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ORLANDO -- Patients with long-standing type 1 diabetes given the bacillus Calmette-Guerin (BCG) vaccine showed modestly better glycemic control through a mechanism that appeared to be epigenetic, according to a long-term follow-up study that has generated controversy here.

Starting after the third year of follow-up in the 46 patients in early-phase trials, hemoglobin A1c levels were lower among patients who got the two doses of the tuberculosis vaccine (6.18% vs 7.07% with placebo and 7.22% among untreated T1D patients, P=0.02).

Among the phase I randomized trial patients followed for 8 years, A1c levels were 6.65% versus 7.22% in the placebo group (P=0.0002), Denise Faustman, MD, PhD, of the Massachusetts General Hospital (MGH) Immunobiology Laboratory in Boston, and colleagues reported at the American Diabetes Association annual meeting, days after .

"The impact of BCG on blood sugars in human T1D appears to be the result of a novel mechanism; a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis" by epigenetic induction of the Treg cells that maintain tolerance to prevent autoimmune disease, according to the late-breaking poster.

"The phase I trial was not designed to track insulin use, but we have documented incidences of patients' [sic] significantly reducing or stopping insulin use for short time periods," a from Faustman's institutional press release said. "These are observations not clinical trial outcomes. The ongoing phase II trial will closely monitor insulin use in all patients."

Implications

"The immune attack is not well understood, but it does sound incredible that such a nonspecific stimulus as having BCG would actually set right that specific attack on the beta cells. So I find it very surprising, but if it's true it is a game changer," Roy Taylor, MD, of Newcastle University in England, commented in an interview with 番茄社区app.

A crowd gathered at the ADA poster, with several attendees asking for selfies with Faustman.

Breathless headlines suggesting a that could type 1 diabetes, based on the npj Vaccines paper, have been having an impact. "I have relatives who are sending me these articles," noted one ADA attendee at the poster.

However, a statement from William Cefalu, MD, ADA chief scientific, medical and mission officer, warned that the "findings must be interpreted with caution and cannot be generalized to the more than 1.5 million Americans living with type 1 diabetes.

"It is also critical to note that all of the study participants continued to use standard insulin therapy throughout the trial; it's not a situation whereby the treatment changed their standard of care (patients no longer required insulin)," he said in the statement.

Study limitations noted by Cefalu included:

• "The study only followed a very small number of patient"
• "The patients with reported positive outcomes achieved only moderately lower A1Cs, which, while marginally statistically significant, cannot be generalized to all patients with type 1 diabetes"
• "The article doesn't account for the natural variability in A1C levels over time, which is well known to occur in this population: they tend to improve in people with type 1 diabetes as they age, particularly as they move out of their teens and early 20s. It's unclear what role that natural history may have played in these subjects, and that provides another significant confounder."

"We never used the word 'cure,'" Faustman told 番茄社区app, countering that a large effect size can be seen small trials. "Where the hemoglobin went down to is not commonly achieved without hypoglycemia." Patients actually self-reported less hypoglycemia than early in the trial or during the 3-year period when they were pre-screened, she said, while nobody changed their meters, pumps, or method of insulin delivery during the 8-year trial period.

Future for BCG in T1D

Cefalu called for an adequately-powered, better-controlled intervention trial to show whether there is any efficacy to the BCG treatment.

The "question and answer" from the MGH also cautioned that further research is needed.

"We do not recommend that anyone take BCG for diabetes nor do we recommend any 'off label' use of BCG. These results are reports from clinical trials and should not be confused with approval from the FDA," it noted.

Six trials with hundreds of patients are ongoing, Faustman said, although phase III might not be necessary, given the long-standing use of this vaccine as safe. "More data to come."

A media relations representative for the ADA noted that the publication of the findings in npj Vaccines days before the scheduled presentation will result in Faustman being barred from presenting at the conference for 2 years.

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