The use of combination immune-modulating therapies with different mechanisms of action likely represents the next major step in managing early-stage and newly diagnosed type 1 diabetes (T1D), experts say.
Current research efforts in T1D aim to move beyond insulin replacement toward disease-modifying approaches that address the underlying autoimmunity. So far, just one agent, the humanized anti-CD3 monoclonal antibody teplizumab (Tzield, Sanofi), has been approved in the United States for individuals aged 1 year or older with stage 2 T1D (two or more islet autoantibodies and dysglycemia) and for children aged 8-17 years with recently diagnosed stage 3 T1D (clinically symptomatic disease).
However, additional agents with different mechanisms of action are likely to be needed in combination for long-term metabolic control, experts say. This approach was illustrated in two case reports presented at the recent Breakthrough T1D Clinical & Research Congress and is being studied in several ongoing clinical trials.
"Teplizumab doesn't get the job done, frankly. It's a nice and important move forward, but it's not capable of getting people off insulin, or even stopping beta cell decline entirely. It slows the rate of decline, which is a win. But it's winning a battle, not winning the war. Obviously, our ultimate goal is to get people off insulin and cure their disease, but we have many steps between where we are now and achieving that goal," Michael J. Haller, MD, professor and chief of pediatric endocrinology at the University of Florida, Gainesville, told Medscape Medical News.
Specifically, Haller said, for individuals who still have some residual beta-cell function, one approach may be to use induction therapy with a potent immunomodulator such as teplizumab or the investigational human anti-thymocyte globulin SAB-142. This could be followed by maintenance therapy with either a metabolic treatment that helps beta cells function better, such as a GLP-1-based drug, or another immune-modulating therapy that's "easier to take, gentler on the rest of the system, and that people can take multiple times or indefinitely."
2 Cases of Combination Approaches
Haller, who is also chair of the TrialNet T1D research network, presented one of the two cases in which this approach was used. The patient was a previously healthy 6-year-old boy who presented in December 2022 with severe diabetic ketoacidosis. He had an A1c of 16.8%, undetectable fasting C-peptide, and positive results for two T1D autoantibodies. Three weeks after he was stabilized on insulin, his C-peptide level in response to a mixed-meal tolerance test was 1.56 ng/mL.
He subsequently received two courses of teplizumab infusion, followed by maintenance therapy with baricitinib (Olumiant, Lilly), a JAK inhibitor already approved for rheumatoid arthritis and alopecia areata and previously shown to preserve beta-cell function.
Subsequent C-peptide levels were 1.48 ng/mL in December 2025 and 1.82 ng/mL in July 2026. His A1c levels at those times were 5.2% and 5.3%, respectively. Nearly 4 years after diagnosis, he experienced no further episodes of diabetic ketoacidosis or severe hypoglycemia and was receiving a very low dose of insulin, with sustained endogenous insulin secretion.
"It's extremely unusual in a kid who presented like he did at his age, to now at almost 11 years old have such a robust C peptide with low insulin requirement and A1c in the low 5s. I will argue that's because of this combination therapy approach," Haller said.
This boy's case was also unusual because both of his parents are physicians who understood the benefit-risk calculation and paid out of pocket for the treatment, Haller noted.
Also at the Breakthrough T1D meeting, Abdulmohsen Bakhsh, MBBS, a consultant endocrinologist at King Faisal Specialist Hospital and Research Centre and an adjunct assistant professor at Alfaisal University, Riyadh, Saudi Arabia, presented the case of a 23-year-old woman with stage 2 T1D (dysglycemia and positive pancreatic autoantibodies) and insulin resistance, with an A1c of 8.4%.
She was treated with the dual GLP-1/GIP agonist tirzepatide and verapamil — a calcium channel blocker previously shown to slow beta-cell destruction — and vitamin D.
Over 18 months, her A1c dropped to 5.3%-5.7%, with 100% time in range on continuous glucose monitoring with little glycemic variability. She lost approximately 8 kg and maintained insulin secretion. Her antibody titers declined, and by 18 months she met the criteria for stage 1 T1D (normoglycemia with preserved C-peptide).
"Most of us say that until we have a therapy that truly induces immune tolerance, which would be actually fixing the immune system entirely and permanently, we're going to need this sort of induction and maintenance therapy model. That's how almost all other autoimmune diseases are treated," said Haller. "That's the model we think will make sense for T1D, and that's what I was hoping to show proof of concept with here."
Studies Examine Combination Approaches
Asked to comment, Breakthrough T1D chief scientific officer Sanjoy Dutta, PhD, pointed out that the two cases are observational and uncontrolled, with only one patient receiving each treatment combination.
"There are caveats here, but this is how science begins," he said.
Dutta also said that combination therapy is part of Breakthrough T1D's recently updated disease-modifying therapy research funding strategy, which maps out a pathway from disease delay to prevention or remission.
"But even in the older version of it our ultimate goal is combination therapies. It could be an immune-immune combination, or an immune plus a beta cell regenerative medicine, which we don't have at the moment for clinical testing. It's definitely a paradigm shift," he noted.
Several ongoing clinical trials are examining combination approaches in T1D. These include:
- The Breakthrough T1D-funded, randomized phase 1/2 WAVE T1D trial, evaluating low-dose anti-thymocyte globulin followed by adalimumab (Humira, AbbVie) or verapamil in new-onset T1D
- Another Breakthrough T1D-funded, randomized, open-label international trial evaluating verapamil alone or in combination with either anti-thymocyte globulin or golimumab (Simponi, Johnson & Johnson) in people with newly diagnosed T1D
- A TrialNet-funded study of rituximab-pvvr (Ruxience, Genentech) alone or followed by abatacept (Orencia, Bristol Myers Squibb)
Which combinations will work best for which individuals, in what sequence, and for how long remains to be determined. Breakthrough T1D is supporting academic research in these areas, with the hope that pharmaceutical companies will then take up the clinical trials, Dutta explained.
When Is the Right Time to Intervene?
Ideally, Dutta said, broader screening would identify more people with stage 2 T1D, allowing treatment to begin at that stage. While there are greater regulatory hurdles to approving drugs for people who have not yet developed clinically symptomatic T1D, stage 2 offers a much longer window for intervention (from 6 months to 2 years or longer) and a greater opportunity to preserve beta-cell function.
In addition, targeting preclinical disease may help families avoid the emotional turmoil surrounding a child's T1D diagnosis.
"Stage 3 gives you a window of 4 weeks to 100 days. It's very narrow for intervening and now you have a family who are devastated with a new diagnosis. It's overwhelming. Even if you have perfectly safe drugs, your window is very narrow in stage 3 but in stage 2, it's long," Dutta said.
Although these approaches have so far focused on preclinical and new-onset T1D, people with longstanding T1D (stage 4) and very little residual beta-cell function have not been forgotten, Haller said.
For these patients, future beta-cell transplantation will also require immune modulation to prevent rejection.
"Many of the patients who will undergo cell replacement are going to benefit from these immune therapies that we're developing, so everybody will benefit regardless of where they are in the process," he said.
Haller is a consultant for Sanofi and for SAB Bio and holds equity in SAB Bio. Bakhsh reported no relevant financial relationships. Dutta is an employee of Breakthrough T1D.
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