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Editorial Diabetes Type 2 Diabetes in a Time of Change—A Tide of Good News James R Gavin III Emory University School of Medicine and Healing Our Village, Inc, Atlanta, Georgia, US T ype 2 diabetes has been definitively characterized as one of the most physiologically complex and heterogeneous metabolic known diseases. The extraordinary depth of knowledge that has been achieved regarding the pathophysiology has helped to stimulate an explosive array of therapeutic regimens and monitoring tools for improving outcomes in this disease. Indeed, the clinical narrative about ‘control’ of diabetes has shifted markedly in the last two years, away from a focus on glucose-mediated vascular complications to defining diabetes control as cardiovascular risk reduction and end organ protection. The new tools for management coupled with new pathophysiologic insights have brought a tide of good news for the millions of people living with type 2 diabetes. Keywords Ominous octet, complex pathophysiology, complementary combination therapy, glucose control Disclosure: James R Gavin III is a consultant for Janssen Pharmaceuticals, Intarcia, Inc., AstraZeneca, Boehringer Ingleheim, Novo Nordisk, Sanofi-Aventis, Abbott Diabetes Care, and Merck. Speaker Bureau for Janssen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: October 26, 2016 Published Online: December 20, 2016 Citation: US Endocrinology, 2016;12(2):81–2 Corresponding Author: James R Gavin III, Healing Our Village, Inc., Emory University School of Medicine, 145 Bayberry Run, Fayetteville, Georgia 30214, US. E: TOU CH MED ICA L MEDIA It hardly seems possible that only 21 years ago, the most exciting concept in type 2 diabetes (T2D) was the contribution of peripheral insulin resistance to disease pathophysiology, and the most important new tool to address this defect was the biguanide, metformin. The dominant conceptualization of the underlying defects accounting for the hyperglycemia of T2D had been introduced by Ralph DeFronzo several years earlier in his Lilly lecture as the ‘triumvirate’ of T2D pathophysiology. 1 The availability of metformin as a treatment tool to address insulin resistance greatly strengthened the ability of clinicians to fashion treatment regimens that appeared to align with the underlying disease process. The excitement generated by metformin has certainly been justified by its performance as foundation therapy for the vast majority of patients with T2D, with its effects on glucose and beyond. 2 This was a good news period for T2D. However, what we have witnessed over the last decade must be considered transformational in both our understanding of the underlying pathology of T2D and the tools that have been developed for its treatment and monitoring. First, our understanding of the defects that drive the hyperglycemia of T2D has been greatly expanded to a more extensive spectrum of defects contributing to hyperglycemia in T2D, prompted by DeFronzo’s introduction of the ‘Ominous Octet’. 3 Indeed, this construct of diabetes initiated a break from the ‘stepped care’ approach to treatment to a more physiological algorithm for making treatment decisions. This alternate approach encourages earlier use of complementary combination therapy and offers a more rational approach that may provide better long-term effects. This approach has gained more traction in recent years, with the emergence of several new developments that offer good news for T2D. Perhaps the most significant advance has been the availability of a broad spectrum of safe, efficacious newer agents that further expand the physiological targets for treatment of T2D, with complementary actions in their mechanisms. 4 This advance is important because these agents have proven to be effective in improving glucose control, while offering benefits for other cardiometabolic risk factors known to have significant impact on the increased coronary heart disease (CHD) mortality of T2D. 5 Thus, in contrast to the fear that such drugs might produce cardiovascular harm in attempts to better control T2D, these newer agents have proven to be not only safe, 6–10 but recently, we have seen evidence of cardiovascular protection in trials using the sodium-glucose transporter-2 (SGLT-2) inhibitor empagliflozin, with the GLP-1 receptor agonists liraglutide 11 and semaglutide, 12 and a similar effect has been seen with bromocriptine-QR. 13 These results have dramatically changed the narrative from a largely unfounded fear of using newer agents to treat T2D 14 to a view that indeed it may be time to realistically pursue reduced cardiovascular events and mortality as outcome measures in diabetes care, especially if the results reported to date prove to represent class effects for many of these agents (that is, the SGLT-2 inhibitors). 81