"Like watching a car crash in slow motion": new data RISE

SAN FRANCISCO – The opposite results of the Restoring Insulin Secretion (RISE) adult drug study with those of the same trial in adolescents illustrate how daunting the prognosis is for young people with type 2 diabetes. been heard here at the American Diabetes Association (ADA) 2019 Scientific Sessions.

The results of the RISE study for adults, reported on June 9, show that improved beta-cell functions during the year of the study in people with prediabetics or new diabetes who received treatment compared to those in the placebo group, however, produced no lasting effects. benefit once the treatment has been stopped.

However, in RISE in adolescents – reported last year at scientific sessions of the ADA – early treatment in adolescents with prediabetes or type 2 diabetes of recent onset for a year did not prevent the deterioration of beta cell function.

"In adults, we are seeing an improvement," but "there has been no continuous improvement in beta cell function in young people [representing] an embarrassing data set, "said Steven E. Kahn, MBChB, RISE investigator, VA Puget Sound's health system from the University of Washington in Seattle, during a press briefing.

"These young people have burned their residual beta cells, there is very little work to do," he said. "Despite the treatment, the children were progressing. [Treatment] does not work. It's scary. "

Indeed, researcher Rier, Kieren J. Mather, MD, Indiana University School of Medicine, Indianapolis, said Medscape Medical News that the observation of type 2 diabetes in young people is "like watching a car crash in slow motion".

And this observation is corroborated by the findings of the TODAY-2 study, discussed at the same press conference at the ADA and reported yesterday by Medscape Medical News.

As part of this trial, approximately 500 young people with type 2 diabetes aged 14 years on average were followed (mean age 25 years) and had alarming consequences. This included a small number of diabetes-related deaths among participants in their mid-twenties and serious cardiovascular, renal, neurological and ophthalmological events related to diabetes, including heart attacks, toe amputations and kidney dialysis. Not to mention that pregnancy complications were unusually high, as well as neonatal morbidity, among girls in the cohort who became pregnant and their offspring compared to baseline rates in the general population.

During a Q & A session following the presentation of the RISE data, a question was asked about measures to be taken with regard to young people with type 2 diabetes, Sonia Caprio, MD, endocrinologist pediatrician from the Yale School of Medicine in New Haven, Connecticut, also an RISE investigator. said, "I'm at the clinic twice a week, the story is very sad, it's a very big challenge."

"The only two drugs we have for the treatment of type 2 diabetes in children do not work, we need other approaches to treatment."

And with respect to the prevention of type 2 diabetes, she said, "This is a difficult issue, especially for children. Early prevention of obesity and, of course, weight loss, but it is a work in progress.

Kahn said it was "imperative for us to better understand the process of the disease in young people to identify what makes their type 2 diabetes so aggressive in ways that can improve long-term outcomes." ".

Long-term treatment required to prevent loss of beta cell function in adults

The RISE trial series is a complex study in which beta cell function is measured using hyperglycemic clamps. In the adult trial, published simultaneously in Diabetic treatments this week, 267 people with prediabetes (decreased glucose tolerance [IGT]; n = 197; 74%) or newly diagnosed type 2 diabetes cases (n = 70, 26%) were studied.

Mather explained, "We wanted to intervene in those on the threshold between IGT and new diabetes."

They were randomized into one of four treatment groups: 12 months of metformin alone; 3 months of insulin glargine followed by 9 months of metformin; 12 months of liraglutide (Victoza, Novo Nordisk) associated with metformin; or 12 months of placebo.

The primary endpoint was beta cell function at 15 months from baseline.

The three active treatment groups resulted in weight reduction during treatment and improvement in HbA_{1 C} compared to placebo; the largest reductions were observed in the liraglutide plus metformin group.

However, despite the benefits of treatment, three months after stopping treatment, no lasting improvement in beta cell function was observed in any group.

Mather said: "We expected some participants to see benefits after the end of treatment, but this was not the case and suggests that long-term management may be necessary for prevent the loss of beta cell function. [in adults]. "

Compare and contrast adults and children for the first time

Kahn then spoke of the contrast between RISE results in adults and adolescents.

"What's unique about the climb [set of trials] did we do the same things [in adults and adolescents] so that we can compare the results. "

It's "the first time" that there is such a comparison, he said.

In the adolescent trial, reported a year ago, 91 pubertal obese youth were randomized to receive 12 months of metformin or 3 months of insulin glargine, followed immediately by 9 months of metformin. .

Children had an average body mass index (BMI) of 37.7 kg / m² and an average HbA_{1 C} 5.7%. In total, 60% had prediabetes (IGT) and the others a type 2 diabetes lasting less than 6 months.

