A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

Sodium glucose co-transporter (SGLT) 2 inhibitors reduce the risk of kidney failure in patients with and without type 2 diabetes (T2D). Although the precise underlying mechanisms for these nephroprotective effects are incompletely understood, various hypotheses have been proposed including reductions in intraglomerular pressure through restoration of tubuloglomerular feedback, blood pressure reduction and favorable effects on vascular function, reduction in tubular workload and hypoxia, and metabolic effects resulting in increased autophagy. Here, we review these mechanisms, which may also explain the beneficial effects of SGLT2 inhibitors on kidney function in patients without T2D

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'

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial

AIMS: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. METHODS: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months\u27 duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-\u3c 5000 mg/g (≥ 22.6-\u3c 565 mg/mmol) and eGFR of ≥ 25-\u3c 90 ml/min/1.73 m RESULTS: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. CONCLUSIONS: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT05901831

Exposure-response relationships of dapagliflozin on cardiorenal risk markers and adverse events:A pooled analysis of 13 phase II/III trials

Aims: Dapagliflozin is a sodium–glucose co-transporter 2 inhibitor that has been developed as oral glucose lowering drug. The original dosefinding studies focused on optimal glycaemic effects. However, dapagliflozin also affects various cardiorenal risk markers and provides cardiorenal protection. To evaluate whether the currently registered doses of 5 and 10 mg are optimal for cardiorenal efficacy and safety, we characterized the relationship between dapagliflozin exposure and nonglycaemic cardiorenal risk markers as well as adverse events. Methods: Data were obtained from a pooled database of 13 24-week randomized controlled clinical trials of the clinical development programme of dapagliflozin. The exposure–response relationship was quantified using population pharmacodynamic and repeated time-to-event models. Results: A dose of 10 mg dapagliflozin resulted in an average individual exposure of 638 ng h/mL (95% prediction interval [PI]: 354–1061 ng h/mL), which translated to 71.2% (95% PI: 57.9–80.5%), 61.1% (95% PI: 58.0–64.8%), 91.3% (95% PI: 85.4–94.6%) and 25.7% (95% PI: 23.5–28.3%) of its estimated maximum effect for fasting plasma glucose, haematocrit, serum creatinine and urinary albumin–creatinine ratio, respectively. Conclusion: We demonstrate that doses higher than 10 mg could provide additional beneficial effects in haematocrit, systolic blood pressure, urinary albumin–creatinine ratio and uric acid, without obvious increases in the rate of adverse events. These results raise the question whether future outcome studies assessing the benefits of higher than currently registered dapagliflozin doses are merited

Precision medicine approaches for diabetic kidney disease:opportunities and challenges

The prevalence of end-stage kidney disease (ESKD) continuously increases worldwide. The increasing prevalence parallels the growth in the number of people with diabetes, which is the leading cause of ESKD. Early diagnosis of chronic kidney disease (CKD) in patients with diabetes and appropriate intervention is important to delay the progression of kidney function decline and prevent ESKD. Rate of CKD progression and response to treatment varies among patients with diabetes, highlighting the need to tailor individual treatment. In this review, we describe recent advances and areas for future studies with respect to precision medicine in diabetic kidney disease (DKD). DKD is a multi-factorial disease that is subject in part to genetic heritability, but is also influenced by various exogenous mediators, such as environmental or dietary factors. Genetic testing so far has limited utility to facilitate early diagnosis, classify progression or evaluate response to therapy. Various biomarker-based approaches are currently explored to identify patients at high risk of ESKD and to facilitate decision-making for targeted therapy. These studies have led to discovery and validation of a couple of inflammatory proteins such as circulating tumour necrosis factor receptors, which are strong predictors of kidney disease progression. Moreover, risk and drug-response scores based on multiple biomarkers are developed to predict kidney disease progression and long-term drug efficacy. These findings, if implemented in clinical practice, will pave the way to move from a one-size-fits-all to a one-fit-for-everyone approach