With 2024 more than halfway complete, the field of endocrinology still finds itself in a revolution in care on multiple fronts. Despite coming on the heels of a June that included the 84th Scientific Sessions of the American Diabetes Association, the month of July continued this trend of fast-paced, clinically relevant updates as healthcare providers welcomed news from both trials and regulatory developments in diabetes and beyond.

In our July 2024 endocrinology month in review, we highlight a pair of regulatory updates, multiple studies on GLP-1 receptor agonists and combination incretin therapies, and the most recent episodes of our flagship endocrinology podcast, Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives.

Endocrinology Pipeline Updates

FDA Accepts NDAs for Crinecerfont in Congenital Adrenal Hyperplasia

The FDA has accepted Neurocrine Biosciences' New Drug Applications for crinecerfont, with Priority Review for treating classic congenital adrenal hyperplasia (CAH) in children, adolescents, and adults. Announced on July 01, 2024, the NDAs cover both capsule and oral solution formulations, with Prescription Drug User Fee Act (PDUFA) target dates set for late December 2024.

Crinecerfont is a selective CRF1 receptor antagonist designed to reduce excess ACTH and adrenal androgens, offering a potential glucocorticoid-independent treatment for CAH due to 21-hydroxylase deficiency (21-OHD). The Phase 3 CAHtalyst studies demonstrated crinecerfont’s efficacy in lowering adrenal androgen levels and reducing glucocorticoid doses to physiologic levels, potentially minimizing the complications associated with long-term steroid use. If approved, crinecerfont would be the first new treatment for CAH in nearly 70 years, marking a significant advancement for this rare endocrine disorder.

FDA Issues Complete Response Letter for Once-Weekly Insulin Icodec

The FDA issued a Complete Response Letter (CRL) to Novo Nordisk for its once-weekly basal insulin icodec, intended for the treatment of diabetes mellitus. Announced on July 10, 2024, the CRL includes requests related to the manufacturing process and the type 1 diabetes indication, which must be addressed before the Biologics License Application (BLA) review can be completed. Novo Nordisk does not expect to fulfill these requests within this year but plans to work closely with the FDA to determine the necessary next steps. This development follows a May 2024 FDA advisory committee meeting that voted 7–4 against concluding that the benefits of insulin icodec outweigh its risks for T1D, though the committee did not evaluate its use for type 2 diabetes. Despite the setback, insulin icodec is approved under the brand name Awiqli in multiple regions, including the European Union, Canada, and Japan, for treating type 1 diabetes and type 2 diabetes.

News and Updates in Incretin Therapies

Tirzepatide Bests Semaglutide in Real-World Weight Loss Analysis

A real-world analysis of data from over 9000 matched pairs of patients has shown that tirzepatide (Mounjaro) induces greater weight loss compared to semaglutide (Ozempic).

The study, which included adults with overweight or obesity, utilized data from the Truveta platform, aggregating electronic health records from US healthcare systems. Results indicated that those receiving tirzepatide were significantly more likely to achieve 5%, 10%, and 15% or greater weight loss compared to those on semaglutide. Weight changes were greater with tirzepatide at 3, 6, and 12 months. The study found no significant difference in gastrointestinal adverse events between the two groups.

Investigators highlighted the study's limitations, including reliance on electronic health records and the potential underreporting of adverse events, but emphasized the value of these findings in understanding the real-world effects of these medications.

Surge in New GLP-1 Prescriptions Driven by Semaglutide's Popularity, Study Shows

Analysis of records from over 40 million US patients has revealed a significant surge in the use of GLP-1 receptor agonists, particularly semaglutide (Ozempic; Wegovy). Data from the TriNetX database, covering 2011 to 2023, shows that more than 800,000 patients initiated GLP-1 receptor agonist therapy during this period, with a pronounced increase starting in 2020 as the weight loss benefits of these medications became more widely recognized.

According to the study, semaglutide has seen a dramatic rise in popularity, accounting for over 88% of new GLP-1 receptor agonist prescriptions in 2023, up from just 31.4% in 2019. The study's findings highlight a broader trend of using these medications not only for type 2 diabetes but increasingly for obesity management, reflecting a significant public health shift. The analysis also noted a change in the demographic profile of new users, who were predominantly female, non-Hispanic White, and had a BMI of 30 kg/m² or greater. The increase in off-label use of these medications for weight management was also observed, with a rise from 0.21% in 2019 to 0.37% in 2023.

Study Finds Semaglutide Can Reduce Risk of Tobacco-Related Healthcare Use

An analysis of real-world data from over 220,000 individuals with type 2 diabetes suggests that semaglutide (Ozempic; Wegovy) may reduce tobacco use disorder-related medical encounters by 12% to 32% compared to other antidiabetic medications.

The study, which used data from the TriNetX database, found semaglutide associated with a significant reduction in these encounters, with the most notable decrease compared to insulins (HR, 0.68; 95% CI, 0.63 to 0.74) and the least compared to other GLP-1 receptor agonists (HR, 0.88; 95% CI, 0.81 to 0.96). Per investigators, these findings aligns with previous research showing semaglutide's potential in lowering risks of substance use disorders. However, investigators caution that the study's retrospective design and reliance on electronic health records pose limitations as well as emphasizing the need for randomized clinical trials before semaglutide can be recommended for off-label use in smoking cessation.

SGLT2 Inhibitor, GLP-1 RA Combination Improves Cardiovascular, Kidney Outcomes in Diabetes

A recent study supports the combined use of SGLT2 inhibitors and GLP-1 receptor agonists to optimize cardiovascular and kidney outcomes in patients with diabetes.

The collaborative meta-analysis, which included 12 randomized controlled trials from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C), found consistent benefits of SGLT2 inhibitors on cardiovascular and kidney outcomes, regardless of concurrent GLP-1 receptor agonist use. Across the 12 trials, 82.1% of 89,183 participants had diabetes, with only 4.2% using GLP-1 receptor agonists at baseline. The analysis revealed that SGLT2 inhibitors reduced major adverse cardiovascular events, hospitalization for heart failure or cardiovascular death, and chronic kidney disease progression with similar efficacy in patients both receiving and not receiving GLP-1 receptor agonists.

Related Video: Brendon Neuen, MBBS, PhD: Optimizing Cardiorenal Prognosis with GLP-1, SGLT2 Combination

Diabetes Dialogue in July 2024

ADA 2024 Diabetes Technology Recap

Released on July 03, 2024, this special edition episode focuses on top highlights and updates in diabetes technology from the 84th American Diabetes Association Scientific Sessions.

In the episode, hosts discuss the SECURE-T2D trial, a study comparing use of simplified meal announcement vs precise carbohydrate counting with the Medtronic MiniMed 780G, and real-world data from Tandem pump users. Later in the episode, hosts discuss their experience on the conference floor getting hands-on interactions with soon to come or recently released diabetes technology showcased at the meeting, including the Sequel Twiist, Abbott’s Libre 3 Plus, and ketone monitors.

CATALYST Trial and Hypercortisolism in T2D, with John Buse, MD, PhD

In this episode, John Buse, MD, PhD, joins hosts for a deep dive into the CATALYST trial and what it means for practitioners as well as patients with type 2 diabetes. Released on July 15, 2024, the trio of experts discuss the trial background, expected prevalence, reaction to results, and the importance of the second part of the trial as the community moves into the future with knowledge of the true prevalence of hypercortisolism in difficult-to-control type 2 diabetes.

Relevant disclosures for Buse include Altimmune, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, Moderna, Novo Nordisk, Tandem, Vertex, and others. Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others.