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Objectives: This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization., Background: PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall., Methods: FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG)., Results: In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years)., Conclusions: Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.)., Competing Interests: Author Disclosures The FOURIER trial was supported by Amgen. Dr. Oyama has received a grant from JSPS Overseas Research Fellowships. Dr. Furtado has received grants and personal fees from AstraZeneca and Bayer; has received personal fees from Servier; and has received research grants from Pfizer, EMS, Aché, Brazilian Ministry of Health, University Health Network, and Lemann Foundation Research Fellowship. Dr. Fagundes has received a grant from The Lemann Foundation as Research Fellowships. Dr. Zelniker has received honoraria from AstraZeneca and Boehringer Ingelheim; and has received research grants from the German Research Foundation and the Austrian Science Funds. Drs. Tang, Kuder, Murphy, and Bergmark are members of the TIMI Study Group, which has received institutional grant support through the Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr. Hamer is an employee of Amgen. Dr. Wang is an employee of Amgen. Dr. Keech has received grants and personal fees from Abbott; has received personal fees from Amgen, AstraZeneca, and Pfizer; has received grants and personal fees from Mylan; has received grants from Sanofi andNovartis, outside the submitted work; and has received personal fees from Bayer, outside the submitted work. Dr. Giugliano has received grants from Amgen; has received honoraria from Amgen, AstraZeneca, Daiichi-Sankyo, Dr. Reddy’s Laboratories, and Merck; and has received consultant fees from Amgen, Akcea, Amarin, Boehringer Ingelheim, Bristol Myers Squibb, CVS Caremark, Daiichi-Sankyo, Esperion, GlaxoSmithKline, Lexicon, Merck, Portola, and Pfizer. Dr. Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, The Medicines Company, MedImmune, Merck, Novartis, and Pfizer; has received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, DalCor, Dr. Reddy’s Laboratories, Intarcia, and Merck. Dr. Bergmark has received grant support from Pfizer, AstraZeneca, and Abbott Vascular; and has received consulting fees from Philips, Abbott Vascular, Servier, Daiichi-Sankyo, Janssen, and Quark., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with type 2 diabetes mellitus have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function. After several large cardiovascular outcome trials with mostly neutral results, 2 studies of the sodium-glucose co-transporter 2 inhibitors (SGLT2is), empagliflozin and canagliflozin, reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred. These findings prompted several analyses to elucidate the mechanisms of action of SGLT2is and have initiated several large clinical trials in patients with HF without type 2 diabetes mellitus. This review summarizes known and possible mechanisms that contribute to these salutary effects of SGLT2is. Also discussed is the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)