Liraglutide was not used in this trial, its use in children was not approved, and it was not considered ethical to create a placebo group, as some children were already suffering from type 2 diabetes, Kahn pointed out.

As in adults, young people also underwent hyperglycemic clamps and oral glucose tolerance tests, performed on different days, at baseline, at 12 months, and at 15 months.

As detailed in a separate simultaneous publication in Diabetes, "The changes in beta cell function were markedly different," said Kahn, between adults and children.

"In young people, beta cells have deteriorated despite the interventions that have been administered to them," he noted, contrasting with the improvement during treatment in adults.

This "favors a more unfavorable trajectory of beta cell damage in young people".

Young people also needed more insulin glargine from the beginning than adults, about twice the amount demanded, said Kahn, so the average youth consumes 70 units / day.

"A much more destructive disease among young people"

"The difference in outcomes between youth and adults is quite clear and points out that type 2 diabetes in young people may have a different underlying pathology and, therefore, a different natural history," Kahn said.

"There is an aggressive resistance to insulin [in these kids] and beta cell failure. It is a much more destructive disease among young people. "

Philip S. Zeitler, MD, PhD, professor of pediatrics-endocrinology at the University of Colorado School of Medicine, Aurora, principal investigator of TODAY studies, told reporters at the press conference that many explanations could have type 2 diabetes in young people.

First, "they seem to over-secrete in relation to the degree of sensitivity to insulin," he explained. So, it could be that "the development of diabetes during puberty is simply more deleterious".

Alternatively, "children who develop diabetes under the stress of puberty are the weakest they are selected by the environment.This is why they contract diabetes earlier."

But even in stage 2 of Tanner, the first phase of puberty, some children already have hypersecretion and insulin resistance, Zeitler said.

Kahn said that the reason why type 2 diabetes is more aggressive in young people remains to be determined. There is, "he said," an urgent need to better understand the reason for these differences and then develop new approaches to slow down and even prevent the progression of beta cell dysfunction "in young people.

"We have kept some samples of RISE, by the time we arrive at EASD [European Association for the Study of Diabetes] meeting [in Barcelona in September]we will have new data on this. "

Zeitler added that in his opinion, "we can not just get the drugs approved, the data suggest something qualitatively different".

Indeed, all physicians agree that children at risk can be identified before puberty and that it is possible to understand who is making the transition and why.

"It's the obvious thing to consider: can we prevent diabetes from developing?" Zeitler wondered.

RISE researcher Thomas A. Buchanan, MD, of Keck Medical School, University of Southern California, Los Angeles, said it was not an easy task.

"What we call diabetes is really a continuum. As people progress, fasting plasma glucose does not change much, so blood glucose is probably the wrong marker, he explained.

"My opinion is that there is no practical way, clinically, to evaluate this otherwise than perhaps a slow increase in HbA._{1 C}. "

It was rare to see children with type 2 diabetes

"In the past, it was rare to see children with type 2 diabetes, but now there are almost as many children with type 2 diabetes as with type 1 diabetes. [in our pediatric clinics]Alvin Powers, MD, Vanderbilt University Medical Center, Nashville, Tenn., Who chaired the press conference at which TODAY-2 and RISE were discussed, told reporters.

Another aspect of this problem is that it disproportionately affects some of the most vulnerable members of society, the doctors said.

Less than 30% of RISE children were Caucasian and investigators reported that the white youth diabetes pattern has remained relatively stable over the past 20 years, which is not the case for other ethnic groups .

In the United States, in particular, black, Hispanic and Native American children have seen their incidence increase considerably, so that among young Native Americans, for example, the rate of type 2 diabetes has "tripled" in the last two years decades, Kahn pointed out.

This highlights the epidemic we face in the United States and around the world. We clearly see the trajectory on the rise. The results are terrible. This is a real problem. It is a beginning of reflection on what will become a reality. [huge] problem in Asia and elsewhere. "

RISE has been funded by grants from various US organizations, including the NIH, which are listed in the article. Additional funding has been provided by ADA, Allergan, Apollo Endosurgery, Abbott and Novo Nordisk. Mather said he received a grant from Novo Nordisk, at the initiative of an investigator, during the course of conducting this study. Kahn said he has served as a paid consultant on advisory boards and has been a member of the Novo Nordisk sponsored clinical trial steering committee. Buchanan reported receiving research assistance from Allergan and Apollo Endosurgery.

Diabetic treatments. Posted online 9 June 2019. Summary

Diabetes. Posted online 9 June 2019. Summary

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