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Reviews/Commentaries/ADA Statements

C O N S E N S U S S T A T E M E N T

Medical Management of Hyperglycemia in


Type 2 Diabetes: A Consensus Algorithm
for the Initiation and Adjustment of
Therapy
A consensus statement of the American Diabetes Association and the
European Association for the Study of Diabetes
DAVID M. NATHAN, MD1 RURY R. HOLMAN, FRCP5 blood glucose–lowering medications to
JOHN B. BUSE, MD, PHD2 ROBERT SHERWIN, MD6 supplement the older therapies, such as
MAYER B. DAVIDSON, MD3 BERNARD ZINMAN, MD7 lifestyle-directed interventions, insulin,
ELE FERRANNINI, MD4 sulfonylureas, and metformin, has in-
creased the number of treatment options
available for type 2 diabetes. Whether
The consensus algorithm for the medical management of type 2 diabetes was published in used alone or in combination with other
August 2006 with the expectation that it would be updated, based on the availability of new blood glucose–lowering interventions,
interventions and new evidence to establish their clinical role. The authors continue to endorse the increased number of choices available
the principles used to develop the algorithm and its major features. We are sensitive to the risks to practitioners and patients has height-
of changing the algorithm cavalierly or too frequently, without compelling new information. An
ened uncertainty regarding the most
update to the consensus algorithm published in January 2008 specifically addressed safety issues
surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications appropriate means of treating this wide-
that now have more clinical data and experience. spread disease (14). Although numerous re-
views on the management of type 2 diabetes
Diabetes Care 32:193–203, have been published in recent years (15–
17), practitioners are often left without a
clear pathway of therapy to follow. We de-

T
he epidemic of type 2 diabetes and beneficial effect on diabetes-specific mi-
the recognition that achieving spe- crovascular complications, including ret- veloped the following consensus approach
cific glycemic goals can substantially inopathy, nephropathy, and neuropathy, to the management of hyperglycemia in the
reduce morbidity have made the effective in the setting of type 1 diabetes (4,5); in nonpregnant adult to help guide health care
treatment of hyperglycemia a top priority type 2 diabetes, more intensive treatment providers in choosing the most appropriate
(1–3). While the management of hyper- strategies have likewise been demon- interventions for their patients with type 2
glycemia, the hallmark metabolic abnor- strated to reduce microvascular compli- diabetes.
mality associated with type 2 diabetes, has cations (6 – 8). Intensive glycemic
historically taken center stage in the treat- management resulting in lower A1C lev- Process
ment of diabetes, therapies directed at els has also been shown to have a benefi- The guidelines and algorithm that follow
other coincident features, such as dyslip- cial effect on cardiovascular disease are derived from two sources. One source
idemia, hypertension, hypercoagulabil- (CVD) complications in type 1 diabetes is the clinical trials that address the effec-
ity, obesity, and insulin resistance, have (9,10); however, current studies have tiveness and safety of the different modal-
also been a major focus of research and failed to demonstrate a beneficial effect of ities of therapy. Here, the writing group
therapy. Maintaining glycemic levels as intensive diabetes therapy on CVD in type reviewed a wide variety of studies related
close to the nondiabetic range as possible 2 diabetes (11–13). to the use of drugs as monotherapy or in
has been demonstrated to have a powerful The development of new classes of combination to lower glycemia. Unfortu-
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
nately, the paucity of high-quality evi-
dence in the form of well-controlled
From the 1Diabetes Center, Massachusetts General Hospital, Boston, Massachusetts; the 2University of North
Carolina School of Medicine, Chapel Hill, North Carolina; the 3Clinical Center for Research Excellence, clinical trials that directly compare differ-
Charles R. Drew University, Los Angeles, California; the 4Department of Internal Medicine, University of ent diabetes treatment regimens remains a
Pisa, Pisa, Italy; the 5Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, major impediment to recommending one
Oxford University, Oxford, U.K.; the 6Department of Internal Medicine and Yale Center for Clinical class of drugs, or a particular combination
Investigation, Yale University School of Medicine, New Haven, Connecticut; and the 7Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
of therapies, over another.
Corresponding author: David. M. Nathan, dnathan@partners.org.. The second source of material that in-
This article is being simultaneously published in 2009 by Diabetes Care and Diabetologia by the American formed our recommendations was clinical
Diabetes Association and the European Association for the Study of Diabetes. judgement, that is, our collective knowl-
An American Diabetes Association consensus statement represents the authors’ collective analysis, evalua- edge and clinical experience, which takes
tion, and opinion at the time of publication and does not represent official association opinion.
DOI: 10.2337/dc08-9025 into account benefits, risks, and costs in the
© 2009 by the American Diabetes Association and Springer. Copying with attribution allowed for any treatment of diabetes. As in all clinical deci-
non-commercial use of the work. sion making, an evidence-based review of

DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009 193


Consensus Statement

the literature must also be supplemented aimed at achieving an A1C level of tervention(s) used to achieve glycemic
by value judgements, where the benefits ⬍7.9%, showed excess CVD mortality in goals. The UKPDS compared three classes
of treatment are weighed against risks and the intensive treatment group (11). Re- of glucose-lowering medications (sulfo-
costs in a subjective fashion. While we sults from the Action in Diabetes and Vas- nylurea, metformin, or insulin) but was
realize that others may have different cular Disease: Preterax and Diamicron unable to demonstrate clear superiority of
judgements, we believe that the recom- MR Controlled Evaluation (ADVANCE) any one drug over the others with regard
mendations made in this new iteration of trial and the Veterans Affairs Diabetes to diabetes complications (6,7). However,
our treatment algorithm will guide ther- Trial, both of which had different inter- the different classes do have variable ef-
apy and result in improved glycemic con- ventions and study populations than fectiveness in decreasing glycemic levels
trol and health status over time. ACCORD, did not demonstrate any ex- (Table 1), and the overarching principle
cess total or CVD mortality with intensive in selecting a particular intervention will
Glycemic goals of therapy regimens that achieved A1C levels com- be its ability to achieve and maintain gly-
Controlled clinical trials, such as the Dia- parable with the 6.5% in ACCORD cemic goals. In addition to their inten-
betes Control and Complications Trial (12,13). However, none of the studies has tion-to-treat analyses demonstrating the
(DCCT) (4) and the Stockholm Diabetes demonstrated a benefit of intensive glyce- superiority of intensive versus conven-
Study in type 1 diabetes (5) and the UK mic control on their primary CVD out- tional interventions, the DCCT and
Prospective Diabetes Study (UKPDS) comes. Our consensus is that an A1C level UKPDS demonstrated a strong correla-
(6,7) and Kumamoto study (8) in type 2 of ⱖ7% should serve as a call to action to tion between mean A1C levels over time
diabetes, have helped to establish the gly- initiate or change therapy with the goal of and the development and progression of
cemic goals of therapy that result in im- achieving an A1C level of ⬍7%. We are retinopathy and nephropathy (23,24).
proved long-term outcomes. The clinical mindful that this goal is not appropriate Therefore, we think it is reasonable to
trials, in concert with epidemiological or practical for some patients, and clinical judge and compare blood glucose–
data (18,19), support decreasing glyce- judgement based on the potential benefits lowering medications, as well as combi-
mia as an effective means of reducing and risks of a more intensified regimen nations of such agents, primarily on the
long-term microvascular and neuropathic needs to be applied for every patient. Fac- basis of their capacity to decrease and
complications. The most appropriate tar- tors such as life expectancy, risk of hypo- maintain A1C levels and according to
get levels for blood glucose, on a day-to- glycemia, and the presence of CVD need their safety, specific side effects, tolerabil-
day basis, and A1C, as an index of chronic to be considered for every patient before ity, ease of use, and expense.
glycemia, have not been systematically intensifying the therapeutic regimen.
studied. However, both the DCCT (4) and Assiduous attention to abnormalities Nonglycemic effects of medications
the UKPDS (6,7) had as their goals the other than hyperglycemia that accom- In addition to variable effects on glyce-
achievement of glycemic levels in the pany type 2 diabetes, such as hyperten- mia, specific effects of individual thera-
nondiabetic range. Neither study was able sion and dyslipidaemia, has been shown pies on CVD risk factors, such as
to maintain A1C levels in the nondiabetic to improve microvascular and cardiovas- hypertension or dyslipidemia, were also
range in their intensive treatment groups, cular complications. Readers are referred considered important. We also included
achieving mean levels over time of ⬃7%, to published guidelines for a discussion of the effects of interventions that may ben-
which is 4 SDs above the nondiabetic the rationale and goals of therapy for the efit or worsen the prospects for long-term
mean. nonglycemic risk factors, as well as rec- glycemic control in our recommenda-
The most recent glycemic goal recom- ommendations on how to achieve them tions. Examples of these would be
mended by the American Diabetes Asso- (1,21,22). changes in body mass, insulin resistance,
ciation, selected on the basis of or insulin secretory capacity in type 2 di-
practicality and the projected reduction Principles in selecting abetic patients.
in complications over time, is, in general, antihyperglycemic interventions
an A1C level of ⬍7% (1). The most recent Our choice of specific antihyperglycemic Choosing specific diabetes
glycemic goal set by the International Di- agents is predicated on their effectiveness interventions and their roles in
abetes Federation is an A1C level of in lowering glucose, extraglycemic effects treating type 2 diabetes
⬍6.5%. The upper limit of the nondia- that may reduce long-term complica- Numerous reviews have focused on the
betic range is 6.1% (mean ⫾ SD. A1C tions, safety profiles, tolerability, ease of characteristics of the specific diabetes in-
level of 5 ⫾ 2%) with the DCCT/UKPDS- use, and expense. terventions listed below (25–34). In addi-
standardized assay, which has been pro- tion, meta-analyses and reviews have
mulgated through the National Effectiveness in lowering glycaemia summarized and compared the glucose-
Glycohemoglobin Standardization Pro- Except for their differential effects on gly- lowering effectiveness and other charac-
gram (NGSP) and adopted by the vast ma- cemia, there are insufficient data at this teristics of the medications (35–37). The
jority of commercially available assays time to support a recommendation of one aim here is to provide enough informa-
(20). Several recent clinical trials have class of glucose-lowering agents, or one tion to justify the choices of medications,
aimed for A1C levels ⱕ6.5% with a vari- combination of medications, over others the order in which they are recom-
ety of interventions (11,12). The results of with regard to effects on complications. In mended, and the use of combinations of
the Action to Control Cardiovascular Risk other words, the salutary effects of ther- therapies. Unfortunately, there is a dearth
in Diabetes (ACCORD) study, which had apy on long-term complications appear to of high-quality studies that provide head-
the primary objective of decreasing CVD be predicated predominantly on the level to-head comparisons of the ability of the
with interventions aimed at achieving an of glycemic control achieved rather than medications to achieve the currently rec-
A1C level of ⬍6.0% vs. interventions on any other specific attributes of the in- ommended glycemic levels. The authors

