Research Original Investigation Risk of Progression to Diabetes Among Older Adults With Prediabetes
Invited Commentary
LESS IS MORE
Prediabetes—A Risk Factor Twice Removed
Kenneth Lam, MD; Sei J. Lee, MD, MAS
The concept of prediabetes (and similar concepts of im-
paired fasting glucose and impaired glucose tolerance) for-
mally emerged in the 1990s to better characterize the incre-
mental pathophysiology leading to the eventual development
of diabetes.1 It is defined by
Related article page 511
ranges of disordered glucose
values between normal and
diabetes (eg, hemoglobin A1c
Multimedia
levels, 5.7%-6.4% [to con-
vert to the proportion of total
hemoglobin, multiply by 0.01]). We treat it as a risk factor for
diabetes; in midlife, those with a hemoglobin A1c level of 6.0%
to 6.5% have 20 times the risk of developing diabetes com-
pared with those with a hemoglobin A1c level of 5.0%.2
In this issue of JAMA Internal Medicine, Rooney and
colleagues3 explore the association between prediabetes
and outcomes in older adults. Using data from the Atheroscle-
rosis Risk in Community Study, the authors examined the
6-year natural progression of glycemic measures in 3412 older
adults aged 70 to 91 years (mean age, 75 years) without dia-
betes. They found that prediabetes was present in up to 59%
of individuals depending on the definition used (hemoglobin
A1c levels of 5.7%-6.4% or fasting blood glucose levels of 100-
125 mg/dL [to convert to millimoles per liter, multiply by
0.0555]). Prediabetes was a risk factor for diabetes compared
with normoglycemia (hazard ratio, 3.0-3.2; range depending on
the definition of prediabetes), but participants were more likely
to regress to normoglycemia (13%-44%) or die (16%-19%) than
progress to diabetes (8%-9%). Furthermore, all-cause mortal-
ity for those with prediabetes was similar to those with nor-
moglycemia (hazard ratio, 0.83-1.07). Thus, prediabetes ap-
pears to be a weaker risk factor for diabetes in older adults.
The results of Rooney et al3 suggest that the concept of
prediabetes may be of limited importance for older adults.
While diabetes was an acute, symptomatic, and invariably
fatal disease when originally described, it has become an
asymptomatic chronic condition because of early detection
and the widespread availability of effective treatment.4 For
most patients, it is the end-organ vascular complications that
results from years of poorly controlled diabetes that cause
symptoms. Therefore, the modern definition of diabetes is
conceptually closer to being a risk factor itself (eg, something
that portends future disease) than an illness (eg, something
that patients experience). Prediabetes, then, is a risk factor
twice removed; it is a risk factor for diabetes, which itself
may be most accurately described as a risk factor for end-
organ vascular disease.
The 2020 guidelines from the American Diabetes Asso-
ciation advocate that all patients with prediabetes be moni-
tored annually for the development of type 2 diabetes, and that
patients be referred to Diabetes Prevention Programs for weight
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loss and physical activity.5 Therefore, the results reported by
Rooney and colleagues3 have important implications for these
guidelines while raising broader issues on how we define and
address risk factors in older patients.
First, in older adults with frailty and limited life expec-
tancy, prediabetes is irrelevant and can safely be ignored. Be-
cause the benefits of prediabetes management are most likely
accrued 10 or more years in the future, older adults with frailty
and limited life expectancy are unlikely to benefit from pre-
diabetes management. Guidelines should clarify that predia-
betes is a concept that should be reserved for healthier, middle-
aged adults rather than older adults with frailty.
Second, in healthy adults older than 75 years (the mean age
of the study participants), we should recognize that prediabetes,
as a risk factor twice removed, should be lower priority than symp-
tomatic conditions (which are affecting patients immediately) or
traditional risk factors. Older persons may spend up to 2 hours
a day engaging in health care–related activities.6 Diagnosing pre-
diabetes and then expending time and effort discussing manage-
ment strategies should not come at the expense of attending to
other issues of immediate importance to the patient. For all but
the healthiest of older adults older than 75 years, the current rec-
ommendations for annual monitoring and weight loss are likely
low yield. Future long-term cohort studies should explicitly ex-
amine whether prediabetes increases the risk of mortality and
morbidity in healthy older adults. In the interim, guideline man-
agement of prediabetes in persons older than 75 years should be
individualized, much in the way that cancer screening is
individualized based on life expectancy, expected benefit, and
patient values and preferences.7
Third, if the diagnostic thresholds for prediabetes devel-
oped in middle-aged adults are less applicable to older adults,
we should reexamine whether diabetes diagnostic thresh-
olds, which are also developed in middle-aged adults, are valid
for older adults. If most older adults with prediabetes revert
to normoglycemia, how many older adults with mild diabe-
tes (eg, hemoglobin A1c levels of 6.5%-7.0%) revert to predia-
betes or even normoglycemia? Additional studies are needed
to determine whether newly diagnosed mild diabetes in older
adults leads to adverse outcomes if left untreated. If it does not,
shifting the cutoffs for diagnosing diabetes in older adults
would help us focus treatment on those older adults for whom
diabetes is likely to result in symptomatic end-organ dam-
age, while avoiding identifying many older adults for whom
diabetes is unlikely to cause harm.
For middle-aged adults, a new diagnosis of diabetes can
lead to substantial morbidity and mortality; thus, focusing on
risk factors, such as prediabetes, is high-value and appropri-
ate in a middle-aged population. However, for many older
adults, new-onset diabetes will often be mild and asymptom-
atic and only one of many potentially life-threatening condi-
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 Risk of Progression to Diabetes Among Older Adults With Prediabetes Original Investigation Research

tions. This study shows that identifying prediabetes in older value care for older adults, we should focus our care and re-
adults should be regarded as a low priority, as it rarely leads search on what matters most to older adults and deprioritize
to incident diabetes or adverse outcomes. To ensure high- twice-removed risk factors, such as prediabetes.

ARTICLE INFORMATION
Author Affiliations: Division of Geriatrics,
Department of Medicine, University of California,
San Francisco (Lam, Lee); Geriatrics, Palliative and
Extended Care Service Line, San Francisco
Veterans Affairs Health Care System, San Francisco,
California (Lam, Lee).
Corresponding Author: Kenneth Lam, MD,
4150 Clement Street, Bldg 1, Room 207,
San Francisco, CA 94121
(kenneth.lam2@ucsf.edu).
Published Online: February 8, 2021.
doi:10.1001/jamainternmed.2020.8773
Conflict of Interest Disclosures: Dr Lee reported
grants from the US Department of Veterans Affairs
Health Services Research & Development
Investigator Initiated Research program (15-434)
and the National Institute on Aging (R01AG047897
and R01AG057751) outside the submitted work. No
other disclosures were reported.
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