ACCORD Lipid: Interview with Dr Henry Ginsberg

HDL Forum spoke with Dr Henry Ginsberg, Principal Investigator of the ACCORD Lipid Trial, a late-breaker clinical trial at the American College of Cardiology Scientific Sessions, Atlanta, USA, 14-16 March, 2010.

The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010. Published on-line 14 March 2010. DOI:10.1056/NEJMoa1001282.

 ACCORD Lipid showed that adding fenofibrate to simvastatin did not significantly impact on primary or secondary cardiovascular outcomes for the total study population. Patients treated with the combination had an 8% lowering of primary outcome events (a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) versus simvastatin monotherapy (hazard ratio 0.92, 95% CI 0.79-1.08, p=0.32). However, as with other trials reported at ACC, doctors should look into the fine print. 

 And among the fine print was an interesting finding relating to a predefined subgroup analysis in patients with high-density lipoprotein cholesterol (HDL-C) levels in the lowest tertile (HDL-C ¡Ü34 mg/dL or 0.88 mol/L) and elevated triglycerides in the highest tertile (¡Ý204 mg/dL or 2.3 mmol/L). In this group, there was a strong trend to an interaction between the presence of this combination lipid phenotype and treatment (p=0.057) with the suggestion of a 31% additional reduction in the primary outcome compared with simvastatin alone. Individual tertile analyses were also performed for HDL-C and triglycerides, but did not show significant interactions with treatment. 

 HDL Forum discussed findings and implications of ACCORD Lipid with Dr Ginsberg.

 Will ACCORD Lipid impact on the management of dyslipidemia in type 2 diabetes?

 Dr Ginsberg: In my opinion, I believe that clinicians should not only measure low-density lipoprotein cholesterol (LDL-C) routinely but also HDL-C and triglycerides. In those type 2 diabetes patients with low levels of HDL-C (in the low 30¡¯s mg/dL) and elevated triglycerides (>200 mg/dL), after statin therapy has optimized their LDL-C level, add-on fenofibrate therapy could be considered.  This approach is consistent with current guidelines. ACCORD Lipid therefore reinforces guideline recommendations. Combination fenofibrate-statin treatment should be targeted to this selected group of patients with significant dyslipidemia.

 In routine practice, what proportion of patients is likely to have this lipid profile?

Dr Ginsberg: In ACCORD Lipid, 17% of patients met these criteria for low HDL-C and elevated triglycerides. Taking a conservative estimate for a prevalence of 15%, if 25 million Americans have diabetes, then we are talking about 4 million people affected.  Therefore the proportion of patients likely to be affected overall is substantial.

 The other subgroup analysis of interest was that showing a gender interaction, with evidence of benefit in men but potential harm in women with fenofibrate-simvastatin combination treatment. Does that mean that fenofibrate should not be used in women?

 Dr Ginsberg: First, it is noteworthy that in the patient population that should be targeted for add-on fenofibrate (low HDL-C and elevated triglycerides), this gender issue disappeared. This suggests that type 2 diabetic women with high triglycerides and low HDL-C obtain the same benefit from fenofibrate-statin combination therapy as men in this subgroup. However, I believe that if type 2 diabetic women do not have elevated triglycerides (.>200 mg/dL) or low HDL-C (<35 mg/dl), they should not be considered for fenofibrate therapy.

Clearly we need to investigate this gender effect further. Additional analyses are underway to evaluate reasons for this potential excess risk in women. For example, did this effect relate to the fact that women in the study were less likely to have suffered a prior cardiovascular event, or had higher HDL-C levels?

 Looking at the ACCORD Lipid data, can we say anything about the relative importance of low HDL-C and elevated triglycerides?

 Dr Ginsberg: In terms of lipid-modifying efficacy, fenofibrate is more efficacious in lowering triglycerides (especially in patients with high triglycerides) than in raising HDL-C levels.  However, I think we need to go back to the data to see if we can dissect out which effect is more relevant to reducing residual cardiovascular risk, low HDL-C or elevated triglycerides.

 What ongoing studies will help to address this issue?

 Dr Ginsberg: There are two outcomes studies with niacin (nicotinic acid) added to statin therapy in dyslipidemic patients at high cardiovascular risk, AIM-HIGH and HPS2-THRIVE. Both studies are likely to report in 2013. I am particularly interested in the results of AIM-HIGH, given that the patient population is very much like the group which we had planned for in ACCORD Lipid. 

 The larger study, HPS2-THRIVE has enrolled about 20,000 patients. This study is evaluating the effect of niacin combined with laropiprant, an antiflushing agent. However, there is no niacin control (to evaluate the safety of laropiprant). Additionally the study population is mixed (Chinese and European). Safety may be a particular issue.

 After this, there are studies with the cholesteryl ester transfer protein (CETP) inhibitors, dalcetrapib and anacetrapib. These will be critical studies in terms of the ¡°HDL-hypothesis¡±.

 Is there an ideal category of patients that we should aim to target?

 Dr Ginsberg: In the ideal world, the patient population for study should be those with low HDL-C (<40 mg/dL in men, <50 mg/dL in women) and elevated triglycerides (lower limit of 175-180 mg/dL). Targeting this dyslipidemia could result in 25% additional benefit in terms of cardiovascular risk reduction.

 Finally, your take home message from ACCORD Lipid?

 Dr Ginsberg: I think that ACCORD Lipid has demonstrated that dyslipidemia management in type 2 diabetes requires a targeted approach based on the lipid profile of individual patients. The large majority of patients will not likely benefit from the addition of a fibrate after LDL-C is reduced to goal with a statin. However, I believe that patients with both low HDL-C and elevated triglycerides do require additional intervention, which is consistent with current guidelines.

For the moment, the subgroup analysis from ACCORD Lipid suggests that adding fenofibrate can provide additional cardiovascular risk reduction in patients on a statin who still have both low HDL-C and elevated triglycerides.  However, further investigation is needed to verify this. We await the results of ongoing trials with niacin to evaluate the relative importance of HDL-C and triglycerides to residual cardiovascular risk in type 2 diabetes patients.