R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s
`C O N S E N S U S
`S T A T E M E N T
`
`Management of Hyperglycemia in Type 2
`Diabetes: A Consensus Algorithm for the
`Initiation and Adjustment of Therapy
`A consensus statement from the American Diabetes Association and the
`European Association for the Study of Diabetes
`
`1
`DAVID M. NATHAN, MD
`2
`JOHN B. BUSE, MD, PHD
`MAYER B. DAVIDSON, MD
`4
`ROBERT J. HEINE, MD
`
`3
`
`5
`RURY R. HOLMAN, FRCP
`6
`ROBERT SHERWIN, MD
`7
`BERNARD ZINMAN, MD
`
`T he epidemic of type 2 diabetes in the
`
`latter part of the 20th and in the
`early 21st century, and the recogni-
`tion that achieving specific glycemic goals
`can substantially reduce morbidity, have
`made the effective treatment of hypergly-
`cemia a top priority (1–3). While the
`management of hyperglycemia, the hall-
`mark metabolic abnormality associated
`with type 2 diabetes, has historically had
`center stage in the treatment of diabetes,
`
`therapies directed at other coincident fea-
`tures, such as dyslipidemia, hyperten-
`sion, hypercoagulability, obesity, and
`insulin resistance, have also been a major
`focus of research and therapy. Maintain-
`ing glycemic levels as close to the non-
`diabetic range as possible has been
`demonstrated to have a powerful
`beneficial impact on diabetes-specific
`complications, including retinopathy, ne-
`phropathy, and neuropathy in the setting
`
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massa-
`chusetts; the 2University of North Carolina School of Medicine, Chapel Hill, North Carolina; the 3Clinical
`Trials Unit, Charles R. Drew University, Los Angeles, California; the 4Diabetes Center, VU University Medical
`Center, Amsterdam, the Netherlands; the 5Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology
`and Metabolism, Oxford University, Oxford, U.K.; the 6Department of Internal Medicine and Endocrinol-
`ogy, Yale University School of Medicine, New Haven, Connecticut; and the 7Departments of Endocrinology
`and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
`Address correspondence and reprint requests to David M. Nathan, MD, Diabetes Center, Massachusetts
`General Hospital, Boston, MA 02114. E-mail: dnathan@partners.org.
`This document was reviewed and approved by the Professional Practice Committee of the American
`Diabetes Association and by an ad hoc committee of the European Association for the Study of Diabetes (Ulf
`Smith, Gothenburg, Sweden; Stefano Del Prato, Pisa, Italy; Clifford Bailey, Birmingham U.K.; and Bernard
`Charbonnel, Nantes, France).
`D.M.N. has received research grants for investigator-initiated research from Aventis and Novo Nordisk.
`J.B.B. has conducted research and/or served on advisory boards under contract between the University of
`North Carolina and Amylin, Becton Dickinson, Bristol-Myers Squibb, Hoffman-LaRoche, Lilly, Novo Nor-
`disk, Merck, Novartis, Pfizer, and Sanofi-Aventis. M.B.D. has received research support from Eli Lilly, Merck,
`and Pfizer; has served on advisory boards for Amylin, GlaxoSmithKline, Merck, Sanofi-Aventis; and has been
`on speakers bureaus for Amylin, Eli Lilly, GlaxoSmithKline, and Pfizer. R.J.H. has received research support
`from GlaxoSmithKline, Minimed-Medtronic, Novartis, and Novo Nordisk and has served on advisory boards
`for Amylin, Bristol-Myers Squibb, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis. R.R.H. has
`received research support from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sante´, Novo Nordisk, Pfizer,
`and Pronova and has served on advisory boards and/or received honoraria for speaking engagements from
`Amylin, GlaxoSmithKline, Lilly, Merck Sharp & Dome, Novartis, and Sanofi-Aventis. R.S. has served on
`advisory boards for Amylin, Bristol-Myers Squibb, Eli Lilly, Merck, and Takeda. B.Z. has received research
`support from Eli Lilly, GlaxoSmithKline, Novartis, and Novo Nordisk and has been a member of scientific
`advisory boards and/or received honoraria for speaking engagements from Amylin, Eli Lilly, GlaxoSmith-
`Kline, Johnson & Johnson, Merck, Novartis, Pfizer, Sanofi-Aventis, and Smiths Medical.
