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Trends in
Endocrinology & Metabolism
Science & Society
‘diabetes’. Rather, diabetes is a complex to activation of pathways that can effect
The time is now for new, series of metabolic derangements, includ- toxic consequences: polyol, hexosamine,
lower diabetes ing hyperlipidemia, insulin resistance, and protein kinase C (PKC), and advanced
diagnostic thresholds hyperinsulinemia and/or autoimmune glycation end-product [3]. Illustratively,
inflammatory mechanisms that lead to glycemic activation of the toxic PKC path-
Stanley S. Schwartz, 1,2,* β-cell dysfunction or failure, resulting in way induces changes in both vascular
Amy W. Rachfal, 3 and hyperglycemia, as well as many other (e.g., vascular epithelial growth factor)
Barbara E. Corkey 4 adverse outcomes [5,6]. That said, and inflammatory pathways (e.g., nitric
dysglycemia is a useful, widely studied, oxide synthesis) that, in turn, can cause
easily obtainable biomarker that has impaired β-cell function, insulin resistance,
Current thresholds for diagnosing been used for decades for diabetes and micro- and macrovascular complica-
diabetes are outdated and do not mellitus (DM) diagnosis. Although it is tions in susceptible patients [3]. In fact, it
vital to continue to investigate additional is hypothesized that even moderately in-
represent advancements in dis-
and better biomarkers of this complex creased blood glucose (i.e., prediabetes
ease understanding or ability to
disease to more effectively target those levels) can lead to negative effects in sus-
impact course. Today, evidence most at risk [5], continued use, for now, ceptible patients [3,4]. Although, why
supports intervening earlier along of dysglycemia as a biomarker for DM di- some patients may be more susceptible
the disease continuum to mitigate agnosis is the best means of practically to complications with lower glycemic
transition to frank disease and exacting change in the clinical manage- thresholds has not been fully elucidated.
delay/reduce adverse clinical out- ment of our patients. However, it is im- It may be due to a different threshold trig-
comes. We believe it is time for portant to note that the use of glycemia ger flux into these toxic pathways, a multi-
lower diabetes diagnostic criteria. as a biomarker and as diagnostic criteria plication effect of more than one pathway,
should by no means imply hyperglycemia and other genetic patient characteristics,
as the only therapeutic target for patients metabolic abnormalities, and comorbidi-
with this multifaceted disease. ties [3–5]. Further research is warranted
The current glycemic thresholds for diag- to increase our ability to target interven-
nosing diabetes were set more than two We propose that the time is right to shift tions to individual patients.
decades ago (1997) [1]. Since then sub- the paradigm to include all non-normal
stantial advancements have occurred re- glucose and glucose tolerance with the This hypothesis is illustrated by micro- and
garding understanding of the disease disease of diabetes, removing the term macrovascular complications associated
continuum, multifactorial etiology, underly- prediabetes from the current lexicon, with the non-normal glycemic/prediabetic
ing pathophysiologic mechanisms, and thus diagnosing diabetes using current state. For example, although diagnostic
the potential to impact the course of dis- glycemic thresholds for prediabetes thresholds were, in part, informed by epi-
ease and comorbidities. The fact that the (Figure 1) [7]. demiologic studies of diabetic retinopathy
prediabetic condition itself is associated incidence in the 1990s, suggesting glyce-
with micro- and macrovascular complica- We believe an artificial distinction exists mic levels above which retinopathy preva-
tions is almost as important as the number between prediabetes and diabetes. The lence increased in linear fashion, it is now
who will progress to overt diabetes [2–4]. pathophysiology of prediabetes includes known that diabetic retinopathy occurs in
As complications of diabetes begin early insulin resistance, impaired incretin action, 8–12% patients with prediabetes, with
in the progression from normal glucose insulin hypersecretion, increased lipolysis, some estimates as high as 24%, and that
tolerance to frank disease, we propose a and ectopic lipid storage, all of which retinopathy begins earlier than previously
call to action to re-evaluate the diabetes damage the β-cell and are also central fea- thought, or is detected, with neuroinflam-
diagnostic criteria and broaden and evolve tures of overt diabetes [6,8,9]. Indeed, in- mation proceeding vascular damage
the discussion surrounding treating this creased fasting insulin secretion, insulin [1,3,4,10]. In fact, the traditional microvas-
complex metabolic disease, with the aim resistance, and β-cell damage and dys- cular diabetes complications of retinopa-
of improving our patients’ long-term function occur on a continuum and are thy, neuropathy, and nephropathy all
health. largely dysfunctional prior to formal diabe- occur at a substantive rate within patients
tes diagnosis [3]. Damage to cells and classified as prediabetic (11–25% with ev-
It is clear that hyperglycemia alone does tissues is set in motion early, even with idence of peripheral neuropathy and predi-
not define or adequately represent minimal abnormal glycemic patterns, due abetes is a strong independent predictor

Trends in Endocrinology & Metabolism, Month 2021, Vol. xx, No. xx 1


Diabetes
≥ 6.5 ≥ 126
< 6.5 < 126
Prediabetes
≥ 5.7 ≥ 100
< 5.7 < 100
Normal
Hb A1C, FPG,
% mg/dl
Figure 1. Proposed shift to rational diabetes diagnosis thresholds. Diabetes diagnosis based on meeting any one of three criteria. Current diabetes and prediabetes
classification criteria shown on left [7]. Abbreviations: FPG, fasting plasma glucose; HbA1C, glycated hemoglobin; OGTT, oral glucose tolerance test; PG, plasma glucose.
