Medical Management of Hyperglycemia in
Type 2 Diabetes: A Consensus Algorithm
for the Initiation and Adjustment of
Therapy
A consensus statement of the American Diabetes Association and the
European Association for the Study of Diabetes
DAVID M. NATHAN, MD1
JOHN B. BUSE, MD, PHD2
MAYER B. DAVIDSON, MD3
ELE FERRANNINI, MD4
RURY R. HOLMAN, FRCP5
ROBERT SHERWIN, MD6
BERNARD ZINMAN, MD7
The consensus algorithm for the medical management of type 2 diabetes was published in
August 2006 with the expectation that it would be updated, based on the availability of new
interventions and new evidence to establish their clinical role. The authors continue to endorse
the principles used to develop the algorithm and its major features. We are sensitive to the risks
of changing the algorithm cavalierly or too frequently, without compelling new information. An
update to the consensus algorithm published in January 2008 specifically addressed safety issues
surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications
that now have more clinical data and experience.
Diabetes Care 31:1–11, 2008
The epidemic of type 2 diabetes andthe recognition that achieving spe-cific glycemic goals can substantially
reduce morbidity have made the effective
treatment of hyperglycemia a top priority
(1–3). While the management of hyper-
glycemia, the hallmark metabolic abnor-
mality associatedwith type 2 diabetes, has
historically taken center stage in the treat-
ment of diabetes, therapies directed at
other coincident features, such as dyslip-
idemia, hypertension, hypercoagulabil-
ity, obesity, and insulin resistance, have
also been a major focus of research and
therapy. Maintaining glycemic levels as
close to the nondiabetic range as possible
has been demonstrated to have a powerful
beneficial effect on diabetes-specific mi-
crovascular complications, including ret-
inopathy, nephropathy, and neuropathy,
in the setting of type 1 diabetes (4,5); in
type 2 diabetes, more intensive treatment
strategies have likewise been demon-
strated to reduce microvascular compli-
cations (6 – 8). Intensive glycemic
management resulting in lower A1C lev-
els has also been shown to have a benefi-
cial effect on cardiovascular disease
(CVD) complications in type 1 diabetes
(9,10); however, current studies have
failed to demonstrate a beneficial effect of
intensive diabetes therapy onCVD in type
2 diabetes (11–13).
The development of new classes of
blood glucose–lowering medications to
supplement the older therapies, such as
lifestyle-directed interventions, insulin,
sulfonylureas, and metformin, has in-
creased the number of treatment options
available for type 2 diabetes. Whether
used alone or in combination with other
blood glucose–lowering interventions,
the increased number of choices available
to practitioners and patients has height-
ened uncertainty regarding the most
appropriate means of treating this wide-
spreaddisease (14).Althoughnumerous re-
views on themanagement of type2diabetes
have been published in recent years (15–
17), practitioners are often left without a
clear pathway of therapy to follow. We de-
veloped the following consensus approach
to themanagement of hyperglycemia in the
nonpregnant adult to help guide health care
providers in choosing the most appropriate
interventions for their patients with type 2
diabetes.
Process
The guidelines and algorithm that follow
are derived from two sources. One source
is the clinical trials that address the effec-
tiveness and safety of the different modal-
ities of therapy. Here, the writing group
reviewed a wide variety of studies related
to the use of drugs as monotherapy or in
combination to lower glycemia. Unfortu-
nately, the paucity of high-quality evi-
dence in the form of well-controlled
clinical trials that directly compare differ-
ent diabetes treatment regimens remains a
major impediment to recommending one
class of drugs, or a particular combination
of therapies, over another.
The second source of material that in-
formed our recommendations was clinical
judgement, that is, our collective knowl-
edge and clinical experience, which takes
into account benefits, risks, and costs in the
treatment of diabetes. As in all clinical deci-
sion making, an evidence-based review of
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From the 1Diabetes Center, Massachusetts General Hospital, Boston,Massachusetts; the 2University of North
Carolina School of Medicine, Chapel Hill, North Carolina; the 3Clinical Center for Research Excellence,
Charles R. Drew University, Los Angeles, California; the 4Department of Internal Medicine, University of
Pisa, Pisa, Italy; the 5Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism,
Oxford University, Oxford, U.K.; the 6Department of Internal Medicine and Yale Center for Clinical
Investigation, Yale University School of Medicine, New Haven, Connecticut; and the 7Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Corresponding author: David. M. Nathan, dnathan@partners.org..
