Macrovascular Residual Risk Studies

COMMENT

To the authors’ knowledge, this was the first meta-analysis to compare the efficacy of lipid-lowering therapy for cardiovascular risk reduction in diabetic versus non-diabetic patients.
The authors selected double-blind randomized clinical trials allowing calculation of results in both subgroups. These criteria excluded some major studies such as WOSCOPS, assessing pravastatin, BIP, assessing bezafibrate, and CARDS, assessing atorvastatin, which had no subgroups of patients with diabetes.

Primarily a meta-analysis on the efficacy of standard-dose statin therapy

Although studies investigating the efficacy of statins or fibrates were considered for inclusion, the active treatment was a fibrate (gemfibrozil) in only 2 of the 12 studies finally selected. The 2 fibrate studies (VA-HIT and HHS) included a total of 6,598 patients, whereas 74,227 patients had been included in the 10 statin trials. In addition, no trials assessing the efficacy of high-dose statin therapy had been published at that time. Therefore, results of this meta-analysis are primarily related to the efficacy of statins prescribed at standard doses.

Similar relative risk reductions were seen for primary outcomes in both diabetic and non-diabetic patients and in primary and secondary prevention. However, Figure 1 shows that diabetic patients had a significantly higher absolute risk of major coronary events than non-diabetic patients. Thus, absolute risk reduction was higher in diabetic patients who were those who benefited most of the active treatments.
The huge discrepancy between the number of patients included in the statin and fibrate trials precludes any valid comparison between the efficacy of monotherapies using one or the other class of drugs. In addition, there were only 135 diabetic patients in the HHS study of gemfibrozil included in the primary prevention analysis; the impressive 68% CHD risk reduction reported in these patients was not significant because of lack of statistical power. Nevertheless, in the same study, gemfibrozil reduced CHD risk by 30% in the 3,946 patients without diabetes. Regarding secondary prevention, gemfibrozil reduced CHD risk by 27% and 17% in patients with and without diabetes, respectively.

This suggests that risk reduction was more or less of the same magnitude with gemfibrozil and with statins, despite different impact on lipid profile. Although the authors do not elaborate on this point, a greater decrease in LDL-C was seen in patients on statins and a greater decrease in triglycerides was seen in patients on gemfibrozil.

Lipid-targeted monotherapies insufficiently reduce vascular risk in patients with and without diabetes

This meta-analysis is an important source of information about the magnitude of the residual risk left unaddressed following a lipid-lowering monotherapy, mainly based on statins: 79% and 77% of major coronary events were not prevented in diabetic and non-diabetic patients, respectively, irrespective of the prevention setting.

One of the most promising strategies to reduce the modifiable component of this huge residual vascular risk is to take advantage of the differential effect of statins and fibrates on atherogenic lipid fractions. In the SAFARI trial,1 a simvastatin-fenofibrate combination was significantly more effective than simvastatin alone at reducing LDL cholesterol and triglycerides and increasing HDL cholesterol. Determining whether such a combination can improve clinical outcomes and significantly reduce residual vascular risk was one of the objectives of the ACCORD trial.

Table 1. Numbers of patients with and without diabetes included in gemfibrozil and statin trials
included in the meta-analysis by Costa et al.

 

Figure 1: Event rate for major coronary event:
A in primary prevention trials (mean weighted follow-up 4.5 years)    
B in secondary prevention trials (mean weighted follow-up 5.1 years)