of chronic kidney disease) [3,4]. Impor-
tantly, processes leading to these charac-
teristic microvascular complications are in
place long before they manifest. Further,
increasing hyperglycemia has been inde-
pendently associated with accelerated
cognitive decline in prediabetes [11]. Sim-
ilarly, macrovascular complications occur
in patients with non-normal glycemic pa-
rameters [4,8]. Prediabetic dysglycemia
increases risk for cardiovascular (CV)
disease, including myocardial infarction,
congestive heart failure, coronary artery
disease, arthrosclerosis, and CV death
[4,8]. Indeed many patients with prediabe-
tes have concomitant risk factors for CV
disease, including insulin resistance,
obesity, and other features of metabolic
syndrome [8,9]. Moreover, prediabetes in-
creases risk for cerebrovascular diseases,
including stroke, and is commonly comorbid
with peripheral artery disease, although the
link has not been fully elucidated [8].
2 Trends in Endocrinology & Metabolism, Month 2021, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
≥ 200
< 200
≥ 140
< 140
PG after
OGTT,
mg/dl
Although a full discussion of the treatment of
‘prediabetes’ is outside the scope of this
brief call to action, we believe interventions
aimed at patients prior to frank diabetes
have the potential to both decrease the risk
of progression to diabetes, as well as de-
crease micro- and macrovascular complica-
tions [2,4,7,9,12]. It is our belief that all
patients should be treated with diet and
lifestyle modifications and our contention
that antidiabetic agents, which also have
additional benefits beyond simply reducing
glycemic levels, such as reduction of CV/
renal risk, should be given preference.
Which interventions to consider should be
based on individual patient characteristics,
mechanism of action of said interventions,
safety profile, clinical studies, goals of
treatment, as well as treating physician
experience. Lifestyle intervention is recom-
mended by the American Diabetes Associa-
tion and is a safe and cost-effective measure
that can lower the risk of progression to type
Diabetes
≥ 5.7 ≥ 100 ≥ 140
< 5.7 < 100 < 140
Normal
Hb A1C, FPG, PG after
% mg/dl OGTT,
mg/dl
Trends in Endocrinology & Metabolism
2 diabetes as well as promote weight
loss, with 14% versus 23% progressing
after 3 years after lifestyle modification or
control, respectively, based on a meta-
analysis of 16 randomized, controlled trials
[7,12]. Further, evaluation of whether antidia-
betic, antiobesity agents or treatments, in-
cluding bariatric procedures, can reduce
progression of prediabetes to diabetes in
patients with impaired glucose tolerance is
an area of active research [2,4,9]. Risk re-
duction versus placebo of >25% has been
found for certain agents that show promise
but are not without side effects [2,4,13].
The recently published STOP DIABETES
trial highlights the potential of combination
therapy designed to correct underlying
pathophysiologies (e.g., impaired insulin
secretion and resistance) to substantively
impact patient outcomes in a real-world set-
ting [2]. Indeed, Kanat et al. have suggested
combination therapy, with each component
aimed at type 2 diabetes prevention and
Trends in Endocrinology & Metabolism
restoration of normal glucose tolerance,
would especially prevent microvascular
complications [13]. Unfortunately, to date,
research related to use of pharmacologic
agents to reduce micro- and macrovascular
complications in prediabetes is limited,
though we believe it is reasonable to hy-
pothesize that agents directed at patho-
physiologies associated with prediabetes
(e.g., hyperglycemia, insulin resistance, im-
paired insulin secretion, etc.) may have a
positive impact in patient health, particularly
those with increased risk factors. We be-
lieve lowering the threshold of DM diagno-
sis allows clinicians to use approved
antidiabetic agents for individual patients
with the goal of assessing the effectiveness
of therapies as well as practically exacting
change in the clinical management of their
patients and the course of their disease.