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Table 1—Summary of glucose-lowering interventions

Expected decrease
in A1C with
Intervention monotherapy (%) Advantages Disadvantages
Tier 1: well-validated core
Step 1: initial therapy
Lifestyle to decrease weight and
increase activity 1.0–2.0 Broad benefits Insufficient for most within
first year
Metformin 1.0–2.0 Weight neutral GI side effects, contraindicated
with renal insufficiency
Step 2: additional therapy
Insulin 1.5–3.5 No dose limit, rapidly effective, One to four injections daily,
improved lipid profile monitoring, weight gain,
hypoglycemia, analogues
are expensive
Sulfonylurea 1.0–2.0 Rapidly effective Weight gain, hypoglycemia
(especially with
glibenclamide or
chlorpropamide)
Tier 2: less well validated
TZDs 0.5–1.4 Improved lipid profile Fluid retention, CHF, weight
(pioglitazone), potential gain, bone fractures,
decrease in MI (pioglitazone) expensive, potential increase
in MI (rosiglitazone)
GLP-1 agonist 0.5–1.0 Weight loss Two injections daily, frequent
GI side effects, long-term
safety not established,
expensive
Other therapy
␣-Glucosidase inhibitor 0.5–0.8 Weight neutral Frequent GI side effects, three
times/day dosing, expensive
Glinide 0.5–1.5a Rapidly effective Weight gain, three times/day
dosing, hypoglycemia,
expensive
Pramlintide 0.5–1.0 Weight loss Three injections daily,
frequent GI side effects,
long-term safety not
established, expensive
DPP-4 inhibitor 0.5–0.8 Weight neutral Long-term safety not
established, expensive
a
Repaglinide more effective in lowering A1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction.

highly recommend that such studies be are associated with lower A1C levels over as an effective means of controlling glyce-
conducted. However, even in the absence time and decreased long-term complica- mia in the long term. The most convinc-
of rigorous, comprehensive studies that tions (38). ing long-term data indicating that weight
directly compare the efficacy of all avail- loss effectively lowers glycemia have been
able glucose-lowering treatments and Lifestyle interventions generated in the follow-up of type 2 dia-
their combinations, we feel that there are The major environmental factors that in- betic patients who have had bariatric sur-
enough data regarding the characteristics crease the risk of type 2 diabetes are over- gery. In this setting, with a mean
of the individual interventions to provide nutrition and a sedentary lifestyle, with sustained weight loss of ⬎20 kg, diabetes
the guidelines below. consequent overweight and obesity is virtually eliminated (42– 45). In addi-
An important intervention that is (39,40). Not surprisingly, interventions tion to the beneficial effects of weight loss
likely to improve the probability that a that reverse or improve these factors have on glycemia, weight loss and exercise im-
patient will have better long-term control been demonstrated to have a beneficial prove coincident CVD risk factors, such
of diabetes is to make the diagnosis early, effect on control of glycemia in estab- as blood pressure and atherogenic lipid
when the metabolic abnormalities of dia- lished type 2 diabetes (41). Unfortu- profiles, and ameliorate other conse-
betes are usually less severe. Lower levels nately, the high rate of weight regain has quences of obesity (41,46,47). There are
of glycemia at the time of initial therapy limited the role of lifestyle interventions few adverse consequences of such life-

