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
`
`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
`
`1
`DAVID M. NATHAN, MD
`2
`JOHN B. BUSE, MD, PHD
`MAYER B. DAVIDSON, MD
`4
`ELE FERRANNINI, MD
`
`3
`
`RURY R. HOLMAN, FRCP
`6
`ROBERT SHERWIN, MD
`7
`BERNARD ZINMAN, MD
`
`5
`
`The consensus algorithm for the medical management of type 2 diabetes was published in
`August 2006 with the expectation that it would be updated, based on the availability of new
`interventions and new evidence to establish their clinical role. The authors continue to endorse
`the principles used to develop the algorithm and its major features. We are sensitive to the risks
`of changing the algorithm cavalierly or too frequently, without compelling new information. An
`update to the consensus algorithm published in January 2008 specifically addressed safety issues
`surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications
`that now have more clinical data and experience.
`
`T he epidemic of type 2 diabetes and
`
`the recognition that achieving spe-
`cific glycemic goals can substantially
`reduce morbidity have made the effective
`treatment of hyperglycemia a top priority
`(1–3). While the management of hyper-
`glycemia, the hallmark metabolic abnor-
`mality associated with type 2 diabetes, has
`historically taken center stage in the treat-
`ment of diabetes, therapies directed at
`other coincident features, such as dyslip-
`idemia, hypertension, hypercoagulabil-
`ity, obesity, and insulin resistance, have
`also been a major focus of research and
`therapy. Maintaining glycemic levels as
`close to the nondiabetic range as possible
`has been demonstrated to have a powerful
`
`Diabetes Care 32:193–203,
`
`beneficial effect on diabetes-specific mi-
`crovascular complications, including ret-
`inopathy, nephropathy, and neuropathy,
`in the setting of type 1 diabetes (4,5); in
`type 2 diabetes, more intensive treatment
`strategies have likewise been demon-
`strated to reduce microvascular compli-
`cations (6 – 8). Intensive glycemic
`management resulting in lower A1C lev-
`els has also been shown to have a benefi-
`cial effect on cardiovascular disease
`(CVD) complications in type 1 diabetes
`(9,10); however, current studies have
`failed to demonstrate a beneficial effect of
`intensive diabetes therapy on CVD in type
`2 diabetes (11–13).
`The development of new classes of
`
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Diabetes Center, Massachusetts General Hospital, Boston, Massachusetts; the 2University of North
`Carolina School of Medicine, Chapel Hill, North Carolina; the 3Clinical Center for Research Excellence,
`Charles R. Drew University, Los Angeles, California; the 4Department of Internal Medicine, University of
`Pisa, Pisa, Italy; the 5Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism,
`Oxford University, Oxford, U.K.; the 6Department of Internal Medicine and Yale Center for Clinical
`Investigation, Yale University School of Medicine, New Haven, Connecticut; and the 7Samuel Lunenfeld
`Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
`Corresponding author: David. M. Nathan, dnathan@partners.org..
`This article is being simultaneously published in 2009 by Diabetes Care and Diabetologia by the American
`Diabetes Association and the European Association for the Study of Diabetes.
`An American Diabetes Association consensus statement represents the authors’ collective analysis, evalua-
`tion, and opinion at the time of publication and does not represent official association opinion.
`DOI: 10.2337/dc08-9025
`© 2009 by the American Diabetes Association and Springer. Copying with attribution allowed for any
`non-commercial use of the work.
`
`blood glucose–lowering medications to
`supplement the older therapies, such as
`lifestyle-directed interventions, insulin,
`sulfonylureas, and metformin, has in-
`creased the number of treatment options
`available for type 2 diabetes. Whether
`used alone or in combination with other
`blood glucose–lowering interventions,
`the increased number of choices available
`to practitioners and patients has height-
`ened uncertainty regarding the most
`appropriate means of treating this wide-
`spread disease (14). Although numerous re-
`views on the management of type 2 diabetes
`have been published in recent years (15–
`17), practitioners are often left without a
`clear pathway of therapy to follow. We de-
`veloped the following consensus approach
`to 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 derived from two sources. One source
`is the clinical trials that address the effec-
`tiveness and safety of the different modal-
`ities of therapy. Here, the writing group
`reviewed a wide variety of studies related
`to the use of drugs as monotherapy or in
`combination to lower glycemia. Unfortu-
`nately, the paucity of high-quality evi-
`dence in the form of well-controlled
`clinical trials that directly compare differ-
`ent diabetes treatment regimens remains a
`major impediment to recommending one
`class of drugs, or a particular combination
`of therapies, over another.
