556 Diabetes Care Volume 47, April 2024

Individualizing Treatment of Matthew C. Riddle

Type 2 Diabetes After Metformin:

More Insights From GRADE
Diabetes Care 2024;47:556–561 | https://doi.org/10.2337/dci24-0008

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The Glycemia Reduction Approaches in
Diabetes: A Comparative Effectiveness
Study (GRADE) compared several classes
of glucose-lowering agents for people
with type 2 diabetes (T2D) who were al-
ready being treated with lifestyle inter-
vention and metformin (1). Its goal was
to provide guidance in selecting second-
line therapy for individuals in this impor-
tant group, which had not previously
been evaluated in a large, long-term
comparative effectiveness study (2). At
entry, the 5,047 participants averaged a
4.2-year duration of diabetes, HbA1c
7.5%, and BMI 34.3. Equal numbers
were randomized to add glargine, glime-
piride, liraglutide, or sitagliptin while con-
tinuing metformin. The primary measure
of outcome was durability of glycemic
control, defined as maintaining HbA1c be-
low 7.0%. When HbA1c exceeded that
level, insulin was to be added as rescue
therapy: glargine for the glimepiride, lira-
glutide, or sitagliptin arms and aspart for
the glargine arm. The study also assessed
medical outcomes, the incidence of side
THE GRADE STUDY
5.0 years, and retention in the study was
over 90%. HbA1c values declined initially
with all treatments but then rose steadily;
71% of participants reached 7.0% or
higher by the end of observation. Main-
tenance of glycemic control was better
with glargine and liraglutide than with
the two oral agents, but the differences
were small. In comparison with all other
treatments, liraglutide was associated
with a 16% lower and glargine a 13%
lower risk of HbA1c rising to 7% or above.
Even less contrast between treatments
was reported for complications of diabe-
tes. The authors concluded that “the in-
cidences of microvascular complications
and death were not materially differ-
ent.” Cardiovascular events and deaths
were relatively few. Only when these
were combined as “any cardiovascular”
event was a “possible difference” favor-
ing better outcomes with liraglutide
suggested.
These findings are reassuring. The
well-known progressive nature of T2D
was evident, but all of the commonly
patients whose glucose levels are no lon-
ger controlled with metformin.
NEW ANALYSES FROM GRADE
However, the question posed by the
GRADE investigators has not been fully
addressed. That is: how can we best
match each treatment option to the
needs of each person? This issue of Dia-
betes Care contains a collection of 10
additional articles prepared by the
GRADE investigators that may aid deci-
sions in clinical practice. Some of their
features are summarized in Table 1.
Three of them concern clinical and
physiologic features that are associated
with success in maintaining glycemic
control, both overall and with specific
forms of treatment (5–7). Four others
compare the several treatments in their
association with end points other than
glycemic control. The end points are all-
cause mortality (8), a composite of gly-
cemic control without weight gain or
hypoglycemia (9), quality of life (10),
and depression or diabetes distress

effects, and several psychosocial and be-
havioral measures. GRADE is an impor-
tant study because it posed important
questions and was large, long-term, and
randomized.
MAIN RESULTS FROM GRADE
The GRADE investigators published two
reports of the main results in 2022 (3,4).
The mean duration of observation was
used agents controlled glucose levels
for a substantial period of time. No new
adverse effects were seen, and previ-
ously recognized side effects—notably
hypoglycemia with glargine and glime-
piride and gastrointestinal symptoms
with liraglutide—seldom impeded their
use. Clinical providers may conclude
that any of these agents can be recom-
mended for a broad population of
(11). Two articles describe associations
of depression or diabetes distress at
entry with long-term outcomes with
the different treatments (12,13). A fi-
nal analysis describes the use of res-
cue therapy with insulin when the
originally assigned second-line treat-
ment no longer keeps HbA1c below
7.5% (14). Each of these articles de-
serves a few comments.

Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health & Science University, Portland, OR
Corresponding author: Matthew C. Riddle, riddlem@ohsu.edu
This article is part of a special article collection available at https://diabetesjournals.org/collection/2066/Reports-from-the-GRADE-Study.
This article is featured in podcasts available at diabetesjournals.org/care/pages/diabetes_care_on_air.
