Hyperglycemia in dm ada 2012
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This document provides a position statement from the American Diabetes Association and European Association for the Study of Diabetes on the management of hyperglycemia in type 2 diabetes. It recommends a patient-centered approach to treatment that considers individual patient needs, preferences, and tolerances. The statement reviews the evidence on glycemic control and outcomes, discusses the increasing complexity of treatment options, and emphasizes the importance of shared decision making between clinicians and patients.
![relies on the consumption of resources
(both public and private).
Patient involvement in the medical
decision making constitutes one of the
core principles of evidence-based medi-
cine, which mandates the synthesis of best
available evidence from the literature with
the clinician’s expertise and patient’s own
inclinations(26).Duringtheclinicalencoun-
ter, the patient’s preferred level of involve-
ment should be gauged and therapeutic
choices explored, potentially with the uti-
lization of decision aids (21). In a shared
decision-making approach, clinician and
patient act as partners, mutually exchanging
information and deliberating on options, in
order toreach a consensusonthe therapeu-
tic course of action (27). There is good ev-
idence supporting the effectiveness of this
approach (28). Importantly, engaging pa-
tients in health care decisions may enhance
adherence to therapy.
BACKGROUND
Epidemiology and health care
impact
Both the prevalence and incidence of type 2
diabetes are increasing worldwide, particu-
larlyin developing countries, in conjunction
with increased obesity rates and westerni-
zation of lifestyle. The attendant economic
burden for health care systems is skyrocket-
ing, owing to the costs associated with treat-
ment and diabetes complications. Type 2
diabetes remains a leading cause of car-
diovascular disorders, blindness, end-stage
renal failure, amputations, and hospitaliza-
tions. It is also associated with increased risk
of cancer, serious psychiatric illness, cogni-
tive decline, chronic liver disease, acceler-
ated arthritis, and other disabling or deadly
conditions. Effective management strategies
are of obvious importance.
Relationship of glycemic control
to outcomes
It is well established that the risk of micro-
vascular and macrovascular complications
is related to glycemia, as measured by
HbA1c; this remains a major focus of ther-
apy (29). Prospective randomized trials
have documented reduced rates of micro-
vascular complications in type 2 diabetic
patients treated to lower glycemic targets.
In the UK Prospective Diabetes Study
(UKPDS) (30,31), patients with newly di-
agnosed type 2 diabetes were randomized
to two treatment policies. In the standard
group, lifestyle intervention was the main-
stay with pharmacological therapy used
only if hyperglycemia became severe. In the
more intensive treatment arm, patients were
randomly assigned to either a sulfonylurea
or insulin, with a subset of overweight
patients randomized to metformin. The
overall HbA1c achieved was 0.9% lower
in the intensive policy group compared
with the conventional policy arm (7.0%
vs. 7.9%). Associated with this difference in
glycemic control was a reduction in the risk
of microvascular complications (retinopa-
thy, nephropathy, neuropathy) with inten-
sive therapy. A trend toward reduced rates
of myocardial infarction in this group did
not reach statistical significance (30). By
contrast, substantially fewer metformin-
treated patients experienced myocardial
infarction, diabetes-related and all-cause
mortality (32), despite a mean HbA1c only
0.6% lower than the conventional policy
group. The UKPDS 10-year follow-up
demonstrated that the relative benefit of
having been in the intensive management
policy group was maintained over a de-
cade, resulting in the emergence of statisti-
cally significant benefits on cardiovascular
disease (CVD)end pointsandtotalmortality
in those initially assigned to sulfonylurea/
insulin, and persistence of CVD benefits
with metformin (33), in spite of the fact
that the mean HbA1c levels between the
groups converged soon after the ran-
domized component of the trial had
concluded.
In 2008, three shorter-term studies
[Action to Control Cardiovascular Risk in
Diabetes (ACCORD) (34), Action in Dia-
betes and Vascular Disease: Preterax and
Diamicron Modified-Release Controlled
Evaluation (ADVANCE) (35), Veterans Af-
fairs Diabetes Trial (VADT) (36)] reported
the effects of two levels of glycemic control
on cardiovascular end points in middle-
aged and older individuals with well-
established type 2 diabetes at high risk for
cardiovascular events. ACCORD and VADT
aimed for an HbA1c ,6.0% using complex
combinations of oral agents and insulin.
ADVANCE aimed for an HbA1c #6.5%
using a less intensive approach based on
the sulfonylurea gliclazide. None of the
trials demonstrated a statistically signif-
icant reduction in the primary combined
cardiovascular end points. Indeed, in
ACCORD, a 22% increase in total mortality
with intensive therapy was observed,
mainly driven by cardiovascular mortality.
An explanation for this finding has re-
mained elusive, although rates of hypogly-
cemia were threefold higher with intensive
treatment. It remains unclear, however, if
hypoglycemia was responsible for the ad-
verse outcomes, or if other factors, such as
more weight gain, or simply the greater
complexity of therapy, contributed. There
were suggestions in these trials that patients
without overt CVD, with shorter duration
of disease, and lower baseline HbA1c,
benefited from the more intensive strat-
egies. Modest improvements in some
microvascular end points in the studies
were likewise demonstrated. Finally, a
meta-analysis of cardiovascular out-
comes in these trials suggested that every
HbA1c reduction of ;1% may be associ-
ated with a 15% relative risk reduction in
nonfatal myocardial infarction, but
without benefits on stroke or all-cause
mortality (36).
Overview of the pathogenesis of
type 2 diabetes
Any rise in glycemia is the net result of
glucose influx exceeding glucose outflow
from the plasma compartment. In the fast-
ing state, hyperglycemia is directly related
to increased hepatic glucose production.
In the postprandial state, further glucose
excursions result from the combination
of insufficient suppression of this glucose
output and defective insulin stimulation
of glucose disposal in target tissues, mainly
skeletal muscle. Once the renal tubular
transport maximum for glucose is excee-
ded, glycosuria curbs, though does not
prevent, further hyperglycemia.
Abnormal islet cell function is a key
and requisite feature of type 2 diabetes. In
early disease stages, insulin production is
normal or increased in absolute terms,
but disproportionately low for the degree
of insulin sensitivity, which is typically
reduced. However, insulin kinetics, such
as the ability of the pancreatic b-cell to
release adequate hormone in phase with
rising glycemia, are profoundly compro-
mised. This functional islet incompetence
is the main quantitative determinant of
hyperglycemia (37) and progresses over
time. In addition, in type 2 diabetes, pan-
creatic a-cells hypersecrete glucagon, fur-
ther promoting hepatic glucose production
(38). Importantly, islet dysfunction is not
necessarily irreversible. Enhancing insulin
action relieves b-cell secretory burden, and
any intervention that improves glycemiad
from energy restriction to, most strikingly,
bariatric surgerydcan ameliorate b-cell
dysfunction to an extent (39). More re-
cently recognized abnormalities in the in-
cretin system (represented by the gut
hormones, glucagon-like peptide 1 [GLP-1],
and glucose-dependent insulinotropic
peptide [GIP]) are also found in type 2
diabetes, but it remains unclear whether
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![Ideally, the principle of insulin use is
the creation of as normal a glycemic profile
as possible without unacceptable weight
gain or hypoglycemia (73). As initial ther-
apy, unless the patient is markedly hyper-
glycemic and/or symptomatic, a “basal”
insulin alone is typically added (74). Basal
insulin provides relatively uniform insulin
coverage throughout the day and night,
mainly to control blood glucose by sup-
pressing hepatic glucose production in
between meals and during sleep. Either
intermediate-acting (neutral protamine
Hagedorn [NPH]) or long-acting (insulin
glargine [A21Gly,B31Arg,B32Arg hu-
man insulin] or insulin detemir [B29Lys
(´-tetradecanoyl),desB30 human insulin])
formulations may be used. The latter two
are associated with modestly less overnight
hypoglycemia (insulin glargine, insulin de-
temir) than NPH and possibly slightly less
weight gain (insulin detemir), but are
more expensive (75,76). Of note, the dos-
ing ofthesebasalinsulin analogsmaydiffer,
with most comparative trials showing a
higher average unit requirement with insu-
lin detemir (77).
Although the majority of patients
with type 2 diabetes requiring insulin
therapy can be successfully treated with
basal insulin alone, some, because of pro-
gressive diminution in their insulin secre-
tory capacity, will require prandial insulin
therapy with shorter-acting insulins. This
is typically provided in the form of the
rapid insulin analogs, insulin lispro
(B28Lys,B29Pro human insulin), insulin
aspart (B28Asp human insulin), or insulin
glulisine (B3Lys,B29Glu human insulin),
which may be dosed just before the meal.
They result in better postprandial glucose
control than the less costly human regular
insulin, whose pharmacokinetic profile
makes it less attractive in this setting.
Ideally, an insulin treatment program
should be designed specifically for an in-
dividual patient, to match the supply of
insulin to his or her dietary/exercise hab-
its and prevailing glucose trends, as revealed
throughself-monitoring.Anticipatedglucose-
lowering effects should be balanced with
the convenience of the regimen, in the
context of an individual’s specific therapy
goals (Fig. 1).
Proper patient education regarding
glucose monitoring, insulin injection
technique, insulin storage, recognition/
treatment of hypoglycemia, and “sick
day” rules is imperative. Where available,
certified diabetes educators can be in-
valuable in guiding the patient through
this process.
