Conference Coverage

GRACE: Insulin Glargine Fails to Halt Atherosclerosis Progression



MUNICH – Insulin glargine and omega-3 fatty acids failed to retard carotid atherosclerosis progression in patients with diabetes or prediabetes at high cardiovascular risk in the GRACE trial.

Compared with standard glycemic care, insulin glargine provided a nonsignificant difference of –0.0030 mm/year in the primary end point of rate of change in maximum carotid intima media thickness (CIMT) at 12 carotid sites.

For the secondary outcomes, which included four segments of the common carotid artery and eight segments of the common carotid and bifurcation sites, the long-acting basal insulin resulted in slight but statistically significant annualized differences in maximum CIMT of –0.0033 mm/year and –0.0045 mm/year, respectively.

Patrice Wendling/IMNG Medical Media

Dr. Eva Lonn

"Although not conclusive, our study suggests a beneficial effect of insulin glargine on vascular disease progression," Dr. Eva Lonn said at the annual congress of the European Society of Cardiology. "These findings raise the possibility that longer term treatment might result in cardiovascular event reduction."

This hypothesis is currently under evaluation in extended follow-up of ORIGIN (Outcome Reduction With an Initial Glargine Intervention), the parent trial of GRACE (Glucose Reduction and Atherosclerosis Continuing Evaluation).

With regard to omega-3 fatty acids, no significant differences were observed for the primary outcome (difference 0.0009 mm/yr), or the secondary outcomes in the common carotid (–0.0004 mm/yr) and common carotid and bifurcation sites (0.0022 mm/year), reported Dr. Lonn, professor of medicine at McMaster University and director of the vascular research ultrasound laboratory at the Population Health Research Institute, both in Hamilton, Ontario.

Given the neutral effect of omega-3 fatty acids, the focus in diabetes should be on proven therapies such as lipid-lowering and blood pressure–lowering drugs and glycemic control, she said in an interview. There is no harm, however, should patients wish to take the supplements.

Discussant John E. Deanfield said there was no evidence of benefit or harm from either treatment, and pointed out that the results of GRACE are concordant with those reported from the larger ORIGIN trial.

In that trial, insulin glargine reduced the risk of developing type 2 diabetes by 28% among patients with prediabetes, but had a neutral effect on cardiovascular outcomes (N. Engl. J. Med. 2012;367:319-28). Omega-3 fatty acids reduced triglyceride levels, but also failed to reduce the rate of cardiovascular events (N. Engl. J. Med. 2012;367:309-18).

After a median clinical follow up of 6.2 years in GRACE, Dr. Lonn reported that rates of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were similar between the insulin glargine and standard care groups (18.6% vs. 16.9%), as was all-cause mortality (17.1% vs. 17.4%).

Dr. Deanfield said the lack of benefit from either treatment was disappointing and suggested the GRACE authors might have been better served by choosing the common carotid segment as their primary outcome, rather than one of their secondary outcomes.

He also noted that there is controversy over whether IMT itself is the best measure of structural arterial disease, with a recent meta-analysis demonstrating a lack of relationship between progression of CIMT and hazard for cardiovascular events (Lancet 2012;379:2053-62).

Patrice Wendling/IMNG Medical Media

Dr. John E. Deanfield

"Finally, the reporting strategy for IMT in this trial – which shows the change in IMT levels over 5 years without giving us, as yet, the baseline absolute levels of IMT – is interesting and might be missing a trick in terms of our understanding of this signal," said Dr. Deanfield, professor of cardiology at University College London.

A total of 1,184 patients recruited from 32 centers in seven countries received open-label insulin glargine injection or standard glycemic care, and double-blinded therapy with a 1-g/day omega-3 supplement containing eicosapentaenoic acid 465 mg plus docosahexaenoic acid 375 mg or matching placebo.

Patients had to be at least 50 years old (mean age 63 years) and have prediabetes or newly diagnosed type 2 diabetes or early type 2 diabetes, and be at high cardiovascular risk.

At baseline, 49% had a history of cardiovascular disease, 80% had hypertension, 60% had hyperlipidemia and 10% were current smokers. CIMT efficacy results were based on 1,091 patients with at least one adequate carotid ultrasound. Median follow-up from baseline to last CIMT scan was 5 years.

Insulin glargine was well tolerated and safe, with the most common reasons for discontinuation being patient preference in 76 patients and hypoglycemia in 9, Dr. Lonn said.

The study was funded by Sanofi; omega-3 fatty acid supplements and matching placebo were provided by Pronova BioPharma. Dr. Lonn reported research grants, lecture fees, and/or consulting fees from Astra-Zeneca, Canadian Institutes of Health Research, GlaxoSmithKline, Heart and Stroke Foundation of Canada, Merck, Novartis, Servier, and Sanofi. Dr. Deanfield reported consulting and speakers bureau participation for Pfizer, Merck, Roche, Takeda, Novartis, Sanofi, and Danone.

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