'Like Watching a Car Crash in Slow Motion': New RISE data

June 10, 2019

SAN FRANCISCO — Contrasting findings of the Restoring Insulin Secretion (RISE) adult medication study with those of the same trial in adolescents illustrate just how dreadful the prognosis is for youth with type 2 diabetes, physicians heard here at the American Diabetes Association (ADA) 2019 Scientific Sessions.

Results of the adult RISE study, reported June 9, show that those with prediabetes or new-onset diabetes who received treatment had improvements in beta-cell function during the year of the study compared with those on placebo, but this did not produce any lasting benefit once treatment was stopped.

However, in RISE in adolescents — reported last year at the ADA Scientific Sessions — early treatment in teens with prediabetes or recent-onset type 2 diabetes for a year failed to prevent deterioration in beta-cell function.

"In adults, we see an improvement," but, "there was no sustained improvement in beta-cell function in youth [representing] a troublesome set of data," said RISE investigator Steven E. Kahn, MBChB, of VA Puget Sound Health Care System, University of Washington, Seattle, speaking at a press briefing.

"These youngsters have burned out their residual beta cells. There is very little to work with," he observed. "Despite treatment, the kids were progressing. [Treatment] is not working. This is scary."

Indeed fellow RISE investigator Kieren J. Mather, MD, Indiana University School of Medicine, Indianapolis, told Medscape Medical News that observing type 2 diabetes in youth is "like watching a car crash in slow motion."

And that observation is borne out by the findings from the TODAY-2 study, discussed during the same press conference at ADA and reported yesterday by Medscape Medical News.

In that trial, around 500 youths diagnosed with type 2 diabetes at an average age of 14 years were followed down the line (average age 25) and showed alarming consequences. This included a small number of deaths from diabetes-related causes among participants in their mid-20s and severe cardiovascular, renal, neurological, and ophthalmological events related to diabetes, including heart attacks, toe amputations, and renal dialysis, among other things. And not to mention the fact that pregnancy complications were exceptionally high, as was neonatal morbidity, among girls in the cohort who became pregnant and their offspring compared with background rates for the general population.

During a Q&A session following the presentation of the RISE data, when asked what could be done about youth with type 2 diabetes, Sonia Caprio, MD, a pediatric endocrinologist from Yale School of Medicine, New Haven, Connecticut, who is also a RISE investigator, said: "I am in 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 kids are not working. We need other approaches for treatment."

And with regards to preventing type 2 diabetes from developing in the first place, she observed: "That's a tough question, particularly for the kids. Early prevention of obesity, and obviously weight loss, but it's a work in progress."

Kahn said it is "imperative for us to better understand the disease process in youth in order to identify what makes their type 2 diabetes so aggressive so that we can improve long-term outcomes."

Long-Term Treatment Required to Prevent Beta-Cell Function Loss in Adults

The RISE set of trials are complex studies in which beta-cell function is measured using hyperglycemic clamps. In the adult trial, which was simultaneously published in Diabetes Care this week, 267 individuals with prediabetes (impaired glucose tolerance [IGT]; n = 197; 74%) or recently diagnosed type 2 diabetes (n = 70; 26%) were studied.

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

They were randomized to 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) combined with metformin; or 12 months of placebo.

The primary outcome was beta-cell function at 15 months compared with baseline. 

All three active treatment groups produced on-treatment reductions in weight and improvements in HbA1c compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group.

However, despite on-treatment benefits, 3 months after therapy withdrawal there were no sustained improvements in beta-cell function in any group.

Mather said: "We expected some of the participants would have seen beneficial effects after treatment ended; however, that was not the case and suggests long-term management may be required to prevent loss of beta-cell function [in adults]."

Comparing and Contrasting Adults and Kids for the First Time

Kahn then spoke about the contrast in findings between RISE in adults and adolescents.

"What is unique about the RISE [set of trials] is that we did the same interventions [in adults and adolescents] so we can compare the findings."

This "is the first time" there has been such a comparison, he emphasized.

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

The kids had a mean body mass index (BMI) of 37.7 kg/m2 and an average HbA1c of 5.7%. Overall, 60% had prediabetes (IGT) and the remainder had type 2 diabetes of less than 6 months' duration.

Liraglutide was not used in this trial, as it is not approved for use in children, and it was not felt to be ethical to have a placebo group, as some of the kids already had type 2 diabetes, Kahn noted.  