Implementation strategies
Initial drug therapy. It is generally
agreed that metformin, if not contraindi-
cated and if tolerated, is the preferred and
most cost-effective first agent (42) (Fig. 2
and Supplementary Figs.). It is initiated at,
or soon after, diagnosis, especially in pa-
tients in whom lifestyle intervention alone
has not achieved, or is unlikely to achieve,
HbA1c goals. Because of frequent gastroin-
testinal side effects, it should be started at a
low dose with gradual titration. Patients
with a high baseline HbA1c (e.g., $9.0%)
have a low probability of achieving a near-
normal target with monotherapy. It may
therefore be justified to start directly
with a combination of two noninsulin
agents or with insulin itself in this circum-
stance (78). If a patient presents with sig-
nificant hyperglycemic symptoms and/or
has dramatically elevated plasma glucose
concentrations (e.g., .16.7–19.4 mmol/L
[.300–350 mg/dL]) or HbA1c (e.g.,
$10.0–12.0%), insulin therapy should be
strongly considered from the outset. Such
treatment is mandatory when catabolic
features are exhibited or, of course, if
ketonuria is demonstrated, the latter re-
flecting profound insulin deficiency. Im-
portantly, unless there is evidence of type 1
diabetes, once symptoms are relieved,
glucotoxicity resolved, and the metabolic
state stabilized, it may be possible to taper
insulin partially or entirely, transferring to
noninsulin antihyperglycemic agents, per-
haps in combination.
If metformin cannot be used, another
oral agent could be chosen, such as a
sulfonylurea/glinide, pioglitazone, or a
DPP-4 inhibitor; in occasional cases where
weight loss is seen as an essential aspect of
therapy, initial treatment with a GLP-1
receptor agonist might be useful. Where
available, less commonly used drugs (AGIs,
colesevelam, bromocriptine) might also be
considered in selected patients, but their
modest glycemic effects and side-effect
profiles make them less attractive candi-
dates. Specific patient preferences, char-
acteristics, susceptibilities to side effects,
potential for weight gain and hypoglycemia
should play a major role in drug selection
(20,21). (See Supplementary Figs. for ad-
aptations of Fig. 2 that address specific
patient scenarios.)
Advancing to dual combination therapy.
Figure 2 (and Supplementary Figs.) also
depicts potential sequences of escalating
glucose-lowering therapy beyond met-
formin. If monotherapy alone does not
achieve/maintain an HbA1c target over
;3 months, the next step would be to
add a second oral agent, a GLP-1 recep-
tor agonist, or basal insulin (5,10). No-
tably, the higher the HbA1c, the more
likely insulin will be required. On average,
any second agent is typically associated
with an approximate further reduction in
HbA1c of ;1% (70,79). If no clinically
meaningful glycemic reduction (i.e., “non-
responder”) is demonstrated, then, adher-
ence having been investigated, that agent
should be discontinued, and another
with a different mechanism of action
substituted. With a distinct paucity of
long-term comparative-effectiveness trials
available, uniform recommendations on
the best agent to be combined with metfor-
min cannot be made (80).Thus, advantages
and disadvantages of specific drugs for each
patient should be considered (Table 1).
Some antihyperglycemic medications
lead to weight gain. This may be associ-
ated with worsening markers of insulin
resistance and cardiovascular risk. One
exception may be TZDs (57); weight gain
associated with this class occurs in asso-
ciation with decreased insulin resistance.
Although there is no uniform evidence that
increases in weight in the range observed
with certain therapies translate into a sub-
stantially increased cardiovascular risk, it
remains important to avoid unnecessary
KEY POINTS
c Glycemic targets and glucose-lowering
therapies must be individualized.
c Diet, exercise, and education remain
the foundation of any type 2 diabetes
treatment program.
c Unless there are prevalent contra-
indications, metformin is the op-
timal first-line drug.
c After metformin, there are limited
data to guide us. Combination
therapy with an additional 1–2 oral
or injectable agents is reasonable,
aiming to minimize side effects
where possible.
c Ultimately, many patients will require
insulin therapy alone or in com-
bination with other agents to
maintain glucose control.
c All treatment decisions, where possi-
ble, should be made in conjunction
with the patient, focusing on his/her
preferences, needs, and values.
c Comprehensive cardiovascular risk
reduction must be a major focus of
therapy.
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![weight gain by optimal medication selec-
tion and dose titration.
For all medications, consideration
should also be given to overall tolerability.
Even occasional hypoglycemia may be
devastating, if severe, or merely irritating,
if mild (81). Gastrointestinal side effects
may be tolerated by some, but not others.
Fluid retention may pose a clinical or
merely an aesthetic problem (82). The
risk of bone fractures may be a specific con-
cern in postmenopausal women (57).
It must be acknowledged that costs
are a critical issue driving the selection of
glucose-lowering agents in many environ-
ments. For resource-limited settings, less
expensive agents should be chosen. How-
ever, due consideration should be also
given to side effects and any necessary
monitoring, with their own cost impli-
cations. Moreover, prevention of morbid
Figure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential
sequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis
(unless there are explicit contraindications). If the HbA1c target is not achieved after ;3 months, consider one of the five treatment options combined
with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical
introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with
the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of
therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be
used in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where
available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin,
select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is
reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line
therapy, especially when HbA1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to more
complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-
drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c $10.0–12.0%). DPP-4-i, DPP-4
inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. a
Consider beginning at this
stage in patients with very high HbA1c (e.g., $9%). b
Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular
meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c
See Table 1 for additional potential adverse effects and risks, under
“Disadvantages.” d
Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. e
Certain noninsulin agents may be
continued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia
($16.7–19.4 mmol/L [$300–350 mg/dL]; HbA1c $10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.).
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![long-term complications will likely reduce
long-termexpensesattributedtothedisease.
Advancing to triple combination ther-
apy. Some studies have shown advantages
of adding a third noninsulin agent to a
two-drug combination that is not yet or
no longer achieving the glycemic target
(83–86). Not surprisingly, however, at
this juncture, the most robust response
will usually be with insulin. Indeed, since
diabetes is associated with progressive
b-cell loss, many patients, especially those
with long-standing disease, will eventually
need to be transitioned to insulin, which
should be favored in circumstances where
the degree of hyperglycemia (e.g., $8.5%)
makes it unlikely that another drug will be
of sufficient benefit (87). If triple combina-
tion therapy exclusive of insulin is tried, the
patient should be monitored closely, with
the approach promptly reconsidered if it
proves to be unsuccessful. Many months
of uncontrolled hyperglycemia should
specifically be avoided.
In using triple combinations the es-
sential consideration is obviously to use
agents with complementary mechanisms
of action (Fig. 2 and Supplementary Figs.).
Increasing the number of drugs heightens
the potential for side effects and drug–drug
interactions, raises costs, and negatively im-
pacts patient adherence. The rationale, ben-
efits,and sideeffectsof each new medication
should be discussed with the patient. The
clinical characteristics of patients more or
less likely to respond to specific combina-
tions are, unfortunately, not well defined.
Transitions to and titrations of insulin.
Most patients express reluctance to be-
ginning injectable therapy, but, if the
practitioner feels that such a transition is
important, encouragement and education
can usually overcome such reticence. In-
sulin is typically begun at a low dose (e.g.,
0.1–0.2 U kg21
day21
), although larger
amounts (0.3–0.4 U kg21
day21
) are rea-
sonable in the more severely hyperglyce-
mic. The most convenient strategy is
with a single injection of a basal insulin,
with the timing of administration depen-
dent on the patient’s schedule and overall
glucose profile (Fig. 3).
Although extensive dosing instruc-
tions for insulin are beyond the scope of
this statement, most patients can be taught
to uptitrate their own insulin dose based
on several algorithms, each essentially in-
volving the addition of a smalldose increase
if hyperglycemia persists (74,76,88). For
example, the addition of 1–2 units (or, in
those already on higher doses, increments
of 5–10%) to the daily dose once or twice
weeklyifthe fasting glucose levelsare above
the preagreed target is a reasonable ap-
proach (89). As the target is neared, dosage
adjustments should be more modest and
occur less frequently. Downward adjust-
ment is advisable if any hypoglycemia oc-
curs. During self-titration, frequent contact
(telephone, e-mail) with the clinician may
be necessary. Practitioners themselves can,
of course, also titrate basal insulin, but this
would involve more intensive contact with
the patient than typically available in rou-
tine clinical practice. Daily self-monitoring
of blood glucose is of obvious importance
during this phase. After the insulin dose is
stabilized, the frequency of monitoring
should be reviewed (90).
Consideration should be given to the
addition of prandial or mealtime insulin
coverage when significant postprandial
glucose excursions (e.g., to .10.0 mmol/L
[.180 mg/dL]) occur. This is suggested
when the fasting glucose is at target but
the HbA1c remains above goal after 3–6
months of basal insulin titration (91). The
same would apply if large drops in glucose
occur during overnight hours or in be-
tween meals, as the basal insulin dose is
increased. In this scenario, the basal insulin
dose would obviously need to be simulta-
neously decreased as prandial insulin is ini-
tiated. Although basal insulin is titrated
primarily against the fasting glucose, gen-
erally irrespective of the total dose, practi-
tioners should be aware that the need for
prandialinsulintherapywillbecomelikelythe
more the daily dose exceeds 0.5 U kg21
day21
, especially as it approaches 1 U kg21
day21
. The aim with mealtime insulin is to
blunt postprandial glycemic excursions,
Figure 3dSequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the
optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the degree of
hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In
patients willing to take more than one injection and who have higher HbA1c levels ($9.0%), twice-
daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be
considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable
fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime in-
sulin, consisting of one to three injections of rapid-acting analogs (see text for details). A less
studied alternativedprogression from basal insulin to a twice-daily premixed insulindcould be
also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime
insulin. The figure describes the number of injections required at each stage, together with the relative
complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with
dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulin
agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically
stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education
regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to,
hypoglycemia are critical in any patient on insulin therapy. Mod., moderate.
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![these procedures. The majority of patients
are able to stop some, or even all, of their
antihyperglycemic medications, although
the durability of this effect is not known
(105).
