When added to statins, fenofibrate failed to improve outcome in patients with type 2 diabetes. In addition, lowering systolic blood pressure to 120 mm Hg or lower was no better than the traditional target of 140 mm Hg. These are the main results of the two arms of ACCORD (Action to Control Cardiovascular Risk in Diabetes Study), which were presented this morning at the ACC in Atlanta and published simultaneously in the New England Journal of Medicine.
Together with the NAVIGATOR trial, the results of ACCORD suggest that the prevention and treatment of type 2 diabetes, already a major concern, is likely to be an even more difficult task, as once promising approaches show limited or no beneficial effects.
In the fenofibrate arm of the study, 5,518 patients with type 2 diabetes taking simvastatin were randomized to either fenofibrate or placebo and followed for 4.7 years. There was no difference between the two groups in the annual rate of the primary outcome, which was composed of nonfatal MI, nonfatal stroke, or CV death (2.2% in the fenofibrate group versus 2.4% in the placebo group, HR 0.92, CI 0.79-1.08, p=0.32).
According to prespecified analyses of subgroups, the investigators reported a possible benefit for men and possible harm for women (interaction p =0.01) and a possible benefit for patients who had both high baseline triglycerides and low HDL cholesterol (interaction p=0.057). The investigators concluded that “these results do not support the routine use of combination fibrate-statin therapy rather than statin therapy alone, to reduce cardiovascular risk in the majority of patients with type 2 diabetes who are at high risk for cardiovascular disease.”
In response to a question from the editors of CardioExchange, Henry Ginsberg, who presented the results of the fibrate study, discussed the intriguing subgroup result in women:
On further analyses (not done yet), I think that this will be related to a greater proportion of women without prior CVD and with lower triglyceride levels and higher HDL levels compared to the men. In our dyslipidemic subgroup, there was no gender difference. I would suspect (but have not looked yet) that more women in our dyslipidemic group had prior CVD. Notably, in the FIELD study, there was no gender difference.
In the blood pressure control arm of the study, 4,733 type 2 diabetics were randomized to the standard target systolic blood pressure of 140 mm Hg or lower or a more aggressive target of 120 mm Hg or lower. Although at one year blood pressure was significantly lower in the intensive-therapy group (119,3 mm Hg versus 133.5 mm Hg), there was no significant difference between the groups in the annual rate of the primary composite outcome (nonfatal MI, nonfatal stroke, or CV death), 1.87% in the intensive therapy group versus 2.09% in the standard-therapy group.
The annual rate of stroke, a prespecified secondary outcome, was significantly reduced from 0.53% in the standard therapy group to 0.32% in the intensive therapy group (HR 0.59, CI 0.39-0.89, p=0.01). There were more serious adverse events caused by drug therapy in the intensive treatment group than in the standard treatment group (3.3% versus 1.3%, p<0.001).
The stroke results, according to the investigators, were consistent with the results of previous meta-analyses. The authors calculated that 89 patients would need to receive intensive therapy for 5 years to prevent one stroke.
In an accompanying editorial, Peter Nilsson wrote that “unfortunately, the design and results of the ACCORD BP study leave unresolved the issue of the optimal blood-pressure target in patients with diabetes.” Nilsson also discusses the NIH’s ongoing SPRINT (Systolic Blood Pressure Intervention Trial); since it has a design similar to ACCORD BP but with patients without diabetes, he writes that “it is worth considering whether the funds would be better used for other studies” or for programs to improve hypertension control.
Sanjay Kaul sent the following comment to CardioBrief:
“The results of ACCORD are not entirely unexpected given the mixed track record of the fibrate class of lipid modifying agents. The results in the subset of individuals with elevated TG and low HDL are interesting. Even though this analysis was prespecified, and despite the fact that it makes biological sense, a positive interaction in a subgroup when the overall trial results are null, is difficult to interpret. Previous trials with fibrates (Helsinki Heart Study, Bezafibrate Infarction Protection Study, FIELD) have also yielded positive results, illustrating the requirement of a permissive environment of elevated TG or low HDL for these agents to be effective. Greater improvements in HDL and TG levels in this subgroup might contribute to these results. Perhaps the proper place for fenofibrate is in this particular subgroup of patients, i.e., patients with elevated TG and low HDL while on statins. In ACCORD, about 20% (941/4548) of patients had this profile.”