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Consensus Statement

style interventions other than difficulty in with specific safety issues, as well as other Although the onset of the glucose-
incorporating them into usual lifestyle characteristics of regimens, including side lowering effect of sulfonylurea mono-
and sustaining them and the usually mi- effects, tolerability, ease of use, long-term therapy is relatively rapid compared with,
nor musculoskeletal injuries and poten- adherence, expense, and the nonglycemic for example, the thiazolidinediones
tial problems associated with neuropathy, effects of the medications. Type 2 diabetes (TZDs), maintenance of glycemic targets
such as foot trauma and ulcers, that may is a progressive disease characterized by over time is not as good as monotherapy
occur as a result of increased activity. The- worsening glycemia; higher doses and ad- with a TZD or metformin (55). Sulfonyl-
oretically, effective weight loss, with its ditional medications are required over urea therapy was implicated as a potential
pleiotropic benefits, safety profile, and time if treatment goals are to be met. cause of increased CVD mortality in the
low cost, should be the most cost-effective Metformin. In most of the world, met- University Group Diabetes Program
means of controlling diabetes—if it could formin is the only biguanide available. Its (UGDP) study (56). Concerns raised by
be achieved and maintained over the long major effect is to decrease hepatic glucose the UGDP that sulfonylureas, as a drug
term. output and lower fasting glycemia. Typi- class, may increase CVD mortality in type
Given these beneficial effects, which cally, metformin monotherapy will lower 2 diabetes were not substantiated by the
are usually seen rapidly—within weeks to A1C levels by ⬃1.5 percentage points UKPDS or ADVANCE study (6,12). The
months—and often before there has been (27,49). It is generally well tolerated, with glycemic benefits of sulfonylureas are
substantial weight loss (47), a lifestyle in- the most common adverse effects being nearly fully realized at half-maximal
tervention program to promote weight gastrointestinal. Metformin monotherapy doses, and higher doses should generally
loss and increase activity levels should, is not usually accompanied by hypoglyce- be avoided.
with rare exceptions, be included as part mia and has been used safely, without Glinides. Like the sulfonylureas, the
of diabetes management. Weight loss of as causing hypoglycemia, in patients with glinides stimulate insulin secretion, al-
little as 4 kg will often ameliorate hyper- prediabetic hyperglycemia (50). Met- though they bind to a different site within
glycemia. However, the limited long-term formin interferes with vitamin B12 ab- the sulfonylurea receptor (28). They have
success of lifestyle programs to maintain sorption but is very rarely associated with a shorter circulating half-life than the sul-
glycemic goals in patients with type 2 di- anemia (27). The major nonglycemic ef- fonylureas and must be administered
abetes suggests that the large majority of fect of metformin is either weight stability more frequently. Of the two glinides cur-
patients will require the addition of med- or modest weight loss, in contrast with rently available in the U.S., repaglinide is
ications over the course of their diabetes. many of the other blood glucose–
almost as effective as metformin or the
lowering medications. The UKPDS dem-
sulfonylureas, decreasing A1C levels by
Medications onstrated a beneficial effect of metformin
⬃1.5 percentage points. Nateglinide is
The characteristics of currently available therapy on CVD outcomes (7), which
somewhat less effective in lowering A1C
glucose-lowering interventions, when needs to be confirmed. Renal dysfunction
than repaglinide when used as mono-
used as monotherapy, are summarized in is considered a contraindication to met-
therapy or in combination therapy
Table 1. The glucose-lowering effective- formin use because it may increase the
ness of individual therapies and combina- risk of lactic acidosis, an extremely rare (57,58). The risk of weight gain is similar
tions demonstrated in clinical trials is (less than 1 case per 100,000 treated pa- to that for the sulfonylureas, but hypogly-
predicated not only on the intrinsic char- tients) but potentially fatal complication cemia may be less frequent, at least with
acteristics of the intervention but also on (51). However, recent studies have sug- nateglinide, than with some sulfonylureas
the duration of diabetes, baseline glyce- gested that metformin is safe unless the (58,59).
mia, previous therapy, and other factors. estimated glomerular filtration rate falls to ␣-Glucosidase inhibitors. ␣-Glucosi-
A major factor in selecting a class of drugs, ⬍30 ml/min (52). dase inhibitors reduce the rate of diges-
or a specific medication within a class, to Sulfonylureas. Sulfonylureas lower gly- tion of polysaccharides in the proximal
initiate therapy or when changing ther- cemia by enhancing insulin secretion. In small intestine, primarily lowering post-
apy, is the ambient level of glycemic con- terms of efficacy, they appear to be similar prandial glucose levels without causing
trol. When levels of glycemia are high to metformin, lowering A1C levels by hypoglycemia. They are less effective in
(e.g., A1C ⬎8.5%), classes with greater ⬃1.5 percentage points (26,49). The ma- lowering glycemia than metformin or the
and more rapid glucose-lowering effec- jor adverse side effect is hypoglycemia, sulfonylureas, reducing A1C levels by
tiveness, or potentially earlier initiation of which can be prolonged and life threaten- 0.5– 0.8 percentage points (29). Since
combination therapy, are recommended; ing, but such episodes, characterized by a carbohydrate is absorbed more distally,
however, patients with recent-onset dia- need for assistance, coma, or seizure, are malabsorption and weight loss do not oc-
betes often respond adequately to less in- infrequent. However, severe episodes are cur; however, increased delivery of carbo-
tensive interventions than those with relatively more frequent in the elderly. hydrate to the colon commonly results in
longer-term disease (48). When glycemic Chlorpropamide and glibenclamide increased gas production and gastrointes-
levels are closer to the target levels (e.g., (known as glyburide in the U.S. and Can- tinal symptoms. In clinical trials, 25– 45%
A1C ⬍7.5%), medications with lesser po- ada), are associated with a substantially of participants have discontinued ␣-glu-
tential to lower glycemia and/or a slower greater risk of hypoglycemia than other cosidase inhibitor use as a result of this
onset of action may be considered. second-generation sulfonylureas (glicla- side effect (29,60).
Obviously, the choice of glycemic zide, glimepiride, glipizide, and their ex- One clinical trial examining acarbose as
goals and the medications used to achieve tended formulations), which are a means of preventing the development of
them must be individualized for each pa- preferable (Table 1) (53,54). In addition, diabetes in high-risk individuals with im-
tient, balancing the potential for lowering weight gain of ⬃2 kg is common follow- paired glucose tolerance showed an unex-
A1C and anticipated long-term benefit ing the initiation of sulfonylurea therapy. pected reduction in severe CVD outcomes