In lean patients, consideration should
be given to the possibility of latent autoim-
mune diabetes in adults (LADA), a slowly
progressive form of type 1 diabetes. These
individuals, while presenting with mild
hyperglycemia, often responsive to oral
agents, eventually develop more severe
hyperglycemia and require intensive insu-
lin regimens (106).Measuring titresofislet-
associated autoantibodies (e.g., anti-GAD)
may aid their identification, encouraging a
more rapid transition to insulin therapy.
Sex/racial/ethnic/genetic differences
While certain racial/ethnic features that
increase the risk of diabetes are well recog-
nized [greater insulin resistance in Latinos
(107), more b-cell dysfunction in East
Asians (108)], using this information to
craft optimal therapeutic strategies is in its
infancy. This is not surprising given the
polygenic inheritance pattern of the dis-
ease. Indeed, while matching a drug’s
mechanism of action to the underlying
causes of hyperglycemia in a specific patient
seems logical, there are few data that com-
pare strategies based on this approach
(109). There are few exceptions, mainly
involving diabetes monogenic variants of-
ten confused with type 2 diabetes, such as
maturity-onset diabetes of the young
(MODY), several forms of which respond
preferentially to sulfonylureas (110).
While there are no prominent sex differ-
ences in the response to various antihyper-
glycemic drugs, certain side effects (e.g.,
bone loss with TZDs) may be of greater
concern in women.
Comorbidities
Coronary artery disease. Given the fre-
quency with which type 2 diabetic patients
develop atherosclerosis, optimal manage-
mentstrategies for those with orathighrisk
for coronary artery disease (CAD) are
important. Since hypoglycemia may ex-
acerbate myocardial ischemia and may
cause dysrhythmias (111), it follows that
medications that predispose patients to
this adverse effect should be avoided, if
possible. If they are required, however, to
achieve glycemic targets, patients should
be educated to minimize risk. Because of
possible effects on potassium channels in
the heart, certain sulfonylureas have been
proposed to aggravate myocardial ischemia
througheffectsonischemicpreconditioning
(112), but the actual clinical relevance of this
remains unproven. Metformin may have
some cardiovascular benefits and would
appear to be a useful drug in the setting
of CAD, barring prevalent contraindica-
tions (32). In a single study, pioglitazone
was shown to reduce modestly major ad-
verse cardiovascular events in patients
with established macrovascular disease.
It may therefore also be considered, unless
heart failure is present (60). In very pre-
liminary reports, therapy with GLP-1 re-
ceptor agonists and DPP-4 inhibitors has
been associated with improvement in ei-
ther cardiovascular risk or risk factors, but
there are no long-term data regarding clin-
ical outcomes (113). There are very limited
data suggesting that AGIs (114) and bromo-
criptine (115) may reduce cardiovascular
events.
Heart failure. With an aging population
and recent decreases in mortality after
myocardial infarction, the diabetic patient
with progressive heart failure is an in-
creasingly common scenario (116). This
population presents unique challenges
given their polypharmacy, frequent hos-
pitalizations, and contraindications to
various agents. TZDs should be avoided
(117,118). Metformin, previously contra-
indicated in heart failure, can now be used
if the ventricular dysfunction is not se-
vere, if patient’s cardiovascular status is
stable, and if renal function is normal
(119). As mentioned, cardiovascular ef-
fects of incretin-based therapies, includ-
ing those on ventricular function, are
currently under investigation (120).
Chronic kidney disease. Kidney disease
is highly prevalent in type 2 diabetes, and
moderate to severe renal functional im-
pairment (eGFR ,60 mL/min) occurs in
approximately 20–30% of patients
(121,122). The individual with progres-
sive renal dysfunction is at increased risk
for hypoglycemia, which is multifactorial.
Insulin and, to some degree, the incretin
hormones are eliminated more slowly, as
are antihyperglycemic drugs with renal
excretion. Thus, dose reduction may be
necessary, contraindications need to be
observed, and consequences (hypoglyce-
mia, fluid retention, etc.) require careful
evaluation.
Current U.S. prescribing guidelines
warn against the use of metformin in
patients with a serum creatinine $133
mmol/L ($1.5 mg/dL) in men or 124
mmol/L ($1.4 mg/dL) in women. Metfor-
min is eliminated renally, and cases of lactic
acidosis have been described in patients
with renal failure (123). There is an
ongoing debate, however, as to whether
these thresholds are too restrictive and
that those with mild–moderate renal im-
pairment would gain more benefit than
harm from using metformin (124,125). In
the U.K., the National Institute for Health
and Clinical Excellence (NICE) guidelines
are less proscriptive and more evidence-
based than those in the U.S., generally al-
lowing use down to a GFR of 30 mL/min,
with dose reduction advised at 45 mL/min
(14). Given the current widespread report-
ing of estimated GFR, these guidelines
appear very reasonable.
Most insulin secretagogues undergo
significant renal clearance (exceptions in-
clude repaglinide and nateglinide) and
the risk of hypoglycemia is therefore
higher in patients with chronic kidney
disease (CKD). For most of these agents,
extreme caution is imperative at more severe
degrees of renal dysfunction. Glyburide
(known as glibenclamide in Europe),
which has a prolonged duration of
action and active metabolites, should
be specifically avoided in this group.
Pioglitazone is not eliminated renally, and
therefore there are no restrictions for use
in CKD. Fluid retention may be a concern,
however. Among the DPP-4 inhibitors,
sitagliptin, vildagliptin, and saxagliptin
share prominent renal elimination. In the
face of advanced CKD, dose reduction is
necessary. One exception is linagliptin,
which is predominantly eliminated enter-
ohepatically. For the GLP-1 receptor ago-
nists exenatide is contraindicated in stage
4–5 CKD (GFR ,30 mL/min) as it is re-
nally eliminated; the safety of liraglutide is
not established in CKD though pharmaco-
kinetic studies suggest that drug levels are
unaffected as it does not require renal func-
tion for clearance.
More severe renal functional impair-
ment is associated with slower elimina-
tion of all insulins. Thus doses need to be
titrated carefully, with some awareness
for the potential for more prolonged
activity profiles.
Liver dysfunction. Individuals with type
2 diabetes frequently have hepatosteatosis
as well as other types of liver disease
(126). There is preliminary evidence that
patients with fatty liver may benefit from
treatment with pioglitazone (45,127,128).
It should not be used in an individual with
active liver disease or an alanine transami-
nase level above 2.5 times the upper limit of
normal. In those with steatosis but milder
liver test abnormalities, this insulin sensi-
tizer may be advantageous. Sulfonylureas
can rarely cause abnormalities in liver tests
1374 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org
Position Statement](https://image.slidesharecdn.com/hyperglycemiaindmada2012-151031230308-lva1-app6891/85/Hyperglycemia-in-dm-ada-2012-11-320.jpg)
Hyperglycemia in dm ada 2012
- 1. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) SILVIO E. INZUCCHI, MD 1 RICHARD M. BERGENSTAL, MD 2 JOHN B. BUSE, MD, PHD 3 MICHAELA DIAMANT, MD, PHD 4 ELE FERRANNINI, MD 5 MICHAEL NAUCK, MD 6 ANNE L. PETERS, MD 7 APOSTOLOS TSAPAS, MD, PHD 8 RICHARD WENDER, MD 9 DAVID R. MATTHEWS, MD, DPHIL 10,11,12 G lycemic management in type 2 di- abetes mellitus has become increas- ingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties re- garding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore per- plexed as to the optimal strategies for their patients. As a consequence, the American DiabetesAssociation(ADA)andtheEuropean Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guide- line documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written in- corporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowl- edged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbid- ity and mortality; the aggressive manage- ment of cardiovascular risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits. These recommendations should be considered within the context of the needs, preferences, and tolerances of each patient; individualization of treatment is the cor- nerstone of success. Our recommenda- tions are less prescriptive than and not as algorithmic as prior guidelines. This fol- lows from the general lack of comparative- effectiveness research in this area. Our intent is therefore to encourage an appre- ciation of the variable and progressive nature of type 2 diabetes, the specific role of each drug, the patient and disease factors that drive clinical decision making (20–23), and the constraints imposed by age and comorbidity (4,6). The implemen- tation of these guidelines will require thoughtful clinicians to integrate current evidence with other constraints and im- peratives in the context of patient-specific factors. PATIENT-CENTERED APPROACHdEvidence-based advice depends on the existence of primary source evidence. This emerges only from clinical trial results in highly selected patients, using limited strategies. It does not address the range of choices available, or the order of use of additional therapies. Even if such evidence were available, the data would show median responses and not address the vital question of who responded to which therapy and why (24). Patient-centered care is defined as an ap- proach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensur- ing that patient values guide all clinical de- cisions” (25). This should be the organizing principle underlying health care for indi- viduals with any chronic disease, but given our uncertainties in terms of choice or se- quence of therapy, it is particularly appro- priate in type 2 diabetes. Ultimately, it is patients who make the final decisions re- garding their lifestyle choices and, to some degree, the pharmaceutical interventions they use; their implementation occurs in the context of the patients’ real lives and c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c From the 1 Section of Endocrinology, Yale University School of Medicine and Yale-New Haven Hospital, New Haven, Connecticut; the 2 International Diabetes Center at Park Nicollet, Minneapolis, Minnesota; the 3 Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; the 4 Diabetes Center/Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands; the 5 Department of Medicine, University of Pisa School of Medicine, Pisa, Italy; 6 Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany; the 7 Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California; the 8 Second Medical Department, Aristotle Uni- versity Thessaloniki, Thessaloniki, Greece; the 9 Department of Family and Community Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; the 10 Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, U.K.; the 11 National Institute for Health Research (NIHR), Oxford Biomedical Research Centre, Oxford, U.K.; and the 12 Harris Manchester College, University of Oxford, Oxford, U.K. Corresponding author: Silvio E. Inzucchi, silvio.inzucchi@yale.edu. DOI: 10.2337/dc12-0413 This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 .2337/dc12-0413/-/DC1. S.E. Inzucchi and D.R. Matthews were co-chairs for the Position Statement Writing Group. R.M. Bergenstal, J.B. Buse, A.L. Peters, and R. Wender were the Writing Group for the ADA. M. Diamant, E. Ferrannini, M. Nauck, and A. Tsapas were the Writing Group for the EASD. This article is being simultaneously published in 2012 in Diabetes Care and Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes. © 2012 by the American Diabetes Association and Springer-Verlag. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0/ for details. See accompanying editorial, p. 1201. 1364 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org R e v i e w s / C o n s e n s u s R e p o r t s / A D A S t a t e m e n t s P O S I T I O N S T A T E M E N T
