June 11, 2012 (Philadelphia, Pennsylvania) — In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, a 2x2 factorial-designed study, treatment with omega-3 fatty acids failed to reduce cardiovascular events in patients with type 2 diabetes and patients with impaired fasting glucose or impaired glucose tolerance . During a median follow-up of 6.2 years, the rate of death from cardiovascular causes among those treated with placebo and those treated with omega-3 fatty acids was virtually identical.
In addition, ORIGIN also showed that treatment with basal insulin glargine (Lantus, Sanofi) failed to reduce the composite end point of MI, stroke, and death from cardiovascular causes . Treatment with insulin glargine did reduce the progression to diabetes in a cohort of patients with impaired fasting glucose or impaired glucose tolerance at baseline.
Dr Hertzel Gerstein (McMaster University, Hamilton, ON), who presented the results of the ORIGIN insulin glargine study today here at the American Diabetes Association (ADA) 2012 Scientific Sessions, called the results "neutral" in terms of the primary end point. Gerstein explained that there had been some concerns going back years that giving diabetic patients insulin could lead to an acceleration of cardiovascular disease. That said, the researchers hypothesized that regulating blood glucose levels with insulin glargine might prevent future cardiovascular events.
"We went into the trial with the hypothesis that insulin glargine might reduce the risk of cardiovascular outcomes and other serious outcomes," said Gerstein. "We showed that it did not, in fact, reduce the risk and had a neutral effect. The study was very successful in that regard, because there is a very clear and unambiguous finding on the result. We clearly know things that we didn't know before with respect to insulin."
Other ORIGIN investigators were reassured with the findings.
"As you may know, there are many people with coronary artery disease or cardiovascular disease that have disturbed glucose metabolism," Dr Lars Ryden (Karolinska Institutet, Stockholm, Sweden), one of the study investigators, told the media during a press conference announcing the results. "Some of them walk around with hidden diabetes. For a cardiologist, it is much more difficult to use insulin than an expert, so for me, the data are reassuring that this type of insulin is safe to use, easy to use, does not cause my patient a lot of hypoglycemia, and does not carry any risk of treatment-related cancer."
The results of the studies are published online today in the New England Journal of Medicine.
The ORIGIN Study
The ORIGIN study is an international double-blind study with a 2x2 factorial design. In total, 12 537 patients with cardiovascular disease or at high risk for cardiovascular events who had an impaired fasting glucose, impaired glucose tolerance, or diabetes were randomly assigned to receive insulin glargine, with a target fasting glucose of <95 mg/dL, or standard care; and to receive n-3 fatty acids, containing at least 900 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or placebo.
In one arm of the ORIGIN study, the researchers assessed cardiovascular outcomes in patients randomized to treatment with titrated insulin glargine or standard care. Insulin glargine is used to normalize fasting plasma glucose levels below 100 mg/dL, with elevations above 100 mg/dL suggesting there is insufficient endogenous insulin secretion to overcome underlying insulin resistance.
Treatment with basal insulin glargine failed to reduce the risk of the primary composite end point of MI, stroke, or death from cardiovascular causes. After 6.2 years of follow-up, the primary outcome event rate was 16.6% in the insulin glargine-treated patients and 16.1% in the usual-care arm, a nonsignificant difference. Other event rates, including total mortality, total MIs, total strokes, death from cardiovascular causes, hospitalizations for heart failure, and revascularization, among others, were not significantly different in the insulin glargine and usual-care study arms.
Among 1456 patients without diabetes at randomization, those assigned to insulin glargine were 28% less likely to have diabetes develop from the time of randomization until the first oral glucose-tolerance test when compared with patients assigned to usual care. After a second oral glucose-tolerance test 100 days after insulin was stopped, patients without diabetes assigned to insulin were 20% less likely to have had diabetes develop. Overall, the incidence of severe hypoglycemia was low in the insulin-treatment arm, reported at 1.00 case per 100 person-years of follow-up. An episode of nonsevere symptomatic hypoglycemia was reported in 57% of patients treated with insulin glargine and in 25% of patients receiving usual care.
