The mechanisms of formation and the nature of the altered amino acid side chains formed on proteins subjected to oxidant attack are reviewed. The use of stable products of protein side chain oxidation as potential markers for assessing oxidative damage in vivo in humans is discussed. The methods developed in the authors laboratories are outlined, and the advantages and disadvantages of these techniques compared with other methodologies for assessing oxidative damage to proteins and other macromolecules. Evidence is presented to show that protein oxidation products are sensitive markers of oxidative damage, that the pattern of products detected may yield information as to the nature of the original oxidative insult, and that the levels of oxidized side-chains can, in certain circumstances, be much higher than those of other markers of oxidation such as lipid hydroperoxides.

Background: SGLT inhibitors reduce the risk of cardiovascular (CV) events in patients with heart failure (HF) and chronic kidney disease regardless of diabetes status. Although the SOLOIST-WHF and SCORED trials enrolled high CV risk patients with T2DM, participants had a wide range of baseline A1C values. Thus, the present analysis evaluated the effects of sotagliflozin relative to placebo on cardiovascular (CV) death and total HF-related outcomes by baseline A1C range. Methods: SOLOIST-WHF had no baseline A1C entry criteria (baseline median = 7.1%, range = 4.5, 15.0%), while SCORED randomized patients with T2DM and an A1C ≥7% at screening (8.3%, 6.5, 17.3%). Natural cubic splines from Poisson regression models estimated the relationships between continuous A1C and the primary endpoint for both studies: total number of CV deaths, hospitalizations for HF, and urgent visits for HF. Results: Within each trial, patients with higher baseline A1C experienced higher event rates (spline effect p=0.0349 and 0.0014 for SOLOIST-WHF and SCORED, respectively). Sotagliflozin reduced the primary outcome in each trial (p for treatment <0.0001 for both SOLOIST-WHF and SCORED) and this did not differ across A1C (p for interaction >0.10; Figure). Conclusion: Sotagliflozin was effective in reducing the risk of CV death and HF-related events independent of baseline A1C. Disclosure R.Aggarwal: None. D.L.Bhatt: Board Member; Bristol-Myers Squibb Company, Research Support; Lexicon Pharmaceuticals, Inc., Sanofi, Lilly, Boehringer Ingelheim Inc., AstraZeneca, Novo Nordisk. M.Szarek: Consultant; Amarin Corporation, ESPERION Therapeutics, Inc., Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Lexicon Pharmaceuticals, Inc., Regeneron, Sanofi, Bayer Inc. M.J.Davies: Employee; Lexicon Pharmaceuticals, Inc. P.L.Banks: Employee; Lexicon Pharmaceuticals, Inc. B.Pitt: Consultant; Bayer Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., KBP Bioscience, Merck & Co., Inc. P.G.Steg: Advisory Panel; Merck & Co., Inc., Consultant; Sanofi, Amarin Corporation, Amgen Inc., BMS, PhaseBio Pharmaceuticals, Inc., Idorsia Pharmaceuticals Ltd., Novartis AG, Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Lexicon Pharmaceuticals, Inc.