COMMENTARY

The RISE Study: Where Do We Go From Here?

Steven E. Kahn, MBChB

Disclosures

September 20, 2019

Editorial Collaboration

Medscape &

Type 2 diabetes is a worldwide epidemic affecting all races and ethnicities, and with the increases in incidence in youth, we can now add that it also affects virtually all ages.

The RISE (Restoring Insulin Secretion) studies, which I helped lead, aimed to find new approaches to slow the progressive loss of beta-cell function that characterizes the progression from impaired glucose tolerance or prediabetes to type 2 diabetes. On the basis of the literature, we chose medication interventions that we hoped would improve beta-cell function after 12 months of treatment. Then, as a critical component, we withdrew the interventions for 3 months to determine whether we would see any lasting benefit.[1]

The adult medication study[2] had four intervention groups:

  • metformin alone for 12 months;

  • insulin glargine for 3 months, where we titrated individuals to achieve a fasting glucose of 80-90 mg/dL, followed by metformin for 9 months;

  • liraglutide combined with metformin for 12 months; and

  • placebo.

What Were the Findings?

Participants in the three active medication arms had stable or improved beta-cell function while receiving treatment, with the most dramatic improvement occurring in those receiving the combination of liraglutide and metformin. We had hoped that at least one of these groups would demonstrate continued improvement in beta-cell function 3 months later, after the medications had been washed out.

Unfortunately, none of the improvements were preserved. Everybody returned to baseline, suggesting that although we get benefit while using these drugs, it dissipates when the drugs are withdrawn.

An important message from these findings is that if we're going to intervene in individuals with impaired glucose tolerance, prediabetes, or early type 2 diabetes, we need to continue for prolonged periods of time.

No Benefit, Progression of Disease in Youth

The youth cohort[3] had the same basic metabolic condition as the adults. Here, we used two interventions: metformin alone for 12 months, and glargine for 3 months followed by metformin for 9 months. These interventions are identical to those used in two of the four adult arms, allowing us to directly compare the impact of these interventions in youth versus adults.

We did not see a benefit in youth in terms of stability or an increase in beta-cell function, which is the first contrast to what we saw in adults. Second, the disease, as indicated by beta-cell function, had dramatically progressed at the end of the 3-month washout, consistent with what we've been seeing more recently in the literature—that youth seem to have a more aggressive disease.

Where Do We Go From Here?

This information sets up the scientific community to ask a number of questions. What is it about prediabetes or diabetes in youth that makes the disease more aggressive than in adults? How do we go about identifying what these differences might be? Will the identification of differences provide potential targets for intervention that would allow us to slow progression in youth—and then potentially also translate that to adults?

We would then be in the position to look at continued therapy or potential bursts of therapy with washout periods and assess whether these therapies slow the progression of disease, and ultimately prevent the complications of type 2 diabetes.

One might be somewhat disappointed that the adult study didn't see a sustained effect of any of the interventions when they were withdrawn. But this is why we do science. We've learned a lot from this, and the knowledge we gained leads us to think about alternative possible treatment options down the road.

From a therapeutic point of view, our approaches have to start including some attempt to reduce weight. The more we reduce the demand on the dysfunctional beta cell, the better outcomes we will see. Weight loss surgery isn't for everybody, but it's one option. Another option would be drugs that produce dramatic amounts of weight loss. These are options that need more testing and which future studies need to address.

As for diabetes in youth, why are these kids progressing more rapidly? We are left with the possibility that the disease may be somewhat different in youth. Is it genetically determined? Could epigenetic changes be driving these youth to have a more hyperresponsive beta cell that fails more rapidly? Could it be some other problem in the input to or within the islet itself?

These are all areas that can be explored, hopefully resulting in new therapeutics and ultimately a reduction in this diabetes epidemic.

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