Need for Renoprotective Therapies for Chronic Kidney Disease in T1D
Merlin C. Thomas, Sophia Zoungas, Nordin M.J. Hanssen, Sybil A. McAuley and Mark E. Cooper
Kidney Disease: The Forgotten Legacy of Type 1 Diabetes. Diabetes Care. 2025 Aug 1;48(8):1299-1308.
As people with type 1 diabetes (T1D) live longer, chronic kidney disease (CKD) has become an increasingly important — and increasingly prevalent — long-term complication. While modern diabetes management has dramatically reduced the incidence of severe albuminuria and kidney failure, it has not slowed the underlying rate of kidney function decline. The treatment of CKD in T1D has not substantively changed in 25 years, and the incidence of end-stage kidney disease is now rising again. This review, authored by researchers from Diabeter Centrum Amsterdam/ Amsterdam UMC, Monash University, anf Alfred Health examines why T1D has been left behind in the development of renoprotective therapies and what needs to happen to change that.
The authors synthesise evidence from clinical trials, registry studies, and mechanistic research on the natural history of CKD in T1D, the limitations of current standard of care, and the potential role of adjunctive renoprotective therapies including SGLT2 inhibitors, GLP-1 receptor agonists, and aldosterone antagonists. The review specifically addresses the safety challenges that have prevented translation of these therapies — proven effective in type 2 diabetes — to patients with T1D.
Key findings:
- Glucose control alone is not sufficient to prevent CKD: Long-term DCCT/EDIC data show that intensive glycaemic control delays but does not ultimately prevent kidney function decline — it is cumulative glucose exposure over a lifetime that drives nephron loss.
- Improved survival has made CKD more prevalent: The same interventions that have extended lives in T1D have increased the number of patients living long enough to experience progressive kidney function loss. End-stage kidney disease incidence in T1D is now rising.
- "Double diabetes" compounds kidney risk: At least one quarter of adults with T1D now show features of the metabolic syndrome. Insulin resistance — independent of glucose levels — contributes to CKD progression through hyperfiltration, glomerulosclerosis, and maladaptive tubular metabolism.
- SGLT2 inhibitors show promise but carry a critical safety risk: Available data suggest SGLT2 inhibitors reduce hyperfiltration and albuminuria in T1D through mechanisms independent of glucose control. However, their use carries a two- to threefold increased risk of diabetic ketoacidosis, a serious barrier to routine use that has not yet been resolved.
- GLP-1 receptor agonists offer potential but evidence in T1D is sparse: While GLP-1RAs have demonstrated kidney protection in type 2 diabetes, trials in T1D are small and show only modest metabolic benefits, with increased hypoglycaemia and DKA risk. Larger trials with high-dose weekly formulations are ongoing.
- Aldosterone antagonism addresses residual risk but with limitations: RAS inhibition remains the standard of care for CKD in T1D but fails to prevent decline in patients without macroalbuminuria. Aldosterone escape is associated with accelerated GFR loss, and mineralocorticoid receptor antagonists show promise — but hyperkalemia and acute kidney injury risk remain significant concerns.
- Kidney protection must become foundational, not an add-on: The authors argue that early renoprotection should be a standard component of T1D care for all patients — not reserved for those with established CKD — given the near-universal trajectory towards kidney function decline with increasing disease duration and age.
T1D has been largely bypassed by the renoprotective revolution that has transformed outcomes in type 2 diabetes. Despite compelling biological rationale for using SGLT2 inhibitors, GLP-1 receptor agonists, and aldosterone antagonists in T1D, the evidence base is thin and the safety concerns — particularly DKA risk — are real. Comprehensive, adequately powered clinical trials specifically designed for T1D are urgently needed. Without them, clinicians are left prescribing off-label based on extrapolated data, while kidney failure rates in this population continue to rise.
Concluding, the authors state
"Comprehensive studies are needed to ensure type 1 diabetes is not left behind in the development of renoprotective therapies."
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