New treatments for diabetic nephropathy?

Renal failure secondary to diabetes is one of the three microvascular diabetic complications. In many ways, it is the most feared since there is not only the inevitable outcome of end-stage renal failure (ESRF) requiring dialysis or transplantation, but also a greatly increased risk of both small vessel and large vessel complications, especially cardiovascular disease (CVD).

The good news is that rates of development of ESRF in people with type 1 diabetes appear to be declining. We presume that this reflects better (albeit inadequate) levels of glyceamic control along with attention to blood pressure and lipids. The bad news is that diabetes accounts for the majority of patients with ESRF in the United States, due to the epidemic of type 2 diabetes (T2DM).

Current management of diabetic nephropathy (DN) is to reduce progression from microalbuminuria to persistent proteinuria and ultimately declining renal function by reduction of blood pressure (BP) and hyperglycaemia. The primacy of ACE-inhibitors (and ARBs) has, in my view, been over-emphasised and the decline in kidney function is only delayed rather than halted. New treatments are urgently needed.

Trials of bardoxalone, a drug which reduces oxidative stress and inflammation, were promising but have ultimately been halted due to adverse events. Now, four other randomized controlled trials (RCTs) are on-going to assess new agents.

The first, and possibly least-inspiring, is a trial of allopurinol (the PERL study), set up on the basis that elevated uric acid levels are seen in patients with DN. Two other studies are assessing the impact on DN of drugs which are already licensed for the treatment of T2DM. CARMELINA is a CV safety study of linagliptin (vs. placebo) which has secondary renal end-points and has been set up on the basis that DPP-4 is highly expressed in renal tissue. CREDENCE is a five-year study of the sodium-glucose co-transporter inhibitor, canagliflozin, which has primary renal end-points and is examining the hypothesis that the reduction in both GFR and albumin excretion seen with the drug is renoprotective.

Finally, the SONAR study examines the impact of atrasentan, a member of a new class of therapeutic agents (in diabetes, at least), known as endothelin receptor inhibitors. A small pilot study (RADAR) published earlier this year has shown promising impacts on albumin excretion rate, BP and triglycerides, leading to the current RCT in over 4,000 patients. Watch this space….

Professor Steve Bain