Symposium 8.2 – Diabetic nephropathy in 2021

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

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Nephroprotective antidiabetic drugs: a prescription algorithm

Clara Garcia Carro, Spain

Diabetic kidney disease (DKD) is one of the major complications of diabetes and the leading cause of chronic kidney disease (CKD) worldwide. Around 10% of these patients progress to end-stage renal disease (ESRD), but even more develop cardiovascular disease and infections and die before needing renal replacement therapy. The main strategies to prevent the development and attenuate progression of DKD in the last decades were intensive glycaemic control and renin-angiotensin-aldosterone system (RAS) blockade. However, this approach has not achieved optimal results. In recent years two new groups of therapeutic agents, the sodium-glucose co-transporter-2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists, have been introduced and presented promising results in reducing cardiovascular risk and progression to ESRD in DKD patients. Several biological mechanisms could explain the nephroprotective effects of these agents, including restoration of normal tubule-glomerular feedback, direct anti-inflammatory and antifibrotic effects, and mitigation of renal hypoxia.

Figure 1. Mechanisms of action of SGLT2 inhibitors and GLP-1 receptor agonists

According to the latest guidelines on the treatment strategies for type 2 diabetes mellitus (T2DM) issued by the American Diabetes Association, the first-line interventions are lifestyle changes and the introduction of metformin. The choice of the second antidiabetic depends on the assessed cardiovascular risk. In patients with the established atherosclerotic disease, either GLP-1 agonists or SGLT2 inhibitors are the first option, provided that eGFR is ≥30 mL/min. Otherwise, SGLT2 inhibitors are the preferred option in patients with heart failure or CKD with eGFR ≥30 mL/min. Based on recent researches, these therapies are suitable in more than 30% of diabetic patients, and the number may rise if the eGFR threshold for SGLT2 use is lowered to 25 mL/min based on the results from the DAPA-CKD study. The recently published KDIGO guidelines have already embraced this lower threshold for dapagliflozin initiation. Also, the KDIGO guidelines embrace SGLT2 inhibitors as first-line therapy with metformin and GLP1 agonists as the second preferred choice for patients with cardiac and cardiovascular comorbidities.

Nevertheless, despite the proven benefits and safety profile of both SGLT2 inhibitors and GLP1 agonists, they remain underused in practice. Older age, long duration of diabetes, malignancies, recent hospitalizations, and clinicians’ inertia are common barriers to their initiation. Thus, besides clear therapeutical algorithms, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.

Beyond antidiabetic drugs for DKD: what is new and upcoming

Beatriz Fernandez Fernandez, Spain

Type 2 diabetes mellitus has become an epidemic with rapidly increasing prevalence worldwide. The recently introduced SGLT2 inhibitors have changed the landscape of antidiabetic treatment presenting promising results in reducing renal and cardiovascular risk in these patients. Nevertheless, there are several ongoing phases 3 and 2 trials evaluating other therapeutic approaches in this population which target different levels of pro-inflammatory response in DKD: gene expression, abnormal cell events, activation of signalling pathways, functional and structural changes.

Figure 2. Potential therapeutic approaches to DKD in clinical trials

Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with CKD and type 2 diabetes. Furthermore, results from the recently concluded FIDELIO-DKD study added lower risks of CKD progression and cardiovascular events to the benefits demonstrated by this therapeutic. Bardoxolone is an investigational, once-daily, orally administered anti-inflammatory and tissue-protective antioxidant inflammation modulator which has initially been investigated a decade ago in stage 4 CKD patients with type 2 diabetes. Even though initial results were promising in terms of increasing eGFR, the research was terminated for safety concerns. Nevertheless, three years ago a Phase 3 Bardoxolone Methyl in DKD (AYAME) study was initiated and results are expected next year. Endothelin receptor (ETR) antagonists are a class of strong vasodilators capable of stopping the process of cell division. They act on ETRA and/or ETRB to prevent endothelin 1 effects including hypertension, albuminuria, insulin resistance, inflammation, fibrosis, and endothelial dysfunction. Avosentan was the first ETR antagonist investigated in overt DKD, but the study was terminated due to excess cardiovascular events. Atrasentan, predominantly targeting ETRA, was investigated in RADAR and SONAR studies which included type 2 diabetic patients with DKD treated with the maximum tolerated dose of RAS inhibitor. Atrasentan reduced the risk of renal events in the examined cohort, but this effect was associated with a high risk of heart failure hospitalization. A highly selective ETRA antagonist zibotentan initially investigated as an anti-cancer drug candidate, is currently being considered alone and combined with dapagliflozin for renoprotective effect in patients with CKD and eGFR between 20 and 60 mL/min.

The results of this trial are expected next year. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic and anti-inflammatory properties clinically used for decades in the treatment of peripheral vascular disease. A currently recruiting trial shall examine the possible renoprotective role of pentoxifylline in DKD on estimated 2510 participants and a follow-up period of ten years. Thromboxane is another possible target for anti-inflammatory action in glomerular blood vessels. Selonsertib, a selective apoptosis signal-regulating kinase 1 was also evaluated for safety and efficacy in moderate to advanced DKD, and although it didn’t meet its primary endpoint, exploratory post hoc analyses suggest that it may slow DKD progression. Last but not least, mesenchymal stem cell (MSC)-based therapy has important biological and therapeutic implications for curtailing DKD progression. Thus, there are several ongoing randomized controlled trials considering the source, optimal cell number, and route of delivery in diabetic patients expected to advance the MSC-based therapy.