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(60). This potential benefit of ␣-glucosidase mended, the consensus group members insulin secretion. Exendin-4 has homol-
inhibitors needs to be confirmed. unanimously advised against using rosi- ogy with the human GLP-1 sequence but
Thiazolidinediones. Thiazolidinedio- glitazone. Currently, in the U.S., the has a longer circulating half-life. It binds
nes (TZDs or glitazones) are peroxisome TZDs are approved for use in combina- avidly to the GLP-1 receptor on the pan-
proliferator–activated receptor ␥ modula- tion with metformin, sulfonylureas, creatic ␤-cell and augments glucose-
tors; they increase the sensitivity of mus- glinides, and insulin. mediated insulin secretion (32). Synthetic
cle, fat, and liver to endogenous and Insulin. Insulin is the oldest of the cur- exendin-4 (exenatide) was approved for
exogenous insulin (“insulin sensitizers”) rently available medications and, there- use in the U.S. in 2005 and is adminis-
(31). The data regarding the blood glu- fore, the treatment with which we have tered twice per day by subcutaneous in-
cose–lowering effectiveness of TZDs the most clinical experience. It is also the jection. Although there are less published
when used as monotherapy have dem- most effective at lowering glycemia. Insu- data on this new compound than the
onstrated a 0.5–1.4 percentage point lin can, when used in adequate doses, de- other blood glucose–lowering medica-
decrease in A1C. The TZDs appear to crease any level of elevated A1C to, or tions, exendin-4 appears to lower A1C
have a more durable effect on glycemic close to, the therapeutic goal. Unlike the levels by 0.5–1 percentage points, mainly
control, particularly compared with other blood glucose–lowering medica-
by lowering postprandial blood glucose
sulfonylureas (55). The most common tions, there is no maximum dose of insu-
levels (78 – 81). Exenatide also suppresses
adverse effects with TZDs are weight lin beyond which a therapeutic effect will
gain and fluid retention, with peripheral glucagon secretion and slows gastric mo-
not occur. Relatively large doses of insulin
edema and a twofold increased risk for (ⱖ1 unit/kg), compared with those re- tility. It is not associated with hypoglyce-
congestive heart failure (61,62). There quired to treat type 1 diabetes, may be mia but causes a relatively high frequency
is an increase in adiposity, largely sub- necessary to overcome the insulin resis- of gastrointestinal disturbances, with 30 –
cutaneous, with some reduction in vis- tance of type 2 diabetes and lower A1C to 45% of treated patients experiencing one
ceral fat shown in some studies. The the target level. Although initial therapy is or more episodes of nausea, vomiting, or
TZDs either have a beneficial (pioglita- aimed at increasing basal insulin supply, diarrhea (78 – 81). These side effects tend
zone) or neutral (rosiglitazone) effect usually with intermediate- or long-acting- to abate over time. In published trials, ex-
on atherogenic lipid profiles (63,64). insulins, patients may also require pran- enatide is associated with weight loss of
Several meta-analyses have suggested a dial therapy with short- or rapid-acting ⬃2–3 kg over 6 months, some of which
30 – 40% relative increase in risk for insulins (Fig. 1). The very rapid-acting may be a result of its gastrointestinal side
myocardial infarction (65,66) with rosi- and long-acting insulin analogues have effects. Recent reports have suggested a
glitazone. On the other hand, the Pro- not been shown to lower A1C levels more risk for pancreatitis associated with use of
spective Pioglitazone Clinical Trial in effectively than the older, rapid-acting or GLP agonists; however, the number of
macrovascular events (PROactive) dem- intermediate-acting formulations (71– cases is very small and whether the rela-
onstrated no significant effects of pio- 73). Insulin therapy has beneficial effects tionship is causal or coincidental is not
glitazone compared with placebo on the on triacylglycerol and HDL cholesterol clear at this time. Currently, exenatide
primary CVD outcome (a composite of levels, especially in patients with poor is approved for use in the U.S. with sul-
all-cause mortality, nonfatal and silent glycemic control (74), but is associated fonylurea, metformin, and/or a TZD.
myocardial infarction, stroke, major leg with weight gain of ⬃2– 4 kg, which is Several other GLP-1 agonists and for-
amputation, acute coronary syndrome, probably proportional to the correction of mulations are under development.
coronary artery bypass graft or percuta- glycemia and predominantly the result of Amylin agonists (pramlintide). Pram-
neous coronary intervention, and leg re- the reduction of glycosuria. Insulin ther- lintide is a synthetic analogue of the ␤-cell
vascularization) after 3 years of follow-up apy is also associated with hypoglycemia, hormone amylin. It is administered sub-
(67). Pioglitazone was associated with a albeit much less frequently than in type 1 cutaneously before meals and slows gas-
16% reduction in death, myocardial in- diabetes. In clinical trials aimed at normo- tric emptying, inhibits glucagon
farction, and stroke—a controversial sec- glycemia and achieving a mean A1C of production in a glucose-dependent fash-
ondary end point reported to have ⬃7%, severe hypoglycemic episodes (de-
ion, and predominantly decreases post-
marginal statistical significance (67). fined as requiring help from another per-
prandial glucose excursions (33). In
Meta-analyses have supported a possible son to treat) occurred at a rate of between
clinical studies, A1C has been decreased
beneficial effect of pioglitazone on CVD one and three per 100 patient-years
risk (68). Although the data are less than (8,75–77), compared with 61 per 100 pa- by 0.5– 0.7 percentage points (82). The
conclusive for a CVD risk with rosiglita- tient-years in the DCCT intensive therapy major clinical side effects of this drug are
zone or a CVD benefit with pioglitazone, group (4). Insulin analogues with longer, gastrointestinal in nature. ⬃30% of
we have previously advised (69) caution nonpeaking profiles decrease the risk of treated participants in the clinical trials
in using either TZD on the basis that they hypoglycemia modestly compared with have developed nausea, but this side ef-
are both associated with increased risks of NPH, and analogues with very short du- fect tends to abate with time on therapy.
fluid retention and congestive heart fail- rations of action reduce the risk of hypo- Weight loss associated with this medica-
ure and an increased incidence of frac- glycemia compared with regular insulin tion is ⬃1–1.5 kg over 6 months; as with
tures in women and perhaps in men (76,77). exenatide, some of the weight loss may be
(55,61,62,70). Although the meta- Glucagon-like peptide-1 agonists (ex- the result of gastrointestinal side effects.
analyses discussed above are not conclu- enatide). Glucagon-like peptide-1 Currently, pramlintide is approved for
sive regarding the potential cardiovascular (GLP-1) 7–37, a naturally occurring pep- use in the U.S. only as adjunctive therapy
risk associated with rosiglitazone, given tide produced by the L-cells of the small with regular insulin or rapid-acting insu-
that other options are now recom- intestine, potentiates glucose-stimulated lin analogues.