- 2. relies on the consumption of resources (both public and private). Patient involvement in the medical decision making constitutes one of the core principles of evidence-based medi- cine, which mandates the synthesis of best available evidence from the literature with the clinician’s expertise and patient’s own inclinations(26).Duringtheclinicalencoun- ter, the patient’s preferred level of involve- ment should be gauged and therapeutic choices explored, potentially with the uti- lization of decision aids (21). In a shared decision-making approach, clinician and patient act as partners, mutually exchanging information and deliberating on options, in order toreach a consensusonthe therapeu- tic course of action (27). There is good ev- idence supporting the effectiveness of this approach (28). Importantly, engaging pa- tients in health care decisions may enhance adherence to therapy. BACKGROUND Epidemiology and health care impact Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particu- larlyin developing countries, in conjunction with increased obesity rates and westerni- zation of lifestyle. The attendant economic burden for health care systems is skyrocket- ing, owing to the costs associated with treat- ment and diabetes complications. Type 2 diabetes remains a leading cause of car- diovascular disorders, blindness, end-stage renal failure, amputations, and hospitaliza- tions. It is also associated with increased risk of cancer, serious psychiatric illness, cogni- tive decline, chronic liver disease, acceler- ated arthritis, and other disabling or deadly conditions. Effective management strategies are of obvious importance. Relationship of glycemic control to outcomes It is well established that the risk of micro- vascular and macrovascular complications is related to glycemia, as measured by HbA1c; this remains a major focus of ther- apy (29). Prospective randomized trials have documented reduced rates of micro- vascular complications in type 2 diabetic patients treated to lower glycemic targets. In the UK Prospective Diabetes Study (UKPDS) (30,31), patients with newly di- agnosed type 2 diabetes were randomized to two treatment policies. In the standard group, lifestyle intervention was the main- stay with pharmacological therapy used only if hyperglycemia became severe. In the more intensive treatment arm, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomized to metformin. The overall HbA1c achieved was 0.9% lower in the intensive policy group compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference in glycemic control was a reduction in the risk of microvascular complications (retinopa- thy, nephropathy, neuropathy) with inten- sive therapy. A trend toward reduced rates of myocardial infarction in this group did not reach statistical significance (30). By contrast, substantially fewer metformin- treated patients experienced myocardial infarction, diabetes-related and all-cause mortality (32), despite a mean HbA1c only 0.6% lower than the conventional policy group. The UKPDS 10-year follow-up demonstrated that the relative benefit of having been in the intensive management policy group was maintained over a de- cade, resulting in the emergence of statisti- cally significant benefits on cardiovascular disease (CVD)end pointsandtotalmortality in those initially assigned to sulfonylurea/ insulin, and persistence of CVD benefits with metformin (33), in spite of the fact that the mean HbA1c levels between the groups converged soon after the ran- domized component of the trial had concluded. In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD) (34), Action in Dia- betes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) (35), Veterans Af- fairs Diabetes Trial (VADT) (36)] reported the effects of two levels of glycemic control on cardiovascular end points in middle- aged and older individuals with well- established type 2 diabetes at high risk for cardiovascular events. ACCORD and VADT aimed for an HbA1c ,6.0% using complex combinations of oral agents and insulin. ADVANCE aimed for an HbA1c #6.5% using a less intensive approach based on the sulfonylurea gliclazide. None of the trials demonstrated a statistically signif- icant reduction in the primary combined cardiovascular end points. Indeed, in ACCORD, a 22% increase in total mortality with intensive therapy was observed, mainly driven by cardiovascular mortality. An explanation for this finding has re- mained elusive, although rates of hypogly- cemia were threefold higher with intensive treatment. It remains unclear, however, if hypoglycemia was responsible for the ad- verse outcomes, or if other factors, such as more weight gain, or simply the greater complexity of therapy, contributed. There were suggestions in these trials that patients without overt CVD, with shorter duration of disease, and lower baseline HbA1c, benefited from the more intensive strat- egies. Modest improvements in some microvascular end points in the studies were likewise demonstrated. Finally, a meta-analysis of cardiovascular out- comes in these trials suggested that every HbA1c reduction of ;1% may be associ- ated with a 15% relative risk reduction in nonfatal myocardial infarction, but without benefits on stroke or all-cause mortality (36). Overview of the pathogenesis of type 2 diabetes Any rise in glycemia is the net result of glucose influx exceeding glucose outflow from the plasma compartment. In the fast- ing state, hyperglycemia is directly related to increased hepatic glucose production. In the postprandial state, further glucose excursions result from the combination of insufficient suppression of this glucose output and defective insulin stimulation of glucose disposal in target tissues, mainly skeletal muscle. Once the renal tubular transport maximum for glucose is excee- ded, glycosuria curbs, though does not prevent, further hyperglycemia. Abnormal islet cell function is a key and requisite feature of type 2 diabetes. In early disease stages, insulin production is normal or increased in absolute terms, but disproportionately low for the degree of insulin sensitivity, which is typically reduced. However, insulin kinetics, such as the ability of the pancreatic b-cell to release adequate hormone in phase with rising glycemia, are profoundly compro- mised. This functional islet incompetence is the main quantitative determinant of hyperglycemia (37) and progresses over time. In addition, in type 2 diabetes, pan- creatic a-cells hypersecrete glucagon, fur- ther promoting hepatic glucose production (38). Importantly, islet dysfunction is not necessarily irreversible. Enhancing insulin action relieves b-cell secretory burden, and any intervention that improves glycemiad from energy restriction to, most strikingly, bariatric surgerydcan ameliorate b-cell dysfunction to an extent (39). More re- cently recognized abnormalities in the in- cretin system (represented by the gut hormones, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic peptide [GIP]) are also found in type 2 diabetes, but it remains unclear whether care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1365 Inzucchi and Associates
- 3. these constitute primary or secondary de- fects (40). In most patients with type 2 diabetes, especially the obese, insulin re- sistance in target tissues (liver, muscle, adipose tissue, myocardium) is a promi- nent feature. This results in both glucose overproduction and underutilization. Moreover,anincreaseddeliveryoffattyacids to the liver favors their oxidation, which contributes to increased gluconeogenesis, whereas the absolute overabundance of lip- ids promotes hepatosteatosis (41). Antihyperglycemic agents are directed at one or more of the pathophysiological defects of type 2 diabetes, or modify physiological processes relating to appetite or to nutrient absorption or excretion. Ultimately, type 2 diabetes is a disease that is heterogeneous in both pathogenesis and in clinical manifestationda point to be considered when determining the optimal therapeutic strategy for individual patients. ANTIHYPERGLYCEMIC THERAPY Glycemic targets The ADA’s “Standards of Medical Care in Diabetes” recommends lowering HbA1c to ,7.0% in most patients to reduce the incidence of microvascular disease (42). This can be achieved with a mean plasma glucose of ;8.3–8.9 mmol/L (;150–160 mg/dL); ideally, fasting and premeal glu- cose shouldbe maintained at ,7.2 mmol/L (,130 mg/dL) and the postprandial glu- cose at ,10 mmol/L (,180 mg/dL). More stringent HbA1c targets (e.g., 6.0– 6.5%) might be considered in selected patients (with short disease duration, long life expectancy, no significant CVD) if this can be achieved without significant hypo- glycemia or other adverse effects of treat- ment (20,43). Conversely, less stringent HbA1c goalsde.g., 7.5–8.0% or even slightly higherdare appropriate for pa- tientswithahistoryofseverehypoglycemia, limited life expectancy, advanced complica- tions, extensive comorbid conditions and those in whomthe target is difficult to attain despite intensive self-management educa- tion, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin (20,44). The accumulated results from the aforementioned type 2 diabetes cardio- vascular trials suggest that not everyone benefits from aggressive glucose man- agement. It follows that it is important to individualize treatment targets (5,34–36). The elements that may guide the clinician in choosing an HbA1c target for a specific patient are shown in Fig. 1. As mentioned earlier, the desires and values of the pa- tient should also be considered, since the achievement of any degree of glucose con- trol requires active participation and com- mitment (19,23,45,46). Indeed, any target could reflect an agreement between pa- tient and clinician. An important related concept is that the ease with which more intensive targets are reached influences treatment decisions; logically, lower tar- gets are attractive if they can be achieved with less complex regimens and no or minimal adverse effects. Importantly, uti- lizing the percentage of diabetic patients who are achieving an HbA1c ,7.0% as a quality indicator, as promulgated by vari- ous health care organizations, is inconsis- tent with the emphasis on individualization of treatment goals. Therapeutic options Lifestyle. Interventions designed to im- pact an individual’s physical activity lev- els and food intake are critical parts of type 2 diabetes management (47,48). All patients should receive standardized gen- eral diabetes education (individual or group, preferably using an approved cur- riculum), with a specific focus on dietary interventions and the importance of in- creasing physical activity. While encourag- ing therapeutic lifestyle change is important at diagnosis, periodic counseling should also be integrated into the treatment program. Weight reduction, achieved through dietary means alone or with adjunctive medical or surgical intervention, improves glycemic control and other cardiovascular riskfactors.Modestweightloss(5–10%)con- tributes meaningfully to achieving improved glucose control.Accordingly,establishing a goal of weight reduction, or at least weight maintenance, is recommended. Dietary advice must be personalized (49). Patients should be encouraged to eat healthy foods that are consistent with the prevailing population-wide dietary rec- ommendations and with an individual’s preferences and culture. Foods high in fiber (suchasvegetables,fruits,wholegrains,and Figure 1dDepiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Greater concerns about a particular domain are represented by in- creasing height of the ramp. Thus, characteristics/predicaments toward the left justify more stringent efforts to lower HbA1c, whereas those toward the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs, and values. This “scale” is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with per- mission from Ismail-Beigi et al. (20). 1366 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org Position Statement
