T2D
Conditions
Keywords
acetazolamide, SGLT2 inhibition, GFR dip, dose-finding
Brief summary
The study aims to determine the acute efficacy and safety of three sequential doses of acetazolamide (62.5 mg, 125 mg, 250 mg) each for 2 weeks in 20 patients with T2D receiving background SGLT2i therapy.
Detailed description
Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D) and is associated with an increased risk of kidney failure, cardiovascular disease, and premature death. Although current standard-of-care therapies, including renin-angiotensin-aldosterone system inhibitors (RAASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and non-steroidal mineralocorticoid receptor antagonists (nsMRA), slow CKD progression, patients continue to experience substantial residual risk of kidney function decline despite treatment. Hyperfiltration remains a central driver of CKD progression and represents an important therapeutic target. Acetazolamide is a carbonic anhydrase inhibitor that has been used clinically for decades and has been shown to reduce glomerular hyperfiltration by increasing distal sodium delivery. Previous studies have demonstrated that acetazolamide produces an acute, reversible reduction in glomerular filtration rate (GFR), although its effects in patients with T2D receiving background SGLT2i therapy have not been evaluated. The Adding AcetazolamIde on top of SGLT2 inhibition in Persons wtih Type 2 Diabetes (DIPPER) pilot study is a phase II, open-label, single-arm, dose-escalation trial evaluating acetazolamide added to background SGLT2i therapy for 16 weeks. The study will evaluate the effect of acetazolamide on glomerular hyperfiltration, as measured by the acute, reversible change in measured GFR following each treatment period. The investigators will also study other important markers such as GFR recovery during washout periods, albuminuria, blood pressure, body weight, body composition, and safety and tolerability. The results of this study will help determine whether adding acetazolamide to SGLT2i therapy safely enhances SGLT2 inhibition's effects on renal hemodynamics, supporting its further evaluation as a potential treatment strategy for patients with T2D.
Interventions
DRUGAcetazolamide 62.5 mg
Oral acetazolamide 62.5 mg twice daily for 2 weeks
DRUGAcetazolamide 125 mg
Oral acetazolamide 125 mg twice daily for 2 weeks
Oral acetazolamide 250 mg twice daily for 2 weeks
DRUGDapagliflozin 10mg
Oral dapagliflozin 10 mg once daily for 16 weeks
Sponsors
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed and dated written informed consent. 2. Adult (≥18 years) at the time of consent 3. Established T2D diagnosis as per Diabetes Canada 4. HbA1c ≤10.0% 5. eGFR ≥45 ml/min/1.73m2 6. BP ≤160/90 and ≥90/60 mmHg 7. BMI 18.5-45.0 kg/m2 8. On stable dose of maximally tolerated RAASi for ≥30 days
Exclusion criteria
1. Established diagnosis of type 1 diabetes as per Diabetes Canada 2. With known or suspected hypersensitivity or allergy to acetazolamide, dapagliflozin or related products 3. Iodine intolerance 4. Untreated urinary or genital tract infection 5. Serum potassium \<3.5 mmol/L 6. Serum bicarbonate \<22 mEq/L 7. Use of carbonic anhydrase inhibitor in the 30 days prior to screening 8. Liver disease (hepatic cirrhosis, alcohol/drug abuse ≥3 months, or serum AST, ALT, or total bilirubin \>3X the upper limit of normal) 9. Severe glaucoma 10. Acute coronary syndrome, stroke or transient ischemic attack within 30 days prior to screening 11. Active pregnancy, breastfeeding or planning to become pregnant during study period 12. Participation in another drug trial within 30 days of screening 13. Patient not able to understand and comply with study requirements, based on Investigator's judgment. 14. Any other clinical condition that, based on Investigator's judgement, would jeopardize patient safety during trial participation or would affect the study outcome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Iohexol Measured GFR | From baseline to the end of treatment at 16 weeks | The primary outcome of this study is the absolute change in measured GFR during each 2-week course of acetazolamide, while on background dapagliflozin therapy. GFR will be measured using plasma clearance of the iohexol contrast agent. The initial "dip" in GFR was selected as the primary outcome as it provides an early and measurable indicator of the treatment effect on kidney physiology. A transient reduction in GFR is a known physiological response to both acetazolamide and SGLT2i, reflecting their effects on hyperfiltration. Assessing this early change allows evaluation of the immediate physiological response to combination therapy but also acts as an indicator of the potential longer-term renal benefits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diastolic Blood Pressure | From baseline to the end of treatment at 16 weeks | Diastolic blood pressure will be measured as per Hypertension Canada and assessed using an automated vital signs monitor (Connex Vital Signs Monitor, Welch Allyn). |
| Change in Body Weight | From baseline to the end of treatment at 16 weeks | — |
| Mean Arterial Pressure | From baseline to the end of treatment at 16 weeks | Mean blood pressure will be measured as per Hypertension Canada and assessed using an automated vital signs monitor (Connex Vital Signs Monitor, Welch Allyn). |
| Percent Fat Mass | From baseline to the end of treatment at 16 weeks | Bioimpedance analysis will be performed to determine percent body fat. |
| Percent Extracellular Fluid | From baseline to the end of treatment at 16 weeks | Bioimpedance analysis will be performed to determine the percent extracellular fluid. |
| Percent Total Body Water | From baseline to the end of treatment at 16 weeks | Bioimpedance analysis will be performed to determine percent total body water. |
| Urine Albumin-to-Creatinine (UACR) | From baseline to the end of treatment at 16 weeks | UACR will be quantified by measuring albumin and creatinine excretion using the average of three FMV samples. |
| Measured GFR Recovery | From baseline to the end of treatment at 16 weeks | Measured GFR through iohexol clearance will be used to determine GFR recovery to baseline following each washout period. |
| Systolic Blood Pressure | From baseline to the end of treatment at 16 weeks. | Systolic blood pressure will be measured as per Hypertension Canada and assessed using an automated vital signs monitor (Connex Vital Signs Monitor, Welch Allyn). |
| eGFR | From baseline to the end of treatment at 16 weeks | Measured using spot urine and FMV urine collection for serum creatinine, standardized per 1.73m2 body surface area. And estimated using CKD-EPI 2021 equation. |
Countries
Canada
Contacts
CONTACTCheng Xu
CONTACTLuxcia Kugathasan
PRINCIPAL_INVESTIGATORDavid Z.I Cherney, MD CM, PhD, FRCPC
University Health Network, Toronto General Hospital
Outcome results
None listed