For all those who wish to fight the residual risk of nephropathy in patients with type 2 diabetes, the most recently published analysis conducted in participants of the FIELD study are very encouraging.
Dose reductions of fenofibrate, the active treatment assessed in the FIELD study, are recommended in patients with impaired renal function and this PPARα agonist is contraindicated in patients with severe renal disease. This is based on the increase in plasma creatinine occurring early after initiation of fenofibrate therapy. However, the FIELD study not only shows the reversibility of this early increase but also indicates that fenofibrate has a renoprotective effect in patients with type 2 diabetes.
A pre-specified analysis of renal outcomes during treatment and after drug cessation compared changes in renal function, classically assessed by changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes treated for 5 years with fenofibrate or placebo. The FIELD study was also designed to compare the changes in plasma creatinine levels between the active treatment group and the placebo group. As expected, plasma creatinine levels increased early in patients treated with fenofibrate. However, 8 weeks after treatment cessation, plasma creatinine was actually significantly lower in fenofibrate-treated patients. The FIELD investigators state that this early, reversible increase does not reflect a deterioration of renal function but is probably due to an effect of fenofibrate on the synthesis of creatinine.
The other remarkable finding of this analysis is that fenofibrate exerts a renoprotective effect in patients with type 2 diabetes. Indeed, after 5 years of treatment and after the washout period, eGFR decrease was significantly lower in fenofibrate-treated patients than in those allocated to placebo. Although confirmation by further studies is needed, this remarkable effect strongly suggests that we have here a major breakthrough in terms of management of residual risk of nephropathy in diabetic patients. Suffice to say that kidney disease remains the first cause of mortality in patients with diabetes to stress the clinical importance of this finding.
What the FIELD study cannot tell is by which mechanism(s) fenofibrate exerts its renoprotective effect. There is now a growing body of evidence showing that, given on top of background statin therapy, fenofibrate may also reduce the residual risk of other microvascular complications of diabetes. We may speculate that a common mechanism explains why the FIELD and ACCORD studies demonstrated that fenofibrate reduces nephropathy, retinopathy, and amputations with a predominantly microvascular etiology in patients with type 2 diabetes. Whether the effects on lipids and/or the pleiotropic effects on blood vessels of this PPARα agonist are at the origin of its clinical effects remains to be clarified.
In this context, results of the REALIST studies, which are part of the R3i research program, are awaited with great interest. In particular, the REALIST microvascular study will show whether atherogenic dyslipidemia is associated with the microvascular complications of diabetes, in particular diabetic nephropathy. These results should be released very soon.
Supposing that REALIST shows a significant association of low HDL-C and/or elevated TG levels with microvascular complications of diabetes, two issues will remain to be addressed: are these two abnormalities risk factors of microvascular complications or just markers of the underlying pathophysiology? And, will interventions that increase HDL-C or lower TG levels result in significant reductions of microvascular risk?
Answering the first question will require an extensive amount of research. Regarding HDL-C and TG as therapeutic targets, the unexpected negative results of the AIM-HIGH trial remind us that clinical benefits are not the natural consequence of demonstrated effects on the components of atherogenic dyslipidemia. Only well-conducted clinical outcome trials can produce the evidence on which modern medicine is based. This is the general rule to which all therapeutic agents currently developed with the aim of reducing Residual Vascular Risk will be submitted.
On the same token, a study designed to assess the clinical efficacy of fenofibrate in a population of diabetic patients presenting with atherogenic dyslipidemia would be very informative. No such study has been hitherto conducted. The FIELD and ACCORD study included unselected diabetic patients and analyses performed in those with and without atherogenic dyslipidemia were only secondary objectives.
What will be the next advances in the area of residual vascular risk reduction? One should not forget that adoption of a healthy lifestyle by people at risk will remain the first step of any RVR reduction strategy. But, hopefully, new, effective pharmacological agents will emerge. PPARα/γ agonists, CETP inhibitors, fish oils and other molecules are currently in development. Whether using PCSK9 inhibitors – to overcome the self-limiting effect of statins and thus reduce more effectively LDL-C – may help reduce RVR is also a topic of interest. But whatever their mechanisms of action, all these agents will have to demonstrate clinical benefits before being recommended in clinical practice.
1. Davis TME, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011;54:280–90.
2. National Institutes of Health. NIH stops clinical trial on combination cholesterol treatment [press release]. May 26, 2011. http://www.theheart.org/article/1231453.do