Diabetes drug sits at the center of this dementia and brain health question.
Doctors are testing SGLT2 inhibitors — a class of drugs originally developed for type 2 diabetes — because mounting evidence suggests they can reduce kidney stone risk by roughly 30 to 40 percent. A large-scale study published in JAMA Internal Medicine, conducted by researchers at Mass General Brigham, found that patients treated with SGLT2 inhibitors like empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) had approximately a 31 percent lower risk of kidney stones compared to patients using GLP-1 receptor agonists over a median follow-up of 192 days. That finding has opened a serious conversation about repurposing these medications for a condition that affects nearly one in ten Americans at some point in their lives. The connection between diabetes drugs and kidney stones may seem unlikely, but the biological mechanisms are surprisingly straightforward. These drugs increase urinary citrate, raise urine volume, and lower uric acid levels — all factors that directly inhibit stone formation.
What makes this particularly relevant for readers following brain health and dementia care is the growing recognition that chronic kidney disease and repeated kidney stone episodes are associated with cognitive decline and cerebrovascular risk. Managing kidney health is, in many ways, managing brain health. This article covers how SGLT2 inhibitors work against kidney stones, what the clinical trials show, the limitations of current evidence, and what this could mean for patients both with and without diabetes. For older adults already managing multiple conditions — diabetes, hypertension, early cognitive changes — the prospect of a single medication addressing more than one problem is genuinely appealing. But the research is still in its early stages, and the gap between observational promise and proven clinical benefit remains real.
Table of Contents
- What Are SGLT2 Inhibitors and Why Are They Being Tested for Kidney Stones?
- What Does the Clinical Evidence Actually Show?
- Could These Drugs Help People Who Don’t Have Diabetes?
- What Clinical Trials Are Currently Underway?
- What Are the Risks and Limitations of This Approach?
- The Kidney-Brain Connection and Why This Research Matters for Dementia Care
- Where Is This Research Heading?
- Conclusion
- Frequently Asked Questions
What Are SGLT2 Inhibitors and Why Are They Being Tested for Kidney Stones?
SGLT2 inhibitors work by blocking sodium-glucose cotransporter 2 in the kidneys, which prevents glucose from being reabsorbed into the blood. The result is that excess sugar gets excreted in the urine. That mechanism, straightforward enough for blood sugar management, turns out to have several downstream effects on urine chemistry that are directly relevant to stone prevention. The drugs cause osmotic diuresis — essentially, they increase urine volume, which dilutes the minerals that clump together to form stones. They also raise urinary pH, which specifically reduces the risk of uric acid stones, and they lower blood uric acid levels overall. Perhaps the most compelling mechanism involves urinary citrate. One study showed that empagliflozin produced a nearly 50 percent increase in urinary citrate compared to placebo over just four weeks.
Citrate is one of the body’s natural defenses against calcium crystal formation — it binds to calcium in the urine and prevents it from linking with oxalate or phosphate to form stones. For context, the standard medical treatment for recurrent kidney stones is potassium citrate supplements, which many patients struggle to tolerate due to gastrointestinal side effects. If an SGLT2 inhibitor can achieve a similar citrate boost while also managing blood sugar, the clinical logic for testing it becomes clear. The comparison to existing stone prevention strategies matters. Current options are limited: drink more water, restrict dietary oxalate, take potassium citrate, or use thiazide diuretics. None of these approaches work particularly well for every patient, and compliance is notoriously poor. An SGLT2 inhibitor would not replace these measures, but it could provide an additional tool — especially for patients who are already taking these drugs for diabetes and happen to be stone formers.
What Does the Clinical Evidence Actually Show?
The numbers from multiple studies converge on a consistent signal. The JAMA Internal Medicine study from Mass General Brigham found that SGLT2 inhibitor users experienced 14.9 kidney stone events per 1,000 person-years, compared to 21.3 events per 1,000 person-years among GLP-1 receptor agonist users — a 31 percent relative risk reduction. When compared against DPP4 inhibitor users, the benefit was a 26 percent lower kidney stone risk, with rates of 14.6 versus 19.9 events per 1,000 person-years. A separate meta-analysis covering five clinical trials and over 11.6 million patients found that kidney stones occurred in 1.27 percent of SGLT2 inhibitor users versus 1.56 percent in control groups, translating to 40 percent decreased odds compared to placebo and 34 percent decreased odds compared to other active diabetes drugs. A target trial emulation study published in Diabetes Care in February 2025 added further weight, reporting a 33 percent lower recurrence rate of kidney stones among patients starting an SGLT2 inhibitor compared with those starting a GLP-1 receptor agonist.
this corresponded to 51 fewer active cases of kidney stones per 1,000 person-years — a meaningful reduction for a condition that tends to recur and that drives significant emergency department visits. However, context matters. The absolute magnitude of benefit in diabetic populations is modest: roughly one to two fewer stone events per 1,000 patient-years. That means for any individual patient, the chance of personally benefiting from stone prevention is small, even if the population-level signal is real. Most of this evidence comes from observational studies and post-hoc analyses of trials that were designed to measure cardiovascular or renal outcomes, not kidney stones specifically. Observational data, no matter how large the dataset, cannot fully account for confounding factors — patients prescribed SGLT2 inhibitors may differ from those prescribed other drugs in ways that independently affect stone risk.