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Consensus Statement

Figure 1—Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The
algorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixed
insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion
of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.

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Nathan and Associates

preprandial levels that are in range, post-


TITRATION OF METFORMIN prandial levels, usually measured 90 –120
min after a meal, may be checked. They
1. Begin with low-dose metformin (500 mg) taken once or twice per day with should be ⬍10 mmol/l (180 mg/dl) to
meals (breakfast and/or dinner) or 850 mg once per day. achieve A1C levels in the target range.
2. After 5–7 days, if gastrointestinal side effects have not occurred, advance dose Attempts to achieve target glycemic
to 850, or two 500 mg tablets, twice per day (medication to be taken before levels with regimens including sulfonyl-
breakfast and/or dinner). ureas or insulin may be associated with
3. If gastrointestinal side effects appear as doses advanced, decrease to previous modest hypoglycemia, with glucose levels
lower dose and try to advance the dose at a later time. in the 3.1–3.9 mmol/l (55–70 mg/dl)
4. The maximum effective dose can be up to 1,000 mg twice per day but is often range. These episodes are generally well
850 mg twice per day. Modestly greater effectiveness has been observed with tolerated, easily treated with oral carbo-
doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose hydrate such as glucose tablets or 120 –
that can be used. 180 ml (4 – 6 oz) of juice or nondiet soda,
5. Based on cost considerations, generic metformin is the first choice of therapy. and rarely progress to more severe hypo-
A longer-acting formulation is available in some countries and can be given once glycemia, including loss of consciousness
per day. or seizures.

Algorithm
Dipeptidyl peptidase four inhibitors. tient is the key player in the diabetes care The algorithm (Fig. 2) takes into account
GLP-1 and glucose-dependent insulino- team and should be trained and empow- the characteristics of the individual inter-
tropic peptide (GIP), the main insulino- ered to adjust medications with the guid- ventions, their synergies, and expense.
tropic peptides of intestinal origin ance of health care professionals to achieve The goal is to achieve and maintain A1C
(incretins), are rapidly degraded by glycemic goals and to prevent and treat hy- levels of ⬍7% and to change interven-
dipeptidyl peptidase four (DPP-4). DPP-4 poglycemia. Many patients may be man- tions at as rapid a pace as titration of med-
is a member of a family of cell membrane aged effectively with monotherapy; ications allows when target glycemic goals
proteins that are expressed in many tis- however, the progressive nature of the dis- are not being achieved. Mounting evi-
sues, including immune cells (34). DPP-4 ease will require the use of combination dence suggests that aggressive lowering of
inhibitors are small molecules that en- therapy in many, if not most, patients over glycemia, especially with insulin therapy,
hance the effects of GLP-1 and GIP, in- time, to achieve and maintain glycemia in in newly diagnosed diabetes can result in
creasing glucose-mediated insulin the target range. sustained remissions, i.e., normoglyce-
secretion and suppressing glucagon se- The measures of glycemia that are ini- mia without need for glucose-lowering
cretion (83,84). The first oral DPP-4 in- tially targeted on a day-to-day basis are medications (87,88). Type 2 diabetes is a
hibitor, sitagliptin, was approved by the fasting and preprandial glucose levels. progressive disease (89), and patients
Food and Drug Administration in Octo- Self-monitoring of blood glucose (SMBG) should be informed that they are likely to
ber 2006 for use as monotherapy or in is an important element in adjusting or require the addition of glucose-lowering
combination with metformin or TZDs. adding new interventions and, in partic- medications over time.
Another DPP-4 inhibitor, vildagliptin, ular, in titrating insulin doses. The need The amylin agonists, ␣-glucosidase
was approved in Europe in February for and number of required SMBG mea- inhibitors, glinides, and DPP-4 inhibitors
2008, and several other compounds are surements are not clear (85) and are de- are not included in the two tiers of pre-
under development. In clinical trials per- pendent on the medications used. Oral ferred agents in this algorithm, owing to
formed to date, DPP-4 inhibitors lower glucose-lowering regimens that do not in- their lower or equivalent overall glucose-
A1Clevels by 0.6 – 0.9 percentage points clude sulfonylureas or glinides, and are lowering effectiveness compared with the
and are weight neutral and relatively well therefore not likely to cause hypoglyce- first- and second-tier agents and/or to
tolerated (83,84). They do not cause hy- mia, usually do not require SMBG (86). their limited clinical data or relative ex-
poglycemia when used as monotherapy. However, SMBG may be used to deter- pense (Table 1). However, they may be
A fixed-dose combination pill with met- mine whether therapeutic blood glucose appropriate choices in selected patients.
formin is available. The potential for this targets are being achieved and for adjust-
class of compounds to interfere with im- ment of treatment regimens without requir- Tier 1: well-validated core therapies
mune function is of concern; an increase ing the patient to have laboratory-based These interventions represent the best es-
in upper respiratory infections has been blood glucose testing. Insulin therapy re- tablished and most effective and cost-
reported (34). quires more frequent monitoring. effective therapeutic strategy for achieving
The levels of plasma or capillary glu- the target glycemic goals. The tier one algo-
How to initiate diabetes therapy and cose (most meters that measure finger- rithm is the preferred route of therapy for
advance interventions stick capillary samples are adjusted to most patients with type 2 diabetes.
Except in rare circumstances, such as dia- provide values equivalent to plasma glu- Step 1: lifestyle intervention and met-
betic ketoacidosis or patients who are ex- cose) that should result in long-term gly- formin. Based on the numerous demon-
tremely catabolic or hyperosmolar or who cemia in the nondiabetic target range, as strated short- and long-term benefits that
are unable to hydrate themselves ade- measured by A1C, are fasting and pre- accrue when weight loss and increased
quately (see SPECIAL CONSIDERATIONS/PATIENTS prandial levels between 3.9 and 7.2 levels of activity are achieved and main-
below), hospitalization is not required for mmol/l (70 and 130 mg/dl). If A1C levels tained, as well as the cost-effectiveness of
initiation or adjustment of therapy. The pa- remain above the desired target despite lifestyle interventions when they succeed,

DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009 199


Consensus Statement

ally respond to oral medications, even if


symptoms of ehyperglycemia are present
(48).
Step 3: further adjustments. If lifestyle,
metformin, and sulfonylurea or basal in-
sulin do not result in achievement of tar-
get glycemia, the next step should be to
start, or intensify, insulin therapy (Fig. 1).
Intensification of insulin therapy usually
consists of additional injections that
might include a short- or rapid-acting in-
sulin given before selected meals to re-
duce postprandial glucose excursions
(Fig. 1). When insulin injections are
started, insulin secretagogues (sulfonyl-
urea or glinides) should be discontinued,
or tapered and then discontinued, since
they are not considered to be synergistic.
Although addition of a third oral agent
Figure 2—Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle inter- can be considered, especially if the A1C
ventions at every visit and check A1C every 3 months until A1C is ⬍7% and then at least every 6 level is close to target (A1C ⬍8.0%), this
months. The interventions should be changed if A1C is ⱖ7%. aSulfonylureas other than glyben- approach is usually not preferred, as it is
clamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. no more effective in lowering glycemia,
See text box, entitled TITRATION OF METFORMIN. See Fig. 1 for initiation and adjustment of insulin. and is more costly, than initiating or in-
CHF, congestive heart failure. tensifying insulin (91).

the consensus is that lifestyle interven- its effect on glycemia, absence of weight Tier 2: less well-validated therapies
tions should be initiated as the first step in gain or hypoglycemia, generally low level In selected clinical settings, this second-
treating new-onset type 2 diabetes (Fig. of side effects, high level of acceptance, tier algorithm may be considered. Specif-
2). These interventions should be imple- and relatively low cost. Metformin treat- ically, when hypoglycemia is particularly
mented by health care professionals with ment should be titrated to its maximally undesirable (e.g., in patients who have
appropriate training— usually registered effective dose over 1–2 months, as toler- hazardous jobs), the addition of exenatide
dietitians experienced in behavioral mod- ated (see text box, entitled Titration of or pioglitazone may be considered. Rosi-
ification—and be sensitive to ethnic and Metformin). Rapid addition of other glu- glitazone is not recommended. If promo-
cultural differences among populations. cose-lowering medications should be tion of weight loss is a major consideration
Moreover, lifestyle interventions to im- considered in the setting of persistent and the A1C level is close to target (⬍8.0%),
prove glucose, blood pressure, and lipid symptomatic hyperglycemia. exenatide is an option. If these interventions
levels, and to promote weight loss or at Step 2: addition of a second medica- are not effective in achieving target A1C, or
least avoid weight gain, should remain an tion. If lifestyle intervention and the are not tolerated, addition of a sulfonylurea
underlying theme throughout the man- maximal tolerated dose of metformin fail could be considered. Alternatively, the tier
agement of type 2 diabetes, even after to achieve or sustain the glycemic goals, two interventions should be stopped and
medications are used. For the 10 –20% of another medication should be added basal insulin started.
patients with type 2 diabetes who are not within 2–3 months of the initiation of
obese or overweight, modification of di- therapy or at any time when the target
etary composition and activity levels may A1C level is not achieved. Another medi- Rationale for selecting specific
play a supporting role, but medications cation may also be necessary if metformin combinations
are still generally required early in the is contraindicated or not tolerated. The More than one medication will be neces-
course of diabetes (see SPECIAL CONSIDER- consensus regarding the second medica- sary for the majority of patients over time.
ATIONS/PATIENTS below). tion added to metformin was to choose Selection of the individual agents should
The authors recognize that for most either insulin or a sulfonylurea (Fig. 2). As be made on the basis of their glucose-
individuals with type 2 diabetes, lifestyle discussed above, the A1C level will deter- lowering effectiveness and other charac-
interventions fail to achieve or maintain mine in part which agent is selected next, teristics listed in Table 1. However, when
the metabolic goals either because of fail- with consideration given to the more ef- adding second antihyperglycemic medi-
ure to lose weight, weight regain, progres- fective glycemia-lowering agent, insulin, cations, the synergy of particular combi-
sive disease, or a combination of factors. for patients with an A1C level of ⬎8.5% nations and other interactions should be
Therefore, our consensus is that met- or with symptoms secondary to ehyper- considered. In general, antihyperglyce-
formin therapy should be initiated con- glycemia. Insulin can be initiated with a mic drugs with different mechanisms of
currently with lifestyle intervention at basal (intermediate- or long-acting) insu- action will have the greatest synergy. In-
diagnosis. Metformin is recommended as lin (see Fig. 1 for suggested initial insulin sulin plus metformin (92) is a particularly
the initial pharmacological therapy, in the regimens) (90). However, many newly di- effective means of lowering glycemia
absence of specific contraindications, for agnosed type 2 diabetic patients will usu- while limiting weight gain.

