Chlorthalidone

A genome-wide analysis of chlorthalidone-induced glucose changes in white and black participants from the PEAR‑2 trial identified an intronic single‑nucleotide polymorphism (rs9943291) in HMGCS2 that reached genome‑wide significance in black subjects. Carriers of the G allele experienced a mean glucose increase of +16.29 mg/dL compared with +2.80 mg/dL in non‑carriers. The finding replicated independently in hydrochlorothiazide‑treated subjects from the PEAR study, and a cross‑study meta‑analysis confirmed the variant’s significance. Since HMGCS2 plays a key role in ketogenesis and cholesterol synthesis—pathways essential for glucose homeostasis—the results point to a promising candidate gene mediating thiazide‑induced hyperglycemia. These insights may eventually guide personalized selection of antihypertensive therapy.

Fig. 1 Distribution of glucose change post‐treatment showing the interindividual variability of the response among PEAR‐2 and PEAR participants. (Singh S, et al., 2018)

In genetic hypercalciuric stone‑forming rats fed hydroxyproline to induce calcium oxalate stones, the combination of potassium citrate and chlorthalidone reduced urinary calcium more than either agent alone and uniquely lowered urine oxalate, leading to a significant decrease in stone formation. Neither monotherapy altered stone burden. Chlorthalidone alone increased vertebral trabecular bone and cortical bone area, and improved trabecular mechanical properties, but adding potassium citrate provided no additional skeletal benefit. Thus, the dual therapy effectively prevents stones, but only chlorthalidone enhances bone quality in this model.

Fig. 2 Kidney stones and calcification. (Krieger NS, et al., 2021)