The Renal Hemodynamic Effect of SGLT2 Inhibition in Patients with Type 1 Diabetes
Background—The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks' sodium glucose cotransporter 2 (SGLT2) inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes (T1D).
Methods and Results—Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow; ERPF) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 ml/min/1.73m2, n=27) or normal GFR (T1D-N, GFR 90-134 ml/min/1.73m2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system (RAAS) mediators and nitric oxide (NO) were measured under clamped euglycemic (4-6 mmol/L) and hyperglycemic (9-11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by -33 ml/min/1.73m2 with empagliflozin in T1D-H, (GFR 172±23 to 139±25 ml/min/1.73 m2, p<0.01). This effect was accompanied by declines in plasma NO and ERPF and an increase in renal vascular resistance (all p<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced HbA1c significantly in both groups, despite lower insulin doses in each group (p≤0.04).
Conclusions—In conclusion, short-term treatment with the SGLT2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms.
Clinical Trial Registration Information—www.clinicaltrials.gov. Identifier: NCT01392560.
- Renal hyperfiltration
- SGLT2 inhibition
- tubuloglomerular feedback
- Diabetic nephropathy
- nitric oxide
- renal physiology
- renin angiotensin system
- tubular transport
- hypertension, kidney
- diabetes (kidney)
- Received July 17, 2013.
- Revision received October 11, 2013.
- Accepted October 17, 2013.