© 2024 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not
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diabetesjournals.org/care Riddle 557

Table 1—Summary of new reports from GRADE

Article (reference no.) Target of analysis New findings Confirmatory findings Take-home messages
Garvey et al. (5) Baseline clinical predictors Better durability of control in Better durability of control All these agents can be used
of durability of glycemic older people overall when HbA1c not very for second-line therapy
control No baseline features predict high Early intervention is safe and
between-treatment Liraglutide and glargine effective, even for older
differences are slightly more people
effective than
glimepiride and
sitagliptin
Utzschneider et al. (6) Insulin sensitivity and Poor immediate response to Greater sensitivity and Sitagliptin is less effective
secretion as predictors sitagliptin when sensitivity better secretion favor when insulin sensitivity is
of glycemic control is low control overall low
Rasouli et al. (7) Effects of treatments on Liraglutide improved Insulin sensitivity seemed Differing effects on b-cell

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sensitivity and secretion secretion while fasting and stable during treatment function suggest sitagliptin
after oral glucose may be best suited to
Glimepiride improved treating postprandial
secretion only while hyperglycemia, glimepiride
fasting to fasting hyperglycemia
Sitagliptin improved secretion
only after oral glucose
Banerji et al. (8) All-cause mortality as end Numeric imbalance of deaths, Low mortality rate limits More experience with
point fewer with liraglutide between-treatment liraglutide is needed to
comparisons guide its use as second-
line therapy
Kirkman et al. (9) Three-part composite end No baseline predictors other Glycemic control without Conclusions are limited by
point than treatment assignment weight gain or lack of information on the
hypoglycemia importance of
maintained better with gastrointestinal side effects
liraglutide
Cherrington et al. (10) Quality of life as end point Improvement with liraglutide No treatment worsened People with obesity may
in the first year associated quality of life benefit from liraglutide’s
with weight loss effect on weight
Gonzalez et al. (11) Depression or distress as Improvement in the first year No treatment worsened Contrary to expectation,
end point with both liraglutide and depression or distress glargine did not worsen
glargine distress
Cherrington et al. (12) Effect of depression or Baseline depression or
distress on glycemia distress did not
independently affect
glycemia
Hoogendoorn et al. (13) Effect of depression or Depression or distress was Emotion-related
distress on medication associated with reduced nonadherence to diabetes
adherence adherence treatment may have
occurred but did not affect
glycemic control in GRADE
Hollander et al. (14) Insulin as rescue therapy Glargine was well accepted Despite nonadherence to
and continued as second- insulin as rescue therapy,
line treatment but was not individualized choices by
routinely used as rescue site investigators and
therapy participants maintained
good glycemic control

Garvey et al. (5) report associations be-
tween easily obtained clinical information
and success in maintaining HbA1c below
7% in the whole study population and
with each treatment option. Participants
who were older than 60 years had better
glycemic responses than those who were
younger. Understandably, lower HbA1c
prior to second-line treatment predicted
better maintenance of control during the
study with all treatments. A multivariable
model showed that, independent of other
factors, glargine and liraglutide maintained
HbA1c below 7% slightly longer than glime-
piride and sitagliptin, consistent with the
earlier report (3). There also was a new
observation: sitagliptin was particularly in-
effective in improving glycemic control in
the first year of treatment. However, none
of the baseline characteristics emerged as
a strong predictor of between-treatment
differences in long-term glycemic control.
Utzschneider et al. (6) extend these
findings by examining some physiologic
558 Commentary
characteristics of the participants. They as-
sessed associations of glycemic outcomes
with insulin sensitivity of tissues and insu-
lin secretion after an oral glucose load. Se-
rial oral glucose tolerance tests were
performed at the beginning of the study
and at intervals during follow-up. Estab-
lished modeling procedures were used to
derive information about insulin sensitiv-
ity and secretion from these tests. The
models could not reliably use data from
the glargine arm of the study, so the anal-
ysis focused on glimepiride, liraglutide,
and sitagliptin. Both greater insulin sensi-
tivity and greater insulin secretion were
associated with better glycemic control
during treatment with all three agents.
However, participants in the lowest third
of insulin sensitivity had especially poor
glycemic control in the first year of treat-
ment with sitagliptin.