`Simultaneous publication: This article is being simultaneously published in 2006 in Diabetes Care and
`Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes.
`
`Abbreviations: CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; GLP-1,
`glucagon-like peptide 1; SMBG, self-monitoring of blood glucose; TZD, thiazolidinedione; UKPDS, U.K.
`Prospective Diabetes Study.
`DOI: 10.2337/dc06-9912
`© 2006 by the American Diabetes Association, Inc., and Springer-Verlag. Copying with attribution
`allowed for any noncommercial use of the work.
`
`of type 1 diabetes (4,5); in type 2 diabetes,
`more intensive treatment strategies have
`likewise been demonstrated to reduce
`complications (6 – 8). Intensive glycemic
`management resulting in lower HbA1c
`(A1C) levels has also been shown to have
`a beneficial effect on cardiovascular dis-
`ease (CVD) complications in type 1 dia-
`betes (9,10); however, the role of
`intensive diabetes therapy on CVD in type
`2 diabetes remains under active investiga-
`tion (11,12). Some therapies directed at
`lowering glucose levels have additional
`benefits with regard to CVD risk factors,
`while others lower glucose without addi-
`tional benefits.
`The development of new classes of
`blood glucose–lowering medications to
`supplement the older therapies, such as
`lifestyle-directed interventions, insulin,
`sulfonylureas, and metformin, has in-
`creased the treatment options for type 2
`diabetes. Whether used alone or in com-
`bination with other blood glucose–
`lowering interventions, the availability of
`the newer agents has provided an in-
`creased number of choices for practitio-
`ners and patients and heightened
`uncertainty regarding the most appropri-
`ate means of treating this widespread dis-
`ease. Although numerous reviews on the
`management of type 2 diabetes have been
`published in recent years (13–16), prac-
`titioners are often left without a clear
`pathway of therapy to follow. We devel-
`oped the following consensus approach
`to the management of hyperglycemia in
`the nonpregnant adult to help guide
`health care providers in choosing the
`most appropriate interventions for their
`patients with type 2 diabetes.
`
`Process
`The guidelines and algorithm that follow
`are based on clinical trials that have ex-
`amined different modalities of therapy of
`type 2 diabetes and on the authors’ clini-
`cal experience and judgment, keeping in
`mind the primary goal of achieving and
`maintaining glucose levels as close to the
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`Management of hyperglycemia in type 2 diabetes
`
`Table 1—Summary of antidiabetic interventions as monotherapy
`
`Expected decrease
`in A1C (%)
`
`Advantages
`
`Disadvantages
`
`1–2
`
`1.5
`
`1.5–2.5
`
`1.5
`0.5–1.4
`
`Low cost, many benefits
`
`Fails for most in 1st year
`
`Weight neutral, inexpensive
`
`GI side effects, rare lactic acidosis
`
`No dose limit, inexpensive,
`improved lipid profile
`Inexpensive
`Improved lipid profile
`
`Injections, monitoring, hypoglycemia,
`weight gain
`Weight gain, hypoglycemia*
`Fluid retention, weight gain, expensive
`
`Interventions
`
`Step 1: initial
`Lifestyle to decrease weight
`and increase activity
`Metformin
`Step 2: additional therapy
`Insulin
`
`Sulfonylureas
`TZDs
`Other drugs
`␣-Glucosidase inhibitors
`
`Exenatide
`
`Glinides
`Pramlintide
`
`Frequent GI side effects, three times/
`day dosing, expensive
`Injections, frequent GI side effects,
`expensive, little experience
`Three times/day dosing, expensive
`Injections, three times/day dosing,
`frequent GI side effects, expensive,
`little experience
`*Severe hypoglycemia is relatively infrequent with sulfonylurea therapy. The longer-acting agents (e.g. chlorpropamide, glyburide 关glibenclamide兴, and sustained-
`release glipizide) are more likely to cause hypoglycemia than glipizide, glimepiride, and gliclazide. †Repaglinide is more effective at lowering A1C than nateglinide.
