Acetazolamide Therapy and Kidney Function in Persons with Non-albuminuric Diabetes Mellitus Type 1

Key Points Low-dose acetazolamide reversibly lowered GFR in persons with type 1 diabetes mellitus, suggesting a possible role in relieving glomerular hyperfiltration. Low doses of acetazolamide were well tolerated in persons with type 1 diabetes. Background Sodium-glucose cotransporter-2 inhibitors (SGLT2is) lower the risk of kidney failure in persons with type 2 diabetes. The presumed mechanism of action is through greater delivery of sodium to the distal tubule and activation of tubuloglomerular feedback, which lowers GFR and intraglomerular pressure. SGLT2is are not approved for use in persons with type 1 diabetes because of the risk of diabetic ketoacidosis. Acetazolamide, a proximal tubule diuretic, delivers more sodium to the distal nephron and may activate tubuloglomerular feedback in a similar way to SGLT2is without a higher risk of diabetic ketoacidosis. The kidney effects and safety of acetazolamide in persons with type 1 diabetes have not been well studied. Methods We conducted a dose-escalation trial to determine the effects of three dosages of oral acetazolamide (62.5, 125, and 250 mg, all twice daily) in 12 persons with type 1 diabetes. Participants were treated for 2 weeks, followed by a 2-week washout period before exposure to the next dosage level. Blood and urine chemistries, as well as iohexol-measured GFR, were assessed before and after each treatment interval. We aimed to identify a dose that maximized measured GFR reductions while minimizing adverse effects. Results The mean age was 46±17 years, 100% were White, and 75% were female. The mean measured GFR was 89±18 ml/min per 1.73 m 2 at baseline. Acetazolamide reduced measured GFR by 15% (95% confidence interval [CI], 9 to 21), 14% (95% CI, 7 to 21), and 15% (95% CI, 10 to 21) after 2 weeks at the 62.5, 125, and 250 mg twice-daily dosage levels, respectively. The measured GFR reduction was fully reversed after each 2-week washout. Serum bicarbonate was reduced by 2.3, 4.2, and 4.4 mEq/L with escalating doses, and no episodes of hypokalemia (<3.5 mEq/L) were observed. Conclusions Among persons with type 1 diabetes and preserved kidney function, acetazolamide caused an acute, reversible reduction in measured GFR without effects on glucose metabolism. Clinical Trial registry name and registration number: Acetazolamide in Persons with Type 1 Diabetes, NCT05473364.