This article is being simultaneously published in 2008 by Diabetes Care and Diabetologia by the American
Diabetes Association and the European Association for the Study of Diabetes.
An American Diabetes Association consensus statement represents the authors’ collective analysis, evalua-
tion, and opinion at the time of publication and does not represent official association opinion.
DOI: 10.2337/dc08-9025
© 2008 by the American Diabetes Association and Springer. Copying with attribution allowed for any
non-commercial use of the work.
R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s
C O N S E N S U S S T A T E M E N T
DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 1
Diabetes Care Publish Ahead of Print, published online October 22, 2008
Copyright American Diabetes Association, Inc., 2008
the literature must also be supplemented
by value judgements, where the benefits
of treatment are weighed against risks and
costs in a subjective fashion. While we
realize that others may have different
judgements, we believe that the recom-
mendations made in this new iteration of
our treatment algorithm will guide ther-
apy and result in improved glycemic con-
trol and health status over time.
Glycemic goals of therapy
Controlled clinical trials, such as the Dia-
betes Control and Complications Trial
(DCCT) (4) and the Stockholm Diabetes
Study in type 1 diabetes (5) and the UK
Prospective Diabetes Study (UKPDS)
(6,7) and Kumamoto study (8) in type 2
diabetes, have helped to establish the gly-
cemic goals of therapy that result in im-
proved long-term outcomes. The clinical
trials, in concert with epidemiological
data (18,19), support decreasing glyce-
mia as an effective means of reducing
long-termmicrovascular and neuropathic
complications. The most appropriate tar-
get levels for blood glucose, on a day-to-
day basis, and A1C, as an index of chronic
glycemia, have not been systematically
studied. However, both theDCCT (4) and
the UKPDS (6,7) had as their goals the
achievement of glycemic levels in the
nondiabetic range. Neither studywas able
to maintain A1C levels in the nondiabetic
range in their intensive treatment groups,
achieving mean levels over time of �7%,
which is 4 SDs above the nondiabetic
mean.
Themost recent glycemic goal recom-
mended by the American Diabetes Asso-
ciat ion, selected on the basis of
practicality and the projected reduction
in complications over time, is, in general,
an A1C level of�7% (1). Themost recent
glycemic goal set by the International Di-
abetes Federation is an A1C level of
�6.5%. The upper limit of the nondia-
betic range is 6.1% (mean � SD. A1C
level of 5� 2%) with the DCCT/UKPDS-
standardized assay, which has been pro-
mulga t ed through the Nat iona l
Glycohemoglobin Standardization Pro-
gram (NGSP) and adopted by the vastma-
jority of commercially available assays
(20). Several recent clinical trials have
aimed for A1C levels �6.5% with a vari-
ety of interventions (11,12). The results of
the Action to Control Cardiovascular Risk
in Diabetes (ACCORD) study, which had
the primary objective of decreasing CVD
with interventions aimed at achieving an
A1C level of �6.0% vs. interventions
aimed at achieving an A1C level of
�7.9%, showed excess CVD mortality in
the intensive treatment group (11). Re-
sults from the Action in Diabetes and Vas-
cular Disease: Preterax and Diamicron
MR Controlled Evaluation (ADVANCE)
trial and the Veterans Affairs Diabetes
Trial, both of which had different inter-
ventions and study populations than
ACCORD, did not demonstrate any ex-
cess total or CVDmortality with intensive
regimens that achieved A1C levels com-
parable with the 6.5% in ACCORD
(12,13). However, none of the studies has
demonstrated a benefit of intensive glyce-
mic control on their primary CVD out-
comes. Our consensus is that an A1C level
of�7% should serve as a call to action to
initiate or change therapy with the goal of
achieving an A1C level of �7%. We are
mindful that this goal is not appropriate
or practical for some patients, and clinical
judgement based on the potential benefits
and risks of a more intensified regimen
needs to be applied for every patient. Fac-
tors such as life expectancy, risk of hypo-
glycemia, and the presence of CVD need
to be considered for every patient before
intensifying the therapeutic regimen.
Assiduous attention to abnormalities
other than hyperglycemia that accom-
pany type 2 diabetes, such as hyperten-
sion and dyslipidaemia, has been shown
to improve microvascular and cardiovas-
cular complications. Readers are referred
to published guidelines for a discussion of
the rationale and goals of therapy for the
nonglycemic risk factors, as well as rec-
ommendations on how to achieve them
(1,21,22).