`GI, gastrointestinal.
`
`0.5–0.8
`
`Weight neutral
`
`0.5–1.0
`
`1–1.5†
`0.5–1.0
`
`Weight loss
`
`Short duration
`Weight loss
`
`nondiabetic range as possible. The pau-
`city of high-quality evidence in the form
`of clinical trials that directly compare differ-
`ent diabetes treatment regimens remains a
`major impediment to recommending one
`class of drugs, or a particular combination
`of therapies, over another. While the al-
`gorithm that we propose is likely to en-
`gender debate, we hope that
`the
`recommendations will help guide the
`therapy of type 2 diabetes and result in
`improved glycemic control and health
`status over time.
`
`Glycemic goals of therapy
`Controlled clinical trials, such as the Dia-
`betes Control and Complications Trial
`(DCCT) (4) and the Stockholm Diabetes
`Intervention Study (5) in type 1 diabetes
`and the U.K. Prospective Diabetes Study
`(UKPDS) (6,7) and Kumamoto Study (8)
`in type 2 diabetes, have helped to estab-
`lish the glycemic goals of therapy that re-
`sult in improved long-term outcomes.
`Although the various clinical trials have
`had different designs, interventions, and
`measured outcomes, the trials, in concert
`with epidemiologic data (17,18), support
`decreasing glycemia as an effective means
`of reducing long-term microvascular and
`neuropathic complications. The most ap-
`propriate target levels for blood glucose,
`on a day-to-day basis, and A1C, as an in-
`dex of chronic glycemia, have not been
`systematically studied. However, both the
`
`DCCT (4) and the UKPDS (6,7) had as
`their goals the achievement of glycemic
`levels in the nondiabetic range. Neither
`study was able to sustain A1C levels in the
`nondiabetic range in their intensive-
`treatment groups, achieving mean levels
`over time of ⬃7%, 4 SDs above the non-
`diabetic mean.
`The most recent glycemic goal recom-
`mended by the American Diabetes Asso-
`ciation, selected on the basis of
`practicality and the projected reduction
`in complications over time, is “in general”
`an A1C level ⬍7% (19). For “the individ-
`ual patient,” the A1C should be “as close
`to normal (⬍6%) as possible without sig-
`nificant hypoglycemia.” The most recent
`glycemic goal set by the European Union–
`International Diabetes Federation is an
`A1C level ⬍6.5%. The upper limit of the
`nondiabetic range is 6.1% (mean A1C of
`5% ⫹ 2 SD) with the DCCT-standardized
`assay, which has been promulgated
`through the National Glycohemoglobin
`Standardization Program (NGSP) and
`adopted by the vast majority of commer-
`cially available assays (20). Our consen-
`sus is that an A1C of ⱖ7% should serve as
`a call to action to initiate or change ther-
`apy with the goal of achieving an A1C
`level as close to the nondiabetic range as
`possible or, at a minimum, decreasing the
`A1C to ⬍7%. We are mindful that this
`goal is not appropriate or practical for
`some patients, and clinical judgment,
`
`based on the potential benefits and risks
`of a more intensified regimen, needs to be
`applied for every patient. Factors such as
`life expectancy and risk for hypoglycemia
`need to be considered for every patient
`before intensifying therapeutic regimens.
`Assiduous attention to abnormalities
`other than hyperglycemia that accom-
`pany type 2 diabetes, such as hyperten-
`sion and dyslipidemia, has been shown to
`improve microvascular and cardiovascu-
`lar complications. Readers are referred to
`published guidelines for a discussion of
`the rationale and goals of therapy for the
`nonglycemic risk factors, as well as rec-
`ommendations as to how to achieve them
`(1,21,22).
`
`Principles in selecting
`antihyperglycemic interventions
`Choosing specific antihyperglycemic
`agents is predicated on their effectiveness
`in lowering glucose, extraglycemic effects
`that may reduce long-term complica-
`tions, safety profiles, tolerability, and
`expense.