Further physiologic studies are reported
by Rasouli et al. (7). They modeled data
from oral glucose tolerance tests for par-
ticipants in all treatment arms and showed
differences between the four agents in
their effects on insulin sensitivity and se-
cretion during the course of the study. In-
sulin sensitivity remained constant in all
treatment arms after the first year. In the
first year of treatment, an apparent im-
provement of sensitivity was observed
with glargine. This was likely due to an arti-
fact in the analytic method due to the
presence of glargine and its metabolites,
but the investigators rightly suggest that a
favorable effect of glargine on insulin sen-
sitivity cannot be excluded. Glargine had
little effect on insulin secretion, but the
other three agents all enhanced b-cell
function in the first year. However, this
benefit declined over time, especially
with liraglutide. Moreover, the specific
b-cell effects differed between agents.
Liraglutide potentiated insulin secretion
to glucose both during fasting and after a
glucose load. Sitagliptin did not potenti-
ate insulin secretion during fasting but en-
hanced it during the glucose tolerance
test, although less so than liraglutide. Gli-
mepiride potentiated secretion during
fasting but had little effect after oral glu-
cose. These differences in mode of action
may be relevant to clinical decisions, as
will be discussed later.
All-cause mortality is examined by
Banerji et al. (8). The earlier report of
medical outcomes in GRADE noted no
clear between-treatment difference in
mortality, but the cumulative incidence
curve for liraglutide seemed to rise less
rapidly than that for other treatments
near the end of observation. The present
article presents mortality data more fully.
A total of 153 deaths were reported, with
0.59 deaths per 100 participant-years.
This low rate was expected because the
group had a relatively short duration of
diabetes and few established illnesses,
which limits the statistical power of the
analysis. However, the glargine, glimepir-
ide, and sitagliptin groups had similar
numbers of deaths (42, 43, and 41, re-
spectively), while the group assigned to
liraglutide had 27 deaths. Equal mortality
risk was reported for glimepiride com-
pared with linagliptin in the Cardiovascu-
lar Outcome Study of Linagliptin Versus
Glimepiride in Type 2 Diabetes (CARO-
LINA) (15) and for glargine compared
with oral therapies in the Outcome Re-
duction With Initial Glargine Intervention
(ORIGIN) trial (16), studies that were well
powered to identify differences in mortal-
ity. The lower absolute number of deaths
with liraglutide in GRADE is thus an out-
lier that calls for more attention. Even so,
the numbers are too low to draw strong
conclusions. Moreover, at 10%, the frac-
tion of deaths in GRADE for which the
cause is unknown is larger than that in
most trials assessing mortality, limiting
comparison of treatment groups by cause
of death.
The article by Kirkman et al. (9) explores
use of a composite end point in GRADE.
Their three-part composite consisted of
HbA1c higher than 7.5%, a weight increase
of 5% or more, or hypoglycemia, defined
as any event requiring assistance or more
than one episode of nonsevere hypoglyce-
mia. As expected, liraglutide outperformed
the other agents by this measure, main-
taining glycemic control without these un-
desired effects. This observation is consistent
with other analyses using composites of
HbA1c, weight change, and hypoglycemia
that have compared liraglutide favorably
with other treatments (17). However, the
analysis from GRADE has some limitations.
There is no consensus on how end points
for weight change or hypoglycemia should
be defined and weighted regarding their
likely relation to the medical status of study
participants (18). In this case, most hypogly-
cemia events were nonsevere, self-reported
by participants, and not objectively con-
firmed. Whether such events are linked to
harm in this relatively healthy population is
not clear. Also, the composite did not include
Diabetes Care Volume 47, April 2024
gastrointestinal symptoms, the leading side
effect of liraglutide. Gastrointestinal symp-
toms were listed in the main GRADE report
along with severe hypoglycemia as “serious
and targeted” adverse events and were re-
ported by 44% of participants assigned to lir-
aglutide (3). Finally, the GRADE analysis did
not identify any baseline characteristics that
were clearly predictive of the composite out-
come. Although reassuringly confirmatory of
prior reports, the present analysis does not
add much new insight regarding individualiz-
ing second-line treatment in this population.
Findings regarding health-related qual-
ity of life (HRQoL) as an outcome of thera-
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pies are reported by Cherrington et al.
(10). The investigators used three vali-
dated questionnaires to assess HRQoL:
the Quality of Well-Being Self-Administered
Scale (QWB-SA) and the 36-Item Short-
Form Health Survey mental and physical
component scales (MCS and PCS). None of
these measures worsened during the study
with any of the treatments. The main be-
tween-treatment difference was a greater
improvement of PCS score with liraglutide
in the first year that was not sustained later
in the study. Mediation analyses suggested
the initial benefit with liraglutide was re-
lated to weight loss and was most evident
among participants with higher BMI.