- 6. legumes), low-fat dairy products, and fresh fish should be emphasized. High-energy foods, including those rich in saturated fats, and sweet desserts and snacks should be eaten less frequently and in lower amounts (50–52). Patients who eventually lose and keep weight off usually do so after numerous cycles of weight loss and relapse. The health care team should remain non- judgmental but persistent, revisiting and encouraging therapeutic lifestyle changes frequently, if needed. As much physical activity as possible should be promoted, ideally aiming for at least 150 min/week of moderate activity including aerobic, resistance, and flexi- bility training (53). In older individuals, or those with mobility challenges, so long as tolerated from a cardiovascular standpoint, any increase in activity level is advantageous. At diagnosis, highly motivated pa- tients with HbA1c already near target (e.g., ,7.5%) could be given the opportunity to engage in lifestyle change for a period of 3–6 months before embarking on pharmacotherapy (usually metformin). Those with moderate hyperglycemia or in whom lifestyle changes are anticipated to be unsuccessful should be promptly started on an antihyperglycemic agent (also usually metformin) at diagnosis, which can later be modified or possibly discontinued if lifestyle changes are suc- cessful. Oral agents and noninsulin injectables. Important properties of antihyperglyce- mic agents that play a role in the choice of drug(s) in individual patients are summa- rized in Table 1. Ultimately, the aims of controlling glycemia are to avoid acute osmotic symptoms of hyperglycemia, to avoid instability in blood glucose over time, and to prevent/delay the develop- ment of diabetes complications without adversely affecting quality of life. Infor- mation on whether specific agents have this ability is incomplete; an answer to these questions requires long-term, large- scale clinical trialsdnot available for most drugs. Effects on surrogate measures for glycemic control (e.g., HbA1c) generally reflect changes in the probability of de- veloping microvascular disease but not necessarily macrovascular complications. Particularly from a patient standpoint, stability of metabolic control over time may be another specific goal. Metformin, a biguanide, remains the most widely used first-line type 2 diabetes drug; its mechanism of action predomi- nately involves reducing hepatic glucose production (54,55). It is generally consid- ered weight-neutral with chronic use and does not increase the risk of hypoglycemia. Metformin is associated with initial gastro- intestinal side effects, and caution is ad- vised to avoid its use in patients at risk for lactic acidosis (e.g., in advanced renal in- sufficiency, alcoholism), a rare complica- tion of therapy. As noted earlier, there may be some cardiovascular benefits from this drug, but the clinical trial data are not robust. The oldest oral agent class is the sulfo- nylurea insulin secretagogues. Through the closure of ATP-sensitive potassium channels on b-cells, these drugs stimulate insulin release (56). While effective in con- trolling glucose levels, their use is associ- ated with modest weight gain and risk of hypoglycemia. In addition, studies have demonstrated a secondary failure rate that may exceed other drugs, ascribed to an exacerbation of islet dysfunction (57). Shorter-acting secretagogues, the megliti- nides (or glinides), stimulate insulin re- lease through similar mechanisms but may be associated with less hypoglycemia (58). They require more frequent dosing, however. Thiazolidinediones (TZDs) are per- oxisome proliferator–activated receptor g activators (59) that improve insulin sen- sitivity in skeletal muscle and reduce he- patic glucose production (54,55). They do not increase the risk of hypoglycemia and may be more durable in their effective- ness than sulfonylureas and metformin (57). Pioglitazone appeared to have a mod- est benefit on cardiovascular events as a secondary outcome in one large trial in- volving patients with overt macrovascular disease (60). Another agent of this class, rosiglitazone, is no longer widely available owing to concerns of increased myocardial infarction risk (61). Pioglitazone has re- cently been associated with a possible in- creased risk of bladder cancer (62). Recognized side effects of TZDs include weight gain, fluid retention leading to edema and/or heart failure in predisposed individuals, and increased risk of bone fractures (57,60). Drugs focused on the incretin system have been introduced more recently (63). The injectable GLP-1 receptor agonists mimic the effects of endogenous GLP-1, thereby stimulating pancreatic insulin se- cretion in a glucose-dependent fashion, suppressing pancreatic glucagon output, slowing gastric emptying, and decreasing appetite. Their main advantage is weight loss, which is modest in most patients but can be significant in some. A limiting side effect is nausea and vomiting, particularly early in the course of treatment. Concerns regarding an increased risk of pancreatitis remain unresolved. The oral dipeptidyl peptidase 4 (DPP-4) inhibitors enhance circulating concentrations of active GLP-1 and GIP (64). Their major effect appears to be in the regulation of insulin and glucagon secretion; they are weight neutral. Typically, neither of the incretin- based classes cause hypoglycemia by themselves. Two agents that are used infrequently in the U.S.and Europe are the a-glucosidase inhibitors (AGIs), which retard gut carbohy- drate absorption (65), and colesevelam, a bile acid sequestrant whose mechanism of glucose-lowering action remains poorly understood and whose major additional benefit is LDL-cholesterol reduction (66). Both have gastrointestinal effects, mainly flatulence with AGIs and constipation with colesevelam. The dopamine agonist bromocriptine is only available in the U.S. as an antihyperglycemic agent (67). Its mechanism of action and precise role areunclear. The amylinagonist,pramlintide, is typically reserved for patients treated with intensive insulin therapy, usually in type 1 diabetes mellitus; it decreases post- prandial glucose excursions by inhibiting glucagon secretion and slowing gastric emptying (68). The glucose-lowering effectiveness of noninsulin pharmacological agents is said to be high for metformin, sulfonylureas, TZDs, and GLP-1 agonists (expected HbA1c reduction ;1.0–1.5%) (1,69,70), and generally lower for meglitinides, DPP-4 inhibitors, AGIs, colesevelam, and bromocriptine (;0.5–1.0%). How- ever, older drugs have typically been tested in clinical trial participants with higher baseline HbA1c, which is itself as- sociated with greater treatment emergent glycemic reductions, irrespective of ther- apy type. In head-to-head studies, any differential effects on glucose control are small. So agent- and patient-specific prop- erties, such as dosing frequency, side-effect profiles, cost, and other benefits often guide their selection. Insulin. Due to the progressive b-cell dysfunction that characterizes type 2 di- abetes, insulin replacement therapy is fre- quently required (71). Importantly, most patients maintain some endogenous insu- lin secretion even in late stages of disease. Accordingly, the more complex and in- tensive strategies of type 1 diabetes are not typically necessary (72). care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1369 Inzucchi and Associates
- 7. Ideally, the principle of insulin use is the creation of as normal a glycemic profile as possible without unacceptable weight gain or hypoglycemia (73). As initial ther- apy, unless the patient is markedly hyper- glycemic and/or symptomatic, a “basal” insulin alone is typically added (74). Basal insulin provides relatively uniform insulin coverage throughout the day and night, mainly to control blood glucose by sup- pressing hepatic glucose production in between meals and during sleep. Either intermediate-acting (neutral protamine Hagedorn [NPH]) or long-acting (insulin glargine [A21Gly,B31Arg,B32Arg hu- man insulin] or insulin detemir [B29Lys (´-tetradecanoyl),desB30 human insulin]) formulations may be used. The latter two are associated with modestly less overnight hypoglycemia (insulin glargine, insulin de- temir) than NPH and possibly slightly less weight gain (insulin detemir), but are more expensive (75,76). Of note, the dos- ing ofthesebasalinsulin analogsmaydiffer, with most comparative trials showing a higher average unit requirement with insu- lin detemir (77). Although the majority of patients with type 2 diabetes requiring insulin therapy can be successfully treated with basal insulin alone, some, because of pro- gressive diminution in their insulin secre- tory capacity, will require prandial insulin therapy with shorter-acting insulins. This is typically provided in the form of the rapid insulin analogs, insulin lispro (B28Lys,B29Pro human insulin), insulin aspart (B28Asp human insulin), or insulin glulisine (B3Lys,B29Glu human insulin), which may be dosed just before the meal. They result in better postprandial glucose control than the less costly human regular insulin, whose pharmacokinetic profile makes it less attractive in this setting. Ideally, an insulin treatment program should be designed specifically for an in- dividual patient, to match the supply of insulin to his or her dietary/exercise hab- its and prevailing glucose trends, as revealed throughself-monitoring.Anticipatedglucose- lowering effects should be balanced with the convenience of the regimen, in the context of an individual’s specific therapy goals (Fig. 1). Proper patient education regarding glucose monitoring, insulin injection technique, insulin storage, recognition/ treatment of hypoglycemia, and “sick day” rules is imperative. Where available, certified diabetes educators can be in- valuable in guiding the patient through this process. Implementation strategies Initial drug therapy. It is generally agreed that metformin, if not contraindi- cated and if tolerated, is the preferred and most cost-effective first agent (42) (Fig. 2 and Supplementary Figs.). It is initiated at, or soon after, diagnosis, especially in pa- tients in whom lifestyle intervention alone has not achieved, or is unlikely to achieve, HbA1c goals. Because of frequent gastroin- testinal side effects, it should be started at a low dose with gradual titration. Patients with a high baseline HbA1c (e.g., $9.0%) have a low probability of achieving a