`Effectiveness in lowering glycemia.
`Apart from their differential effects on gly-
`cemia, there are insufficient data at this
`time to support a recommendation of one
`class of glucose-lowering agents, or one
`combination of medications, over others
`with regard to effects on complications. In
`other words, the salutary effects of ther-
`apy on long-term complications appear to
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`be predicated predominantly on the level
`of glycemic control achieved rather than
`on any other specific attributes of the in-
`tervention(s) used to achieve glycemic
`goals. The UKPDS compared three classes
`of glucose-lowering medications (sulfo-
`nylurea, metformin, or insulin) but was
`unable to demonstrate clear superiority of
`any one drug over the others with regard
`to complications (6,7). However, the dif-
`ferent classes do have variable effective-
`ness in decreasing glycemic levels (Table
`1), and the overarching principle in se-
`lecting a particular intervention will be its
`ability to achieve and maintain glycemic
`goals. In addition to the intention-to-treat
`analyses demonstrating the superiority of
`intensive versus conventional interven-
`tions, the DCCT and UKPDS demon-
`strated a strong correlation between mean
`A1C levels over time and the develop-
`ment and progression of retinopathy and
`nephropathy (23,24). Therefore, we
`think it is reasonable to judge and com-
`pare blood glucose–lowering medica-
`tions, and the combinations of such
`agents, primarily on the basis of the A1C
`levels that are achieved and on their spe-
`cific side effects, tolerability, and expense.
`Nonglycemic effects of medications.
`In addition to variable effects on glyce-
`mia, specific effects of individual thera-
`pies on CVD risk factors, such as
`hypertension or dyslipidemia, were also
`considered important. We also included
`the effects of interventions that may ben-
`efit or worsen the prospects for long-term
`glycemic control in our recommenda-
`tions. Examples of these would be
`changes in body mass, insulin resistance,
`or insulin secretory capacity in type 2 di-
`abetic patients.
`
`Choosing specific diabetes
`interventions and their roles in
`treating type 2 diabetes
`Numerous reviews have focused on the
`characteristics of the specific diabetes in-
`terventions listed below (25–33). The aim
`here is to provide enough information to
`justify the choices of medications, the or-
`der in which they are recommended, and
`the utility of combinations of therapies.
`Unfortunately, there is a dearth of high-
`quality studies that provide head-to-head
`comparisons of the ability of the medica-
`tions to achieve the currently recom-
`mended glycemic levels. The authors
`highly recommend that such studies be
`conducted. However, even in the absence
`of rigorous, comprehensive studies that
`directly compare the efficacy of all avail-
`
`able glucose-lowering treatments, and
`their combinations, we feel that there are
`enough data regarding the characteristics
`of the individual interventions to provide
`the guidelines below.
`An important intervention that is
`likely to improve the probability that a
`patient will have better long-term control
`of diabetes is to make the diagnosis early,
`when the metabolic abnormalities of dia-
`betes are usually less severe. Lower levels
`of glycemia at time of initial therapy are
`associated with lower A1C over time and
`decreased long-term complications (34).
`Lifestyle interventions. The major envi-
`ronmental factors that increase the risk of
`type 2 diabetes, presumably in the setting
`of genetic risk, are overnutrition and a
`sedentary lifestyle, with consequent over-
`weight and obesity (35). Not surprisingly,
`interventions that reverse or improve
`these factors have been demonstrated to
`have a beneficial effect on control of gly-
`cemia in established type 2 diabetes (36).
`While there is still active debate regarding
`the most beneficial types of diet and exer-
`cise, weight loss almost always improves
`glycemic levels. Unfortunately, the high
`rate of weight regain has limited the role
`of lifestyle interventions as an effective
`means of controlling glycemia long term.
`The most convincing long-term data that
`weight loss effectively lowers glycemia
`have been generated in the follow-up of
`type 2 diabetic patients who have had
`bariatric surgery (37,38). In this setting,
`diabetes is virtually erased, with a mean
`sustained weight loss of ⬎20 kg (37,38).