`The second source of material that in-
`formed our recommendations was clinical
`judgement, that is, our collective knowl-
`edge and clinical experience, which takes
`into account benefits, risks, and costs in the
`treatment of diabetes. As in all clinical deci-
`sion making, an evidence-based review of
`
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`Consensus Statement
`
`the literature must also be supplemented
`by value judgements, where the benefits
`of treatment are weighed against risks and
`costs in a subjective fashion. While we
`realize that others may have different
`judgements, we believe that the recom-
`mendations made in this new iteration of
`our treatment algorithm will guide ther-
`apy and result in improved glycemic con-
`trol and health status over time.
`
`Glycemic goals of therapy
`Controlled clinical trials, such as the Dia-
`betes Control and Complications Trial
`(DCCT) (4) and the Stockholm Diabetes
`Study in type 1 diabetes (5) and the UK
`Prospective Diabetes Study (UKPDS)
`(6,7) and Kumamoto study (8) in type 2
`diabetes, have helped to establish the gly-
`cemic goals of therapy that result in im-
`proved long-term outcomes. The clinical
`trials, in concert with epidemiological
`data (18,19), support decreasing glyce-
`mia as an effective means of reducing
`long-term microvascular and neuropathic
`complications. The most appropriate tar-
`get levels for blood glucose, on a day-to-
`day basis, and A1C, as an index of chronic
`glycemia, have not been systematically
`studied. However, both 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 maintain A1C levels in the nondiabetic
`range in their intensive treatment groups,
`achieving mean levels over time of ⬃7%,
`which is 4 SDs above the nondiabetic
`mean.
`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 of ⬍7% (1). The most recent
`glycemic goal set by the International Di-
`abetes Federation is an A1C level of
`⬍6.5%. The upper limit of the nondia-
`betic range is 6.1% (mean ⫾ SD. A1C
`level of 5 ⫾ 2%) with the DCCT/UKPDS-
`standardized assay, which has been pro-
`m u l g a t e d t h r o u g h t h e N a t i o n a l
`Glycohemoglobin Standardization Pro-
`gram (NGSP) and adopted by the vast ma-
`jority of commercially available assays
`(20). Several recent clinical trials have
`aimed for A1C levels ⱕ6.5% with a vari-
`ety of interventions (11,12). The results of
`the Action to Control Cardiovascular Risk
`in Diabetes (ACCORD) study, which had
`the primary objective of decreasing CVD
`with interventions aimed at achieving an
`A1C level of ⬍6.0% vs. interventions
`
`aimed at achieving an A1C level of
`⬍7.9%, showed excess CVD mortality in
`the intensive treatment group (11). Re-
`sults from the Action in Diabetes and Vas-
`cular Disease: Preterax and Diamicron
`MR Controlled Evaluation (ADVANCE)
`trial and the Veterans Affairs Diabetes
`Trial, both of which had different inter-
`ventions and study populations than
`ACCORD, did not demonstrate any ex-
`cess total or CVD mortality with intensive
`regimens that achieved A1C levels com-
`parable with the 6.5% in ACCORD
`(12,13). However, none of the studies has
`demonstrated a benefit of intensive glyce-
`mic control on their primary CVD out-
`comes. Our consensus is that an A1C level
`of ⱖ7% should serve as a call to action to
`initiate or change therapy with the goal of
`achieving an A1C level of ⬍7%. We are
`mindful that this goal is not appropriate
`or practical for some patients, and clinical
`judgement based on the potential benefits
`and risks of a more intensified regimen
`needs to be applied for every patient. Fac-
`tors such as life expectancy, risk of hypo-
`glycemia, and the presence of CVD need
`to be considered for every patient before
`intensifying the therapeutic regimen.
