Hope for Patients With Type 1 Diabetes and Chronic Kidney Disease

The management of chronic kidney disease (CKD) in patients with diabetes has been transformed over the past 4 years. But studies have focused mainly on patients with type 2 diabetes (T2D), and patients with type 1 diabetes (T1D) have largely been left out. Health inequalities between these patient groups have been widening. I therefore relished the opportunity to attend the session on CKD in T1D at the 59th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Hamburg, Germany.

Recent data have firmly established SGLT2 inhibitors and the nonsteroidal mineralocorticoid antagonist (nsMRA) finerenone as additional key therapeutic pillars, alongside renin-angiotensin system (RAAS) inhibition, in this population. This transformation was reflected in the Kidney Disease: Improving Global Outcomes 2022 clinical practice guideline for diabetes management in CKD. But the seminal studies that have driven this transformation (such as CREDENCE, DAPA-CKD, EMPA-KIDNEY, FIDELIO-DKD, and FIGARO-DKD) recruited patients with and without T2D but not patients with T1D.

Moreover, Novo Nordisk announced earlier this month that the FLOW trial (once-weekly injectable semaglutide kidney outcomes trial) will be ending early. Results from an interim analysis met certain prespecified criteria for stopping the trial early for efficacy. This development suggests that GLP-1 receptor agonists might also become a new therapeutic pillar of CKD management in the future. But the FLOW trial, too, recruited only patients with T2D and CKD.

Understandably, my patients with T1D and CKD are frustrated that they are not eligible for these potentially life-changing treatments for CKD that can reduce the progression of CKD and decrease the risk for adverse cardiovascular (CV) and kidney outcomes. It is well known that CKD is an independent risk factor for CV disease. Tragically, most patients with CKD die from a CV event well before they need renal replacement therapy. I share my patients' frustrations.

Peter Rossing, MD, DMSc, head of complications research at Steno Diabetes Center in Copenhagen, began the EASD session with a call to action, acknowledging that CKD in T1D has largely been forgotten.

Katherine Tuttle, MD, clinical professor of nephrology at Providence Medical Research Center in Spokane, Washington, provided an overview of the contemporary epidemiology of CKD in T1D. She presented unpublished results from the CURE-CKD 2013–2022 US registry study, which suggested a 27.9% prevalence of CKD in T1D using laboratory testing and diagnosis codes.

Hiddo Heerspink, PhD, PharmD, professor of clinical trials and personalized medicine at University Medical Center in Groningen, Netherlands, surveyed the ongoing clinical trials in patients with T1D and CKD. He confirmed that this is a major unmet need and a clear opportunity to develop newer therapies to better treat this hitherto neglected group of individuals.

There have been no new therapies for patients with T1D and CKD for three decades, said Heerspink. Captopril was demonstrated to reduce the risk for kidney failure in these patients in 1993. The impact of allopurinol in T1D and CKD was investigated in the PERL trial, and its results were published in 2020. Unfortunately, no clinically meaningful benefits of serum urate reduction were found on kidney outcomes with allopurinol in patients with T1D and CKD.

Among the main barriers to developing new therapies for patients with T1D and CKD are the endpoints often used to investigate a new drug: end-stage kidney disease (ESKD) and doubling of serum creatinine. These are late-stage complications of CKD that require large clinical trials of long duration to demonstrate a clinically meaningful benefit.

Such trials are challenging in the context of T1D; surrogate endpoints such as glomerular filtration rate (GFR) slope or change in albuminuria can be used to overcome this barrier. Unpublished data from the CSG-Captopril trial demonstrated that proteinuria closely follows disease progression and predicts ESKD in T1D. Conversely, early reduction in proteinuria is associated with kidney protection.

Heerspink initially focused on finerenone in T1D, using albuminuria as a surrogate endpoint. Finerenone targets mineraloreceptor (MR) overactivation, which may contribute to progression of CKD and CVD in patients with diabetes. In T2D and CKD, the FIDELITY pooled analysis demonstrated that finerenone was associated with a 23% relative risk reduction in hard kidney outcomes and a significant reduction in albuminuria over time. In fact, the protective effect of finerenone was almost completely explained by its albumin-lowering efficacy.

There is increasing acceptance that albuminuria can be used a "bridging" biomarker to translate evidence for kidney protection with finerenone from T2D to T1D, given the fulfilment of certain criteria.

FINE-ONE is a currently active phase 3 trial exploring the impact of finerenone in 220 patients with T1D and CKD. Key exclusion criteria include T2D, treatment with SGLT2 inhibitor medications, GLP-1 receptor agonists, or other MRAs. Additionally, those with symptomatic heart failure with reduced ejection fraction and clinical indications for MRA therapy were also excluded. The primary endpoint is change in urinary albumin-to-creatinine ratio from baseline over 6 months.

Heerspink also discussed atrasentan, an endothelin A receptor antagonist (ERA). Endothelin is a potent vasoconstrictor that is implicated in the progression of CKD. In the SONAR trial, atrasentan conferred kidney protection and reduced albuminuria in patients with T2D and CKD. Again, like finerenone, the protective effect of atrasentan results almost entirely from the reduction in albuminuria.

The mechanistic ASPIRE study is investigating the combination of sotagliflozin (an SGLT1 and -2 inhibitor) and ambrisentan (another ERA) on albuminuria in patients with T1D and CKD. The rationale for the combination is that ERAs cause fluid retention, but the diuretic-like effect of SGLT inhibitors might help reduce it while enhancing kidney protection. It is also hypothesized that the ERA might mitigate the risk for diabetic ketoacidosis with SGLT inhibitors.

Finally, the collaborative STENO-1 study is a 5-year intervention study with clinically meaningful endpoints of cardiorenal outcomes (four-point major adverse cardiovascular events, hospitalization for heart failure, CKD, ESKD, and reduction of estimated GFR) in patients with T1D and various cardiorenal profiles. On the basis of their profiles, participants will receive different medications, including semaglutide, sotagliflozin, finerenone, ezetimibe, and PCSK9 inhibitors, to test the concept of personalized medicine.

In conclusion, hope is on the horizon for new therapies for patients with T1D and CKD. Meanwhile, the focus remains on individualized glycemic management, RAAS inhibition, and the appropriate consideration of CV health.

Dr Fernando is a general practitioner near Edinburgh, Scotland, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.

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Cite this: Hope for Patients With Type 1 Diabetes and Chronic Kidney Disease - Medscape - Oct 23, 2023.