`Studies of the pharmacologic treatment of
`obesity have been characterized by high
`drop-out rates, low sustainability, and
`side effects; weight loss medications can-
`not be recommended as a primary ther-
`apy for diabetes at this time. In addition to
`the beneficial effects of weight loss on gly-
`cemia, weight loss and exercise improve
`coincident CVD risk factors, such as
`blood pressure and atherogenic lipid pro-
`files, and ameliorate other consequences
`of obesity (37– 40). There are few adverse
`consequences of such lifestyle interven-
`tions other than the difficulty in incorpo-
`rating them into usual
`lifestyle and
`sustaining them and the usually minor
`musculoskeletal injuries and potential
`problems associated with neuropathy,
`such as foot trauma and ulcers, that may
`occur with increased activity. Theoreti-
`cally, effective weight loss, with its pleio-
`tropic benefits, safety profile, and low
`cost, should be the most cost-effective
`
`Nathan and Associates
`
`means of controlling diabetes, if it could
`be achieved and maintained long term.
`Given these beneficial effects, a life-
`style intervention program to promote
`weight loss and increase activity levels
`should, with rare exceptions, be included
`as part of diabetes management. The ben-
`eficial effects of such programs are usually
`seen rapidly, within weeks to months,
`and often before there has been substan-
`tial weight loss (41). Weight loss of as lit-
`tle as 4 kg will often ameliorate
`hyperglycemia. However, the limited
`long-term success of lifestyle programs to
`maintain glycemic goals in patients with
`type 2 diabetes suggests that a large ma-
`jority of patients will require the addition
`of medications over the course of their
`diabetes.
`Medications. The characteristics of cur-
`rently available antidiabetic interven-
`tions, when used as monotherapy, are
`summarized in Table 1. The glucose-
`lowering effectiveness of individual ther-
`apies and combinations demonstrated in
`clinical trials is predicated not only on the
`intrinsic characteristics of the interven-
`tion, but also on the baseline glycemia,
`duration of diabetes, previous therapy,
`and other factors. A major factor in select-
`ing a class of drugs, or a specific medica-
`tion within a class, to initiate therapy or
`when changing therapy, is the ambient
`level of glycemic control. When levels of
`glycemia are high (e.g., A1C ⬎8.5%),
`classes with greater and more rapid glu-
`cose-lowering effectiveness, or potentially
`earlier initiation of combination therapy,
`are recommended; conversely, when gly-
`cemic levels are closer to the target levels
`(e.g., A1C ⬍7.5%), medications with
`lesser potential to lower glycemia and/or a
`slower onset of action may be considered.
`Obviously, the choice of glycemic goals
`and the medications used to achieve them
`must be individualized for each patient,
`balancing the potential for lowering A1C
`and anticipated long-term benefit with
`specific safety issues, as well as other char-
`acteristics of regimens, including side ef-
`fects, tolerability, patient burden and
`long-term adherence, expense, and the
`nonglycemic effects of the medications.
`Finally, type 2 diabetes is a progressive
`disease with worsening glycemia over
`time. Therefore, addition of medications
`is the rule, not the exception, if treatment
`goals are to be met over time.
`Metformin. Metformin is the only bi-
`guanide available in most of the world. Its
`major effect is to decrease hepatic glucose
`output and lower fasting glycemia. Typi-
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`Management of hyperglycemia in type 2 diabetes
`
`cally, metformin monotherapy will lower
`A1C by ⬃1.5 percentage points (27,42).
`It is generally well tolerated, with the
`most common adverse effects being gas-
`trointestinal. Although always a matter of
`concern because of its potentially fatal
`outcome, lactic acidosis is quite rare (⬍1
`case per 100,000 treated patients) (43).
`Metformin monotherapy is usually not
`accompanied by hypoglycemia and has
`been used safely, without causing hypo-
`glycemia, in patients with pre-diabetic
`hyperglycemia (44). The major nonglyce-
`mic effect of metformin is either weight
`stability or modest weight loss, in contrast
`to many of the other blood glucose–
`lowering medications. The UKPDS dem-
`onstrated a beneficial effect of metformin
`therapy on CVD outcomes that needs to
`be confirmed (7).
