A new HDV-LIS T1D trial readout from OPTI-2 shows a liver-targeted fast-acting insulin cut hypoglycemia risk in type 1 diabetes (T1D). The phase 2b data lined up against standard lispro in 226 patients.

Klara Rachel Klein, MD, PhD, presented at the American Diabetes Association (ADA) 2026 Scientific Sessions in New Orleans. Klein directs the Endocrinology, Diabetes, and Obesity Clinical Research unit at University of North Carolina School of Medicine, Chapel Hill.

Why liver-directed insulin matters

Insulin is the only T1D therapy, but puts patients at risk of dangerous lows. Hepatic-directed vesicle (HDV) insulin from Diasome Pharmaceuticals uses a phospholipid matrix that binds to short-acting insulin and steers it to the liver. The goal: mimic insulin delivery in people without diabetes.

Klein called liver-selective dosing exciting because of glycogen storage: "by insulinizing the liver, you can take up glucose and store that glucose as glycogen, which can then be released during periods of hypoglycemia," she told Medscape Medical News.

She added: "Every day, people are walking a tightrope."

How OPTI-2 was set up

OPTI-2 is a randomized, double-blind, 27-site phase 2b study. It tested HDV combined with lispro (HDV-LIS) vs standard insulin lispro:

• HDV-LIS arm (n = 112): median baseline A1c 7.4%, mean age 46.5 years.
• Lispro arm (n = 114): median baseline A1c 7.3%, mean age 43.9 years.

All patients used multiple daily insulin therapy with once-daily insulin degludec as basal insulin. All wore a Dexcom G7 continuous glucose monitor (CGM) for the HDV-LIS T1D trial.

OPTI-2 ran a 12-week dose-optimization phase, then 13 weeks of maintenance. The prespecified primary endpoint was a composite: A1c noninferiority at week 12 plus superiority on hypoglycemia metrics in the last 6 weeks of dose optimization.

A1c noninferiority cleared

A1c reductions ran similar between arms in the HDV-LIS T1D trial:

• Week 12: 0.34 percentage points (HDV-LIS) vs 0.42 (lispro). Estimated difference 0.08, P = .26.
• Week 25: 0.31 vs 0.38 percentage points. Estimated difference 0.07, P = .40.

At both checkpoints, the A1c gap stayed under the FDA's < 0.1 percentage-point limit needed to claim noninferiority.

Hypoglycemia drops in maintenance

For hypoglycemia, 14 of 15 prespecified CGM metrics favored HDV-LIS. They met noninferiority during the 12-week titration period. But they narrowly missed superiority. During maintenance, HDV-LIS hit superiority on several secondary endpoints:

• 28% drop in 24-hour level 2 hypoglycemia (< 54 mg/dL) events (rate ratio 0.72, P = .014).
• 33% drop in daytime level 2 hypoglycemia events (0.67, P = .009).
• 28% drop in 24-hour percent time below 54 mg/dL (0.72, P = .017).
• 32% drop in daytime percent time below 54 mg/dL (0.68, P = .010).
• 36% drop in 24-hour extended hypoglycemia events (0.64, P = .029).

Level 2 hypoglycemia ran 25% lower with HDV-LIS than with lispro across the study. Serious hypoglycemia events (level 3, needing assistance) were absent in the HDV-LIS arm. Five hit the lispro arm (P = .0598).

Safety mirrored standard care

Treatment-emergent adverse events (TEAEs) tracked closely between arms. The HDV-LIS T1D trial found:

• TEAEs: 53.6% HDV-LIS vs 50.0% lispro.
• Serious treatment-related AEs: 1 (0.9%) vs 8 (7.0%).
• AE-related drug discontinuation: 0 vs 2 (1.8%).

No deaths showed up. No diabetic ketoacidosis. No clinically meaningful hepatic safety signals.

What comes next

Klein said a phase 3 HDV-LIS T1D trial is planned. She framed OPTI-2 as a possible shift in insulin safety:

"OPTI-2 suggests that HDV-LIS can decouple glycemic control from hypoglycemia risk," she said.

Session moderator Daniel J. Rubin, MD, called the data promising. Rubin is professor of medicine at the Lewis Katz School of Medicine at Temple University, Philadelphia. He directs clinical research in the section of endocrinology, diabetes, and metabolism at Temple. He told Medscape Medical News: "I think it's a really interesting mechanism and the data are promising. It's a phase 2 trial and certainly justifies a larger phase 3 trial."

Rubin noted liver toxicity is a concern with liver-targeted drugs. He said no safety signals appeared here.

Diasome funded the study. Coverage on Medigear.uk tracks how the HDV-LIS T1D trial reshapes care.

Source: Originating coverage based on Medscape Medical News reporting on the OPTI-2 trial presented by Klara Rachel Klein, MD, PhD, of the University of North Carolina School of Medicine, Chapel Hill, at the American Diabetes Association (ADA) 2026 Scientific Sessions in New Orleans. Outside commentary from Daniel J. Rubin, MD, Lewis Katz School of Medicine at Temple University, Philadelphia. Funded by Diasome Pharmaceuticals.