Becky McCall

September 24, 2014

VIENNA — ORIGINALE, the long-term follow-up to the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial looking at the effect of insulin glargine (Lantus, Sanofi) on cardiovascular risk in type 2 diabetes, confirms that targeting a normal fasting plasma glucose over 6 years improves long-term metabolic status and has a "neutral" effect on health outcomes.

Of note, fewer cases of new diabetes were seen in people with prediabetes who received insulin compared with standard care in the follow-up study.

Discussing the results of ORIGINALE during a press briefing at the European Association for the Study of Diabetes 2014 Meeting, lead investigator Hertzel Gerstein, MD, Population Health Institute chair in diabetes research at McMaster University, Hamilton, Ontario, said: "During the ORIGIN trial we found that treatment with insulin reduced the incidence of new diabetes in patients who did not have diabetes at the beginning of the trial."

"Now, with ORIGINALE, we see a consistent glycemic effect." Giving insulin may reduce new diabetes, even after stopping treatment, he said.

"The notion that the pancreatic function is irreversibly impaired is probably wrong, and there are probably ways that we can reverse this. The intensive glucose lowering may have restored some endocrine pancreatic function. I think this is an interesting finding," he added.

Asked to comment, David Lau, MD, professor of medicine, biochemistry, and molecular biology at the University of Calgary, Alberta, said this hypothesis may not be as far-fetched as it first sounds, with emerging data to support the concept of potentially using insulin therapy earlier in the course of diabetes.

"Animal data at EASD show that islet-amyloid deposition may be the culprit that eventually leads to beta-cell loss, which is an early event that occurs even before the development of type 2 diabetes," Dr. Lau explained.

He added that a new National Institutes of Health–funded clinical trial, Restoring Insulin Secretion (RISE), is under way to investigate whether medication or surgical-intervention strategies can retard progressive beta-cell dysfunction in prediabetes or early type 2 diabetes.

Others agreed that this is a strategy for which there is now some real hard evidence that deserves further investigation.

The ORIGINALE results were reported as a poster at the conference.

ORIGIN Trial Neutral but Reassuring

Published in the New England Journal of Medicine in 2012 and reported at the American Diabetes Association meeting the same year, the ORIGIN trial involved 12,500 participants at high risk for cardiovascular events, most of whom also had early type 2 diabetes. A minority, around 12%, had impaired fasting glucose and/or impaired glucose tolerance instead (prediabetes). Participants received either insulin glargine or standard of care (generally oral antidiabetic agents).

The trial primarily looked at whether the risk for cardiovascular events could be reduced by providing enough basal insulin to normalize fasting plasma glucose levels (<5.3 mmol/L) over a median of 6.2 years. The effect on cancer outcomes was also investigated. A separate arm randomized participants to omega-3 fatty acids or placebo.

The trial was negative, showing no impact of either omega-3 fatty acids or insulin glargine in reducing a composite end point of myocardial infarction, stroke, or cardiovascular death.

However, the results were also hailed as reassuring, indicating that it is safe to use insulin early in the course of type 2 diabetes without fear of increasing cardiovascular events or cancer, both of which had been concerns.

And insulin also reduced the progression to diabetes in patients with impaired fasting glucose and/or impaired glucose tolerance, another end point.

But these effects came at the cost of more hypoglycemia and more weight gain, and doctors said at the time they would be unlikely to employ insulin this early in the course of diabetes.

ORIGINALE Examines Legacy Effects: 10,000 More Person-Years

Now the follow-up study, ORIGINALE, examines any legacy health effects of insulin glargine or omega-3 fatty acids after stopping these therapies. After completing 6.2 years in the ORIGIN study, nearly 6000 participants continued into ORIGINALE, receiving whatever therapy their physicians deemed appropriate.

This "enabled investigators to accrue an additional 10,000 person-years of experience on insulin and 1000 events during follow-up; this is further to the existing 72,000 person-years of experience from ORIGIN," reported Dr. Gerstein.

There was no change in any cardiovascular outcomes or cancer (ie, a continued neutral effect was seen).

But during the median of 6.2 years of active therapy followed by more than 2 years of passive follow-up, new diabetes cases were found in 278 patients in the insulin group (37.7%) vs 300 patients (41.7%) receiving standard care (odds ratio [OR], 0.85; P = .12).

The slightly looser definition of new or "possible" diabetes was evident in 41.2% of the insulin group vs 47.7% receiving standard care (OR, 0.70; P = .014).

Dr. Gerstein said these latest data are encouraging and warrant further research. "This type of therapy can change the natural history of the disease process, at least over the period of time we investigated," he noted.

Increasing Evidence for Early Intervention in Early Diabetes

Also commenting, Rury Holman, MD, director of the University of Oxford Diabetes Trials Unit, United Kingdom, said that the use of insulin in early type 2 diabetes was examined in a study conducted in China and published in 2008 (Lancet. 2008;371:1753-1760).

"After treatment of new-onset diabetes with insulin, treatment was stopped two weeks after normal glucose levels were achieved. But then one year later, half of these patients were still controlled," he recounted.

"The idea that early use preserves some function does appear to be supported by the evidence," he told Medscape Medical News.

And Alan J. Garber, MD, of Baylor College of Medicine, Houston, Texas, agreed that ORIGINALE shows that a treatment that reduces the work of the pancreas, in this case glucose reduction with insulin, reduces the deterioration in glycemic control that leads to prediabetes and diabetes.

Similar observations have been made with alpha-glucosidase inhibitors and with agents that improve insulin sensitivity such as metformin and especially the thiazolidinediones, he noted.

Dr. Gerstein continued that the next wave of research in diabetes was most likely going to be related to diabetes remission and regression and identifying ways to do this with pharmaceuticals and other approaches.

"There's smoke here, so let's find the fire!" he concluded.

The ORIGIN study was funded by Sanofi. Dr. Gerstein has consulted for Sanofi, as well as other insulin manufacturers. Dr. Lau reports he is a member of an advisory board, or equivalent, for Amgen, AstraZeneca, Novo Nordisk, Covidien, Valeant, Boehringer-Ingelheim, Lilly, and a member of a s peaker's bureau for Amgen, AstraZeneca, Lilly, Boehringer-Ingelheim, Novo Nordisk, Merck, and Valeant. He is also in receipt of grants for clinical trials from CDA, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, and Novo Nordisk. Dr. Garber reports that he has received consultant honoraria from Tethys Bioscience and Viking Therapeutics; consultant/speaker honoraria from Eisai and Santarus; advisory-board honoraria from Halozyme; advisory-board/consultant honoraria from Takeda; and advisory-board/consultant/speaker honoraria from Merck and Novo Nordisk. Dr. Holman disclosed research funding from Bayer, Bristol-Myers Squibb, and MSD and honoraria from Amgen, Bayer, Elcelyx, Jannsen, MSD, Novartis, and Novo Nordisk.

European Association for the Study of Diabetes 2014 Meeting; September 18, 2014; Vienna, Austria. Abstract 1270

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