FDA Approves Significant New Treatment for Chronic Weight Management

The FDA has approved tirzepatide (Zepbound; Eli Lilly and Company) injection as the first and only approved medication for obesity that activates both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) hormone receptors.¹

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The drug will have a list price of $1,059.87, which is approximately 20% less than the 2.4 mg semaglutide injection indicated for weight loss. Lilly announced a commercial savings card program to help increase access for patients who may benefit.

Individuals with commercial insurance with coverage for Zepbound may be eligible to pay $25 for a one-month or three-month prescription. Individuals with commercial insurance without coverage for Zepbound may be eligible to pay as low as $550 for a one-month prescription.

"Obesity is a chronic disease that can result in serious health complications, including heart disease, stroke and diabetes. Despite our knowledge of obesity as a treatable, chronic disease, people living with obesity still face many challenges in their health and weight management journey," said Joe Nadglowski, president and chief executive officer of the Obesity Action Coalition, in a press release.¹ "New treatment options bring hope to the many people with obesity who struggle with this disease and are seeking better options for weight management."

Preclinical and clinical trials have shown that dual GIP/GLP-1 agonist therapy produces superior glucose control and weight loss compared to selective GLP-1 receptor agonists.²

Zepbound is approved for adults with obesity with a BMI of 30 kg/m² or greater, or overweight individuals with a BMI of 27 kg/m² or greater who also have weight-related medical problems, including hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease.

GLP-1 and GIP are classified as incretins, which are expressed throughout the body, in areas such as pancreatic beta cells and the gastrointestinal tract. GLP-1 and GIP have been found to increase insulin from beta cells and glucose uptake by muscles while lowering blood glucose. GLP-1 stimulates glucose-dependent reduction of glucagon from alpha cells, lowering glucose production from the liver, and reducing blood glucose.

Zepbound’s mechanisms of action include stimulation of first- and second-phase insulin secretion and decreased glucagon levels in a glucose-dependent manner. Zepbound has been shown to inhibit gastric emptying, reduce fasting and postprandial glucose concentration, reduce food intake, and lower body weight in patients with type 2 diabetes, as well as increasing insulin sensitivity.

Clinical trials have shown that coadministration of a GIP and GLP-1R agonist significantly elevates insulin response while suppressing glucagon secretion vs. separate administration of either hormone alone.²

Zepbound should be used along with a reduced-calorie diet and increased physical activity and should not be used with other tirzepatide-containing products or GLP-1 receptor agonist drugs. The medication has not been evaluated in patients with a history of pancreatitis or with severe gastrointestinal disease.

The FDA based the regulatory action on findings from the Phase 3 SURMOUNT-1 and SURMOUNT-2 trials. SURMOUNT-1 enrolled in 2,539 adults with obesity at an average starting weight of 231 lbs. At 72 weeks, Zepbound used as an adjunct to diet and exercise produced substantial weight loss compared with placebo. At a dose of 15 mg, those taking Zepbound lost an average of 48 lbs., whereas the 5 mg dose led to an average 34 lbs. weight loss compared to 7 lbs. with placebo. Further, one in three patients administered the 15 mg dose of Zepbound lost more than 58 lbs., which accounts to 25% of total body weight vs. 1.5% on placebo.

Gastrointestinal adverse events (AEs) associated with Zepbound were sometimes severe. The most commonly reported AEs were nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection-site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, and gastroesophageal reflux disease.

Zepbound is expected to be available in the United States by the end of 2023 across six dosage strengths: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg.

"Unfortunately, despite scientific evidence to the contrary, obesity is often seen as a lifestyle choice—something that people should manage themselves," said Leonard Glass, MD, senior vice president global medical affairs, Lilly Diabetes and Obesity.¹ "For decades, diet and exercise have been a go-to, but it's not uncommon for a person to have tried 20-30 times to lose weight with this approach. Research now shows that the body may respond to a calorie-deficit diet by increasing hunger and reducing feelings of fullness, making weight loss more difficult. Lilly is aiming to eliminate misperceptions about this disease and transform how it can be managed."

References

1. FDA Approves Lilly's Zepbound™ (tirzepatide) for Chronic Weight Management, a Powerful New Option for the Treatment of Obesity or Overweight with Weight-Related Medical Problems. Eli Lilly and Company. News release. November 8, 2023. https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-zepboundtm-tirzepatide-chronic-weight

2. Rosenstock, J, et. al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6. Accessed November 8, 2023.