Nephrolithiasis, a recurrent and chronic disease afflicting 12% of the world’s population, imposes substantial morbidity and economic burden across all races, genders, and ages. Among the factors associated with developing kidney stones, type 2 diabetes mellitus (T2DM) confers up to 3-fold increased risk, driven by mechanisms such as insulin resistance and altered urinary constituents and pH.¹ The surge in novel antidiabetic and weight loss medications has renewed interest in their potential for kidney stone prevention. This report focuses on emerging data for 3 different classes of medications in this area (Table 1): thiazolidinediones (or glitazones), sodium glucose cotransporter 2 (SGLT2) inhibitors, and anorexiants.

Table 1. Medication Classes, Mechanisms, Potential Effects, and Stone Composition Studied

Glitazones act on nuclear transcription factors to increase insulin response in liver, fat, and skeletal muscle. Animal studies have suggested that improved insulin sensitivity may also occur in the kidney, raising urine pH through improved buffer production (ammoniagenesis).² In a randomized, double-blind controlled trial, Maalouf et al treated 36 uric acid stone formers with or without T2DM using either pioglitazone 30 mg or placebo for 6 months.² Employing an inpatient unit with fixed metabolic diet and compared with controls before and at the end of the study, participants on pioglitazone exhibited a small increase in both urine pH (∼0.22 units) and ammonium excretion (Figure 1), along with mild weight gain (2%-3%) and increased urinary calcium excretion (∼16%). Alas, its limited physiologic benefit for stone prevention and pioglitazone’s position as a third- or fourth-line T2DM treatment have curtailed its use in mainstream uric acid stone prevention.

SGLT2 inhibitors are approved and widely used in T2DM for glycemic control, cardiovascular health, and reno-protective benefits, acting on the proximal tubule to cause glucosuria and osmotic natriuresis. Like traditional diuretics, the natriuresis only lasts for about 1 week, but the persistent glucosuria is believed to increase urine volume and inhibit citrate reabsorption while increasing urinary bicarbonate excretion.³ The question of whether these urinary alterations translate into fewer stones has retrospectively been assessed by a number of registry and electronic medical record/claims datasets where SGLT2 inhibitors were initiated for management of T2DM and not for stone prevention. Nevertheless, starting an SGLT2 inhibitor (typically empagliflozin) reduced incident or first stone formation by 25% (Table 2),^4-9 or by 5 events per 1000 person-years (from roughly 20 to 15). The data for its use in prevention of recurrence are still emerging but seem promising, particularly in recurrent stone formers with recently active disease (2024 Canadian target trial emulation study; Table 2, far right column).

Table 2. Selected Studies Comparing Diabetic Stone Risk in Adults Using Sodium Glucose Cotransporter 2 Inhibitors vs Comparators

The role of SGLT2 inhibitors in nondiabetic stone formers was addressed by SWEETSTONE, a randomized, double-blinded placebo-controlled phase 2 trial that compared single 24-hour urine studies of 53 stone formers on usual diets who were treated with empagliflozin vs placebo for 2 weeks.¹⁰ Empagliflozin reduced urinary supersaturation (SS) of calcium phosphate by 36% in calcium stone formers and SS of uric acid by 30% in uric acid stone formers. Although the findings were statistically significant, the SS risk categories in both stone groups did not change; in other words, no clinical effect would have been expected on these medications. Furthermore, several of the urinary findings were more likely attributable to dietary changes between collections and not SGLT2 inhibitor administration. Thus, the extent to which SGLT2 inhibitors benefit nondiabetic individuals requires further investigation.

Combination phentermine (sympathomimetic) and topiramate (antiepileptic) is a Food and Drug Administration–approved weight loss medication that improves glucose control and diabetes progression for people with obesity (BMI ≥ 30 kg/m²) or who are overweight (BMI 27-30 kg/m²) with ≥ 1 weight-related conditions. Because topiramate increases urine pH through carbonic anhydrase inhibition, we recruited 19 participants into the POUND OUT study, an 18-month, open-label, randomized, controlled feasibility trial in adult recurrent uric acid stone formers with obesity, normal renal function, and diabetes. After 18 months and using an intention-to-treat analysis, the phentermine/topiramate group had a 52.5% reduction in CT stone volume (Figure 2) compared with an 8.6% increase in control stone volume primarily treated with potassium citrate. The drug group also had statistically significant benefits in secondary outcomes including weight loss (∼22 lb), improved hemoglobin A1c levels, higher urine pH, and decreased uric acid SS. However, due to persistent bicarbonate loss and high urine pH, the drug group had higher calcium phosphate SS and low urinary citrate, a key inhibitor of stone formation, at the study end (mean citrate 309 vs 951 mg/d) compared with controls.

In summary, T2DM is associated with a higher risk of nephrolithiasis, and newer antidiabetic and weight loss medications may play a larger future role in preventing stones in this population. Pioglitazone improves renal insulin sensitization and ammoniagenesis, but its role in clinical uric acid stone prevention appears limited. Emerging data from registries and target trial emulations strengthen the evidence supporting the use of SGLT2 inhibitors, primarily empagliflozin, in T2DM to alter urinary composition for incident and recurrent stone prevention. With recent Food and Drug Administration approval for its use in nondiabetic patients with heart failure or chronic kidney disease, SGLT2 inhibitors have great potential to benefit many stone formers, but most published studies are retrospective. Large-scale clinical trials will be needed to identify the best target population for this medication compared with standard preventative therapies. Finally, the novel use of phentermine/topiramate for uric acid stone prevention appears safe, tolerable, and effective at reducing not only stone burden but also some of the comorbidities associated with obesity. While promising, these findings require further validation in larger trial settings that include citrate replacement before this therapy can be recommended for standard practice.

Funding for POUND OUT was provided by National Institutes of Health Grant R21DK122317 to Dr Canales.