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Early insulin failed to prevent cardiac events: from the annual scientific sessions of the American Diabetes Association.

PHILADELPHIA--The primary end point may not have shown benefit, but some assurances about the safety of insulin glargine have emerged from Sanofi's ORIGIN (Outcome Reduction With Initial Glargine Intervention) study.

In ORIGIN, neither insulin glargine nor n-3 fatty acid supplementation reduced the risk for adverse cardiovascular outcomes in a 6-year study of more than 12,000 adults with cardiovascular risk factors and either diabetes or prediabetes. However, the addition of basal insulin glargine in the prediabetes group did reduce the risk for progression to type 2 diabetes. And, there were no increased risks for cardiovascular end points with insulin glargine.

On the one hand, said Dr. Matthew C. Riddle Jr., head of the diabetes section at Oregon Health and Science University, Portland, the findings don't support the use of insulin in people who don't meet the criteria for diabetes. "Despite lower glucose levels, routine early use of basal insulin glargine is not better than guideline-based standard care in limiting important health outcomes in this population over this duration of treatment," he said at the meeting.

But, Dr. Riddle said, "basal insulin glargine is now the best-studied glucose-lowering drug available, and no new safety concerns appear to limit its use in people with diagnosed diabetes when needed, including early in the course of diabetes and in the presence of significant cardiovascular risk."

And, although cancer incidence was not defined as a primary end point of the study, analyses in ORIGIN showed that cancer rates were identical between the insulin glargine and standard-care groups, at 1.32 per 100 person-years. Concern about glargine and cancer was raised in September 2009 with a series of articles published in the journal Diabetologia, some of which suggested a link based primarily on population-based data.

Long before the issue of cancer risk, there had been concern about increased cardiovascular risk, ORIGIN principal investigator Dr. Hertzel C. Gerstein noted. "For 90 years there's been debate in the literature, where many doctors have said that insulin causes cardiovascular disease. Wrong. It may do that in a rat, but it's certainly not doing it in humans. A randomized trial is the best way to test these hypotheses," he noted.

In all, said Dr. Gerstein, professor of medicine and director of the division of endocrinology and metabolism at McMaster University Ontario, "As a person who treats people with diabetes, I think this adds a huge amount of reassurance. We now know there is no reason to be worried about using insulin early in the course of diabetes."

In a 2 by 2 factorial design, ORIGIN randomized 12,537 patients with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine titrated to achieve a target fasting blood glucose level of 95 mg/dL or less or to standard care (including routine use of antidiabetic, antihypertensive and antihyperlipidemic medications), and to either a 1-g daily capsule containing at least 900 mg of ethyl esters of n-3 fatty acids or placebo.

The co-primary outcomes for the insulin glargine arm of the study were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. For the n-3 fatty acids arm, the primary outcome was death from cardiovascular causes.

Results of the two study arms were published in separate articles in the New England Journal of Medicine (doi: 10.1056/NEJMoa1203859 and 10.1056/NEJMoa1203858).

At a median follow-up of 6.2 years, rates of incident cardiovascular outcomes were similar in the insulin glargine and standard-care groups, at 2.94 and 2.85 per 100 person-years, respectively. Rates for the second co-primary outcome were also not significantly different, at 5.52 versus 5.28 per 100 person-years, respectively. There also were no significant differences in mortality (hazard ratio, 0.98) or microvascular events (HR, 0.97), and the effect of the intervention on the two co-primary outcomes was similar across subgroups, Dr. Gerstein reported.

However, among the 1,456 study participants who did not have diabetes at baseline, the 737 who were randomized to insulin glargine were 28% less likely than were the 719 in the standard-care group to develop type 2 diabetes, based on an oral glucose tolerance test (OGTT) administered 3-4 weeks after glargine was stopped. The difference was 25% vs. 31% (P = .0006). At a second OGTT after 3 months, new diabetes had been diagnosed in 30% of the glargine group versus 35% of the standard-care group (odds ratio, 0.8).

The incidence of a first episode of severe hypoglycemia was 1.0 per 100 person-years in the glargine group versus 0.3 in the standard-care group (P less than .001). Rates of nonsevere hypoglycemia were 16.7 versus 5.2 per 100 person-years. The proportion of each group that experienced no symptomatic hypoglycemia was 43% with glargine versus 75% with standard care.

Participants in the glargine group gained a median weight of 1.6 kg, while those in the standard-care group lost a median of 0.5 kg.

In the n-3 fatty acid study arm, the incidence of the primary outcome, cardiovascular death, was 9.1% for those receiving the capsules versus 9.3% for those taking placebo at a median 6.2-year follow-up. Use of

the supplements also had no impact on the rates of major cardiovascular events (16.5% vs. 16.3%, respectively), death from any cause (15.1% vs. 15.4%), or death from arrhythmia (4.6% vs. 4.1%).

However, use of n-3 fatty acids was associated with a greater reduction in triglyceride levels, 23.5 mg/dL, versus 9.0 mg/dL with placebo.

Several possibilities might account for the difference between these findings and those of previous large trials that have found a benefit of fish oil supplements. At least two of those trials used subjects with more severe cardiovascular disease. Also, ORIGIN participants were taking more concomitant medications for lowering cholesterol and blood pressure, noted Dr. Aldo P. Maggioni, director of the Research Centre, Italian Association of Hospital Cardiologists, Florence.

At least three other large trials are currently assessing the use of n-3 fatty acids to prevent cardiovascular disease in low-risk participants, Dr. Maggioni said.

According to Dr. Riddle, "Ninety years after insulin was first used to treat diabetes, we now know its long-term effect on important health outcomes. We believe the ORIGIN trial has added significantly to this understanding."

The ORIGIN study subjects will continue to be observed passively in an extension study called ORIGINALE (Outcome Reduction With an Initial Glargine Intervention and Legacy Effect).

The study was funded by Sanofi. Dr. Riddle is an adviser, consultant, or speaker for, and/or has received research support from, Amylin Pharmaceuticals, Eli Lilly, and Sanofi-Aventis. Dr. Gerstein has those same disclosures for Abbott Diabetes Care, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Novo Nordisk, Roche Pharmaceuticals, Sanofi-Aventis, and Janssen Biotech. Dr. Maggioni is a board member of Sanofi-Aventis and has received research support from Boehringer Ingelheim.


Puts the Insulin-Cancer Story to Bed

I think the findings definitively show that cardiovascular risk is not reduced by early insulin treatment. So this will not change the guidelines in any way. Also, insulin glargine did not appear to increase cancer risk. I think this will finally put to bed the insulin and cancer story. The hazard ratio was as close to unity as possible. It will certainly provide reassurance in many people's minds.

Whether early insulin use prevents diabetes is slightly interesting, but it's not going to change anything in clinical practice. By 100 days, the difference in diabetes was less. People are wondering whether early insulin protects the pancreas, and I don't think these data definitively confirm or refute that. From what we now know, the risks of early insulin--hypoglycemia and weight gain--are greater among those who don't yet have diabetes.

The fish oil side is interesting. We would have liked to see a benefit in reducing cardiovascular death, which is what most people might have predicted. But the reality is that if you treat people with statins and ACE inhibitors, reduce their risk by those mechanisms, fish oil will provide no benefits above and beyond those things.

DR. NAVEED SATTAR is professor of metabolic medicine at the University of Glasgow. He is on the advisory panel for AstraZeneca, Eli Lilly, Merck Sharp & Dohme, and Sanofi-Aventis.
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Author:Tucker, Miriam E.
Publication:Internal Medicine News
Date:Jun 15, 2012
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