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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,
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: Jrgavin3@yahoo.com
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).