Intuitively, controlling diabetic kidney disease should be easy – manage hyperglycemia, manage blood pressure. And the more control, the better, right?
Unfortunately, it hasn’t been so simple.
With effective treatment of hyperglycemia and control of blood pressure, the incidence of end-stage renal disease (ESRD) due to diabetes has reached a plateau in the past 10 years. But the rates of type 2 diabetes continue to increase and along with that, diabetic kidney disease, with its substantial cost. Without kidney disease, people with diabetes might have a far longer lifespan.
But attempts to better manage the devastating complication of diabetic nephropathy with even stricter glycemic and blood pressure control haven’t improved outcomes. Tighter control of blood sugar has led to episodes of severe hypoglycemia, without decreasing risk of death or ESRD. Similarly, driving blood pressure below the usual antihypertensive therapy goals has not reduced the risk of ESRD, even when blockers of the renin-angiotensin-aldosterone system are used.
Failure to impact the risk of ESRD has led researchers to seek new pathways that may result in the kidney disease seen in persons with diabetes. Once identified, such new pathways might result in new therapeutic targets that could ameliorate diabetic nephropathy. Thinking along these lines, researchers had observed that oxidative stress and inflammation play a role in the progression of diabetic kidney disease. That observation led the to question whether giving agents that activate the impaired antioxidant response pathway might slow the progression of kidney disease. And preliminary clinical data indicated that a small molecule called bardoxolone methyl, which had worked in preclinical studies, could actually reduce the serum creatinine in patients with later stages of kidney disease.
Would bardoxolone methyl succeed where our traditional targets – blood pressure, sugar – had failed? A Phase 3 study of this drug, published in this week’s issue of NEJM, showed it did not.
Investigators had enrolled almost 2,200 patients with type 2 diabetes and stage 4 chronic kidney disease –patients who were approaching ESRD, with an estimated glomerular filtration rate of 15-29ml/min/1.73m2. The participants were randomly assigned to receive the study drug, bardoxolone methyl, or a placebo, added to conventional medical therapy. In addition to the primary outcomes of ESRD and death, researchers monitored various measures of kidney disease progression – change in estimated glomerular filtration rate, the amount of protein in their urine – and other outcomes such as weight gain, and admissions to the hospital for heart failure.
But contrary to the suggestions from prior work on this agent, the patients randomly assigned to bardoxolone methyl didn’t have a lower risk of developing ESRD. They were, however, more likely to be hospitalized and even to die from heart failure. With this latter finding, the safety monitoring board for the study recommended stopping the study, which the investigators did.
Moving forward, what can we take from the bardoxolone story? The same increase in heart failure wasn’t observed in the initial, smaller studies, in which muscle spasms and low levels of the electrolyte magnesium were the most common adverse events. Perhaps, as the authors suggest in their discussion, the difference can be attributed to longer period of drug exposure in the present study, or to the fact that the Phase 3 study included patients with more severe kidney disease. Or perhaps the reasons lie elsewhere.
In an accompanying editorial, nephrologists Jonathan Himmelfarb and Katherine Tuttle note that bardoxolone methyl isn’t alone; the failure rate of new drug therapies in clinical trials is greater than 90 percent. “If new therapies for diabetic kidney disease are to benefit patients,” the editorialists write, “fresh approaches will be critical. Given the escalating human and societal costs of diabetic kidney disease, efforts to find new safe and effective therapies remain vital.”