ORIGIN: Insulin Glargine and Omega-3 Do Not Improve Cardiovascular Outcomes in Patients with Type 2 Diabetes

But omega-3 fatty acids significantly reduce triglyceride levels
August 2012, Vol 5, No 5, Special Issue ADA 2012 Highlights - Cardiometabolic Health
Mary Mosley

Cardiovascular (CV) outcomes were not improved with either omega-3 fatty acids or with insulin glargine in a 6-year study of 12,537 patients with dysglycemia and other CV risk factors. The multinational Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial showed that insulin glargine had no effect on cancer, and that it reduced the progression from dysglycemia to diabetes. Hertzel C. Gerstein, MD, MSc, FRCPC, Professor, Department of Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada, presented the CV results of the ORIGIN trial at the 2012 ADA annual meeting.

The ORIGIN trial included patients (mean age, 63.5 years) with type 2 diabetes who had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), as well as CV risk factors. Using a 2 × 2 factorial design, the patients were randomized to insulin glargine or to standard care (without insulin), and to omega-3 fatty acids or to placebo.

All the patients had CV risk factors, 82% had a previous diagnosis of diabetes (average duration, 5 years), and 6% had diabetes detected at the time they were randomized. IFG or IGT was found in 12% of patients.

At baseline, 40% of the patients were not taking any glucose-lowering drugs, 27% were taking metformin, and 30% were taking a sulfonylurea. The median fasting plasma glucose was 125 mg/dL, and the median hemoglobin A1c was 6.4%.

The study questions were (1) does insulin replacement therapy targeting fasting normoglycemia (≤95 mg/dL) with insulin glargine produce a greater reduction of CV outcomes than standard approaches, and (2) does adding omega-3 fatty acids reduce CV death?

CV Outcomes with Insulin Glargine
“Basal insulin glargine has a neutral effect on CV events and cancers, and reduces the progression of diabetes,” said Dr Gerstein.

No difference was seen between the insulin glargine and the standard-care groups in the composite end point of myocardial infarction (MI), stroke, or CV death (adjusted hazard ratio [HR], 1.02), or in the composite end point of MI, stroke, CV death, revascularization, or heart failure (adjusted HR, 1.04). In addition, no difference was seen for all-cause death (adjusted HR, 0.98).

Among the 1456 people without diabetes at baseline, the development of new-onset diabetes was reduced by 28%. This finding was durable at 3 months when these individuals had another oral glucose tolerance test.

The risk for severe hypoglycemia was 0.7% higher in the insulin group (1% vs 0.3% annually with standard care). Overall, the rates of hypoglycemia were low. With insulin glargine, 57% of patients had ≥1 episodes of any hypoglycemic event versus 25% of patients in the standard group. The rate for any hypoglycemia in the insulin group was 17 per 100 person-years versus 5 per 100 person-years.

Patients taking insulin glargine gained a mean of 1.6 kg of body weight compared with a 0.5-kg weight loss with standard care.

CV Outcomes with Omega-3 Fatty Acids
No difference was found between the patients taking omega-3 fatty acids (1 tablet daily) and those taking a placebo in terms of the primary end point of CV death (HR, 0.98). For the secondary composite end point of MI, stroke, or CV death, the finding was also neutral (HR, 1.01).

However, triglycerides were significantly reduced with omega-3 fatty acids, by 23.5 mg/dL compared with 9 mg/dL with placebo (P <.001), from the baseline value of 142 mg/dL in both groups.

The baseline values and reductions in low-density lipoprotein cholesterol were similar in both groups, with reductions of approximately 12 mg/dL from baseline values of 112 mg/dL in each group. Baseline high-density lipo­protein cholesterol values were also similar—46 mg/dL in both groups—with nominal reductions occurring.

Omega-3 supplementation was well tolerated, and adherence was high (88%), said Jackie Bosch, MSc, Associate Professor, School of Rehabilitation Science, McMaster University, who presented the omega-3 results from ORIGIN.

“There was neither benefit nor harm in the participants who were studied,” Ms Bosch commented. “However, the effect of this treatment in other groups, and the effect of a diet rich in omega-3 fatty acids, were not studied.”

Implications of the ORIGIN Trial
“People have been debating the question of whether there are adverse consequences to long-term insulin use for years,” Dr Gerstein said. “This study provides the clearest answer yet to that question: no, there are not.”

He noted that insulin glargine is the best studied of all glucose-lowering drugs with respect to long-term CV outcomes.

Furthermore, “This is the longest and most extensively conducted study of the effect of insulin versus no insulin on cancers,” Dr Gerstein added, and it showed that insulin glargine had no effect on cancer (HR, 1.0). “There is no evidence whatsoever of an effect of the drug on cancer or cancer death.”

Coinvestigator Lars Rydén, MD, PhD, Professor Emeritus, Cardiology Unit, Department of Medicine, Karo­linska Institutet, Sweden, said that there are many people with coronary artery disease or CV disease who actually have disturbed glucose metabolism. “Some of them walk around with hidden diabetes. For a cardiologist, it is much more difficult to use insulin than for an expert endo­crinologist. So for me, it is 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.”

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Last modified: September 26, 2012
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