Background: Both high and low levels of serum potassium measurements are linked with a higher risk of adverse clinical events among patients with type 2 diabetes. The study was aimed at evaluating the implications of the various degrees of initial estimated glomerular filtration rate (eGFR) change on subsequent serum potassium homeostasis following sodium–glucose cotransporter‐2 inhibitor (SGLT2i) initiation among patients with type 2 diabetes. Methods and Results: We used medical data from a multicenter health care provider in Taiwan and recruited 5529 patients with type 2 diabetes with baseline/follow‐up eGFR data available after 4 to 12 weeks of SGLT2i treatment from June 1, 2016, to December 31, 2018. SGLT2i treatment was associated with an initial mean (SEM) eGFR decline of −3.5 (0.2) mL/min per 1.73 m ² in overall study participants. A total of 36.7% (n=2028) of patients experienced no eGFR decline, and 57.9% (n=3201) and 5.4% (n=300) of patients experienced an eGFR decline of 0% to 30% and >30%, respectively. Patients with an initial eGFR decline of >30% were associated with higher variability in consequent serum potassium measurement when compared with those without an initial eGFR decline. Participants with a pronounced eGFR decline of >30% were associated with a higher risk of hyperkalemia ≥5.5 (adjusted hazard ratio,4.59 [95% CI, 2.28–9.26]) or use of potassium binder (adjusted hazard ratio, 2.65 [95% CI, 1.78–3.95]) as well as hypokalemia events <3.0 mmol/L (adjusted hazard ratio, 3.21 [95% CI, 1.90–5.42]) or use of potassium supplement (adjusted hazard ratio, 1.87 [95% CI, 1.37–2.56]) following SGLT2i treatment after multivariate adjustment. Conclusions: Physicians should be aware that the eGFR trough occurs shortly, and consequent serum potassium changes following SGLT2i initiation.

KCNH2 loss-of-function mutations cause long QT syndrome type 2 (LQT2), an inherited cardiac disorder associated with life-threatening ventricular arrhythmia. Through whole-exome sequencing, we discovered a novel AGCGACAC deletion (S981fs) in the hERG gene of an LQT2 patient. Using a heterologous expression system and patch clamping, we found that the mutant K channel had reduced cell surface expression and lower current amplitude compared to the wild type. However, functional expression was restored by lowering temperature and using potassium channel inhibitors or openers (E4031, cisapride, nicorandil). Co-immunoprecipitation experiments confirmed the assembly of mutant proteins with wild-type hERG. Confocal imaging showed decreased hERG distribution on the cell membrane in cells expressing S981fs. Notably, treatment with G418 significantly increased hERG current in wild-type/S981fs heterozygotes. In conclusion, our study identifies a novel hERG mutation leading to impaired Kv11.1 function due to trafficking and nonsense-mediated RNA decay defects. These findings shed light on the mechanisms underlying LQT2 and offer potential therapeutic avenues.

Background: Major clinical trials regarding sodium–glucose cotransporter 2 inhibitors (SGLT2is) have focused on estimated glomerular filtration rate (eGFR) slope and composite kidney outcomes, with limited evaluation of eGFR variability as a kidney outcome or its long-term implications in patients receiving SGLT2i versus placebo. Methods: This retrospective study analyzed 3777 propensity score-matched patients with type 2 diabetes receiving either SGLT2i or dipeptidyl peptidase-4 inhibitor (DPP4i) between June 2016 and December 2021. Each patient had eGFR data at three time points before (−15, −9, and −3 months) and after (3, 9, and 15 months) the drug-index date. eGFR variability was assessed using the coefficient of variation (COV) and standard deviation (SD) of eGFR values. Results: SGLT2i therapy was associated with a significant reduction in eGFR variability by both COV (from 0.072 (0.001) to 0.069 (0.001); p = 0.014) and SD (mL/min/1.73 m²) (from 5.34 (0.07) to 4.82 (0.07); p < 0.001). In contrast, DPP4i therapy resulted in increased COV (from 0.072 (0.001) to 0.080 (0.001); p < 0.001) and no significant improvement in SD (from 5.06 (0.07) to 5.22 (0.07); p = 0.082). Greater reduction in eGFR variability was observed in SGLT2i relative to DPP4i with high pre-treatment eGFR variability, pre-existing chronic kidney disease, or rapid pre-treatment eGFR decline. Greater pre-treatment eGFR variability predicted risk of major adverse kidney events (MAKEs) and abrupt kidney decline in DPP4i-treated patients, but not in those on SGLT2is. SGLT2i consistently reduced the risk of MAKE and abrupt kidney decline across the spectrum of pre-treatment eGFR variability, with a greater risk reduction on the MAKE for SGLT2i versus DPP4i therapy with a higher pre-treatment eGFR variability estimated by SD (p interaction = 0.014). Conclusions: SGLT2i therapy improved eGFR variability and reduced the risk of adverse kidney outcomes compared to DPP4i, particularly in patients with higher pre-treatment eGFR variability.