200 DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009


Nathan and Associates

Special considerations/patients University of North Carolina and Amylin, 6. UK Prospective Diabetes Study (UKPDS)
In the setting of severely uncontrolled di- Becton Dickinson, Bristol-Myers Squibb, Group: Intensive blood glucose control
abetes with catabolism, defined as fasting Hoffman-LaRoche, Eli Lilly, GlaxoSmith- with sulphonylureas or insulin compared
plasma glucose levels ⬎13.9 mmol/l (250 Kline, Novo Nordisk, Merck, Novartis, with conventional treatment and risk of
complication in patients with type 2 dia-
mg/dl), random glucose levels consis- Pfizer, and sanofi aventis. M.B.D. has re-
betes (UKPDS 33). Lancet 352:837– 853,
tently above 16.7 mmol/l (300 mg/dl), ceived research support from Eli Lilly, 1998
A1C above 10%, or the presence of keto- Merck, and Pfizer; has served on advisory 7. UK Prospective Diabetes Study (UKPDS)
nuria, or as symptomatic diabetes with boards for Amylin, GlaxoSmithKline, Group: Effect of intensive blood glucose
polyuria, polydipsia and weight loss, in- Merck, and sanofi aventis; and has been control with metformin on complication
sulin therapy in combination with life- on speakers bureaus for Amylin, Eli Lilly, in overweight patients with type 2 diabe-
style intervention is the treatment of GlaxoSmithKline, and Pfizer. E.F. has tes (UKPDS 34). Lancet 352:854 – 865,
choice. Some patients with these charac- received research support from Astra 1998
teristics will have unrecognized type 1 di- Zeneca, Merck Sharpe & Dohme, and No- 8. Ohkubo Y, Kishikawa H, Araki E, et al.:
abetes; others will have type 2 diabetes vartis and serves on scientific advisory Intensive insulin therapy prevents the
with severe insulin deficiency. Insulin can boards for Amylin, AstraZeneca, Glaxo- progression of diabetic microvascular
complications in Japanese patients with
be titrated rapidly and is associated with SmithKline, Roche, Merck Sharpe & NIDDM: a randomized prospective 6-year
the greatest likelihood of returning glu- Dohme, Novartis, Servier, sanofi aventis, study. Diabetes Res Clin Pract 28:103–117,
cose levels rapidly to target levels. After Boehringer Ingelheim, and Takeda. 1995
symptoms are relieved and glucose levels R.R.H. has received research support 9. Diabetes Control and Complications Trial/
decreased, oral agents can often be added from Bristol-Myers Squibb, GlaxoSmith- Epidemiology of Diabetes Interventions
and it may be possible to withdraw insu- Kline, Merck Sante, Novo Nordisk, Pfizer, and Complications Research Group: In-
lin, if preferred. and Pronova and has served on advisory tensive diabetes therapy and carotid
boards and/or received honoraria for intima–media thickness in type 1 diabe-
Conclusions speaking engagements from Amylin, tes. N Engl J Med 348:2294 –2303, 2003
Type 2 diabetes is epidemic. Its long-term GlaxoSmithKline, Lilly, Merck Sharp & 10. Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions
consequences translate into enormous Dohme, Novartis, and sanofi aventis. R.S. and Complications Research Group: In-
human suffering and economic costs; has served on advisory boards for Amylin, tensive diabetes treatment and cardiovas-
however, much of the morbidity associ- Astra Zeneca, Boehringer Ingelheim, Di- cular disease in patients with type 1
ated with long-term microvascular and Obex, Eli Lilly, Insulet, Merck, Mann- diabetes. N Engl J Med 353:2643–2653,
neuropathic complications can be sub- Kind, and Novartis. B.Z. has received 2005
stantially reduced by interventions that research support from GlaxoSmithKline, 11. The Action to Control Cardiovascular
achieve glucose levels close to the nondi- Merck, Novartis, and Novo Nordisk and Risk in Diabetes Study Group: Effects of
abetic range. Although new classes of has been a member of scientific advisory intensive glucose lowering in type 2 dia-
medications and numerous combinations boards and/or received honoraria for betes. N Engl J Med 358:2545–2559, 2008
have been demonstrated to lower glyce- speaking engagements from Amylin, Eli 12. The ADVANCE Collaborative Group: In-
tensive blood glucose control and vascular
mia, current-day management has failed Lilly, GlaxoSmithKline, Merck, Novartis,
outcomes in patients with type 2 diabetes.
to achieve and maintain the glycemic lev- Pfizer, sanofi aventis, and Servier. N Engl J Med 358:2560 –2572, 2008
els most likely to provide optimal health- 13. Abraira C, Duckworth WC, Moritz T:
care status for people with diabetes. Glycaemic separation and risk factor con-
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