Can we save the kidney in patients with diabetes?

Here are 2 trials on drugs that have very promising results in preventing renal failure in Type 2 diabetes mellitus; canagliflozin and atrasentan.

The SONAR trial.

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.
Prof Hiddo J L Heerspink, PhD Prof Hans-Henrik Parving, MD Dennis L Andress, MD Prof George Bakris, MD Prof Ricardo Correa-Rotter, MD Prof Fan-Fan Hou, MD et al.
Published: April 14, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)30772-X.

This is a trial carried out in Melbourne Australia. It was a phase 3 clinical trial but it had to be stopped because all the endpoints were not being met after 4 years. On analysis of the data the drug was considered effective and SONAR  is back on again.

All participants were adults with type 2 diabetes and chronic kidney disease, with an estimated glomerular filtration rate (eGFR) of 25 to 75 mL/min per 1.73 m² and a urine albumin-to-creatinine ratio of 300 to 5000 mg/g. They had also received a maximum labeled or tolerated dose of a renin-angiotensin system inhibitor, which is standard of care, for at least 4 weeks.

More than 4700 patients completed a 6-week “enrichment period” to assess responses to once-daily atrasentan 0.75 mg.

After the enrichment period, the 2648 patients who responded and met the predefined criteria continued on to randomization, in which either atrasentan, a selective endothelin-receptor antagonist, or placebo was added to standard of care.

What is atrasentan? It is a drug that inhibits endothelin-1. Endothelin-1 (ET-1) is a  potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN). Atrasentan was used in various kinds of cancer and a trial for its use in carcinoma prostate failed to show any benefit. Other drugs in this group are bosentan and avosentan.

Unlike the CREDENCE trial of canagliflozin (Invokana, Janssen), which suggested sizable benefits for these patients, SONAR was stopped in 2017 by AbbVie, the study’s sponsor, because 4 years after its launch, only about half of the end points had been met.

The CREDENCE trial.

RARITAN, N.J., July 16, 2018 — The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the Phase 3 CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) clinical trial, evaluating the efficacy and safety of INVOKANA® (canagliflozin) versus placebo when used in addition to standard of care for patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), is being stopped early based on the achievement of pre-specified efficacy criteria.

The decision is based on a recommendation from the study’s Independent Data Monitoring Committee (IDMC) that met to review the data during a planned interim analysis. This recommendation was based on demonstration of efficacy, as the trial had achieved pre-specified criteria for the primary composite endpoint of end-stage kidney disease (time to dialysis or kidney transplantation), doubling of serum creatinine, and renal or cardiovascular (CV) death, when used in addition to standard of care.

CREDENCE is the first dedicated renal outcomes trial in patients with CKD and T2D on the background of standard of care, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). This randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial evaluates the efficacy and safety of canagliflozin versus placebo in preventing clinically important renal and CV outcomes in patients with T2D and established kidney disease. The trial enrolled approximately 4,400 patients with T2D, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin: creatinine ratio >300 to ≤5,000 mg/g). All patients were required to be on the maximum labeled or tolerated dose of an ACE inhibitor or ARB for more than four weeks prior to randomization.

What is canagliflozin? Canagliflozin is an inhibitor of sodium glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney.It is chemically known as (1S)-1,5-anhydro-1-[3-[[5- (4-fluorophenyl) 2 thienyl]methyl]-4-methylphenyl]-D glucitol hemihydrate. Canagliflozin is used as an adjunct to diet and exercise to improve glycemic control in adult with Type 2 Diabetes Mellitus  It must not be used for Type 1 diabetes or in ketoacidosis or if the eGFR  is < 30 ml/min/1.73 m2, or if the patient has ESRD or is on dialysis. 

Can we predict who is going to get nephropathy in diabetes?

  • Microalbuminuria (also known as moderate albuminuria) is the clinically recognized danger sign but by this time the damage has already started.
  • Hyperfiltration. If your patient has a GFR higher than normal they are at risk, So the caveat is that whenever you diagnose a patient with Type 2 diabetes mellitus check the GFR and check it every 6-12 months as part of your routine workup.
  • How long the patient has had the diabetes. Diabetic nephropathy sets in 10 to 15 years after the onset of diabetes. Remember that it is difficult to pinpoint when type 2 diabetes started as it may be several years after the onset of the disease that the patient seeks medical care.
  • Age. Older people with type 2 diabetes are more likely to have nephropathy.
  • Inheritance. We do not exactly understand how genetics influence the onset of nephropathy but it is more likely to occur if one or both parents and one sibling have diabetes.
  • Obesity is a predictor of diabetic nephropathy.
  • Systemic hypertension is not only a predictor of diabetic nephropathy but may be caused by the renal damage and will contribute to renal damage.
  • The presence of diabetic retinopathy and polyneuropathy should make you check out the GFR and proteinuria as well.

Please read my blog;  Diabetic nephropathy; is there anything new?
Aug 28, 2018 8:18 PM

 

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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