22 April 2010
The ACCORD lipid trial in patients with type 2 diabetes concluded that intensifying lipid modification therapy through combination use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce the rate of fatal CV events, non-fatal myocardial infarction or stroke, as compared with simvastatin alone.
Both the ACCORD BP and lipid trials add to ACCORD’s message on glycaemic control; over-intensification of treatment in type 2 diabetes mellitus provides limited or no overall benefit, and may increase the risk of adverse events.
Level of evidence: Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
NICE guidance on the management of type 2 diabetes recommends that if the cardiovascular (CV) risk is high (as is usual in people with type 2 diabetes) consider adding a fibrate to statin therapy if triglyceride levels remain in the range 2.3 to 4.5mmol/litre despite statin therapy. Health professionals should continue to follow NICE guidance with respect to management of lipid levels in diabetes, but may wish to consider the implications of additional information now available from the ACCORD lipid study when discussing with patients the risks and benefits of adding a fibrate to statin therapy.
What is the background to this?
As the NICE full guideline for diabetes notes, people with type 2 diabetes are at increased CV risk which can be reduced by suitable lipid modification. The hypothesis tested by the ACCORD lipid trial was that in high-risk patients with type 2 diabetes, combination treatment with a fibrate (both to raise HDL cholesterol levels and to lower triglyceride levels) and a statin (to reduce LDL cholesterol levels) would reduce the rate of CV events, as compared with treatment with a statin alone. From within the cohort of patients recruited to the ACCORD blood glucose study, patients were also recruited to two other trials to evaluate the effect of intensifying either systolic blood pressure (BP) control (ACCORD BP trial – see related blog or lipid-modification therapy (ACCORD lipid trial), in people with type 2 diabetes.
What does this study claim?
The ACCORD lipid trial found that combination therapy with fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of CV events, as compared with simvastatin alone. The annual rate of the primary outcome (major fatal or non-fatal cardiovascular event) was 2.2% in thefenofibrate group and 2.4% in the placebo group (hazard ratio [HR]0.92; 95% confidenceinterval [CI]0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome, including total mortality.
The study drug was discontinued by 66 patients (2.4%) in the fenofibrate group and 30 (1.1%) in the placebo group because of a decrease in the estimated GFR. At the last clinic visit, 440 patients (15.9%) in the fenofibrate group and 194 (7.0%) in the placebo group were receiving a reduced dose of either fibrate or placebo because of a decreased estimated GFR (P values not provided). There was a lower incidence of both microalbuminuria and macroalbuminuria in the fenofibrate group than in the placebo group. Despite this there was no significant between-group difference in the incidence of hemodialysis and end-stage renal disease (75 patients in the fenofibrate group vs. 77 in the placebo group).
How does this relate to other studies?
Previously the FIELD study suggested that fenofibrate did not significantly reduce the risk of the primary outcome of coronary events in patients with type 2 diabetes mellitus. As previous fibrate studies in diabetes, or in those without diabetes, did not evaluate the effectiveness of fibrates in patients who were also taking a statin, the ACCORD lipid trial was designed to examine this.
The trial investigated the effectiveness of fenofibrate in patients with type 2 diabetes mellitus who were also taking open-label simvastatin: assessed by giving patients masked fenofibrate or placebo. The expectation was that fenofibrate would increase plasma HDL cholesterol levels and reduce plasma triglyceride levels in patients already receiving simvastatin therapy and that this would result in additional CV benefits. However, the rate of the primary outcome (a composite of non fatal MI or stroke and all-cause CV mortality) did not differ significantly between the fenofibrate group and the placebo group.
The authors claim that there was a suggestion of heterogeneity according to baseline lipid levels found in the group of patients who had both a triglyceride level in the highest third (median triglyceride level 284 mg per decilitre [3.21 mmol per litre]) and an HDL cholesterol level in the lowest third (mean 29.5 mg per decilitre [0.76 mmol per litre]). Despite not reaching conventional levels of statistical significance (P=0.057), the point estimate from this subgroup is similar to those in post-hoc subgroup analyses performed in previous fibrate trials (Helsinki Heart Study, Bezafibrate Infarction Prevention, and FIELD). This supports the view that the addition of fenofibrate to a statin may benefit patients with type 2 diabetes who have substantial dyslipidaemia. This is consistent with NICE guidance on the management of type 2 diabetes that recommends that if the CV risk is high (as is usual in people with type 2 diabetes) consider adding a fibrate to statin therapy if triglyceride levels remain in the range 2.3 to 4.5mmol/litre despite statin therapy (plus appropriate dietary advice and adherence to that advice). The compromising of renal function with the combination, as seen in this study, would perhaps be a balancing factor in decision making, even though an increase in serious renal complications was not found.
For the entire ACCORD lipid cohort only sex had a significant interaction with treatment: men seemed to benefit from fenofibrate therapy, whereas there was a trend toward harm among women. This is in contrast to the results of the FIELD study, in which there was no significant interaction effect between treatment and sex on outcome.
The ACCORD lipid trial concluded that combination therapy with the use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of cardiovascular events, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority patients with type 2 diabetes.
Design: Randomised controlled trial.
Patients: Of the 10,251 patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease who were enrolled in the ACCORD study, 5,518 participants were enrolled in the ACCORD lipid trial, with 2,765 assigned to receive fenofibrate plus simvastatin, and 2,753 assigned to receive placebo plus simvastatin. Baseline characteristics were similar between the two groups (all P>0.05). The mean age was 62 years, and 31% of the patients were female. Thirty-seven percent had a history of a CV event, and about 60% were taking a statin before enrollment.
Intervention and comparison: Patients were randomised to receive combination therapy with open-label simvastatin plus a fenofibrate or open-label simvastatin plus matching placebo. The primary outcome was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or death from CV causes. The mean follow-up was 4.7 years.
Outcomes and results: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (HR 0.92; 95% CI 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (HR 0.91; 95% CI 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high density lipoprotein cholesterol (P=0.057 for interaction). However, the latter did not reach conventional levels of statistical significance.
Sponsorship: National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.
You can find more information on management of hyperlipidaemia, and the rest of the evidence base for fibrates, on the lipids section of NPC.
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