The future of Diabetic Kidney Disease management:reducing the unmet need

Patients with type 2 diabetes run a high risk for progressive renal function loss. Many interventions have been tested to reduce the risk, but we are nowadays still confronted with a high unmet need. To improve on this unmet need, we will have to change the current strategies in drug discovery, clinical trials and clinical practice. Target finding and the search for new interventions has to change to include more individual mechanistic approaches. Drugs will be selected on basis of finding the "individual" mechanism of renal function loss by looking at renal tissue biopsies or new biomarkers in urine or plasma. To test the promising drugs for clinical efficacy and safety and reduce the unmet need, trial design in type 2 diabetes will have to alter. First, selection of patients at risk for progression of renal function loss will need to be more specific. True progressors need to be identified by switching from classical risk determinants (low eGFR and high albuminuria) to new surrogates like steep eGFR slopes. In addition, the investigational drugs should only continue into registration trials in responder populations: patients that show a good response in the target/surrogate risk marker and no bad responses. This way we will improve the success of hard outcome trials, which has been poor in the past decade. We will reduce the unmet need and reduce the number of patients that are exposed to long term trial treatments without any benefit or even harm. Platform design and basket trials will catch the non-responders and switch them to other investigational drugs with different mechanism of action. Drug registration will be much more directed to the individual patients and will lead to improved individual patient medication advices and improved individual efficacy and safety. We are entering the era of precision medicine in nephrology

Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment?

Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment? Albuminuria has been identified as a marker for predicting both cardiovascular and renal risk. From normal to overt proteinuria levels, albuminuria shows a continuous marked increase in risk. This is independent of other well-known cardiovascular and renal risk markers and factors, such as blood pressure, cholesterol, smoking, overweight, and others. The predictive power is not only present in already diseased populations with either nondiabetic or diabetic renal disease, but also in hypertensive and even in otherwise healthy populations.New antihypertensive intervention strategies, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor-antagonists are claimed to have cardioprotective and renoprotective benefits that go beyond blood pressure control. Interestingly, these new therapeutic classes share the ability to lower urinary albumin excretion by an average of 40%, a characteristic that is not observed with the other antihypertensive drug classes. This short-term–induced antiproteinuric effect appears to predict the long-term cardiovascular and renal protection: the more albuminuria is lowered, the more that individual (or group) is protected.These data suggest that albumin is not only a risk marker for cardiovascular and or renal disease, but it may also be a useful target for therapy. Monitoring of albuminuria should be daily practice in subjects at risk for cardiovascular and renal disease. In addition to new clinical trials that prove that albumin can be targeted to obtain cardiovascular protection, guidelines should be made to help the physician in deciding how to measure albumin in the urine, what are normal levels, how to target “abnormal” levels, and how low we should go

Treating diabetic complications; from large randomized clinical trials to precision medicine

In the last decades, many large randomized controlled trials have been conducted to assess the efficacy and safety of new interventions for the treatment of diabetic kidney disease (DKD). Unfortunately, these trials failed to demonstrate additional kidney or cardiovascular protection. One of the explanations for the failure of these trials appears to be the large variation in drug response between individual patients. All trials to date tested a drug which was targeted to a large heterogeneous population assuming that every individual will show a similar beneficial respond to the drug. Post hoc analyses from the past clinical trials, however, suggest that individual patients show a marked variation in drug response. This highlights the need to personalize treatment taking proper account of the characteristics and preferences of individual patients. Transitioning to a personalized therapy approach will have implications for clinical trial designs, drug registration and its use in clinical practice. Successful implementation of personalized medicine thus requires engagement of multiple stakeholders including academic community, pharmaceutical industry, regulatory agencies, health policy makers, physicians and patients. This supplement of Diabetes Obesity and Metabolism provides a summary on the state-of-the-art of personalized medicine in diabetic kidney disease from the views of various stakeholders

Time for clinical decision support systems tailoring individual patient therapy to improve renal and cardiovascular outcomes in diabetes and nephropathy

The current guideline treatment for patients with diabetes and nephropathy to lower the high risk of renal and cardiovascular (CV) morbidity and mortality is based on results of clinical studies that have tested new drugs in large groups of patients with diabetes and high renal/CV risk. Although this has delivered breakthrough therapies like angiotensin receptor blockers, the residual renal/CV risk remains extremely high. Many subsequent trials have tried to further reduce this residual renal/CV risk, without much success. Post hoc analyses have indicated that these failures are, at least partly, due to a large variability in response between and within the patients. The current 'group approach' to designing and evaluating new drugs, as well as group-oriented drug registration and guideline recommendations, does not take this individual response variation into account. Like with antibiotics and cancer treatment, a more individual approach is warranted to effectively optimize individual results. New tools to better evaluate the individual risk change have been developed for improved clinical trial design and to avoid trial failures. One of these tools, the composite multiple parameter response efficacy score , is based on monitoring changes in all available risk factors and integrating them into a prediction of ultimate renal and CV risk reduction. This score has also been modelled into a clinical decision support system for use in monitoring and changing the therapy in individual patients to protect them from renal/CV events. In conclusion, future treatment of renal/CV risk in diabetes should transition from an era of 'one size fits all' into the new era of 'a fit for each size'

New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction

The diuretic effects achieved with sodium glucose co-transporter 2 inhibitors (SGLT2i) may offset fluid retaining effects of the endothelin receptor antagonist (ERA) atrasentan while effects on albuminuria and kidney protection of both drug classes may be complimentary due to distinct mechanisms of action. Here, post-hoc analysis of the SONAR trial, in patients with type 2 diabetes and chronic kidney disease, show that six-weeks treatment with combined SGLT2i/atrasentan versus atrasentan alone decreased body weight, a surrogate for fluid retention, and further decreased albuminuria. Thus, these promising findings support future clinical studies to characterize the long-term efficacy and safety of combined SGLT2i/ERA treatment