Principles in selecting
antihyperglycemic interventions
Our choice of specific antihyperglycemic
agents is predicated on their effectiveness
in lowering glucose, extraglycemic effects
that may reduce long-term complica-
tions, safety profiles, tolerability, ease of
use, and expense.
Effectiveness in lowering glycaemia
Except for their differential effects on gly-
cemia, there are insufficient data at this
time to support a recommendation of one
class of glucose-lowering agents, or one
combination of medications, over others
with regard to effects on complications. In
other words, the salutary effects of ther-
apy on long-term complications appear to
be predicated predominantly on the level
of glycemic control achieved rather than
on any other specific attributes of the in-
tervention(s) used to achieve glycemic
goals. The UKPDS compared three classes
of glucose-lowering medications (sulfo-
nylurea, metformin, or insulin) but was
unable to demonstrate clear superiority of
any one drug over the others with regard
to diabetes complications (6,7). However,
the different classes do have variable ef-
fectiveness in decreasing glycemic levels
(Table 1), and the overarching principle
in selecting a particular intervention will
be its ability to achieve and maintain gly-
cemic goals. In addition to their inten-
tion-to-treat analyses demonstrating the
superiority of intensive versus conven-
tional interventions, the DCCT and
UKPDS demonstrated a strong correla-
tion between mean A1C levels over time
and the development and progression of
retinopathy and nephropathy (23,24).
Therefore, we think it is reasonable to
judge and compare blood glucose–
lowering medications, as well as combi-
nations of such agents, primarily on the
basis of their capacity to decrease and
maintain A1C levels and according to
their safety, specific side effects, tolerabil-
ity, ease of use, and expense.
Nonglycemic effects of medications
In addition to variable effects on glyce-
mia, specific effects of individual thera-
pies on CVD risk factors, such as
hypertension or dyslipidemia, were also
considered important. We also included
the effects of interventions that may ben-
efit or worsen the prospects for long-term
glycemic control in our recommenda-
tions. Examples of these would be
changes in body mass, insulin resistance,
or insulin secretory capacity in type 2 di-
abetic patients.
Choosing specific diabetes
interventions and their roles in
treating type 2 diabetes
Numerous reviews have focused on the
characteristics of the specific diabetes in-
terventions listed below (25–34). In addi-
tion, meta-analyses and reviews have
summarized and compared the glucose-
lowering effectiveness and other charac-
teristics of the medications (35–37). The
aim here is to provide enough informa-
tion to justify the choices of medications,
the order in which they are recom-
mended, and the use of combinations of
therapies. Unfortunately, there is a dearth
of high-quality studies that provide head-
to-head comparisons of the ability of the
medications to achieve the currently rec-
ommended glycemic levels. The authors
Nathan and Associates
2 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008
highly recommend that such studies be
conducted. However, even in the absence
of rigorous, comprehensive studies that
directly compare the efficacy of all avail-
able glucose-lowering treatments and
their combinations, we feel that there are
enough data regarding the characteristics
of the individual interventions to provide
the guidelines below.
An important intervention that is
likely to improve the probability that a
patient will have better long-term control
of diabetes is to make the diagnosis early,
when the metabolic abnormalities of dia-
betes are usually less severe. Lower levels
of glycemia at the time of initial therapy
are associated with lower A1C levels over
time and decreased long-term complica-
tions (38).
