ACCORDION: Does fenofibrate have a legacy effect in lipid-related residual cardiovascular risk in type 2 diabetes?

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Macrovascular Residual Risk Studies

24 April 2017

Long-term follow-up of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid study showed continued cardiovascular benefit in patients originally randomized to fenofibrate with atherogenic dyslipidaemia, defined as triglycerides >204 mg/dl (2.3 mmol/L) and high-density lipoprotein cholesterol (HDL-C) levels <34 mg/dl (0.88 mmol/L).

Elam MB, Ginsberg HN, Lovato LC et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol 2016 Dec 28. doi: 10.1001/jamacardio.2016.4828. [Epub ahead of print]

STUDY SUMMARY

Objective:

To investigate whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes over extended post-trial follow-up of the ACCORD Lipid trial

Study design:

The ACCORD-Lipid trial was a randomized, placebo-controlled, double-blind treatment arm of ACCORD, in which type 2 diabetes patients on simvastatin were randomized to treatment with either fenofibrate or placebo. After completion of the trial, patients were invited to participate in the non-treatment, observation-only ACCORDION study for up to 5 years. Patient recruitment was based on the presence of type 2 diabetes and either pre-existing cardiovascular disease (CVD) or CVD risk factors and HDL-C levels < 50 mg/dl or 1.29 mmol/L (< 55 mg/dl or 1.42 mmol/L for women and African American individuals).

Study population:

In total, 4,644 patients (mean age 62 years, 69% men, 65% with pre-existing cardiovascular disease [CVD], mean low-density lipoprotein cholesterol [LDL-C] levels 99.9 mg/dl) continued in ACCORDION. This cohort was broadly similar to that enrolled in the ACCORD trial.

Efficacy measures:

Primary endpoint: composite of nonfatal myocardial infarction (MI), nonfatal stroke and CVD death.

Secondary endpoints:

· Key secondary composite outcome: primary outcome plus revascularization or hospitalization for congestive heart failure

· Major coronary disease events: fatal coronary event, nonfatal MI, unstable angina

· Individual outcomes: nonfatal MI, nonfatal stroke, total fatal/nonfatal stroke, all-cause mortality, cardiovascular mortality, total fatal/nonfatal congestive heart failure, and CVD-free survival

Methods:

Analyses were conducted using endpoints reported during both the active trial over a mean of 4.7 years and the 5-year passive follow-up period. Kaplan-Meier analysis was used to estimate the number and annual % of patients with a post randomization event, and Cox proportional hazards regression analyses were used to estimate the long-term effect of allocation to fenofibrate or placebo on the primary and secondary outcomes. Analysis was performed for the total study population, as well as the cohort with atherogenic dyslipidaemia, defined as triglycerides >204 mg/dL (2.3 mmol/L) and HDL?C levels <34 mg/dl (0.88 mmol/L

Main results:

Overall, 144 (4.3%) patients in ACCORDION continued or started on fibrate therapy following completion of ACCORD. Over the post-trial follow-up, LDL-C levels decreased slightly (from a mean of 80 mg/dl [2.1 mmol/L] at the first follow-up visit to an average of 77 mg/dl [2.0 mmol/L] in both groups); triglyceride levels decreased in patients orginally allocated to placebo and increased in those originally allocated to fenofibrate (mean of 160.8 mg/dL in both groups); and HDL-C levels decreased to a mean level of 40.5 mg/dL in those originally randomized to fenofibrate (comparable with the original placebo group).

The median total postrandomization follow-up was 9.7 years. The analysis of primary and secondary outcomes showed a similar neutral effect on the total study population. However, reduction in cardiovascular risk observed in the subgroup with atherogenic dyslipidaemia during ACCORD Lipid (~30%) persisted during long-term follow-up in ACCORDION (27%) (Table).

Table. Effect of fenofibrate allocation on cardiovascular risk. Data are given as Hazard ratio (95% CI) except where specified

Outcome	ACCORD Lipid	ACCORDION follow-up	Total follow-up (ACCORD Lipid + ACCORDION)
All patients
Primary	0.92 (0.79-1.08)	0.93 (0.76-1.34)	0.93 (0.83-1.05) p=0.25
Key secondary	0.94 (0.85-1.05)	1.12 (0.95-1.32)	1.00 (0.92-1.10) p=0.32
Subgroup with atherogenic dyslipidaemia
Primary	~30% reduction versus simvastatin alone (12.4% versus 17.3%, p=0.06 for interaction)	-	0.73 (0.56-0.95)*

* P-value for interaction, 0.05

Authors’ conclusion:

The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridaemia and low high-density lipoprotein cholesterol.

COMMENT

The ACCORD Lipid trial did not show a significant effect on cardiovascular risk associated with fenofibrate treatment in type 2 diabetes patients on simvastatin therapy, although there was evidence of potential benefit in patients with atherogenic dyslipidaemia at baseline (1). It has been argued that the lack of benefit in the overall study population may relate to a relatively short treatment duration (<5 years), given that a legacy effect was observed with niacin in the Coronary Drug Project, 9 years after termination of the trial (2).

The results of this report covering passive follow-up of ACCORD Lipid patients in the ACCORDION trial failed to provide support for this hypothesis, and therefore confirmed the lack of benefit observed in the total study population. It is, however, notable that the benefit of fenofibrate suggested in patients with atherogenic dyslipidaemia in ACCORD Lipid persisted during long-term follow-up, reducing cardiovascular risk by 27%, despite the fact that the majority (95%) of patients allocated to fenofibrate did not persist with this treatment during ACCORDION. Thus, this report adds further weight to the rationale for specifically targeting atherogenic ‘diabetic’ dyslipidaemia in type 2 diabetes. Such findings are in line with a meta-analysis of the major fibrate trials showing a similar benefit in patients with this dyslipidaemia, with or without statin treatment compared with those without this dyslipidaemia (3).

While the authors make the point that these prespecified analyses in ACCORDION should be solely regarded as hypothesis generating, the consistency of benefit from accumulating evidence reinforces the key take home messages. First, these results reaffirm atherogenic dyslipidaemia as a contributor to lipid-related residual cardiovascular risk in type 2 diabetes patients. Second, it is clear that targeting this dyslipidaemia may effectively reduce this risk.

References

1. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.

2. Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55.

3. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692–5.

Key words

residual cardiovascular risk; type 2 diabetes; atherogenic dyslipidaemia; ACCORD Lipid; fenofibrate