Could These Drugs Help People Who Don’t Have Diabetes?
One of the more intriguing developments is a study published in eBioMedicine, part of The Lancet family of journals, which found that SGLT2 inhibitors can prevent kidney stones even in non-diabetic patients. The mechanism in these patients appears to involve restoring impaired autophagic flux — essentially, the drugs help kidney cells clean up damaged components that would otherwise contribute to crystal deposition and inflammation. This finding broadens the potential patient population significantly, moving SGLT2 inhibitors from a diabetes-specific bonus to a possible general stone prevention therapy. This matters because the majority of kidney stone patients do not have diabetes. If the stone prevention effect is independent of glucose control, then SGLT2 inhibitors could theoretically be prescribed off-label to chronic stone formers regardless of their metabolic status.
For older adults with cognitive concerns, this is worth noting: recurrent kidney stones often lead to repeated imaging, procedures, opioid prescriptions for pain management, and hospitalizations — all of which carry cognitive risks for aging patients. A preventive medication that reduces these episodes could have indirect but meaningful benefits for brain health and functional independence. That said, prescribing a diabetes drug to a non-diabetic patient raises practical issues. Insurance coverage becomes complicated. The drugs can cause urinary tract infections, genital yeast infections, and in rare cases, diabetic ketoacidosis even in non-diabetic individuals. Any off-label use would need to be weighed carefully against these risks, and right now, no guidelines recommend SGLT2 inhibitors for stone prevention outside of the diabetes context.
What Clinical Trials Are Currently Underway?
Two active clinical trials are specifically designed to test these drugs against kidney stones rather than relying on secondary analysis of diabetes data. The SWEETSTONE Trial is a randomized, double-blind, placebo-controlled cross-over trial testing empagliflozin’s impact on urinary supersaturations in kidney stone formers. Supersaturation is the key measurement here — it reflects how concentrated stone-forming minerals are in the urine and directly predicts crystallization risk. By using a cross-over design, each participant serves as their own control, which increases statistical power and reduces the influence of individual variability. A second study, published in PLOS ONE in 2025, is a prospective pharmacological randomized cross-over single-center study examining dapagliflozin specifically in high-risk patients with recurrent kidney stones.
At the World Congress of Endourology and Technology in 2025, a dedicated State of the Art lecture on diabetic medications and stone prevention underscored the expert consensus that randomized clinical trials specifically designed to confirm these observational findings are warranted, particularly in patients both with and without diabetes. The tradeoff between these two trial approaches is worth understanding. The SWEETSTONE Trial uses a surrogate endpoint — urinary supersaturation — which can be measured relatively quickly but does not directly prove fewer stones will form. The dapagliflozin study examines recurrence in high-risk patients, which is more clinically meaningful but requires longer follow-up and larger sample sizes to detect a difference. Both approaches are necessary, but neither will produce definitive answers overnight. Patients and physicians hoping for clear guidance may need to wait several more years before these trials report mature results.
What Are the Risks and Limitations of This Approach?
The most important limitation is that stone-specific outcomes remain exploratory. No regulatory agency has approved any SGLT2 inhibitor for kidney stone prevention, and the current evidence base — while promising — consists largely of observational studies and post-hoc analyses of trials designed for other endpoints. The difference between “associated with lower risk” and “proven to prevent” is not semantic; it is the difference between a hypothesis and a treatment recommendation. SGLT2 inhibitors carry their own side effect profile that must be weighed against any stone prevention benefit. The most common adverse effects include genital mycotic infections (yeast infections), urinary tract infections, increased urination, and dehydration risk.
For older adults, dehydration is particularly concerning because it can worsen cognitive function, increase fall risk, and paradoxically could promote kidney stone formation in patients who do not maintain adequate fluid intake while on the drug. There have also been rare reports of Fournier’s gangrene and euglycemic diabetic ketoacidosis. These risks are generally manageable in the diabetes population where the cardiovascular and renal benefits clearly outweigh them, but the calculus changes when the primary indication is stone prevention alone. For caregivers managing a loved one with dementia or cognitive impairment, adding another medication to an already complex regimen demands careful consideration. Polypharmacy is one of the most significant and underappreciated risk factors for adverse outcomes in older adults with cognitive decline. Any conversation about SGLT2 inhibitors for stone prevention in this population should involve a thorough medication review and a realistic assessment of whether the modest absolute risk reduction justifies the additional pill burden and monitoring requirements.