"As a clinician who treats patients with diabetes, the study provides a huge amount of reassurance," said Gerstein. "We know that in this study, insulin lowered blood sugar levels and did so safely and effectively. I can look at a patient and say, 'Your blood sugar is not well controlled right now, so let's go ahead and add insulin.' I have a lot more confidence in using it, and for this reason alone it is a useful and important finding."
Treatment With Omega-3 Fatty Acids
In the other randomization, which was presented by Dr Jackie Bosch (McMaster University, Hamilton, ON), patients were treated with 1 g of omega-3 fatty acids and compared with patients who received placebo. Despite reductions in triglyceride levels, which were reduced 14.5 g/dL more among the patients who received the omega-3 fatty acids, treatment failed to reduce the risk of cardiovascular outcomes.
The rate of death from cardiovascular causes was 9.1% in patients treated with placebo and 9.3% in patients treated with omega-3 fatty acids, a nonsignificant difference. In addition, there was no significant treatment effect on any of the secondary end points, including a composite of MI, stroke, or death from cardiovascular causes. Deaths from arrhythmias were also unaffected by treatment with omega-3 fatty acids.
Primary and Other Outcomes
|Outcome||Adjusted hazard ratio (95% CI)|
|Death from cardiovascular causes (primary outcome)||0.98 (0.87–1.10)|
|MI, stroke, or death from cardiovascular causes||1.01 (0.93–1.10)|
|Death from any cause||0.98 (0.89–1.07)|
|Death from arrhythmia||1.10 (0.93–1.30)|
|Fatal and nonfatal MI||1.09 (0.93–1.27)|
|Fatal and nonfatal stroke||0.92 (0.79–1.08)|
|Hospitalization for heart failure||1.02 (0.88–1.19)|
|Revascularization procedure||0.96 (0.87–1.05)|
"Adding 1 g of omega-3 fatty acids for about six years does not reduce cardiovascular outcomes in people with dysglycemia and other cardiovascular risk factors," said Bosch.
The researchers used a food-frequency questionnaire to assess the dietary consumption of omega-3 fatty acids in the treatment and placebo arms. Overall, the baseline dietary consumption of omega-3 fatty acids was 200 mg/day in both arms and 230 mg/day after two years. This is higher than the median intake of omega-3 fatty acids in the general population, but much lower than the currently recommended guidelines of 1 g per day. Fish intake was similar between both treatment arms.
In an email to heartwire , Dr James Stein (University of Wisconsin Medical School, Madison), who was not affiliated with the study, said the results of the fatty-acids study are disappointing but not surprising, given that high-risk patients or those who recently had an ischemic event are well treated with preventive therapies. A drug that further reduces the absolute risk of cardiovascular disease would have to be powerful, something omega-3 fatty acids are not. For successful supplementation with omega-3 fatty acids, patients need to take 3 g to 4 g per day, noted Stein. At smaller doses, the effect is limited to a modest reduction in triglycerides.
The ORIGIN investigators are planning to study patients for an additional two years, at minimum, to determine whether there are any legacy effects of omega-3 fatty-acid supplementation.
The ORIGIN trial is funded by Sanofi. Gerstein received consulting and lecture fees from Sanofi; consulting and/or lecture fees from Bayer, Merck, Novo Nordisk, GlaxoSmithKline, Roche, Novartis, Janssen, Abbott, and AstraZeneca; and grant support from Eli Lilly and Boehringer Ingelheim. Ryden reports consulting fees from Bristol-Myers Squibb and AstraZeneca and lecture fees and grant support from Roche and Sanofi. Bosch reports no conflicts of interest.
Heartwire from Medscape © 2012 Medscape, LLC
Cite this: Insulin Glargine and N-3 Fatty Acids Do Not Reduce CVD Events in Diabetics: ORIGIN - Medscape - Jun 11, 2012.