near- normal target with monotherapy. It may therefore be justified to start directly with a combination of two noninsulin agents or with insulin itself in this circum- stance (78). If a patient presents with sig- nificant hyperglycemic symptoms and/or has dramatically elevated plasma glucose concentrations (e.g., .16.7–19.4 mmol/L [.300–350 mg/dL]) or HbA1c (e.g., $10.0–12.0%), insulin therapy should be strongly considered from the outset. Such treatment is mandatory when catabolic features are exhibited or, of course, if ketonuria is demonstrated, the latter re- flecting profound insulin deficiency. Im- portantly, unless there is evidence of type 1 diabetes, once symptoms are relieved, glucotoxicity resolved, and the metabolic state stabilized, it may be possible to taper insulin partially or entirely, transferring to noninsulin antihyperglycemic agents, per- haps in combination. If metformin cannot be used, another oral agent could be chosen, such as a sulfonylurea/glinide, pioglitazone, or a DPP-4 inhibitor; in occasional cases where weight loss is seen as an essential aspect of therapy, initial treatment with a GLP-1 receptor agonist might be useful. Where available, less commonly used drugs (AGIs, colesevelam, bromocriptine) might also be considered in selected patients, but their modest glycemic effects and side-effect profiles make them less attractive candi- dates. Specific patient preferences, char- acteristics, susceptibilities to side effects, potential for weight gain and hypoglycemia should play a major role in drug selection (20,21). (See Supplementary Figs. for ad- aptations of Fig. 2 that address specific patient scenarios.) Advancing to dual combination therapy. Figure 2 (and Supplementary Figs.) also depicts potential sequences of escalating glucose-lowering therapy beyond met- formin. If monotherapy alone does not achieve/maintain an HbA1c target over ;3 months, the next step would be to add a second oral agent, a GLP-1 recep- tor agonist, or basal insulin (5,10). No- tably, the higher the HbA1c, the more likely insulin will be required. On average, any second agent is typically associated with an approximate further reduction in HbA1c of ;1% (70,79). If no clinically meaningful glycemic reduction (i.e., “non- responder”) is demonstrated, then, adher- ence having been investigated, that agent should be discontinued, and another with a different mechanism of action substituted. With a distinct paucity of long-term comparative-effectiveness trials available, uniform recommendations on the best agent to be combined with metfor- min cannot be made (80).Thus, advantages and disadvantages of specific drugs for each patient should be considered (Table 1). Some antihyperglycemic medications lead to weight gain. This may be associ- ated with worsening markers of insulin resistance and cardiovascular risk. One exception may be TZDs (57); weight gain associated with this class occurs in asso- ciation with decreased insulin resistance. Although there is no uniform evidence that increases in weight in the range observed with certain therapies translate into a sub- stantially increased cardiovascular risk, it remains important to avoid unnecessary KEY POINTS c Glycemic targets and glucose-lowering therapies must be individualized. c Diet, exercise, and education remain the foundation of any type 2 diabetes treatment program. c Unless there are prevalent contra- indications, metformin is the op- timal first-line drug. c After metformin, there are limited data to guide us. Combination therapy with an additional 1–2 oral or injectable agents is reasonable, aiming to minimize side effects where possible. c Ultimately, many patients will require insulin therapy alone or in com- bination with other agents to maintain glucose control. c All treatment decisions, where possi- ble, should be made in conjunction with the patient, focusing on his/her preferences, needs, and values. c Comprehensive cardiovascular risk reduction must be a major focus of therapy. 1370 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org Position Statement
- 8. weight gain by optimal medication selec- tion and dose titration. For all medications, consideration should also be given to overall tolerability. Even occasional hypoglycemia may be devastating, if severe, or merely irritating, if mild (81). Gastrointestinal side effects may be tolerated by some, but not others. Fluid retention may pose a clinical or merely an aesthetic problem (82). The risk of bone fractures may be a specific con- cern in postmenopausal women (57). It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering agents in many environ- ments. For resource-limited settings, less expensive agents should be chosen. How- ever, due consideration should be also given to side effects and any necessary monitoring, with their own cost impli- cations. Moreover, prevention of morbid Figure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential sequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA1c target is not achieved after ;3 months, consider one of the five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two- drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c $10.0–12.0%). DPP-4-i, DPP-4 inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. a Consider beginning at this stage in patients with very high HbA1c (e.g., $9%). b Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c See Table 1 for additional potential adverse effects and risks, under “Disadvantages.” d Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. e Certain noninsulin agents may be continued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia ($16.7–19.4 mmol/L [$300–350 mg/dL]; HbA1c $10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.). care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1371 Inzucchi and Associates
- 9. long-term complications will likely reduce long-termexpensesattributedtothedisease. Advancing to triple combination ther- apy. Some studies have shown advantages of adding a third noninsulin agent to a two-drug combination that is not yet or no longer achieving the glycemic target (83–86). Not surprisingly, however, at this juncture, the most robust response will usually be with insulin. Indeed, since diabetes is associated with progressive b-cell loss, many patients, especially those with long-standing disease, will eventually need to be transitioned to insulin, which should be favored in circumstances where the degree of hyperglycemia (e.g., $8.5%) makes it unlikely that another drug will be of sufficient benefit (87). If triple combina- tion therapy exclusive of insulin is tried, the patient should be monitored closely, with the approach promptly reconsidered if it proves to be unsuccessful. Many months of uncontrolled hyperglycemia should specifically be avoided. In using triple combinations the es- sential consideration is obviously to use agents with complementary mechanisms of action (Fig. 2 and Supplementary Figs.). Increasing the number of drugs heightens the potential for side effects and drug–drug interactions, raises costs, and negatively im- pacts patient adherence. The rationale, ben- efits,and sideeffectsof each new medication should be discussed with the patient. The clinical characteristics of patients more or less likely to respond to specific combina- tions are, unfortunately, not well defined. Transitions to and titrations of insulin. Most patients express reluctance to be- ginning injectable therapy, but, if the practitioner feels that such a transition is important, encouragement and education can usually overcome such reticence. In- sulin is typically begun at a low dose (e.g., 0.1–0.2 U kg21 day21 ), although larger amounts (0.3–0.4 U kg21 day21 ) are rea- sonable in the more severely hyperglyce- mic. The most convenient strategy is with a single injection of a basal insulin, with the timing of administration depen- dent on the patient’s schedule and overall glucose profile (Fig. 3). Although extensive dosing instruc- tions for insulin are beyond the scope of this statement, most patients can be taught to uptitrate their own insulin dose based on several algorithms, each essentially in- volving the addition of a smalldose increase if hyperglycemia persists (74,76,88). For example, the addition of 1–2 units (or, in those already on higher doses, increments of 5–10%) to the daily dose once or twice weeklyifthe fasting glucose levelsare above the preagreed target is a reasonable ap- proach (89). As the target is neared, dosage adjustments should be more modest and occur less frequently. Downward adjust- ment is advisable if any hypoglycemia oc- curs. During self-titration, frequent contact (telephone, e-mail) with the clinician may be necessary. Practitioners themselves can, of course, also titrate basal insulin, but this would involve more intensive contact with the patient than typically available in rou- tine clinical practice. Daily self-monitoring of blood glucose is of obvious importance during this phase. After the insulin dose is stabilized, the frequency of monitoring should be reviewed (90). Consideration should be given to the addition of prandial or mealtime insulin coverage when significant postprandial glucose excursions (e.g., to .10.0 mmol/L [.180 mg/dL]) occur. This is suggested when the fasting glucose is at target but the HbA1c remains above goal after 3–6 months of basal insulin titration (91). The same would apply if large drops in glucose occur during overnight hours or in be- tween meals, as the basal insulin dose is increased. In this scenario, the basal insulin dose would obviously need to be simulta- neously decreased as prandial insulin is ini- tiated. Although basal insulin is titrated primarily against the fasting glucose, gen- erally irrespective of the total dose, practi- tioners should be aware that the need for prandialinsulintherapywillbecomelikelythe more the daily dose exceeds 0.5 U kg21 day21 , especially as it approaches 1 U kg21 day21 . The aim with mealtime insulin is to blunt postprandial glycemic excursions, Figure 3dSequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In patients willing to take more than one injection and who have higher HbA1c levels ($9.0%), twice- daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime in- sulin, consisting of one to three injections of rapid-acting analogs (see text for details). A less studied alternativedprogression from basal insulin to a twice-daily premixed insulindcould be also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Mod., moderate. 1372 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org Position Statement