The Kidney-Brain Connection and Why This Research Matters for Dementia Care
Chronic kidney disease and recurrent kidney stones share more with cognitive decline than most people realize. Impaired kidney function leads to accumulation of uremic toxins, elevated inflammatory markers, and vascular calcification — all of which accelerate cerebrovascular disease and neurodegeneration. A 2023 study in the Journal of the American Society of Nephrology found that even moderate kidney function decline was associated with a 30 percent higher risk of dementia over a 10-year period.
Kidney stones themselves, while usually acute events, can cause chronic kidney damage when they recur frequently or require surgical intervention. If SGLT2 inhibitors can reduce kidney stone recurrence and preserve renal function — and there is separate evidence from the DAPA-CKD and EMPA-KIDNEY trials that they slow chronic kidney disease progression — the downstream effect on brain health could be meaningful. This is speculative, and no trial has directly measured cognitive outcomes in stone formers treated with SGLT2 inhibitors. But the biological plausibility is strong enough that it deserves attention from clinicians managing patients at the intersection of metabolic, renal, and cognitive risk.
Where Is This Research Heading?
The next few years will be decisive. Results from the SWEETSTONE Trial and the dapagliflozin recurrence study should clarify whether the observational signals translate into real-world stone prevention under controlled conditions. If they do, the question will shift from whether SGLT2 inhibitors prevent stones to which patients benefit most — diabetic versus non-diabetic, first-time stone formers versus chronic recurrers, calcium oxalate stones versus uric acid stones.
The eBioMedicine findings on non-diabetic patients and autophagic flux suggest the mechanism may be broad enough to apply across stone types, but this needs direct confirmation. For now, patients with type 2 diabetes who also have a history of kidney stones should discuss SGLT2 inhibitors with their physicians — not as a stone prevention drug specifically, but as a diabetes medication that may carry an added benefit. The evidence is not yet strong enough to justify prescribing these drugs solely for stone prevention, but it is strong enough to influence the choice among diabetes drug classes when a patient happens to be a stone former. That nuanced, patient-specific decision-making is exactly where medicine should be heading.
Conclusion
The research into SGLT2 inhibitors for kidney stone prevention represents a genuinely promising lead in a field that has had few new therapeutic options in decades. Multiple large studies — including the JAMA Internal Medicine analysis from Mass General Brigham, the Diabetes Care target trial emulation, and a meta-analysis of over 11 million patients — consistently show a 26 to 40 percent reduction in kidney stone risk among SGLT2 inhibitor users. The biological mechanisms are plausible: increased urinary citrate, higher urine volume, lower uric acid, and reduced inflammatory pathways all work against stone formation.
But promise is not proof. The absolute benefit is modest, the evidence is largely observational, and dedicated randomized trials are still underway. For readers focused on dementia care and brain health, the takeaway is that kidney health and cognitive health are deeply intertwined, and interventions that protect the kidneys may pay dividends for the brain. Patients and caregivers should bring these findings to their next nephrology or endocrinology appointment — not as a demand for a new prescription, but as an informed starting point for a conversation about comprehensive risk reduction.
Frequently Asked Questions
Are SGLT2 inhibitors FDA-approved for kidney stone prevention?
No. SGLT2 inhibitors like empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) are FDA-approved for type 2 diabetes and certain heart and kidney conditions. Their use for kidney stone prevention is investigational, and dedicated clinical trials like the SWEETSTONE Trial are still ongoing.
How much do SGLT2 inhibitors reduce kidney stone risk?
Across multiple studies, the reduction ranges from 26 to 40 percent depending on the comparison group. The JAMA Internal Medicine study found a 31 percent lower risk compared to GLP-1 receptor agonist users, while a meta-analysis of over 11.6 million patients showed 40 percent decreased odds compared to placebo.
Can non-diabetic patients take SGLT2 inhibitors for kidney stones?
Research published in eBioMedicine (The Lancet) suggests these drugs may prevent kidney stones in non-diabetic patients through a mechanism involving autophagic flux. However, this is not a current clinical recommendation, and off-label use carries risks including urinary tract infections and rare but serious side effects.
What are the side effects of SGLT2 inhibitors?
Common side effects include genital yeast infections, urinary tract infections, increased urination, and dehydration. Rare but serious risks include Fournier’s gangrene and euglycemic diabetic ketoacidosis. For older adults, dehydration is a particular concern as it can affect cognition and increase fall risk.
How do SGLT2 inhibitors prevent kidney stones?
They work through multiple mechanisms: increasing urinary citrate excretion by up to 50 percent (citrate blocks calcium crystal formation), increasing urine volume through osmotic diuresis, lowering blood uric acid levels, raising urinary pH to reduce uric acid stone risk, and inhibiting calcium oxalate crystal formation.
Is this relevant for someone caring for a person with dementia?
Indirectly, yes. Chronic kidney problems are linked to accelerated cognitive decline, and recurrent kidney stones lead to hospitalizations, imaging, and opioid use — all of which carry cognitive risks for older adults. However, adding medications to an already complex regimen requires careful evaluation with a physician to avoid polypharmacy complications.
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