Gonzalez et al. (11) evaluate possible
effects of the several treatments on de-
pression or diabetes distress during the
study. They used validated question-
naires to collect data from participants
for both analyses. The stated goal of the
analysis was to determine whether, as
suggested in earlier literature, emotional
distress is provoked by use of insulin.
Consistent with prior evidence for favor-
able effects upon entering clinical studies
(19), depression and distress scores in
the first year improved with all treat-
ments used in GRADE. However, both
glargine and liraglutide were associated
with larger improvements in the first
year compared with the two oral agents.
Scores were stable later in the study,
with little difference between treatments.
The investigators conclude that they found
“no evidence for a deleterious effect of
basal insulin on emotional distress.”
Two articles assess the effects of de-
pression or diabetes distress at entry to
the study on the main glycemic outcome
and on adherence to treatment with the
assigned study drugs. Cherrington et al.
(12) report that, after adjustment for
other characteristics at baseline, neither
diabetesjournals.org/care
depression nor diabetes distress was as-
sociated with inability to maintain HbA1c
below 7.0%. The companion article by
Hoogendoorn et al. (13) reports that
both depression and diabetes distress
were associated with lower self-reported
adherence to the assigned study medica-
tions. This association was apparent for
depression or distress at baseline as well
as during the course of the study, and it
was not affected by treatment assign-
ment. No clear explanation for discor-
dance between glycemic outcomes and
medication adherence is provided. One
possibility is that self-report of adher-
ence was not always accurate. Another
is that the agents used in the study, all
having a duration of action longer than a
day, maintained their therapeutic effects
even when daily doses were occasionally
missed. In any case, the findings do not
support emotion-related nonadherence
to medications as an important contribu-
tor to between-treatment differences in
glycemic control in this population.
Finally, Hollander et al. (14) describe
experience with rescue insulin in GRADE.
This analysis was not specified in the
original protocol. It was initiated about
halfway through the study to determine
why insulin was not consistently added
within 6 weeks after HbA1c was verified
as higher than 7.5%, as required by proto-
col. Analysis of a subgroup meeting crite-
ria for rescue with basal insulin showed
that glargine was added to glimepiride,
liraglutide, or sitagliptin within 6 weeks in
only 39% of participants and at any time
in 69%. Timely addition of one or more in-
jections of aspart as prandial therapy for
participants in the glargine arm, as re-
quired by protocol, occurred even less
frequently. Site investigators completed a
questionnaire for each participant in this
subgroup. The most common reasons
given for nonadherence were that the par-
ticipant wanted to intensify lifestyle efforts
or medication adherence or was reluctant
to use insulin itself. Lack of adherence to
the protocol could have affected planned
analyses of all treatment groups after the
primary end point was reached.
WHAT HAVE WE LEARNED ABOUT
SECOND-LINE THERAPY?
The GRADE investigators have energeti-
cally sought new information from these
secondary and post hoc analyses, and
they give us much to consider. With all
the treatments, glycemic control was
best maintained for participants older
than 60 years and for those without
markedly elevated HbA1c at baseline.
There was no evidence of excessive side
effects. Thus, there seems to be no rea-
son to delay adding a second agent once
metformin is no longer successful alone
or to withhold treatment for healthy
older people.
Because between-treatment differences
in the main end point and many secondary
end points were small, the GRADE results
suggest there is no clear “best” choice for
second-line treatment in the broad popu-
lation enrolled in this study. Instead, these
results call for greater effort to individual-
ize treatments to each person’s clinical
characteristics and preferences. The analy-
ses reviewed here suggest some ways
each of the randomized treatments might
be considered and prescribed.
Sitagliptin
Sitagliptin fared least well in overall gly-
cemic effectiveness. Its limitations were
often apparent immediately and were
most evident when the starting HbA1c
was high and insulin sensitivity low. Its
effect on b-cell function was limited to
improving insulin secretion after an oral
challenge. On the positive side, side ef-
fects were rare. These observations sug-
gest an optimal clinical profile for its
use. Sitagliptin might be considered for
older people or others for whom side
effects are especially worrisome, when
hyperglycemia is mild and mainly post-
prandial, and when insulin sensitivity is
high. These characteristics are com-
mon in Asian populations where di-
peptidyl peptidase 4 (DPP-4) inhibitors
are widely used. It is noteworthy that
this class of drugs has been reported
to provide better glycemic control for
Asian populations than for other pop-
ulations (20).
