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Therapeutic targets of antidiabetic drugs and kidney stones: A druggable mendelian randomization study and
Maolan Wu1, Cheng He1, Hao Yu1
1Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract:
Diabetes is known to increase the risk of kidney stones, but the influence of antidiabetic drugs on this risk remains uncertain. Genetic instruments for antidiabetic drugs were identified as variants, which were associated with both the expression of genes encoding target proteins of drugs and glycated hemoglobin level (HbA1c). Here, we investigated the effect of antidiabetic drugs on kidney stones in a mendelian randomization (MR) framework, and further explore the potential effect on CaOx stone rat models induced by glyoxylic acid. Genetically proxied thiazolidinediones (PPARG agonists) significantly reduced the risk of kidney stones (OR = 0.42; P=0.004) per 1-SD decrement in HbA1c, while no significant association was noted in sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs. Other antidiabetic drugs were not analyzed due to unclear pharmacological targets or no identified instruments. Additionally, PPARG agonists pioglitazone ameliorated CaOx nephrocalcinosis in glyoxylic acid-induced rats. The summary-data-based MR (SMR) results showed that PPARG mRNA expression in blood or kidney was not associated with kidney stone risk, and thus we performed mediation MR of PPARG agonists, circulating metabolites, and kidney stones. Among 249 circulating metabolites, we identified an indirect effect of PPARG agonists on kidney stones through increasing phospholipids to total lipids ratio in very large VLDL, with a mediated proportion of 6.87% (P = 0.018). Our study provided evidence that PPARG agonists reduced the risk of kidney stones partially via regulating lipid metabolism, and PPARG agonists may be a promising study subject in clinical studies for the prevention of kidney stones.
Insights
PPARG agonists, a type of diabetes medication, were found to significantly lower the risk of kidney stones. This effect is partly mediated by changes in lipid metabolism, suggesting potential for kidney stone prevention.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Diabetes mellitus is a known risk factor for kidney stones.
- The impact of various antidiabetic medications on kidney stone risk is not well-established.
Purpose of the Study:
- To investigate the causal effect of antidiabetic drugs on kidney stone risk using a Mendelian randomization (MR) approach.
- To explore the underlying mechanisms, including effects on lipid metabolism, and validate findings in a rat model.
Main Methods:
- Utilized genetic variants associated with drug targets and glycated hemoglobin (HbA1c) as instrumental variables in a two-sample MR analysis.
- Assessed thiazolidinediones (PPARG agonists), sulfonylureas, SGLT2 inhibitors, and GLP-1 analogs.
- Investigated effects in a glyoxylic acid-induced rat model of calcium oxalate (CaOx) nephrocalcinosis.
- Performed mediation analysis with circulating metabolites.
Main Results:
- Genetically proxied PPARG agonists significantly reduced kidney stone risk (OR=0.42; P=0.004) per 1-SD decrease in HbA1c.
- No significant association was observed for sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs.
- PPARG agonists (pioglitazone) ameliorated CaOx nephrocalcinosis in rats.
- Mediation analysis revealed an indirect effect of PPARG agonists on kidney stones via increased phospholipids to total lipids ratio in very large VLDL (mediated proportion=6.87%; P=0.018).
Conclusions:
- PPARG agonists demonstrate a protective effect against kidney stones, partly through modulation of lipid metabolism.
- These findings suggest PPARG agonists as a potential therapeutic strategy for kidney stone prevention in diabetic patients.
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