SGLT2 Inhibitors for Cystinuria

Overseen By Victoria Hogue

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: SGLT-2 inhibitors

Disqualifiers: Diabetes, Pregnancy, Serious illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 4 weeks

10 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are currently taking SGLT-2 inhibitors, you cannot participate in the trial.

What data supports the effectiveness of the drug Dapagliflozin for treating cystinuria?

Dapagliflozin, a drug used for diabetes, has shown benefits in reducing kidney problems and heart issues in people with chronic kidney disease, which might suggest potential benefits for kidney-related conditions like cystinuria. ^{1 2 3 4 5}

Is dapagliflozin safe for use in humans?

Dapagliflozin, a type of SGLT2 inhibitor, is generally safe for humans but may increase the risk of certain side effects like genital infections, diabetic ketoacidosis (a serious diabetes complication), and volume depletion (loss of bodily fluids). It has been shown to reduce the risk of kidney injury and severe low blood sugar in people with chronic diseases like type 2 diabetes, heart failure, and kidney disease. ^{1 2 3 6 7}

How is the drug dapagliflozin unique for treating cystinuria?

Dapagliflozin is unique because it is an SGLT2 inhibitor, originally developed to lower blood sugar in diabetes, but it also offers protective effects for the heart and kidneys, which might be beneficial for cystinuria, a condition with no standard treatment. ^{1 3 4 8 9}

What is the purpose of this trial?

Cystinuria is an inherited autosomal recessive disorder of the kidney that is the result of an inability to reabsorb cystine from the urine. Supersaturation of cystine in the urine produces crystals that precipitate and form stones in the kidney, which can be a cause of obstruction, infection, and chronic kidney disease. Cystine stones constitute a major health challenge for affected individuals with cystinuria because of the frequent recurrence of painful symptoms and the current absence of effective, patient-accepting treatment. A mainstay of therapy is breaking or preventing the cystine bond on the molecular level such that cystine (which is formed from the joining of two cysteine amino acids and their corresponding sulfur atoms) cannot precipitate in the urine. It is hypothesized that a glucose molecule may be able to do this if introduced into the urine. SGLT-2 inhibitors are a class of drug that are FDA approved to treat diabetes mellitus (DM) and heart failure by inhibiting an enzyme in the kidney that allows for reabsorption of glucose from the urine. This effectively increases the concentration of glucose in the urine. Our hypothesis suggests that administration of this drug to patients with cystine will introduce sufficient glucose into the urine to prevent the formation of cystine stones. To date, there has been no published data on the effectiveness of this therapy for this indication, although the dosage and administration would be identical to that already approved by the FDA for the treatment of DM and heart failure.

Research Team

Marshall Stoller, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults over 18 with cystinuria, documented by urine tests or stone analysis, and a history of cystine kidney stones. It's not for non-English speakers, pregnant or lactating individuals without birth control, those unable to consent, prisoners, diabetics, current or recent SGLT-2 inhibitor users, or anyone with serious illness likely to cause death within 5 years.

Inclusion Criteria

Able and willing to provide consent

able and willing to provide consent

You have been diagnosed with cystinuria based on a urine test or stone analysis.

Exclusion Criteria

I am currently taking SGLT-2 inhibitors.

Non-English primary language

People who are in jail or prison.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive daily oral administration of dapagliflozin to assess its effect on cystine formation in urine

4 weeks

Initial visit, Day 7 visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dapagliflozin

Trial Overview The study is testing if Dapagliflozin (an FDA-approved diabetes drug) can prevent the formation of cystine stones in the kidneys by increasing glucose levels in urine. This preliminary study will explore whether this treatment could be an effective option for patients with cystinuria.

Participant Groups

Group I: Study Drug Experimental Treatment 1 Intervention

The study drug Dapagliflozin

Dapagliflozin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Forxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in United States as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in Canada as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

Dapagliflozin effectively lowers blood sugar levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, with a low risk of hypoglycemia and additional benefits like weight loss and reduced blood pressure.

While it is generally safe, dapagliflozin can increase the risk of genital infections, particularly in women, and its efficacy may be reduced in patients with kidney issues; ongoing trials are investigating its potential cardiovascular and renal protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. Scheen, AJ.[2021]

SGLT2 inhibitors significantly reduce the risk of acute kidney injury (RR 0.75) and show a trend towards lower severe hypoglycemia risk (RR 0.86), indicating a safety benefit in patients with chronic diseases.