Glimepiride
Glimepiride was only slightly less effective
in maintaining glycemic control than lira-
glutide and glargine. Severe hypoglycemia
accompanying its use was uncommon, re-
ported in 2.2% of participants over
5 years of observation. This low risk might
be further reduced by simple precautions.
By protocol the starting dose was at least
1 mg, which immediately provides about
half-maximal glucose lowering. Daily dose
Riddle 559
was titrated within a year to a mean of
more than 4 mg, the usual maximally ef-
fective dose. About a third of participants
in GRADE had HbA1c 7.2% or less at entry;
for them this titration scheme may have
been too aggressive. Perhaps glimepiride
is best suited to individuals who have
HbA1c 7.5% or higher initially, and in some
cases should be started at a 0.5-mg dose
with slow titration. Also, the observation
that glimepiride’s physiologic effect on in-
sulin secretion is mainly during fasting
suggests it may be most effective when
fasting hyperglycemia is prominent.
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Liraglutide
Liraglutide performed well in GRADE, but
not without some concerns. It maintained
glycemic control as well as glargine did,
caused significant weight loss, and im-
proved measures of HRQoL and diabetes-
related distress in the first year. Cardio-
vascular end points showed promising—
but not statistically reliable—trends dur-
ing the study. On the other hand, the
strong improvement of b-cell function
with liraglutide declined after the first
year, at which time weight loss leveled
and patient-reported outcomes merged
with those for other arms of the study.
Forty-four percent of participants assigned
to liraglutide reported gastrointestinal
symptoms, and its use was discontinued
by 23%. Because of the benefits of this
class of drug for cardiovascular and renal
disease, liraglutide is a very appropriate
choice for individuals needing second-line
therapy who have these conditions. How-
ever, GRADE included few participants
with known myocardial infarction or stroke
(6.5%) or estimated glomerular filtration
rates below 60 (2.4%). The GRADE sub-
group for which liraglutide seems most
clearly indicated may be those with signifi-
cant obesity, on the basis of predictable
weight loss that is associated with better
quality of life and perhaps lower cardiovas-
cular risk.
Glargine
As a second-line intervention, glargine
was as effective as liraglutide with respect
to the primary glycemic end point. It was
also well accepted. Nearly all participants
randomized to glargine started it, and only
14% of them discontinued during the
study. The hypothesis that starting glargine
might increase diabetes-related distress
was rejected; a measure of distress in the
560 Commentary
first year was lowest with glargine. Severe
hypoglycemia occurred in 1.3% of partici-
pants who were assigned glargine, fewer
than with glimepiride (2.2%) and similar to
the incidence with liraglutide (1.0%). These
findings argue that glargine, used as basal
insulin without mealtime boluses of rapid-
acting insulin, is well tolerated as second-
line therapy.
At the same time, use of glargine as
rescue therapy when HbA1c rose above
7.0% with the other treatments was un-
expectedly erratic. Glargine was added
to prior treatment less than half the
time the protocol called for it. This ob-
servation raises new questions, which
are discussed below.
LARGER ISSUES RAISED BY GRADE
Like all studies, GRADE has important
limitations. The population was similar
but not identical to a general population
of people needing second-line therapy.
Newer therapies already proven to be
helpful for treating T2D—notably the so-
dium–glucose cotransporter 2 (SGLT2)
blockers and a new class of gut-peptide
agonists represented by tirzepatide—
could not have been included. For these
reasons, the findings of the study cannot
fully be extrapolated to clinical practice
today. Some key lessons, however, are
apparent.
Individualization of Therapy
If several options for second-line therapy
are nearly equal in glycemic effectiveness,
decisions must be based on other distinc-
tive features. Some insights regarding op-
timal use of the specific agents used in
GRADE have just been reviewed. Beyond
characteristics of the drugs themselves,
features of a person who might use them
must be considered. Physiologic aspects
of diabetes in each case are relevant. Is
the person insulin sensitive or resistant?
Does hyperglycemia occur mainly after
meals, or are fasting glucose levels always
high? Lifestyle preferences differ widely,
as do physical capabilities and willingness
to take injected therapies. Tolerance of
various side effects differs as well. Now
that drugs with favorable nonglycemic ef-
fects on cardiovascular and renal disease
are available, these conditions must be
identified. Assessing all these factors is
not easy; it requires expertise and time.