`Assiduous attention to abnormalities
`other than hyperglycemia that accom-
`pany type 2 diabetes, such as hyperten-
`sion and dyslipidaemia, has been shown
`to improve microvascular and cardiovas-
`cular complications. Readers are referred
`to published guidelines for a discussion of
`the rationale and goals of therapy for the
`nonglycemic risk factors, as well as rec-
`ommendations on how to achieve them
`(1,21,22).
`
`Principles in selecting
`antihyperglycemic interventions
`Our choice of specific antihyperglycemic
`agents is predicated on their effectiveness
`in lowering glucose, extraglycemic effects
`that may reduce long-term complica-
`tions, safety profiles, tolerability, ease of
`use, and expense.
`
`Effectiveness in lowering glycaemia
`Except for their differential effects on gly-
`cemia, there are insufficient data at this
`time to support a recommendation of one
`class of glucose-lowering agents, or one
`combination of medications, over others
`with regard to effects on complications. In
`other words, the salutary effects of ther-
`apy on long-term complications appear to
`be predicated predominantly on the level
`of glycemic control achieved rather than
`on any other specific attributes of the in-
`
`tervention(s) used to achieve glycemic
`goals. The UKPDS compared three classes
`of glucose-lowering medications (sulfo-
`nylurea, metformin, or insulin) but was
`unable to demonstrate clear superiority of
`any one drug over the others with regard
`to diabetes complications (6,7). However,
`the different classes do have variable ef-
`fectiveness in decreasing glycemic levels
`(Table 1), and the overarching principle
`in selecting a particular intervention will
`be its ability to achieve and maintain gly-
`cemic goals. In addition to their inten-
`tion-to-treat analyses demonstrating the
`superiority of intensive versus conven-
`tional
`interventions, the DCCT and
`UKPDS demonstrated a strong correla-
`tion between mean A1C levels over time
`and the development and progression of
`retinopathy and nephropathy (23,24).
`Therefore, we think it is reasonable to
`judge and compare blood glucose–
`lowering medications, as well as combi-
`nations of such agents, primarily on the
`basis of their capacity to decrease and
`maintain A1C levels and according to
`their safety, specific side effects, tolerabil-
`ity, ease of use, and expense.
`
`Nonglycemic effects of medications
`In addition to variable effects on glyce-
`mia, specific effects of individual thera-
`pies on CVD risk factors, such as
`hypertension or dyslipidemia, were also
`considered important. We also included
`the effects of interventions that may ben-
`efit or worsen the prospects for long-term
`glycemic control in our recommenda-
`tions. Examples of these would be
`changes in body mass, insulin resistance,
`or insulin secretory capacity in type 2 di-
`abetic patients.
`
`Choosing specific diabetes
`interventions and their roles in
`treating type 2 diabetes
`Numerous reviews have focused on the
`characteristics of the specific diabetes in-
`terventions listed below (25–34). In addi-
`tion, meta-analyses and reviews have
`summarized and compared the glucose-
`lowering effectiveness and other charac-
`teristics of the medications (35–37). The
`aim here is to provide enough informa-
`tion to justify the choices of medications,
`the order in which they are recom-
`mended, and the use of combinations of
`therapies. Unfortunately, there is a dearth
`of high-quality studies that provide head-
`to-head comparisons of the ability of the
`medications to achieve the currently rec-
`ommended glycemic levels. The authors
`
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`Table 1—Summary of glucose-lowering interventions
`
`Nathan and Associates
`
`Expected decrease
`in A1C with
`monotherapy (%)
`
`Advantages
`
`Disadvantages
`
`Intervention
`
`Tier 1: well-validated core
`Step 1: initial therapy
`Lifestyle to decrease weight and
`increase activity
`
`Metformin
`
`Step 2: additional therapy
`Insulin
`
`1.0–2.0
`
`1.0–2.0
`
`1.5–3.5
`
`Broad benefits
`
`Weight neutral
`
`No dose limit, rapidly effective,
`improved lipid profile
`
`Sulfonylurea
`
`1.0–2.0
`
`Rapidly effective
`
`Tier 2: less well validated
`TZDs
`
`0.5–1.4
`
`Improved lipid profile
`(pioglitazone), potential
`decrease in MI (pioglitazone)
`
`GLP-1 agonist
`
`0.5–1.0
`
`Weight loss
`
`Insufficient for most within
`first year
`GI side effects, contraindicated
`with renal insufficiency
`
`One to four injections daily,
`monitoring, weight gain,
`hypoglycemia, analogues
`are expensive
`Weight gain, hypoglycemia
`(especially with
`glibenclamide or
`chlorpropamide)
`
`Fluid retention, CHF, weight
`gain, bone fractures,
`expensive, potential increase
`in MI (rosiglitazone)
`Two injections daily, frequent
`GI side effects, long-term
`safety not established,
`expensive
`
`Other therapy
`␣-Glucosidase inhibitor
`
`Glinide
`
`Pramlintide
`
`0.5–0.8
`
`0.5–1.5a
`
`Weight neutral
`
`Rapidly effective
`
`0.5–1.0
`
`Weight loss
`
`Frequent GI side effects, three
`times/day dosing, expensive
`Weight gain, three times/day
`dosing, hypoglycemia,
`expensive
`Three injections daily,
`frequent GI side effects,
`long-term safety not
`established, expensive
`Long-term safety not
`established, expensive
`aRepaglinide more effective in lowering A1C than nateglinide. CHF, congestive heart failure; GI, gastrointestinal; MI, myocardial infarction.
