Addressing the Lingering Challenge of Hypoglycemia in T1D, With John Buse, MD, PhD

Despite advancements in diabetes technology in recent years, hypoglycemia is still among the most substantial dangers faced by patients with type 1 diabetes (T1D). However, ongoing research into investigational treatments, such as cadisegliatin, is actively working to combat this risk.1,2

While continuous glucose monitors (CGM) and automated insulin delivery (AID) systems are substantially simplifying the process of monitoring and managing this risk, hypoglycemia remains a major barrier to achieving full glucose control. In an exclusive interview with HCPLive, John Buse, MD, PhD, the Verne S. Caviness Distinguished Professor of Medicine and director of the Diabetes Care Center and North Carolina Translational and Clinical Sciences Institute at the University of North Carolina School of Medicine, discussed the lingering issues of CGM and AID technology and their impact on hypoglycemia.1

“Current state-of-the-art therapy are these AID systems, these pumps, and they integrate information from CGMs with an algorithm to help the patient manage their diabetes and select insulin doses,” Buse told HCPLive. “The problem is that when you inject insulin subcutaneously, it first enters what we call the peripheral circulation, whereas Mother Nature intended insulin to go to the liver.”

Buse went on to discuss major issues in insulin delivery, the first of which was the intrinsic difference between subcutaneous versus naturally produced insulin. Typically, AIDs infuse insulin through the skin, which introduces it to the full circulatory system. However, naturally produced insulin is administered directly to the liver. To get the same glucose-canceling effect as natural insulin, AIDs must provide enough to filter through the entire body while still impacting the liver.

Additionally, the sensors used in CGMs typically have an unavoidable lag of around 10-15 minutes. Insulin introduced via injection takes roughly that long to permeate the endothelium and occupy the interstitial space in which the CGM needle is implanted. Buse explains that this can create a gap in timing of 20-30 minutes, meaning that the AID systems cannot respond quickly to overcorrection or rapid changes in activity level. Ultimately, clinicians have no way to prevent this insulin from causing hypoglycemia in the event of a rapid correction in glucose.

To address these issues, parent company vTv Therapeutics has developed cadisegliatin, a novel oral small molecule glucokinase activator, as a potential first-class adjunctive treatment for T1D. Previous trials have displayed cadisegliatin’s effect on the liver, increasing the activity of glucokinase independently of insulin.2

Currently, clinicians have officially completed enrollment in the phase 3 CATT1 trial, which aims to investigate cadisegliatin’s efficacy in adults with T1D currently taking multiple daily insulin injections or continuous subcutaneous insulin infusions, along with CGM. Patients will be randomly assigned to either cadisegliatin 800 mg once daily, twice daily, or placebo. The primary endpoint will measure the incidence of level 2 and 3 hypoglycemic events, while secondary endpoints will include changes in HbA1c, time in target glucose range, and the incidence of diabetic ketoacidosis between groups.2

“There are other mechanisms that are trying to accomplish similar things, but using fundamentally different biology. As an example, cadisegliatin is in development to activate glucokinase, the rate-limiting step in glucose metabolism in the liver,” Buse said. “This should provide for greater shortage of glucose in the liver and for better glucose uptake, particularly in the post-prandial state, which may provide a different way of reducing hypoglycemia.”

In a press statement, vTv Therapeutics stated that topline results from CATT1 are expected in mid 2027.2

Editors’ Note: Buse reports relevant disclosures with Corcept, Dexcom, GentiBio, Novo Nordisk, Amgen, AstraZeneca, Boehringer-Ingelheim, Corcept Therapeutics, and others.

References

1. van Beers CA, DeVries JH. Continuous Glucose Monitoring: Impact on Hypoglycemia. J Diabetes Sci Technol. 2016;10(6):1251-1258. Published 2016 Nov 1. doi:10.1177/1932296816653411

2. vTv Therapeutics. vTv Therapeutics Announces Completion of Enrollment in Phase 3 CATT1 Study of Cadisegliatin in Type 1 Diabetes (T1D). October 5, 2026. Accessed October 6, 2026. https://ir.vtvtherapeutics.com/news-releases/news-release-details/vtv-therapeutics-announces-completion-enrollment-phase-3-catt1