`Sulfonylureas. Sulfonylureas lower gly-
`cemia by enhancing insulin secretion.
`They appear to have an effect similar to
`metformin, and they lower A1C by ⬃1.5
`percentage points (26). The major ad-
`verse side effect is hypoglycemia, but se-
`vere episodes, characterized by need for
`assistance, coma, or seizure, are infre-
`quent. However, such episodes are more
`frequent in the elderly. Episodes can be
`both prolonged and life threatening, al-
`though these are very rare. Several of the
`newer sulfonylureas have a relatively
`lower risk for hypoglycemia (Table 1)
`(45,46). In addition, weight gain of ⬃2 kg
`is common with the initiation of sulfonyl-
`urea therapy. This may have an adverse
`impact on CVD risk, although it has not
`been established. Finally, sulfonylurea
`therapy was implicated as a potential
`cause of increased CVD mortality in the
`University Group Diabetes Program (47).
`Concerns raised by the University Group
`Diabetes Program study that sulfonylurea
`therapy may increase CVD mortality in
`type 2 diabetes were not substantiated by
`the UKPDS (6).
`Glinides. Like the sulfonylureas, the
`glinides stimulate insulin secretion, al-
`though they bind to a different site within
`the sulfonylurea receptor (28). They have
`a shorter circulating half-life than the sul-
`fonylureas and must be administered
`more frequently. Of the two glinides cur-
`rently available in the U.S., repaglinide is
`almost as effective as metformin or the
`sulfonylureas, decreasing A1C by ⬃1.5
`percentage points. Nateglinide is some-
`what less effective in lowering A1C than
`repaglinide when used as monotherapy or
`in combination therapy (48,49). The glin-
`ides have a similar risk for weight gain as
`
`the sulfonylureas, but hypoglycemia may
`be less frequent, at least with nateglinide,
`than with some sulfonylureas (49,50).
`␣-Glucosidase inhibitors. ␣-Glucosi-
`dase inhibitors reduce the rate of diges-
`tion of polysaccharides in the proximal
`small intestine, primarily lowering post-
`prandial glucose levels without causing
`hypoglycemia. They are less effective in
`lowering glycemia than metformin or the
`sulfonylureas, reducing A1C by 0.5– 0.8
`percentage points (29). Since carbohy-
`drate is absorbed more distally, malab-
`sorption and weight loss do not occur;
`however, increased delivery of carbohy-
`drate to the colon commonly results in
`increased gas production and gastrointes-
`tinal symptoms. This side effect has led to
`discontinuation of the ␣-glucosidase in-
`hibitors by 25– 45% of participants in
`clinical trials (29,51). One clinical trial
`examining acarbose as a means of pre-
`venting the development of diabetes in
`high-risk subjects with impaired glucose
`tolerance showed an unexpected reduc-
`tion in severe CVD outcomes (51). This
`potential benefit of ␣-glucosidase inhibi-
`tors needs to be confirmed.
`Thiazolidinediones. Thiazolidinedio-
`nes (TZDs or glitazones) are peroxisome
`proliferator–activated receptor ␥ modula-
`tors; they increase the sensitivity of mus-
`cle, fat, and liver to endogenous and
`exogenous insulin (“insulin sensitizers”)
`(31). The limited data regarding the blood
`glucose–lowering effectiveness of TZDs
`when used as monotherapy have demon-
`strated a 0.5–1.4% decrease in A1C. The
`most common adverse effects with TZDs
`are weight gain and fluid retention. There
`is an increase in adiposity, largely subcu-
`taneous, with redistribution of fat from
`visceral deposits shown in some studies.