As in the adults, the youth also had hyperglycemic clamps and oral glucose tolerance tests performed on separate days at baseline, 12 months, and 15 months.

As detailed in a separate simultaneous publication in Diabetes, "changes in beta-cell function were distinctly different," between the adults and kids, Kahn explained.

"In youth, beta cells deteriorated despite the interventions given to them," he noted, in contrast to the improvement during treatment in adults.

This "supports a more adverse trajectory of beta-cell deterioration in youth."

The youths also required more insulin glargine from the outset than the adults, approximately double the amount, in fact, said Kahn — so that the average youth was on 70 units/day.

"A Much More Destructive Disease in Youth"

"The difference in outcomes between the youth and adults is quite stark and highlights that type 2 diabetes in youth may have a different underlying pathology and, therefore, a different natural history," Kahn emphasized.

"There is aggressive insulin resistance [in these kids] and beta-cell failure. This is a much more destructive disease in youth."

Philip S. Zeitler, MD, PhD, professor of pediatrics-endocrinology, University of Colorado School of Medicine, Aurora, lead investigator of the TODAY studies, told reporters at the press conference that there are a number of possible explanations for the aggressive nature of type 2 diabetes in youth.

Firstly, "they appear to be hypersecreting relative to the degree of insulin sensitivity," he explained. So it could be that "developing diabetes during puberty is just more deleterious."

Alternatively, "the kids who develop diabetes under the stress of puberty are the weakest, being picked out by the environment. That's why they get diabetes earlier."

But even by Tanner stage 2, the earliest phase of puberty, some kids already show hypersecretion and insulin resistance, Zeitler explained.

Kahn said the reason why type 2 diabetes is more aggressive in youth remains to be determined. There is, he says, "an urgent need to better understand why these differences are occurring and to then develop new approaches to slow and even prevent progression of beta-cell dysfunction," among youth.

"We've kept samples from RISE. By the time we get to the EASD [European Association for the Study of Diabetes] meeting [in Barcelona in September], we'll have new data on this."

Zeitler added that, in his opinion, "We can't just focus on getting drugs approved. The data suggest something qualitatively different."

Indeed, the holy grail, all the physicians agreed, is whether children at risk can be identified before they enter puberty and whether it's possible to understand who makes the transition and why.

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

RISE investigator Thomas A. Buchanan, MD, Keck School of Medicine, University of Southern California, Los Angeles, said this is no easy task.

"What we call diabetes is actually a continuum. As people progress, fasting plasma glucose doesn't change much," so glucose is probably the wrong marker, he explained.

"My opinion is that there is no practical way, clinically, to assess this other than, perhaps, slowly rising HbA1c."

It Used to Be Rare to See Kids With Type 2 Diabetes

"It used to be rare to see pediatric patients with type 2 diabetes, but now there are almost as many kids with type 2 diabetes as type 1 [in our pediatric clinics]," Alvin Powers, MD, Vanderbilt University Medical Center, Nashville, Tennessee, who was moderator of the press conference during which both TODAY-2 and RISE were discussed, told journalists.

Another aspect of this problem is that this is disproportionately affecting some of the most vulnerable members of society, said the assembled physicians.

Less than 30% of the kids in RISE were white, and the investigators say that the curve for diabetes among white youths has remained relatively flat over the past 20 years, which is not the case for other ethnicities.

Black, Hispanic, and Native American kids in the United States, in particular, have had significant increases in incidence, so that, among Native American youth, for example, the rate of type 2 diabetes "has tripled" in the past two decades, Kahn emphasized.

It "highlights the epidemic we are facing in the United States and across the world. We clearly see the trajectory upwards. The outcomes are terrible. It's a real problem. And this is an early reflection of what is going to be a [huge] problem in Asia and elsewhere."

RISE was supported by grants from various US organizations, including the NIH, which are listed with the article. Additional funding was provided by the ADA, Allergan, Apollo Endosurgery, Abbott, and Novo Nordisk. Mather has reported receiving an investigator-initiated grant from Novo Nordisk during the conduct of this study. Kahn has reported serving as a paid consultant on advisory boards and has been a steering committee member for Novo Nordisk-sponsored clinical trials. Buchanan has reported receiving research support from Allergan and Apollo Endosurgery. 

Diabetes Care. Published online June 9, 2019. Abstract

Diabetes. Published online June 9, 2019. Abstract

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