Lifestyle interventions
The major environmental factors that in-
crease the risk of type 2 diabetes are over-
nutrition and a sedentary lifestyle, with
consequent overweight and obesity
(39,40). Not surprisingly, interventions
that reverse or improve these factors have
been demonstrated to have a beneficial
effect on control of glycemia in estab-
lished type 2 diabetes (41). Unfortu-
nately, the high rate of weight regain has
limited the role of lifestyle interventions
as an effective means of controlling glyce-
mia in the long term. The most convinc-
ing long-term data indicating that weight
loss effectively lowers glycemia have been
generated in the follow-up of type 2 dia-
betic patients who have had bariatric sur-
gery. In this setting, with a mean
sustained weight loss of�20 kg, diabetes
is virtually eliminated (42–45). In addi-
tion to the beneficial effects of weight loss
on glycemia, weight loss and exercise im-
prove coincident CVD risk factors, such
as blood pressure and atherogenic lipid
profiles, and ameliorate other conse-
quences of obesity (41,46,47). There are
few adverse consequences of such life-
Table 1—Summary of glucose-lowering interventions
Intervention
Expected decrease
in A1C with
monotherapy (%) Advantages Disadvantages
Tier 1: well-validated core
Step 1: initial therapy
Lifestyle to decrease weight and
increase activity 1.0–2.0 Broad benefits Insufficient for most within
first year
Metformin 1.0–2.0 Weight neutral GI side effects, contraindicated
with renal insufficiency
Step 2: additional therapy
Insulin 1.5–3.5 No dose limit, rapidly effective,
improved lipid profile
One to four injections daily,
monitoring, weight gain,
hypoglycemia, analogues
are expensive
Sulfonylurea 1.0–2.0 Rapidly effective Weight gain, hypoglycemia
(especially with
glibenclamide or
chlorpropamide)
Tier 2: less well validated
TZDs 0.5–1.4 Improved lipid profile
(pioglitazone), potential
decrease in MI (pioglitazone)
Fluid retention, CHF, weight
gain, bone fractures,
expensive, potential increase
in MI (rosiglitazone)
GLP-1 agonist 0.5–1.0 Weight loss Two injections daily, frequent
GI side effects, long-term
safety not established,
expensive
Other therapy
�-Glucosidase inhibitor 0.5–0.8 Weight neutral Frequent GI side effects, three
times/day dosing, expensive
Glinide 0.5–1.5a Rapidly effective Weight gain, three times/day
dosing, hypoglycemia,
expensive
Pramlintide 0.5–1.0 Weight loss Three injections daily,
frequent GI side effects,
long-term safety not
established, expensive
DPP-4 inhibitor 0.5–0.8 Weight neutral Long-term safety not
established, expensive
aRepaglinide more effective in lowering A1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction.
Consensus Statement
DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 3
style interventions other than difficulty in
incorporating them into usual lifestyle
and sustaining them and the usually mi-
nor musculoskeletal injuries and poten-
tial problems associated with neuropathy,
such as foot trauma and ulcers, that may
occur as a result of increased activity. The-
oretically, effective weight loss, with its
pleiotropic benefits, safety profile, and
low cost, should be themost cost-effective
means of controlling diabetes—if it could
be achieved and maintained over the long
term.
Given these beneficial effects, which
are usually seen rapidly—within weeks to
months—and often before there has been
substantial weight loss (47), a lifestyle in-
tervention program to promote weight
loss and increase activity levels should,
with rare exceptions, be included as part
of diabetesmanagement.Weight loss of as
little as 4 kg will often ameliorate hyper-
glycemia. However, the limited long-term
success of lifestyle programs to maintain
glycemic goals in patients with type 2 di-
abetes suggests that the large majority of
patients will require the addition of med-
ications over the course of their diabetes.
Medications
The characteristics of currently available
glucose-lowering interventions, when
used as monotherapy, are summarized in
Table 1. The glucose-lowering effective-
ness of individual therapies and combina-
tions demonstrated in clinical trials is
predicated not only on the intrinsic char-
acteristics of the intervention but also on
the duration of diabetes, baseline glyce-
mia, previous therapy, and other factors.
Amajor factor in selecting a class of drugs,
or a specific medication within a class, to
initiate therapy or when changing ther-
apy, is the ambient level of glycemic con-
trol. When levels of glycemia are high
(e.g., A1C �8.5%), classes with greater
and more rapid glucose-lowering effec-
tiveness, or potentially earlier initiation of
combination therapy, are recommended;
however, patients with recent-onset dia-
betes often respond adequately to less in-
tensive interventions than those with
longer-term disease (48). When glycemic
levels are closer to the target levels (e.g.,
A1C�7.5%), medications with lesser po-
tential to lower glycemia and/or a slower
onset of action may be considered.
Obviously, the choice of glycemic
goals and the medications used to achieve
them must be individualized for each pa-
tient, balancing the potential for lowering
A1C and anticipated long-term benefit
with specific safety issues, as well as other
characteristics of regimens, including side
effects, tolerability, ease of use, long-term
adherence, expense, and the nonglycemic
effects of themedications. Type 2 diabetes
is a progressive disease characterized by
worsening glycemia; higher doses and ad-
ditional medications are required over
time if treatment goals are to be met.
Metformin. In most of the world, met-
formin is the only biguanide available. Its
major effect is to decrease hepatic glucose
output and lower fasting glycemia. Typi-
cally, metformin monotherapy will lower
A1C levels by �1.5 percentage points
(27,49). It is generally well tolerated, with
the most common adverse effects being
gastrointestinal. Metformin monotherapy
is not usually a