`The fluid retention usually manifests as
`peripheral edema, though new or wors-
`ened heart failure can occur. The TZDs
`either have a beneficial or neutral effect on
`atherogenic lipid profiles, with pioglita-
`zone having a more beneficial effect than
`rosiglitazone (52,53). The PROactive
`(PROspective pioglitAzone Clinical Trial
`In macroVascular Events) study demon-
`strated no significant effects of pioglita-
`zone compared with placebo on the
`primary CVD outcome (composite of all-
`cause mortality, nonfatal and silent myo-
`cardial
`infarction, stroke, major leg
`amputation, acute coronary syndrome,
`coronary artery bypass graft or percutane-
`ous coronary intervention, and leg revas-
`cularization) after 3 years of follow-up,
`but a 16% reduction in death, myocardial
`
`infarction, and stroke, a secondary end
`point, was reported with marginal statis-
`tical significance (54).
`Insulin.
`Insulin is the oldest of the cur-
`rently available medications and has the
`most clinical experience. Although ini-
`tially developed to treat the insulin-
`deficient type 1 diabetic patient, in whom
`it is life saving, insulin was used early on
`to treat the insulin-resistant form of dia-
`betes recognized by Himsworth and Kerr
`(55). Insulin is the most effective of dia-
`betes medications in lowering glycemia. It
`can, when used in adequate doses, de-
`crease any level of elevated A1C to, or
`close to, the therapeutic goal. Unlike the
`other blood glucose–lowering medica-
`tions, there is no maximum dose of insu-
`lin beyond which a therapeutic effect will
`not occur. Relatively large doses of insulin
`(ⱖ1 unit/kg), compared with those re-
`quired to treat type 1 diabetes, may be
`necessary to overcome the insulin resis-
`tance of type 2 diabetes and lower A1C to
`goal. Although initial therapy is aimed at
`increasing basal insulin supply, usually
`with intermediate- or long-acting insu-
`lins, patients may also require prandial
`therapy with short- or rapid-acting insu-
`lins as well (Fig. 1). Insulin therapy has
`beneficial effects on triglyceride and HDL
`cholesterol levels (56) but is associated
`with weight gain of ⬃2– 4 kg, probably
`proportional to the correction of glycemia
`and owing predominantly to the reduc-
`tion of glycosuria. As with sulfonylurea
`therapy, the weight gain may have an ad-
`verse effect on cardiovascular risk. Insulin
`therapy is also associated with hypoglyce-
`mia, albeit much less frequently than in
`type 1 diabetes. In clinical trials aimed at
`normoglycemia and achieving a mean
`A1C of ⬃7%, severe hypoglycemic epi-
`sodes (defined as requiring help from an-
`other person to treat) occurred at a rate of
`between 1 and 3 per 100 patient-years
`(8,56 –59) compared with 61 per 100 pa-
`tient-years in the DCCT intensive-therapy
`group (4). Insulin analogs with longer,
`nonpeaking profiles may decrease the risk
`of hypoglycemia compared with NPH,
`and analogs with very short durations of
`action may reduce the risk of hypoglyce-
`mia compared with regular insulin
`(60,61). Inhaled insulin was approved in
`the U.S. in 2006 for the treatment of type
`2 diabetes. Published clinical studies to
`date have not demonstrated whether in-
`haled insulin, given as monotherapy
`(62,63) or in combination with an injec-
`tion of long-acting insulin (64), can lower
`A1C to ⱕ7%.
`
`1966
`
`DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006
`
`Boehringer Ex. 2002
`Mylan v. Boehringer Ingelheim
`IPR2016-01563
`Page 4
`
`

`
`Nathan and Associates
`
`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 ref. 71 for more detailed instructions. ⫹Premixed insulins
`are 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.
`
`Glucagon-like peptide 1 agonists (ex-
`enatide). Glucagon-like peptide 1
`(GLP-1) 7-37, a naturally occurring pep-
`tide produced by the L-cells of the small
`intestine, stimulates insulin secretion. Ex-
`endin-4 has homology with the human
`GLP-1 sequence but has a longer circulat-
`ing half-life. It binds avidly to the GLP-1
`receptor on the pancreatic ␤-cell and
`
`potentiates glucose-mediated insulin se-
`cretion (32). Synthetic exendin-4 (ex-
`enatide) was approved for use in the U.S.
`in 2005 and is administered twice per day
`by subcutaneous injection. Although
`there are far less published data on this
`new compound than the other blood glu-
`cose–lowering medications, exendin-4
`appears to lower A1C by 0.5–1 percent-
`
`age points, mainly by lowering postpran-
`dial blood glucose levels (65– 68).