How can an algorithm replace this highly
personal process?
In GRADE, an effort was made to com-
mit all therapeutic choices after random-
ization to a second-line treatment to a
specific protocol. This was successful up
to the time of reaching the primary end
point, but not after. The insulin rescue
plan was not followed. To a trialist, failing
to adhere to protocol is deeply troubling.
Nonadherence to the rescue protocol
surely challenged the planned analyses
after the primary end point.
However, there is a lesson here. Some
of the end points may have been com-
promised, but the GRADE participants
fared well. Most remained active in the
study, patient-reported measures were
generally favorable throughout, and gly-
cemic control remained good. Near the
end of observation, when duration of
T2D was about 8 years, mean HbA1c was
7.1% in all four randomized arms (3).
The participants and site investigators,
together, had individualized treatment in
a variety of ways, off-protocol but none-
theless effective.
Is this not a kind of success? It calls to
mind the experience in ORIGIN (21), a
larger, longer comparative effectiveness
and safety trial that was conducted at dia-
betes centers worldwide. It enrolled par-
ticipants with dysglycemia or early T2D,
together with evidence of high cardiovas-
cular risk, who were using no more than
one oral agent. Those with diagnosed T2D
(about 11,000 participants) had, at entry,
an average disease duration of 5 years
and mean HbA1c 6.5%. They were ran-
domized to add glargine or conventional
step therapy with oral agents. Whereas
the GRADE protocol called for a specific
rescue plan, that in ORIGIN did not. When
a fasting glycemic target was exceeded,
the investigators were to advance ther-
apy according to local guidelines and
their judgement of the participant’s
needs, except for not using glargine in
the conventional care arm. As in GRADE,
good glycemic control was maintained;
the mean HbA1c after more than 5 years
was still close to 6.5% in both arms. Also
as in GRADE, the randomized arms had
equivalent medical outcomes despite
more hypoglycemia with glargine. A les-
son from ORIGIN, as from GRADE, was
that investigators who are experienced
in managing diabetes can effectively indi-
vidualize long-term treatment for many
patients who come to clinic every 3 (in
GRADE) or 4 (in ORIGIN) months.
Diabetes Care Volume 47, April 2024
Can This Be Done Outside a Clinical
Study?
Clinical studies assess the safety and
efficacy of treatments or, as in GRADE,
compare different agents in a selected
population. However, it is said that struc-
tured studies allow better management
than is possible in a real-world clinical set-
ting. Primary care providers are expected,
with the help of treatment algorithms, to
individualize as best they can, but under
less favorable conditions. Some people in
the general population have more chal-
lenging medical conditions and living cir-
cumstances than those in studies. Newer
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therapies can be costly, and formulary ac-
cess varies. Primary providers have lim-
ited time at office visits, and they cannot
keep up with our growing collection of
drugs—some with multiple formulations
and names—and advancing knowledge
of subgroups of patients. For all these
reasons, glycemic control in a community
setting often deteriorates after the first
few years of T2D.
The GRADE experience provides impor-
tant insights about the safety and effective-
ness of the treatments compared and
suggests new ways to deploy them. Just as
important, it suggests we rethink the idea
that T2D must be managed in a primary
care setting. There are many examples of
longitudinal specialty care alongside pri-
mary medical practice. Dentistry, reproduc-
tive medicine, ophthalmology, psychiatry,
and oncology are a few examples. Why not
diabetology? It is claimed there are too
few specialists to take on this challenge,
but that could be corrected. Care for type 1
diabetes is acknowledged to require spe-
cialized support, but not care for T2D, de-
spite its complexities and hazards. Expert
groups like the GRADE investigators could
be built into large health systems to individ-
ualize second- and third-line care of T2D af-
ter lifestyle and metformin. Referral could
be expedited and time for informed deci-
sions assured. It is worth a thought. We
have many effective new treatments; now
we must use them wisely.
We are deeply indebted to the GRADE
investigators for planning and complet-
ing this complex study and now giving us
a collection of new analyses to move our
thinking forward.
Funding. This work was supported in part by
the Rose Hastings and Russell Standley Me-
morial Trusts for Diabetes Research.
diabetesjournals.org/care
Duality of Interest. No potential conflicts of
interest relevant to this article were reported.
M.C.R. is an ad hoc editor of Diabetes Care but
was not involved in any of the decisions regarding
review of the manuscript or its acceptance.
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