RECAP: 2024 Updates in the GLP-1 Space

In the new survey, approximately 82% of adults said they have heard at least a little about GLP-1 medications and 32% said they have heard a lot, increasing from about 7 in 10 adults who had heard a little about the medication and 1 in 5 who had heard a lot in July 2023. When the investigators specifically analyzed those who have been told by a physician they have diabetes, heart disease, or overweight or obesity, approximately 45%, 41%, and 42%, respectively, said they have heard a lot about these drugs.

Furthermore, investigators found that Black adults are somewhat more likely to report taking GLP-1 medication (18%) compared with White individuals (10%) and Hispanic individuals (13%). For adults who have been taking a GLP-1 medication, approximately 62% took it to treat a chronic condition, such as diabetes and heart disease. Approximately 39% took it solely to treat a chronic condition and 24% took it to treat both a chronic condition and for weight loss. About 1 in 4 adults in the study have been taking a GLP-1 solely to lose weight, according to the investigators.

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Treatment with tirzepatide, with and without a continuous positive airway pressure (CPAP) machine, had improvements in apnea-hypopnea index (AHI) from baseline to week 52 for individuals with obstructive sleep apnea (OSA) and obesity, according to results of the SURMOUNT-OSA (NCT05412004) trial. In Study 1, the change in AHI at week 52 was approximately –25.3 events per hours with tirzepatide and –5.3 events per hour with the placebo. For trial 2, the primary endpoint was –29.3 events and –5.5 events, respectively. When looking at the efficacy estimand, the changes were ­–27.4 events and –4.8 events, respectively, and ­–30.4 events and ­­–6.0 events, respectively.

Furthermore, for severity, at baseline in Study 1, approximately 99% who had severe or moderate OSA decreased to 42% at 52 weeks and 20% had scores that no longer qualified for OSA. In Study 2, 99% of individuals with severe or moderate OSA decreased to 40% and 31% no longer qualifying for OSA.

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The primary outcome of composite kidney outcomes included approximately 18.7% with semaglutide reaching this outcome compared with 23.2% with the placebo, meeting prespecified criteria. There was a 24% lower risk of the outcome. Furthermore, investigators found a consistent risk reduction for kidney disease components that included the primary outcome.

For CV outcomes, 14.4% of the patients in the placebo group suffer CV death, nonfatal MI, or non-fatal stroke compared with the semaglutide group at 0.0% of participants who suffered the CV composite outcome, representing an absolute risk reduction of 2.4% for the 3.4 years of follow up, correlating to a 18% relative risk reduction, cardiovascular death, nonfatal MI or non-fatal stroke with semaglutide. Further, there was a 29% reduction in CV death. Approximately 15.8% of patients had a death from any cause compared with 12.8% in the placebo, resulting in a relative risk reduction of 20% with semaglutide. There were only 45 hospitalizations for acute or chronic limb ischemia events.

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Both primary end points and all key secondary end points were met, including improvement in exercise capacity, reduction in the inflammation marker hsCRP, and mean body weight reduction from baseline to 52 weeks. The findings demonstrated that tirzepatide led to an approximate 15.7% body weight reduction compared with placebo, which was about 2.2%. The overall safety profile for tirzepatide was also consistent with previous studies, with the most common adverse events in SUMMIT being gastrointestinal (mild to moderate in severity), and consisted of diarrhea, nausea, constipation, and vomiting. The investigators note that SUMMIT results will continue to be evaluated.

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In November, updated results were announced. In findings from the phase 3 SURMOUNT-1 trial (NCT04184622), the percentage of patients who lost more than 20% of their body weight was over 50% in the tirzepatide 10-mg and 15-mg groups, compared with just 3% in the placebo group. Because obesity is a major risk factor for the development of type 2 diabetes and cardiovascular diseases, reduced body weight is significant.

Investigators found that cardiovascular death or worsening heart failure events occurred in 36 patients (9.9%) of the tirzepatide group, compared with 56 patients (15.3%) in the placebo group. Worsening heart failure events occurred in 29 patients (8%) of the tirzepatide group versus 52 patients (14.2%) in the placebo group, representing a 46% reduction in risk for individuals taking tirzepatide.

In subgroup analyses, tirzepatide reduced worsening heart failure events in every single group. Importantly, data were also promising for patients who were simultaneously taking other medications such as mineralocorticoid receptor agonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) medications.