`Exenatide also suppresses glucagon secre-
`tion and slows gastric motility. It is not
`associated with hypoglycemia but has a
`relatively high frequency of gastrointesti-
`nal side effects, with 30 – 45% of treated
`patients experiencing one or more epi-
`sodes of nausea, vomiting, or diarrhea
`
`DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006
`
`1967
`
`Boehringer Ex. 2002
`Mylan v. Boehringer Ingelheim
`IPR2016-01563
`Page 5
`
`

`
`Management of hyperglycemia in type 2 diabetes
`
`Figure 2—Algorithm for the met-
`abolic management of type 2 dia-
`b e t e s . R e i n f o r c e
`l i f e s t y l e
`intervention at every visit. *Check
`A1C every 3 months until ⬍7%
`and then at least every 6 months.
`⫹Although three oral agents can
`be used, initiation and intensifica-
`tion of insulin therapy is preferred
`based on effectiveness and ex-
`pense. #See Fig. 1 for initiation
`and adjustment of insulin.
`
`(65– 68). In published trials, exenatide is
`associated with an ⬃2- to 3-kg weight
`loss over 6 months, some of which may be
`a result of its gastrointestinal side effects.
`Currently, exenatide is approved for use
`in the U.S. with sulfonylurea and/or
`metformin.
`Amylin agonists (pramlintide). Pram-
`lintide is a synthetic analog of the ␤-cell
`hormone amylin. Currently, pramlintide
`is approved for use in the U.S. only as
`adjunctive therapy with insulin.
`Pramlintide is administered subcuta-
`neously before meals and slows gastric
`emptying, inhibits glucagon production
`in a glucose-dependent fashion, and pre-
`dominantly decreases postprandial glu-
`cose excursions (33). In clinical studies,
`A1C has been decreased by 0.5– 0.7 per-
`centage points (69). The major clinical
`side effects of this drug, which is injected
`before meals, are gastrointestinal in na-
`ture. Approximately 30% of treated par-
`ticipants in the clinical trials have
`developed nausea. Weight loss associated
`with this medication is ⬃1–1.5 kg over 6
`months; as with exenatide, some of the
`weight loss may be the result of gastroin-
`testinal side effects.
`
`How to initiate diabetes therapy and
`advance interventions
`Except in rare circumstances, such as pa-
`tients who are extremely catabolic or hy-
`perosmolar, who are unable to hydrate
`themselves adequately, or with diabetic
`ketoacidosis (see SPECIAL CONSIDERATIONS/
`PATIENTS below), hospitalization is not re-
`
`quired to initiate or adjust therapy. The
`patient is the key player in the diabetes
`care team and should be trained and em-
`powered to prevent and treat hypoglyce-
`mia, as well as to adjust medications with
`the guidance of health care providers to
`achieve glycemic goals. Many patients
`may be managed effectively with mono-
`therapy; however, the progressive nature
`of the disease will require the use of com-
`bination therapy in many, if not most, pa-
`tients over time to achieve and maintain
`glycemia in the target range.
`The measures of glycemia that are ini-
`tially targeted on a day-to-day basis are
`the fasting and preprandial glucose levels.
`Self-monitoring of blood glucose (SMBG)
`is an important element in adjusting or
`adding new interventions and, in partic-
`ular, in titrating insulin doses. The need
`for and number of required SMBG mea-
`surements are not clear (70) but are de-
`pendent on the medications used. Oral
`hypoglycemic regimens that do not in-
`clude sulfonylureas, and are therefore not
`likely to cause hypoglycemia, usually do
`not require SMBG. However, SMBG may
`be used to determine whether therapeutic
`blood glucose targets are being achieved
`and to adjust treatment regimens without
`requiring the patient to have laboratory-
`based blood glucose testing. A fasting glu-
`cose level measured several times per
`week generally correlates well with the
`A1C level. Insulin therapy requires more
`frequent monitoring.
`The levels of plasma or capillary glu-
`co