`
`DPP-4 inhibitor
`
`0.5–0.8
`
`Weight neutral
`
`highly recommend that such studies be
`conducted. However, even in the absence
`of rigorous, comprehensive studies that
`directly compare the efficacy of all avail-
`able glucose-lowering treatments and
`their combinations, we feel that there are
`enough data regarding the characteristics
`of the individual interventions to provide
`the guidelines below.
`An important intervention that is
`likely to improve the probability that a
`patient will have better long-term control
`of diabetes is to make the diagnosis early,
`when the metabolic abnormalities of dia-
`betes are usually less severe. Lower levels
`of glycemia at the time of initial therapy
`
`are associated with lower A1C levels over
`time and decreased long-term complica-
`tions (38).
`
`Lifestyle interventions
`The major environmental factors that in-
`crease the risk of type 2 diabetes are over-
`nutrition and a sedentary lifestyle, with
`consequent overweight and obesity
`(39,40). Not surprisingly, interventions
`that reverse or improve these factors have
`been demonstrated to have a beneficial
`effect on control of glycemia in estab-
`lished type 2 diabetes (41). Unfortu-
`nately, the high rate of weight regain has
`limited the role of lifestyle interventions
`
`as an effective means of controlling glyce-
`mia in the long term. The most convinc-
`ing long-term data indicating that weight
`loss effectively lowers glycemia have been
`generated in the follow-up of type 2 dia-
`betic patients who have had bariatric sur-
`gery. In this setting, with a mean
`sustained weight loss of ⬎20 kg, diabetes
`is virtually eliminated (42– 45). In addi-
`tion to the beneficial effects of weight loss
`on glycemia, weight loss and exercise im-
`prove coincident CVD risk factors, such
`as blood pressure and atherogenic lipid
`profiles, and ameliorate other conse-
`quences of obesity (41,46,47). There are
`few adverse consequences of such life-
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`Consensus Statement
`
`style interventions other than difficulty in
`incorporating them into usual lifestyle
`and sustaining them and the usually mi-
`nor musculoskeletal injuries and poten-
`tial problems associated with neuropathy,
`such as foot trauma and ulcers, that may
`occur as a result of increased activity. The-
`oretically, effective weight loss, with its
`pleiotropic benefits, safety profile, and
`low cost, should be the most cost-effective
`means of controlling diabetes—if it could
`be achieved and maintained over the long
`term.
`Given these beneficial effects, which
`are usually seen rapidly—within weeks to
`months—and often before there has been
`substantial weight loss (47), a lifestyle in-
`tervention program to promote weight
`loss and increase activity levels should,
`with rare exceptions, be included as part
`of diabetes management. Weight loss of as
`little as 4 kg will often ameliorate hyper-
`glycemia. However, the limited long-term
`success of lifestyle programs to maintain
`glycemic goals in patients with type 2 di-
`abetes suggests that the large majority of
`patients will require the addition of med-
`ications over the course of their diabetes.
`
`Medications
`The characteristics of currently available
`glucose-lowering interventions, when
`used as monotherapy, are summarized in
`Table 1. The glucose-lowering effective-
`ness of individual therapies and combina-
`tions demonstrated in clinical trials is
`predicated not only on the intrinsic char-
`acteristics of the intervention but also on
`the duration of diabetes, baseline glyce-
`mia, previous therapy, and other factors.
