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 annual scientific sessions of the American Diabetes Association.
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.
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 were also 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).