Importantly, we are not advocating for
pharmacologic interventions for all patients
with pre-DM glycemic ranges, rather the
ability to practically treat individual patients
based on patient characteristics, mecha-
nism of action of said interventions, safety
profile, clinical studies, goals of treatment,
as well as practical clinical judgement and
expertise.
Earlier intervention has the potential to
provide value to both the patient and the
healthcare system, provided that the inter-
ventions are focused, selective, and pa-
tient specific. We believe early detection
and treatment is appropriate, as duration
of hyperglycemia is a predictor of adverse
outcomes and effective interventions
exist to prevent disease progression and
likely reduce complications [9]. Early treat-
ment could lead to improved health load
for the US based on potential mitigation
of serious downstream clinical outcomes
[9,14]. For example, prediabetes was as-
sociated with statistically higher rates of
ambulatory visits for hypertension; endo-
crine, metabolic, and renal complications;
and general medical conditions and an ad-
ditional $443 for each adult with prediabe-
tes in a healthcare utilization study [14]. It
may be that cost-benefit estimates on recommend a call to action to re-evaluate
treating 'prediabetes' are improved with the diabetes diagnostic criteria.
the use of newer diabetes agents (e.g.,
glucagon-like protein-1 receptor agonists, Declaration of interests
sodium-glucose co-transport 2 inhibitors) S.S.S. is on advisory boards for Salix Pharmaceuticals
that are also associated with reduction in and Arkay Therapeutics and on the Speaker’s Bureau
adverse CV and/or renal outcomes for Salix Pharmaceuticals, Janssen Pharmaceuticals,
Boehringer Ingelheim, Eli Lilly, and Merck. S.S.S. is
[7,9,13,15].
employed and receives financial compensation from
his clinical practice [affiliated with Main Line Health
Providing physicians with more discretion (with no monetary connection)] with no compensation
in treating individual patients with related to the manuscript. A.W.R. is a clinical drug
evidenced-based practice by lowering development consultant. None of her past or current
the diabetes diagnostic thresholds, and clients has provided compensation related to
thereby increasing the likelihood of insur- this manuscript. A.W.R. has been compensated by
S.S.S. for assistance in medical editing and prepara-
ance reimbursement, would be an impor-
tion of the manuscript. Note, A.W.R. meets ICMJE
tant step forward in improving the health
authorship requirements. A.W.R. is self-employed at
of our patients. Further, removing the ter- Stage Gate Partners, LLC with no compensation
minology of ‘pre’diabetes may elevate from Stage Gate Partners related to the manuscript.
both patient and physician perception of B.E.C. confirms she has no conflicts of interest.With
the importance of the diagnosis and the exception of the listed potential conflict of interests
motivation to manage the condition. A above, the authors declare that the research was con-
ducted in the absence of any commercial or financial
personalized approach to detecting and
relationships that could be construed as a potential
managing patients with impaired glucose
conflict of interest.
tolerance based on their individual risk
factors and the benefits, risks, and costs 1
Stanley Schwartz MD, LLC, Main Line Health System,
of various interventions would provide a Wynnewood, PA, USA
2
Emeritus Professor, University of Pennsylvania, Perlman
meaningful advance in the treatment of di-
School of Medicine, Philadelphia, PA, USA
abetes and its complications [15]. 3
Stage Gate Partners, LLC, Ardmore, PA, USA
4
Emeritus Professor, Boston University School of Medicine,
Boston, MA, USA
Although definitive prospective evidence
does not exist at this time, a preponder- *Correspondence:
ance of supportive evidence supports the stschwar@gmail.com (S.S. Schwartz).
logic of beginning treatment (lifestyle https://doi.org/10.1016/j.tem.2021.10.007
modifications, interventions, and/or drugs) © 2021 Elsevier Ltd. All rights reserved.
in patients with non-normal glucose/
glucose tolerance earlier to mitigate impor-
tant deleterious outcomes reaching far be- References
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