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The Outsourcing Facilities Association (OFA) filed a lawsuit against the FDA for the sudden removal of tirzepatide (Zepbound, Mounjaro; Eli Lilly) from the federal drug shortage list. The lawsuit alleges that the action was taken without the required notice and disputes the agency’s warning of “localized supply disruption,” according to a news release from OFA.

The lawsuit alleges that the decision is “reckless and arbitrary” and “lacking any semblance of lawful process.” According to the FDA, compounding facilities may prepare compounded versions of a drug listed on the FDA’s drug shortage list, provided the compound drugs meet the conditions of the federal law. As of October 9, there are currently 117 drugs on the drug shortage list, including amoxicillin powder for suspension, clonazepam, and semaglutide injection (Wegovy, Ozempic; Novo Nordisk). As of October 2, tirzepatide has been marked as resolved.

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On October 17, the FDA stated that it will reevaluate the decision to remove tirzepatide (Zepbound, Mounjaro; Eli Lilly) from the drug shortages list, following a lawsuit brought by the Outsourcing Facilities Association (OFA). During the reevaluation period and until 2 peeks after the agency makes a final decision, the FDA does not intend to take action against the plaintiffs in the case for the violation of the Federal Food, Drug, and Cosmetic Act, which includes the compounding of tirzepatide as a drug that is “essentially a copy of a commercially available drug product,” ”bulk drug substances used in compounding,” and “compounded drugs that are essentially a copy of an FDA‐approved drug product.”

The FDA states that the “FDA intends to treat compounders consistently at this time, meaning that FDA does not intend to take action against compounders for violations arising from the conditions above, for the same duration of time and subject to all the same limitations as described in FDA’s motion and the court’s order.”

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Following the FDA removal of tirzepatide (Mounjaro; Zepbound; Eli Lilly) from the drug shortage list, Novo Nordisk called upon the FDA for the exclusion of compounding pharmacies to provide semaglutide (Ozempic; Wegovy) products, citing difficulties in recreating the molecule in compounding facilities.

The company states, “semaglutide products belong on these lists due to the complexities associated with their formulations, delivery mechanisms, dosage forms, achievement of bioavailability, compounding processes, and physicochemical and analytical testing. We request that FDA convene and consult an advisory committee on compounding to discuss the addition of semaglutide products to both DDC Lists and promulgate regulations adding semaglutide products to the DDC Lists.”

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The FDA has added a new label change for semaglutide (Ozempic; Novo Nordisk) that includes a new section referring to delayed gastric emptying. The label includes postmarking reports showing rare instances of pulmonary aspiration for patients receiving glucagon-like peptide-1 (GLP-1) receptor agonists and undergoing elective surgeries or procedures that require general anesthesia or deep sedation and had “residual gastric contents despite reported adherence to preoperative fasting recommendations.”

According to the label, there are insufficient data to inform the recommendations to mitigate the risk of pulmonary aspiration during anesthesia. This includes recommendations for preoperative fasting and temporarily discontinuing the drug.

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A proposal from the Department of Health and Human Services would cover weight-loss drugs such as semaglutide (Wegovy, Ozempic; Novo Nordisk) under Medicare and Medicaid, expanding access to the therapy for millions of Americans. The potential ruling, proposed under the Biden administration, faces some challenges; however, increased access to the therapy can aid in weight loss to decrease risk of adverse health events and contribute to efforts to reduce obesity in the United States.

Historically, Medicare and Medicaid do not cover semaglutide, preventing many patients from accessing this efficacious therapy. According to the Centers for Medicare and Medicaid, roughly 28 million individuals on Medicaid are considered obese. The proposed rule would extend coverage to around 4 million individuals prescribed semaglutide to reduce excess body weight and maintain long-term weight reduction. Without coverage, these drugs can cost up to $1300 a month for weekly injections.

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The FDA issued a declaratory order affirming that the shortage of tirzepatide (Munjaro, Zepbound; Eli Lilly and Company) injection products is resolved. As a result, compounders will have a limited grace period during which the FDA will not take legal action against them for producing the drug. This transitional period allows 60 days for state-licensed pharmacists and physicians and 90 days for outsourcing facilities to wrap up production and distribution.

To ensure a smooth transition, the FDA extended enforcement discretion for compounders temporarily. State-licensed pharmacists and physicians may continue compounding tirzepatide under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for 60 days, until February 18, 2025. Outsourcing facilities operating under section 503B have a 90-day window, ending March 19, 2025.

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