The Renal Hemodynamic Effect of SGLT2 Inhibition in Patients With Type 1 Diabetes
What is the impact of 8 weeks of treatment with sodium glucose cotransporter 2 (SGLT2) inhibition with empagliflozin 25 mg once daily on renal hyperfiltration, in type 1 diabetic patients?
This was an 8-week, open-label, clinical trial in patients with type 1 diabetes mellitus. Baseline renal assessments were measured to stratify individuals based on having hyperfiltration (TID-H, glomerular filtration rate [GFR] ≥135 ml/min/1.73 m2, n = 27) or normal GFR (TID-N, GFR 90-134 ml/min/1.73 m2, n = 13). The primary study endpoint was change from baseline in GFR with empagliflozin under stable euglycemic and hyperglycemic clamp conditions. Statistical analyses were used to detect within-group and between-group differences in T1D-H and T1D-N groups.
Forty patients successfully completed the study. Treatment with empagliflozin significantly lowered GFR by 33 ml/min/1.73 m2 in T1D-H under euglycemic conditions (baseline: 172 ± 23, 8 weeks: 139 ± 25 ml/min/1.73 m2; p < 0.01). Treatment with empagliflozin did not significantly change GFR in T1D-N under euglycemic conditions (baseline, 117 ± 11, 8 weeks: 126 ± 15, p = 0.15). The between-group difference in change from baseline GFR was significant (p < 0.01). Empagliflozin had a significant effect on GFR in subjects with T1D-H under hyperglycemic clamp conditions; there was no effect in patients with TID-N. The effect on GFR in the TID-H group was accompanied by consistent changes in plasma nitric oxide, effective renal plasma flow, and renal vascular resistance; these parameters were not impacted by treatment with empagliflozin in the TID-N group.
The authors concluded that treatment with the SGLT2 inhibitor empagliflozin attenuated renal hyperfiltration in type 1 diabetics.
The limitations of this small study aside, the authors have provided convincing evidence that pharmacological inhibition of SGLT2 reduces hyperfiltration in type 1 diabetic patients. Hyperfiltration may be one of the processes that contributes to the initiation and progression of diabetic nephropathy. While the pathogenesis of hyperfiltration is complex and multifaceted, there is evidence implicating tubuloglomerular feedback as one of the responsible mechanisms. The ‘tubular hypothesis’ is based on the maladaptive increase in glucose reabsorption along with sodium via SGLT2 in chronically hyperglycemic patients. Increased reabsorption creates a downstream stimulus interpreted as low effective circulating volume, triggering an afferent renal vasodilatory response. The resulting hyperfiltration contributes to glomerular death. SGLT2 inhibition is a novel approach to attenuating hyperfiltration by disrupting the cycle of tubuloglomerular feedback. Many questions remain and future studies should clarify the role and safety of SGLT2 inhibition in primary prevention of diabetic nephropathy and whether a combined strategy of renin-angiotensin-aldosterone system (RAAS) and SGLT2 is beneficial.
Keywords: Sodium, Renin-Angiotensin System, Renal Plasma Flow, Diabetic Nephropathies, Benzhydryl Compounds, Kidney Glomerulus, Glucosides, Hemodynamics, Nitric Oxide, Primary Prevention, Cardiology, Cardiovascular Diseases, Hypoglycemic Agents, Vascular Resistance, Diabetes Mellitus, Disease Progression
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