Insulin Has Small Effect, Fish Oil Has None on IMT: GRACE

Marlene Busko

April 12, 2013

In a study of patients with early type 2 diabetes who were at high risk for cardiovascular events, those who received daily insulin-glargine injections had modestly improved measures of atherosclerosis progression, whereas others who took daily omega-3 polyunsaturated fatty-acid capsules did not obtain this benefit.

These findings, from the Glucose Reduction and Atherosclerosis Continuing Evaluation (GRACE), a substudy of the Outcome Reduction with an Initial Glargine Intervention  (ORIGIN) trial, were published online April 5 in Diabetes Care. Part of the study was presented at the European Society of Cardiology 2012 Congress.

GRACE examined the annual change in carotid artery intima media thickness (IMT), a surrogate for atherosclerosis progression, during 4.9 years of follow-up in a subset of close to 1200 patients from the more than12,000 patients in ORIGIN who were randomly assigned to insulin glargine vs standard care or omega-3 fatty acid vs placebo.

The patients were aged 50 years or older with known cardiovascular disease or risk factors; 90% had early type 2 diabetes, while the rest had prediabetes.

Lead investigator Eva Lonn, MD, from McMaster University, Hamilton, Ontario, told Medscape Medical News that GRACE showed that in this patient population, insulin glargine "was safe [and] well tolerated; it reduced fasting glucose and glycated hemoglobin and also slightly reduced triglycerides, as expected; [it had] no effect on blood pressure or cholesterol; [and] there was a modest benefit on carotid intima media thickness."

Most participants taking insulin glargine maintained "very tight glucose control, with a glycated hemoglobin of 6% or less throughout the study," which was a much tighter glucose control than the control group that used lifestyle changes (diet and exercise) and oral glucose-lowering drugs, she added. Hypoglycemia events were low.

The trial also showed that to prevent atherosclerosis progression in this patient population, omega-3 fatty-acid supplements "are not beneficial and should not be recommended," she said. A meta-analysis of clinical trials of omega-3, which was recently published in the Journal of the American Medical Association, came to a similar conclusion, she noted.

"It is possible that earlier studies that [indicated] a benefit [of omega-3 supplements] showed it in the absence of aggressive background therapy" with statins and blood-pressure–lowering agents, Dr. Lonn said. Perhaps "most patients eat too much...and maybe in a malnourished population, it might be different."

'Modest Benefit on Carotid IMT'

GRACE examined data from participants in ORIGIN who had at least 1 carotid ultrasound: 580 participants were randomly assigned to insulin glargine, 604 to standard glycemic care, 585 to omega-3 fatty-acid supplements, and 599 to placebo (olive oil). Patients in the insulin-glargine group gave themselves a daily evening injection of insulin glargine (Lantus, Sanofi), adjusting the dose to attain a target fasting plasma glucose level of 5.3 mmol/L. Each day, patients in the omega-3 supplement group took a 1-g capsule of Omacor (Pronova BioPharma) that contained 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid, primarily derived from fish oil.

The participants had annual carotid ultrasounds for a median follow-up of 4.9 years. The study's primary outcome was change in maximum carotid IMT for 12 segments from the carotid arteries, and the secondary outcomes were change in the IMT of the common carotid segment and in the common carotid plus bifurcation segments.

Compared with patients in the control group, patients receiving insulin glargine had a statistically nonsignificant 11% reduction in the primary outcome, but they also had significant 18% and 20% reductions in the 2 secondary outcomes.

There were no differences in primary or secondary carotid IMT outcomes among patients taking the omega-3 capsules vs placebo.

"We didn't compare [insulin glargine] with metformin or other pills, so we can't claim it was better or worse," Dr. Lonn said.

The group is investigating long-term effects on hard cardiovascular outcomes in a 5- to 10-year follow-up study, the ORIGIN and Legacy Effects (ORIGINALE) trial.

Data Reaffirm Insulin's Value, Fish Oil's Deficiencies

Asked to comment on GRACE, Sue Kirkman, MD, from the University of North Carolina, Chapel Hill, said that the findings from the patients who took insulin glargine are consistent with those of ORIGIN, the longer parent study. These results "provide a little bit of reassurance that insulin certainly doesn’t seem to be bad for atherosclerosis," contrary to what some clinicians may have believed, she said.

Similarly, consistent with the findings from ORIGIN, the results from the patients who took omega-3 supplements "just really show that there doesn't seem to be any benefit, [even though] for a long time a lot of providers were recommending fish-oil supplements for people with hyperglycemia and high cardiovascular risk," Dr. Kirkman said.

The study was funded by Sanofi. Pronova BioPharma provided capsules containing n-3FA and placebo. Dr. Lonn received grant support from Sanofi. The financial disclosures of the other authors are listed in the article. Dr. Kirkman has disclosed no relevant financial relationships.

Diabetes Care. Published online on April 5, 2013. Abstract