SGLT2 inhibitors and Atrasentan- New options to slow CKD progression in Diabetes

Sodium-glucose transport inhibitors (SGLT2 inhibitors) and Atrasentan are two new and emerging treatment options to slow Chronic kidney disease (CKD) progression in Diabetics. The SGLT2 inhibitors have shown an overwhelming beneficial effect in lowering the risk of end-stage kidney disease. Similarly, Atrasentan which was initially developed to treat cancer has been found to reduce albuminuria and help in curbing the progression of CKD.

Chronic kidney disease (CKD) is a growing worldwide public health problem and diabetes is the leading cause of end-stage renal disease globally. About 850 million people worldwide are affected by kidney disease- a worrying figure, and one that continues to rise. In about one-third of these patients, around 280 million people, diabetes is the cause of kidney failure.DKD still develops in approximately 30% of individuals with type 1 diabetes and nearly 50% of those with type 2 diabetes.

Chronic kidney disease is recognized by an increasing serum creatinine over time. However, some patients may have a normal creatinine early in the course of their chronic kidney disease (CKD). Individuals with abnormal urinary sediment (e.g., proteinuria or hematuria) or abnormal pathology on a kidney biopsy are at risk for progressive kidney failure.

Up till now the treatment options for patients with CKD are limited and often determined by the aetiology of the CKD. The only therapeutic intervention which has been shown to significantly affect CKD disease progression available was RAAS blockade. This was accomplished through ACE inhibitors or angiotensin receptor blockers.

Lately, the CREDENCE study has provided enough evidence that we can help our patients with SGLT2 inhibitors in the management of diabetic nephropathy. It is a much-needed breakthrough and now SGLT2 inhibitors have been added to the armamentarium for the treatment of diabetic nephropathy.

In the double-blind CREDENCE trial patients with type 2 diabetes and chronic kidney disease with albuminuria already on the standard renin-angiotensin-aldosterone blockade and baseline, diabetic therapy was randomized to receive canagliflozin, an oral SGLT2 inhibitor or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000). The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.

The trial had to be stopped earlier than planned because of the study medication showed such an overwhelming beneficial effect. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (HR 0.66; 95% CI, 0.53 to 0.81; p<0.001). In addition, the relative risk of end-stage kidney disease was lowered by 32% (HR 0.68; 95% CI, 0.54 to 0.86; p=0.002). The treatment group also had a lower risk of cardiovascular death.

After that, the SONAR study has shown that the risk of renal events in patients with diabetes and chronic kidney disease could be significantly reduced by atrasentan (an endothelin-receptor antagonist) in selected patients (those who had shown a response to the medication before they were enrolled into the study). A risk reduction of 35% in the composite renal outcome of end-stage kidney disease and doubling serum creatinine could be reached (HR; 0.65 [95% CI 0.49-0.88]; p=0.0047).

According to a study published in The Lancet, Atrasentan is associated with a reduced risk for renal events in patients with type 2 diabetes and chronic kidney disease. The study has endorsed that endothelin receptor antagonists could define the position of this class in the future treatment armamentarium of the diabetes population with high renal and cardiovascular risk.

It is certainly heartening and it can not be denied that these two studies have opened new vistas for patients with diabetic nephropathy. For last so many years no new treatment option has proved to be safe and effective and thus no new drug could be introduced into clinical practice. And the good news is that now we have two new treatments with different therapeutic targets, which we might even combine.

Author Dr.Kartikeya Kohli DNB (Medicine), MRCP, Fellow DNB (Nephrology) is a Consultant Physician and Nephrologist at Sanjeevan Hospital, New Delhi.