However, SGLT2 inhibitors are associated with increased risks of diabetic ketoacidosis (RR 2.57), genital infections (RR 3.75), and volume depletion (RR 1.14), suggesting that these specific adverse events should be closely monitored in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. Qiu, M., Ding, LL., Zhang, M., et al.[2022]

Dapagliflozin (Farxiga) is approved for reducing the risk of declining kidney function and kidney failure in adults with chronic kidney disease, regardless of whether they have type 2 diabetes.

It also helps lower the risk of cardiovascular death and hospitalization for heart failure, highlighting its efficacy in managing both kidney and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. Aschenbrenner, DS.[2023]

SGLT-2 inhibitors, originally designed to lower blood sugar, have shown significant efficacy and safety in protecting cardiovascular and renal health in patients with chronic kidney disease (CKD), beyond just their glucose-lowering effects.

The review highlights five specific SGLT-2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin) that have been tested in cardiovascular outcome trials and are approved for use in Europe and North America, demonstrating their potential benefits in managing heart failure and CKD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter 2 inhibitors in patients with chronic kidney disease. Solomon, J., Festa, MC., Chatzizisis, YS., et al.[2023]

SGLT2-inhibitors, like dapagliflozin, represent a promising new class of oral medications for type 2 diabetes, effectively lowering HbA1c levels without increasing the risk of hypoglycemia, and also contributing to weight loss and reduced blood pressure.

However, there are safety concerns associated with SGLT2-inhibitors, including an increased risk of genital and urinary tract infections, as well as potential links to bladder and breast cancer, which have led to regulatory scrutiny and the need for further large-scale trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes introduction of SGLT2-inhibitors in clinical practice. Cuypers, J., Mathieu, C., Benhalima, K.[2021]

Dapagliflozin is an effective treatment for type 2 diabetes, proven through multiple controlled clinical trials that assess its efficacy, safety, and tolerability.

It is approved by the FDA for use as a standalone therapy or in combination with other glucose-lowering medications, including insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. Davis, PN., Ndefo, UA., Oliver, A.[2021]

SGLT-2 inhibitors have shown potential nephroprotective effects, particularly in diabetic patients with chronic kidney disease (CKD), as confirmed by the CREDENCE study which demonstrated reduced progression to dialysis in patients with impaired kidney function.

The DAPA-CKD study was halted early due to significant nephroprotective effects of dapagliflozin in CKD patients, leading to new treatment guidelines recommending SGLT-2 inhibitors as standard care for diabetic CKD patients, despite their current lack of approval for those with severely reduced kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Antidiabetic SGLT-2 inhibitors prevent progression of chronic kidney disease]. Heine, GH.[2021]

SGLT2 inhibitors represent a promising treatment for type 1 and type 2 diabetes by blocking glucose reabsorption in the kidneys, leading to increased glucose and energy loss through urine, which can help manage hyperglycemia and obesity.

Research indicates that SGLT2 inhibitors are generally safe for kidney function, as evidenced by individuals with familial renal glycosuria who maintain normal kidney health, suggesting that these medications may not adversely affect renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Idris, I., Donnelly, R.[2021]

Dapagliflozin, an SGLT2 inhibitor, significantly reduced the risk of severe kidney outcomes by 39% in patients with chronic kidney disease (CKD), demonstrating its effectiveness regardless of diabetes status.

In addition to its renal benefits, dapagliflozin also lowered the risk of cardiovascular events and all-cause mortality by 29% and 31%, respectively, although there is a noted risk of adverse effects like ketoacidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin for the treatment of chronic kidney disease. Kurata, Y., Nangaku, M.[2022]

References

1. Belgium pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter 2 inhibitors in patients with chronic kidney disease. [2023]

5. England pubmed.ncbi.nlm.nih.gov

SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes introduction of SGLT2-inhibitors in clinical practice. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

[Antidiabetic SGLT-2 inhibitors prevent progression of chronic kidney disease]. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Dapagliflozin for the treatment of chronic kidney disease. [2022]