How should future trials for DKD look like

Christoph Wanner, Germany

Kidney failure is an important outcome for all stakeholders in the healthcare system – patients, physicians, researchers, insurance companies, pharmaceutical firms, and regulators. In recent years the number of studies involving CKD patients has increased. However, it is sometimes difficult to achieve recruitment in numbers necessary to obtain plausible treatment effects. Last year, the International Society of Nephrology convened an international multi-stakeholder meeting to develop a consensus on this topic. A consensus was reached that clinical trial outcomes to represent kidney failure should be comprised of a composite including receipt of a kidney transplant, initiation of dialysis, and death from kidney failure, and may also include outcomes based solely on laboratory measurements of GFR – a sustained low GFR <15mL/min and a sustained percent decline in GFR ≥ 40%. For example, in the EMPAREG-OUTCOME study evaluating the effect of empagliflozin versus placebo on the risk of decline in estimated GFR the composite of 40% decline in eGFR, ESRD, or renal death provided reliable results similar to the traditional 57% decline in eGFR. Nevertheless, it might take years, even decades, to reach suggested endpoints when assessing drugs that are highly efficient in preserving renal function, such as the SGLT2 inhibitors which have been adopted as the new standard of care in DKD patients. This has led to a dilemma on how to design future trials to assess evolving therapeutic options for DKD.

One possibility, as adopted in the recent trials evaluating cardiovascular effects of SGLT2 inhibitors, is to enrol patients with lower baseline eGFR, namely ≤60mL/min, to reach the suggested eGFR threshold sooner. Another alternative is to use the GFR slope as a surrogate endpoint for CKD progression, as is done in the studies on rare diseases. This approach is based on the fact that with sufficient sample size, a treatment effect of 0.75mL/min/1.73m2/year or greater on the total slope over three years or chronic slope predicts a clinical benefit on CKD progression with at least 96% probability. Nevertheless, this alternative has not yet been endorsed in larger trials. Finally, a recently published proposal by the renal guideline groups within the European Renal Association – European Dialysis and Transplantation Association, suggested yet another option which is to adopt a unified set of variables termed Major Adverse Renal Events (MARE). MARE could include three to five items, considered relevant to patients and regulators, while patients reported outcomes should be reported in parallel as a standard set of primary or secondary endpoints in studies on kidney disease of diabetic, hypertensive-vascular, or another origin.

Figure 3. Renal outcome points – Major Adverse Renal Events

A recently published set of proposals addressing this issue suggests creating a network of sites that are continuously recruiting individuals with a certain condition, such as DKD, collecting crucial information and serving as a pool of participants for recruitment to randomized trials, defining endpoints based on lesser declines in eGFR or changes in albuminuria to shorten follow-up, enrolling patients based on biomarker profiles, and new trial design to simultaneously assess several therapeutic agents. More work is needed to overcome current obstacles in adopting these options in the future and certain experiences from the COVID era may be useful in this process.

Further reading

Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045. doi: 10.2215/CJN.11491116.

Cherney DZ, Kanbay M, Lovshin JA. Renal physiology of glucose handling and therapeutic implications. Nephrol Dial Transplant. 2020;35(Suppl 1):i3-i12. doi: 10.1093/ndt/gfz230.

Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24(1):15-30. doi: 10.1016/j.cmet.2016.06.009.

American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98-S110. doi: 10.2337/dc20-S009.

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115. doi: 10.1016/j.kint.2020.06.019.

Jeong SJ, Lee SE, Shin DH, Park IB, Lee HS, Kim KA. Barriers to initiating SGLT2 inhibitors in diabetic kidney disease: a real-world study. BMC Nephrol. 2021;22(1):177. doi: 10.1186/s12882-021-02381-3.

Bakris GL, Agarwal R, Anker SD; FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. doi: 10.1056/NEJMoa2025845

Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol. 2015;26(1):220-9. doi: 10.1681/ASN.2014010012.

Sávio-Silva C, Beyerstedt S, Soinski-Sousa PE, et al. Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells. Stem Cells Int. 2020;2020:8833725. doi: 10.1155/2020/8833725.

Levin A, Agarwal R, Herrington WG; participant authors of the International Society of Nephrology’s 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020;98(4):849-859. doi: 10.1016/j.kint.2020.07.013.

Perkovic V, Koitka-Weber A, Cooper ME, et al. Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME® trial. Nephrol Dial Transplant. 2020;35(12):2103-2111. doi: 10.1093/ndt/gfz179.

Prischl FC, Rossing P, Bakris G, Mayer G, Wanner C. Major adverse renal events (MARE): a proposal to unify renal endpoints. Nephrol Dial Transplant. 2021;36(3):491-497. doi: 10.1093/ndt/gfz212. PMID: 31711188.

Heerspink HJL, List J, Perkovic V. New clinical trial designs for establishing drug efficacy and safety in a precision medicine era. Diabetes Obes Metab. 2018;20 Suppl 3(Suppl Suppl 3):14-18. doi: 10.1111/dom.13417.