Effects of Combination Lipid Therapy in the Management of Patients With Type 2 Diabetes Mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

Abstract

The evidence base demonstrating that statins reduce major events, including in people with diabetes mellitus,1 is arguably as robust as for any cardiovascular therapy. However, many individuals still experience end points despite the use of statins (the Figure). This “residual risk,” which is much higher in people with coexistent cardiovascular disease, is probably most appropriately expressed in absolute terms, acknowledging the development of atherosclerosis over decades rather than the duration of trials and its multifactorial causation. However, the residual risk provides the rationale for testing other lipid-modifying therapies in combination with statins. Figure. Vascular event rates, risk reduction, and residual risk despite statin use in major randomized controlled trials of statins in people with diabetes mellitus. CVD indicates cardiovascular disease; RRR, relative risk reduction; and ARR, absolute risk reduction. People with diabetes mellitus have both qualitative and quantitative lipid changes. They include increased levels of triglycerides, small dense low-density lipoprotein (LDL) particles, and apolipoprotein B, as well as a decrease in levels of high-density lipoprotein (HDL) cholesterol. Fibrates, which are peroxisome proliferator receptor-α agonists, not only reduce triglyceride levels and possibly LDL cholesterol and chylomicron remnants and elevate HDL cholesterol but also are anti-inflammatory. The major beneficial effect of statins is to decrease LDL cholesterol. However, lower levels of HDL cholesterol and possibly increasing levels of triglycerides still denote elevated risk in those taking statins,2,3 even when LDL cholesterol levels are very low,2 and particularly in those with diabetes mellitus.3 The hypothesis tested was whether, on a background of simvastatin 20 to 40 mg, major vascular events were reduced by fenofibrate, dosed according to baseline glomerular filtration rate.4 Overall, among 5518 subjects (mean age, 62 years; 31% female; …