Aims: To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodiumglucose cotransporter-1 and -2, in adults with type 2 diabetes (T2D) and stage 4 chronic kidney disease (CKD4).Materials and Methods: This 52-week, phase 3, randomized (1:1:1), placebocontrolled trial evaluated sotagliflozin 200 mg and sotagliflozin 400 mg once daily in 277 patients with T2D and estimated glomerular filtration rate (eGFR) 15 to 30 mL/ min/1.73 m 2 . The primary endpoint was glycated haemoglobin (HbA1c) reduction with sotagliflozin 400 mg versus placebo at 26 weeks. A hierarchical statistical testing approach was used.Results: The baseline mean HbA1c was 65 ± 12 mmol/mol (8.1% ± 1.1%), systolic blood pressure (SBP) was 144 ± 15 mmHg, and eGFR was 24 ± 4 mL/min/1.73m 2 .Placebo-adjusted changes with sotagliflozin 400 mg were -3 mmol/mol (À0.3%; 95% confidence interval -7 to 0.6 [À0.6 to 0.05]; P = 0.096) and -8 mmol/mol (À0.7%; -13 to -3 [À1.2 to À0.2]; P = 0.003) in HbA1c at Weeks 26 and 52, respectively, À1.5 kg (À3.0 to À0.1) in body weight at Week 26, À5.4 mmHg (À9.4 to À1.3) in SBP at Week 12, and À0.3 mL/min/1.73 m 2 (À2.1 to 1.6; P = 0.776) in eGFR at Week 52. Over 52 weeks, 11.8%, 5.4% and 3.3% of patients receiving placebo and sotagliflozin 200 and 400 mg, respectively, required rescue therapy for hyperglycaemia. Adverse events (AEs) occurred in 82.8%, 86.2% and 81.1% of patients and serious cardiovascular AEs occurred in 12.9%, 3.2% and 4.4% of patients in the placebo and sotagliflozin 200 and 400 mg groups, respectively.Conclusions: After 26 weeks, HbA1c reductions with sotagliflozin were not statistically significant versus placebo in adults with T2D and CKD4. The 52-week safety profile was consistent with results of the SCORED outcomes trial (NCT03242018).

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The adenine nucleotide translocase (ANT) mediates ADP/ATP exchange in mitochondria and is also a critical component of the mitochondrial permeability transition (MPT) pore. Opening of this physiological pore has been implicated as a key step in initiating cell death, hence agents that prevent MPT pore opening may be of potential therapeutic value. The natural product bongkrekic acid is a potent ANT inhibitor that is reported to block MPT opening. We present the design and synthesis of N-acyl iminodiacetic acids as novel inhibitors of ANT-1, using bongkrekic acid as an initial lead. The identification of potent ANT-1 inhibitors from a primary binding assay and the preliminary structure-activity relationship based on these new leads are discussed.Adenine nucleotide translocase (ANT) is an abundant integral mitochondrial inner membrane protein, whose key function is the selective exchange of cytosolic ADP for mitochondrial matrix ATP across the otherwise impermeable inner mitochondrial membrane. By providing the mitochondrial oxidative phosphorylation machinery with substrate for ATP production, and by supplying the cell with a high-energy phosphate source, the ANT-facilitated exchange of ADP and ATP is the most active transport system in aerobic cells and is a critical component in maintaining cellular energy metabolism. 1-3 ANT is also an important component of a protein complex called the mitochondrial permeability transition (MPT) pore, the opening of which has been recognized as a key step in initiating cell death. 4 This relatively non-specific pore can open under pathologic conditions, such as elevated Ca 2+ concentration, oxidative stress, and depletion of adenine nucleotides, which are associated with events such as stroke or myocardial infarction. Pore opening allows cytoplasmic solutes less than 1500 daltons in mass to equilibrate across the inner mitochondrial membrane, causing collapse of mitochondrial membrane potential, swelling and rupture of the outer membrane, and release of toxic macromolecules that induce apoptosis. 5-7 Thus, agents that prevent MPT pore opening may provide a potentially efficacious strategy for the treatment of ischemia/reperfusion injury and for certain neurodegenerative diseases.Two different conformations of ANT have been demonstrated on the basis of interactions with specific ligands, 8 namely the inhibitors atractyloside (ATR) and bongkrekic acid (BKA) (Figure 1). These high-affinity ligands bind to ANT in an asymmetric fashion, either from the matrix (m) or from the cytosolic (c) side of the inner mitochondrial membrane, and they can mutually displace each other. Atractyloside binds to ANT in the c-conformation and induces the permeability transition, while bongkrekic acid interacts with ANT in the m-conformation and inhibits the permeability transition in response to a variety of apoptotic stimuli. 9 This finding suggests that different small molecule ligands of ANT may possess a spectrum of activities, i.e. they may act as cell protective agents targeted for acute tissue...