Neither n-3 fatty acid supplements nor glargine reduced CV events in patients with dysglycemia

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomized about 12,000 patients with cardiovascular (CV) risk factors and dysglycemia to basal insulin glargine or usual care and daily n-3 fatty acid supplementation or olive oil placebo. Patients in the glargine and usual care groups had similar rates of cardiovascular events and mortality, and the fatty acid supplements provided no benefits over placebo.

The glargine and fatty acid studies were published in the New England Journal of Medicine on July 26. The following commentary by Ellis Lader, MD, was published in the ACP Journal Club section of the Sept. 18 Annals of Internal Medicine.

The first of this pair of interesting studies by the Population Health Research Institute asks: Are fasting glucose levels tightly controlled with insulin beneficial in patients with or at high risk for vascular disease early in the course of diabetes? This is asked in the context of several recent trials that bring into question the benefit of tight glycemic control. Only one trial has shown a reduction in events with aggressive glycemic control in patients with type 1 diabetes. In contrast, the ACCORD trial found an increase in mortality with aggressive glycemic control in patients with type 2 diabetes; two other trials found no reduction in event rates. The ORIGIN trial also did not find any CV benefit with aggressive fasting glucose control. Is tight glycemic control no longer a valid goal? Given epidemiologic evidence for the association of higher glucose levels with increased CV risk and support for the biologic plausibility from in vivo and in vitro studies, clinicians can still support good glycemic control as a therapeutic target. However, which hemoglobin A_1c (HbA_1c) targets to aim for and which predictors identify patients at risk for hypoglycemia remain priority questions. In the first ORIGIN trial, the end-of-study, between-group difference in HbA_1c levels was not large (median 6.2% vs 6.5%), yet the absolute increase in severe hypoglycemia was nearly 4%. One wonders whether outcomes would have been different if metformin had been used instead of insulin, given recent data from the BARI-2D trial. Finally, would this cohort of patients have been better served by a weight loss and exercise program, which might have reduced the incidence of diabetes by 58% with no risk for hypoglycemia?

The second study assessed the effects of supplemental n-3 fatty acids in the same population. n-3 or omega(ω)-3 both refer to the location of the first double bond in the fatty acid molecule. There is considerable, mainly observational, evidence that fish consumption, particularly fatty fish, can reduce CV disease and stroke, hence the interest in EPA and DHA (ω-3) supplementation, both of which are found in fish and fish oil. α-linolenic acid is found in nuts and is incompletely and undependably converted to EPA and DHA, so it is not usually considered in supplementation trials. ω-6 fatty acids may feed into biosynthetic pathways of inflammatory mediators and are also not generally supplemented. The ORIGIN investigators used a prescription-strength supplement that contained more ω-3 fatty acids than over-the-counter fish oil products. No benefit was shown other than a small reduction in triglycerides, which have never been associated with reductions in CV risk. Again, we have a good dietary observation proven ineffective when translated into a pill or capsule. Perhaps dietary fish sources contain other substances (not available in fish oil supplements) that improve CV health; fish consumption may be a marker for heart-healthy habits that improve outcomes or may displace other less healthy food from the diet; or the complex associations of ω-3 fatty acids with other substances in intact fish may deliver nutrients in ways that make them function differently from when they are provided in a purified form.

The take-home message seems to be that, at least in this population, there is no benefit to fish oil supplementation. But maybe we should all eat more fish!