- 10. which can be extreme in some individuals, resulting in poor control during the day. Such coverage may be provided by one of two methods. The most precise and flexible prandial coverage is possible with “basal-bolus” therapy, involving the addition of premeal rapid-acting insulin analog to ongoing basal insulin. One graduated approach is to add prandial insulin before the meal responsible for the largest glucose excursiondtypically that with the greatest carbohydrate content,often,butnotalways, the evening meal (92). Subsequently, a sec- ond injection can be administered before the meal with the next largest excursion (often breakfast). Ultimately, a third injection may be added before the smallest meal (often lunch) (93). The actual glycemic benefits of these more advanced regimens after basal insulin are generally modest in typical patients (92). So, again, individualization of therapy is key, incorporating the degree of hyperglycemia needing to be ad- dressed and the overall capacities of the patient. Importantly, data trends from self-monitoring may be particularly help- ful in titrating insulins and their doses within these more advanced regimens to optimize control. A second, perhaps more convenient but less adaptable method involves “pre- mixed” insulin, consisting of a fixed com- bination of an intermediate insulin with regular insulin or a rapid analog. Tradi- tionally, this is administered twice daily, before morning and evening meals. In general, when compared with basal insu- lin alone, premixed regimens tend to lower HbA1c to a larger degree, but often at the expense of slightly more hypogly- cemia and weight gain (94). Disadvan- tages include the inability to titrate the shorter- from the longer-acting compo- nent of these formulations. Therefore, this strategy is somewhat inflexible but may be appropriate for certain patients who eat regularly and may be in need of a simplified approach beyond basal in- sulin(92,93). (An older and less commonly used variation of this two-injection strategy is known as “split-mixed,” involving a fixed amount of intermediate insulin mixed by the patient with a variable amount of regu- lar insulin or a rapid analog. This allows for greater flexibility in dosing.) The key messages from dozens of comparative insulin trials in type 2 diabetes include the following: 1. Any insulin will lower glucose and HbA1c. 2. All insulins are associated with some weight gain and some risk of hypo- glycemia. 3. The larger the doses and the more aggressive the titration, the lower the HbA1c, but often with a greater likeli- hood of adverse effects. 4. Generally, long-acting insulin analogs reduce the incidence of overnight hy- poglycemia, and rapid-acting insulin analogs reduce postprandial glucose excursions as compared with corre- sponding human insulins (NPH, Reg- ular), but they generally do not result in clinically significantly lower HbA1c. Metformin is often continued when basal insulin is added, with studies dem- onstrating less weight gain when the two are used together (95). Insulin secretago- gues do not seem to provide for additional HbA1c reduction or prevention of hypo- glycemia or weight gain after insulin is started, especially after the dose is titrated and stabilized. When basal insulin is used, continuing the secretagogue may minimize initial deterioration of glycemic control. However, secretagogues should be avoided once prandial insulin regi- mens are employed. TZDs should be re- duced in dose (or stopped) to avoid edema and excessive weight gain, al- though in certain individuals with large insulin requirements from severe insulin resistance, these insulin sensitizers may be very helpful in lowering HbA1c and mini- mizing the required insulin dose (96). Data concerning the glycemic benefits of incretin-based therapy combined with basal insulin are accumulating; combina- tion with GLP-1 receptor agonists may be helpful in some patients (97,98). Once again, the costs of these more elaborate combined regimens must be carefully considered. OTHER CONSIDERATIONS Age Older adults (.65–70 years) often have a higher atherosclerotic disease burden, re- duced renal function, and more comor- bidities (99,100). Many are at risk for adverse events from polypharmacy and may be both socially and economically disadvantaged. Life expectancy is reduced, especially in the presence of long-term complications. They are also more likely to be compromised by hypoglycemia; for example, unsteadiness may result in falls and fractures (101), and a tenuous cardiac status may deteriorate into catastrophic events. It follows that glycemic targets for elderly with long-standing or more com- plicated disease should be less ambitious than for the younger, healthier individuals (20). If lower targets cannot be achieved with simple interventions, an HbA1c of ,7.5–8.0% may be acceptable, transition- ing upward as age increases and capacity for self-care, cognitive, psychological and economic status, and support systems decline. While lifestyle modification can be successfully implemented across all age- groups, in the aged, the choice of anti- hyperglycemic agent should focus on drug safety, especially protecting against hypoglycemia, heart failure, renal dys- function, bone fractures, and drug–drug interactions. Strategies specifically mini- mizing the risk of low blood glucose may be preferred. In contrast, healthier patients with long life expectancy accrue risk for vas- cular complications over time. Therefore, lower glycemic targets (e.g., an HbA1c ,6.5–7.0%) and tighter control of body weight, blood pressure, and circulating lipids should be achieved to prevent or delay such complications. This usually re- quires combination therapy, the early in- stitution of which may have the best chance of modifying the disease process and preserving quality of life. Weight The majority of individuals with type 2 diabetes are overweight or obese (;80%) (102). In these, intensive lifestyle inter- vention can improve fitness, glycemic control, and cardiovascular risk factors for relatively small changes in body weight (103). Although insulin resistance is thought of as the predominate driver of diabetes in obese patients, they actually have a similar degree of islet dysfunction to leaner patients (37). Perhaps as a result, the obese may be more likely to require combination drug therapy (20,104). While common practice has favored met- formin in heavier patients, because of weight loss/weight neutrality, this drug is as efficacious in lean individuals (75). TZDs, on the other hand, appear to be more effective in those with higher BMIs, although their associated weight gain makes them, paradoxically, a less attractive option here. GLP-1 receptor agonists are associated with weight reduction (38), which in some patients may be substantial. Bariatric surgery is an increasingly popular option in severe obesity. Type 2 diabetes frequently resolves rapidly after care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1373 Inzucchi and Associates
- 11. these procedures. The majority of patients are able to stop some, or even all, of their antihyperglycemic medications, although the durability of this effect is not known (105). In lean patients, consideration should be given to the possibility of latent autoim- mune diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. These individuals, while presenting with mild hyperglycemia, often responsive to oral agents, eventually develop more severe hyperglycemia and require intensive insu- lin regimens (106).Measuring titresofislet- associated autoantibodies (e.g., anti-GAD) may aid their identification, encouraging a more rapid transition to insulin therapy. Sex/racial/ethnic/genetic differences While certain racial/ethnic features that increase the risk of diabetes are well recog- nized [greater insulin resistance in Latinos (107), more b-cell dysfunction in East Asians (108)], using this information to craft optimal therapeutic strategies is in its infancy. This is not surprising given the polygenic inheritance pattern of the dis- ease. Indeed, while matching a drug’s mechanism of action to the underlying causes of hyperglycemia in a specific patient seems logical, there are few data that com- pare strategies based on this approach (109). There are few exceptions, mainly involving diabetes monogenic variants of- ten confused with type 2 diabetes, such as maturity-onset diabetes of the young (MODY), several forms of which respond preferentially to sulfonylureas (110). While there are no prominent sex differ- ences in the response to various antihyper- glycemic drugs, certain side effects (e.g., bone loss with TZDs) may be of greater concern in women. Comorbidities Coronary artery disease. Given the fre- quency with which type 2 diabetic patients develop atherosclerosis, optimal manage- mentstrategies for those with orathighrisk for coronary artery disease (CAD) are important. Since hypoglycemia may ex- acerbate myocardial ischemia and may cause dysrhythmias (111), it follows that medications that predispose patients to this adverse effect should be avoided, if possible. If they are required, however, to achieve glycemic targets, patients should be educated to minimize risk. Because of possible effects on potassium channels in the heart, certain sulfonylureas have been proposed to aggravate myocardial ischemia througheffectsonischemicpreconditioning (112), but the actual clinical relevance of this remains unproven. Metformin may have some cardiovascular benefits and would appear to be a useful drug in the setting of CAD, barring prevalent contraindica- tions (32). In a single study, pioglitazone was shown to reduce modestly major ad- verse cardiovascular events in patients with established macrovascular disease. It may therefore also be considered, unless heart failure is present (60). In very pre- liminary reports, therapy with GLP-1 re- ceptor agonists and DPP-4 inhibitors has been associated with improvement in ei- ther cardiovascular risk or risk factors, but there are no long-term data regarding clin- ical outcomes (113). There are very limited data suggesting that AGIs (114) and bromo- criptine (115) may reduce cardiovascular events. Heart failure. With an aging population and recent decreases in mortality after myocardial infarction, the diabetic patient with progressive heart failure is an in- creasingly common scenario (116). This population presents unique challenges given their polypharmacy, frequent hos- pitalizations, and contraindications to various agents. TZDs should be avoided (117,118). Metformin, previously contra- indicated in heart failure, can now be used if the ventricular dysfunction is not se- vere, if patient’s cardiovascular status is stable, and if renal function is normal (119). As mentioned, cardiovascular ef- fects of incretin-based therapies, includ- ing those on ventricular function, are currently under investigation (120). Chronic kidney disease. Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal functional im- pairment (eGFR ,60 mL/min) occurs in approximately 20–30% of patients (121,122). The individual with progres- sive renal dysfunction is at increased risk for hypoglycemia, which is multifactorial. Insulin and, to some degree, the incretin hormones are eliminated more slowly, as are antihyperglycemic drugs with renal excretion. Thus, dose reduction may be necessary, contraindications need to be observed, and consequences (hypoglyce- mia, fluid retention, etc.) require careful evaluation. Current U.S. prescribing guidelines warn against the use of metformin in patients with a serum creatinine $133 mmol/L ($1.5 mg/dL) in men or 124 mmol/L ($1.4 mg/dL) in women. Metfor- min is eliminated renally, and cases of lactic acidosis have been described in patients with renal failure (123). There is an ongoing debate, however, as to whether these thresholds are too restrictive and that those with mild–moderate renal im- pairment would gain more benefit than harm from using metformin (124,125). In the U.K., the National Institute for Health and Clinical Excellence (NICE) guidelines are less proscriptive and more evidence- based than those in the U.S., generally al- lowing use down to a GFR of 30 mL/min, with dose reduction advised at 45 mL/min (14). Given the current widespread report- ing of estimated GFR, these guidelines appear very reasonable. Most insulin secretagogues undergo significant renal clearance (exceptions in- clude repaglinide and nateglinide) and the risk of hypoglycemia is therefore higher in patients with chronic kidney disease (CKD). For most of these agents, extreme caution is imperative at more severe degrees of renal dysfunction. Glyburide (known as glibenclamide in Europe), which has a prolonged duration of action and active metabolites, should be specifically avoided in this group. Pioglitazone is not eliminated renally, and therefore there are no restrictions for use in CKD. Fluid retention may be a concern, however. Among the DPP-4 inhibitors, sitagliptin, vildagliptin, and saxagliptin share prominent renal elimination. In the face of advanced CKD, dose reduction is necessary. One exception is linagliptin, which is predominantly eliminated enter- ohepatically. For the GLP-1 receptor ago- nists exenatide is contraindicated in stage 4–5 CKD (GFR ,30 mL/min) as it is re- nally eliminated; the safety of liraglutide is not established in CKD though pharmaco- kinetic studies suggest that drug levels are unaffected as it does not require renal func- tion for clearance. More severe renal functional impair- ment is associated with slower elimina- tion of all insulins. Thus doses need to be titrated carefully, with some awareness for the potential for more prolonged activity profiles. Liver dysfunction. Individuals with type 2 diabetes frequently have hepatosteatosis as well as other types of liver disease (126). There is preliminary evidence that patients with fatty liver may benefit from treatment with pioglitazone (45,127,128). It should not be used in an individual with active liver disease or an alanine transami- nase level above 2.5 times the upper limit of normal. In those with steatosis but milder liver test abnormalities, this insulin sensi- tizer may be advantageous. Sulfonylureas can rarely cause abnormalities in liver tests 1374 DIABETES CARE, VOLUME 35, JUNE 2012 care.diabetesjournals.org Position Statement
- 12. but are not specifically contraindicated; meglitinides can also be used. If hepatic disease is severe, secretagogues should be avoided because of the increased risk of hypoglycemia. In patients with mild he- patic disease, incretin-based drugs can be prescribed, except if there is a coexisting history of pancreatitis. Insulin has no re- strictions for use in patients with liver im- pairment and isindeed the preferred choice in those with advanced disease. Hypoglycemia. Hypoglycemia in type 2 diabetes was long thought to be a trivial issue, as it occurs less commonly than in type 1 diabetes. However, there is emerg- ing concern based mainly on the results of recent clinical trials and some cross- sectional evidence of increased risk of brain dysfunction in those with repeated episodes. In the ACCORD trial, the fre- quency of both minor and major hypo- glycemia was high in intensively managed patientsdthreefold that associated with conventional therapy (129). It remains unknown whether hypoglycemia was the cause of the increased mortality in the intensive group (130,131). Clearly, however, hypoglycemia is more danger- ous in the elderly and occurs consistently more often as glycemic targets are low- ered. Hypoglycemia may lead to dys- rhythmias, but can also lead to accidents and falls (which are more likely to be dan- gerous in the elderly) (132), dizziness (leading to falls), confusion (so other ther- apies may not be taken or taken incor- rectly), or infection (such as aspiration during sleep, leading to pneumonia). Hy- poglycemia may be systematically under- reported as a cause of death, so the true incidence may not be fully appreciated. Perhaps just as importantly, additional con- sequences of frequent hypoglycemia in- clude work disability and erosion of the confidence of the patient (and that of family orcaregivers) toliveindependently.Accord- ingly, in at-risk individuals, drug selection should favor agents that do not precipitate such events and, in general, blood glucose targets may need to be moderated. FUTURE DIRECTIONS/ RESEARCH NEEDSdFor antihyper- glycemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metfor- min monotherapy(70).Thereisasignificant need for high-quality comparative- effectiveness research, not only regarding glycemic control, but also costs and those outcomes that matter most to patientsd quality of life and the avoidance of morbid and life-limiting complications, especially CVD (19,23,70). Another issue about which more data are needed is the concept of du- rability of effectiveness (often ascribed to b-cell preservation), which would serve to stabilize metabolic control and decrease the future treatment burden for patients. Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapyfor an individual patient based on predictors of response and susceptibility to adverse ef- fects. We need more clinical data on how phenotype and other patient/disease char- acteristics should drive drug choices. As new medications are introduced to the type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in stud- ies versus best current treatment, substan- tial enough both in size and duration to provide meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head comparisons of all combina- tions and permutations would be impossi- bly large (133). Informed judgment and the expertise of experienced clinicians will therefore always be necessary. AcknowledgmentsdThis position statement was written by joint request of the ADA and the EASD Executive Committees, which have approved the final document. The process in- volved wide literature review, three face-to-face meetings of the Writing Group, several tele- conferences, and multiple revisions via e-mail communications. We gratefully acknowledge the following experts who provided critical review of a draft of this statement: James Best, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; Henk Bilo, Isala Clinics, Zwolle, the Netherlands; John Boltri, Wayne State University School of Medicine, Detroit, MI; Thomas Buchanan, Keck School of Medicine, University of Southern California, Los Angeles, CA; Paul Callaway, University of Kansas School of Medicine-Wichita, Wichita, KS; Bernard Charbonnel, University of Nantes, Nantes, France; Stephen Colagiuri, The Uni- versity of Sydney, Sydney, Australia; Samuel Dagogo-Jack, The University of Tennessee Health Science Center, Memphis, TN; Margo Farber, Detroit Medical Center, Detroit, MI; Cynthia Fritschi, College of Nursing, University of Illi- nois at Chicago, Chicago, IL; Rowan Hillson, The Hillingdon Hospital, Uxbridge, U.K.; Faramarz Ismail-Beigi, Case Western Reserve University School of Medicine/Cleveland VA Medical Center, Cleveland, OH; Devan Kansagara, Oregon Health & Science University/ Portland VA Medical Center, Portland, OR; Ilias Migdalis, NIMTS Hospital, Athens, Greece; Donna Miller, Keck School of Medicine, University of Southern California, Los Angeles, CA; Robert Ratner, MedStar Health Research Institute/Georgetown University School of Medicine, Washington, DC; Julio Rosenstock, Dallas Diabetes and Endocrine Center at Medi- cal City, Dallas, TX; Guntram Schernthaner, Rudolfstiftung Hospital, Vienna, Austria; Robert Sherwin, Yale University School of Medicine, New Haven, CT; Jay Skyler, Miller School of Medicine, University of Miami, Miami, FL; Geralyn Spollett, Yale University School of Nursing, New Haven, CT; Ellie Strock, In- ternational Diabetes Center, Minneapolis, MN; Agathocles Tsatsoulis, University of Ioannina, Ioannina, Greece; Andrew Wolf, University of Virginia School of Medicine, Charlottesville, VA; Bernard Zinman, Mount Sinai Hospital/ University of Toronto, Toronto, ON, Canada. The American Association of Diabetes Edu- cators, American College of Physicians, and The Endocrine Society, and several other or- ganizations who wished to remain anony- mous nominated reviewers who provided input on the final draft. Such feedback does not constitute endorsement by these groups or these individuals. The final draft was also peer reviewed and approved by the Professional PracticeCommitteeofthe ADAand the Panel for Overseeing Guidelines and Statements of the EASD. We are indebted to Dr. Sue Kirkman of the ADA for her guidance and support during this process. We also thank Carol Hill and Mary Merkin for providing administrative assistance. Funding The three face-to-face meetings and the travel of some of the writing group were sup- ported by the EASD and ADA. D.R. Matthews acknowledges support from the National In- stitute for Health Research. Duality of interest During the past 12 months, the following relationships with companies whose products or services directly relate to the subject matter in this document are declared: R.M. Bergenstal: membership of scientific advisory boards and consultation for or clinical research support with Abbott Diabetes Care, Amylin, Bayer, Becton Dickinson, Boehringer Ingelheim,Calibra,DexCom, Eli Lilly, Halozyme, Helmsley Trust, Hygieia, Johnson & Johnson, Medtronic, NIH, Novo Nordisk, Roche, Sanofi, and Takeda (all under contracts with his employer). Inherited stock in Merck (held by family) J.B. Buse: research and consulting with Amylin Pharmaceuticals, Inc.; AstraZeneca; Biodel Inc.; Boehringer Ingelheim; Bristol- Myers Squibb Company; Diartis Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; Halozyme Therapeutics; Johnson & Johnson; Medtronic MiniMed; Merck & Co., Inc.; Novo Nordisk; Pfizer Inc.; Sanofi; and TransPharma Medical Ltd (all under contracts with his employer) M. Diamant: member of advisory boards of Abbott Diabetes Care, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, Poxel Pharma. Consultancy for: Astra-BMS, Sanofi. Speaker engagements: Eli Lilly, MSD, Novo Nordisk. care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1375 Inzucchi and Associates
- 13. Through Dr. Diamant, the VU University receives research grants from Amylin/Eli Lilly, MSE, Novo Nordisk, Sanofi (all under contracts with the Institutional Research Foundation) E. Ferrannini: membership on scientific advisory boards or speaking engagements for: Merck Sharp & Dohme, Boehringer Ingelheim, GlaxoSmithKline, BMS/AstraZeneca, Eli Lilly & Co., Novartis, Sanofi. Research grant support from: Eli Lilly & Co. and Boehringer Ingelheim S.E. Inzucchi: advisor/consultant to: Merck, Takeda, Boehringer Ingelheim. Research fund- ing or supplies to Yale University: Eli Lilly, Takeda. Participation in medical educational projects, for which unrestricted funding from Amylin, Eli Lilly, Boehringer Ingelheim, Merck, Novo Nordisk, and Takeda was received by Yale University D.R. Matthews: has received advisory board consulting fees or honoraria from Novo Nordisk, GlaxoSmithKline, Novartis, Eli Lilly, Johnson & Johnson, and Servier. He has re- search support from Johnson & Johnson and Merck Sharp & Dohme. He has lectured for Novo Nordisk, Servier, and Novartis M. Nauck: has received research grants (to his institution) from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, Novartis Pharma, GlaxoSmithKline, Novo Nordisk, Roche, and Tolerx. He has re- ceived consulting and travel fees or honoraria for speaking from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Diartis, Eli Lilly & Co., F. Hoffmann-La Roche Ltd, Intarcia Therapeutics, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis Pharma, and Versartis A.L. Peters: has received lecturing fees and/ or fees for ad hoc consulting from Amylin, Lilly, Novo Nordisk, Sanofi, Takeda, Boehringer Ingelheim A. Tsapas: has received travel grant, edu- cational grant, research grant and lecture fees from Merck Serono, Novo Nordisk, and No- vartis, respectively R. 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