have success in lobbying their employers to opt in to insurance coverage for obesity management. However, for those on Medicare or Medicaid, there is currently absolutely no coverage for anti-obesity medications. Patients without coverage are left with the choice of paying out of pocket for a lower-cost generic anti-obesity medication; taking a medication primarily intended for treating other medical conditions such as diabetes or seizures that may also help with weight loss; or, if their BMI and health status is severe enough to satisfy insurance requirements, they may opt for bariatric surgery, a much more widely covered insurance benefit. The Treat and Reduce Obesity Act is a bill that was first introduced to Congress in 2012 and most recently reintroduced in 2021, with the goal of amending the Medicare Social Security Act to authorize insurance coverage of obesity counseling services and FDA-approved anti-obesity medications. This remains the largest hurdle in the obesity treatment landscape: gaining sufficient buy-in from government agencies, employers, and insurers by convincing them that medications targeting the most prevalent chronic disease in the US are actually worth paying for. Subcutaneous injection of a weight loss drug. gettyEli Lilly’s weight loss drug, tirzepatide, showed substantial potential in a large Phase 3 study, the results of which were reported on Thursday, April 28th. The drug - branded as Mounjaro - was approved by the Food and Drug Administration (FDA) on May 13th for blood glucose management in Type 2 diabetics. Obesity may be the next indication. Tirzepatide combines a GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist in a single novel molecule. The drug is administered once-weekly by sub-cutaneous injection. The investigational compound is the first such medicine to deliver more than 20% weight loss on average, compared to placebo, in a Phase 3 study. The average weight reductions rose as the dosage amount of the active ingredient increased. The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies that have been approved for the treatment of obesity. This said, reported side effects were considerable, especially as dosage levels increased. The most common adverse events were nausea (~30%), diarrhea (~20%), constipation (~15%) and vomiting (~10%). If tirzepatide gets approved as a both a blood glucose control and anti-obesity agent, it could become a blockbuster drug. However, this isn’t a sure thing. It will have to overcome pricing and reimbursement obstacles, which have plagued similar treatments. Also, the drug would be in direct competition with Novo Nordisk’s Wegovy (semaglutide). In June of last year, the FDA approved Novo Nordisk’s obesity drug Wegovy, a GLP-1 receptor agonist, which is also administered once-weekly through subcutaneous injection. Wegovy is a higher-dose version of the diabetes drug Ozempic. At the time, Wegovy became the most effective weight loss drug on the market, as it helps patients lose an average of about 15% of their body weight, almost double the rates demonstrated by previous prescription products. Wegovy represented a turning point in the pharmacologic treatment of obesity. In the past, obesity drugs suffered from a negative adverse event profile and relatively poor efficacy. Accordingly, weight loss drugs historically had trouble gaining traction. Not only did they not find many takers, they also tended to have extreme difficulty obtaining insurance coverage. For example, Medicare excludes coverage of all drugs prescribed for obesity. And, unlike the vast majority of other outpatient pharmaceuticals, weight loss drugs are not a mandatory benefit in the Medicaid program. Additionally, when covered by Medicaid plans, obesity drugs are often subject to heavy usage of prior authorization coupled with step edits. Finally, commercial payer coverage of weight loss drugs has been extraordinarily variable. With Wegovy, insurers have apparently changed their tune, at least to some degree. Except for Medicare, which still prohibits obesity drug coverage, a large number of commercial and Medicaid payers are covering Wegovy, albeit with a lot of variability. A comparatively favorable effectiveness profile has probably helped the product’s fortunes with some payers. In 2021, Novo Nordisk achieved approximately $1.2 billion from sales of Wegovy and its older weight loss treatment Saxenda (liraglutide). The company hasn’t provided a precise breakdown of the revenue figures. But, it stands to reason that at present Wegovy is outselling Saxenda. Indeed, according to Novo Nordisk, the number of doctors prescribing Wegovy recently eclipsed Saxenda. Demand for Wegovy has in fact been outstripping supply, which reinforces the notion that reimbursement has been less of an issue than with previous obesity drugs. Perhaps a bigger hurdle for Wegovy has been quality of manufacturing issues, as this has hampered supply. Once this is resolved Novo Nordisk hopes to be on its way to hitting its 2025 sales target for all of its obesity treatments of $3.7 billion, most of which would be represented by Wegovy. Tirzepatide is poised to compete directly with Wegovy. Its effectiveness appears to be even better than Wegovy. The relevant question for payers then becomes tirzepatide’s net price (after rebates). Obviously, at this stage we don’t know what tirzepatide would sell for if approved. Supposing tirzepatide were to have an equal net price this would give it greater cost-effectiveness than Wegovy. On the other hand, in the eyes of payers a higher net price would have to be justified by proportionately greater benefit. How much of a price premium payers would be willing to spend is anyone’s guess. Further complicating matters for all obesity drugs, regardless of effectiveness, is the fact that payers can be shortsighted with respect to their assessment of costs and effectiveness. In some ways, this reflects churn. Every year, approximately 25% of the U.S. population switches health plans. This implies that many payers don’t necessarily adopt a long-term view on the cost-effectiveness of drugs. Ideally, all payers would take a longer term perspective. With so much churn, that’s not likely. Furthermore, some payers continue to lump obesity drugs together with lifestyle medications. It’s hard to dislodge this myopic view. The benefits of weight loss go beyond a reduction in fat. Correspondingly, weight loss can lead to lower prevalence of diabetes, fewer heart attacks and strokes, and less joint pain. Combined with diet and exercise, the new generation of obesity drugs can certainly contribute to weight loss. The question remains, will payers across the board - and especially in the public sector; Medicare and Medicaid - pay enough attention to consistently provide them with favorable coverage? |