`A major factor in selecting a class of drugs,
`or a specific medication within a class, to
`initiate therapy or when changing ther-
`apy, is the ambient level of glycemic con-
`trol. When levels of glycemia are high
`(e.g., A1C ⬎8.5%), classes with greater
`and more rapid glucose-lowering effec-
`tiveness, or potentially earlier initiation of
`combination therapy, are recommended;
`however, patients with recent-onset dia-
`betes often respond adequately to less in-
`tensive interventions than those with
`longer-term disease (48). When glycemic
`levels are closer to the target levels (e.g.,
`A1C ⬍7.5%), medications with lesser po-
`tential to lower glycemia and/or a slower
`onset of action may be considered.
`Obviously, the choice of glycemic
`goals and the medications used to achieve
`them must be individualized for each pa-
`tient, balancing the potential for lowering
`A1C and anticipated long-term benefit
`
`with specific safety issues, as well as other
`characteristics of regimens, including side
`effects, tolerability, ease of use, long-term
`adherence, expense, and the nonglycemic
`effects of the medications. Type 2 diabetes
`is a progressive disease characterized by
`worsening glycemia; higher doses and ad-
`ditional medications are required over
`time if treatment goals are to be met.
`Metformin. In most of the world, met-
`formin is the only biguanide available. Its
`major effect is to decrease hepatic glucose
`output and lower fasting glycemia. Typi-
`cally, metformin monotherapy will lower
`A1C levels by ⬃1.5 percentage points
`(27,49). It is generally well tolerated, with
`the most common adverse effects being
`gastrointestinal. Metformin monotherapy
`is not usually accompanied by hypoglyce-
`mia and has been used safely, without
`causing hypoglycemia, in patients with
`prediabetic hyperglycemia (50). Met-
`formin interferes with vitamin B12 ab-
`sorption but is very rarely associated with
`anemia (27). The major nonglycemic ef-
`fect of metformin is either weight stability
`or modest weight loss, in contrast with
`many of the other blood glucose–
`lowering medications. The UKPDS dem-
`onstrated a beneficial effect of metformin
`therapy on CVD outcomes (7), which
`needs to be confirmed. Renal dysfunction
`is considered a contraindication to met-
`formin use because it may increase the
`risk of lactic acidosis, an extremely rare
`(less than 1 case per 100,000 treated pa-
`tients) but potentially fatal complication
`(51). However, recent studies have sug-
`gested that metformin is safe unless the
`estimated glomerular filtration rate falls to
`⬍30 ml/min (52).
`Sulfonylureas. Sulfonylureas lower gly-
`cemia by enhancing insulin secretion. In
`terms of efficacy, they appear to be similar
`to metformin, lowering A1C levels by
`⬃1.5 percentage points (26,49). The ma-
`jor adverse side effect is hypoglycemia,
`which can be prolonged and life threaten-
`ing, but such episodes, characterized by a
`need for assistance, coma, or seizure, are
`infrequent. However, severe episodes are
`relatively more frequent in the elderly.
`Chlorpropamide and glibenclamide
`(known as glyburide in the U.S. and Can-
`ada), are associated with a substantially
`greater risk of hypoglycemia than other
`second-generation sulfonylureas (glicla-
`zide, glimepiride, glipizide, and their ex-
`tended formulations), which are
`preferable (Table 1) (53,54). In addition,
`weight gain of ⬃2 kg is common follow-
`ing the initiation of sulfonylurea therapy.
`
`Although the onset of the glucose-
`lowering effect of sulfonylurea mono-
`therapy is relatively rapid compared with,
`for example, the thiazolidinediones
`(TZDs), maintenance of glycemic targets
`over time is not as good as monotherapy
`with a TZD or metformin (55). Sulfonyl-
`urea therapy was implicated as a potential
`cause of increased CVD mortality in the
`University Group Diabetes Program
`(UGDP) study (56). Concerns raised by
`the UGDP that sulfonylureas, as a drug
`class, may increase CVD mortality in type
`2 diabetes were not substantiated by the
`UKPDS or ADVANCE study (6,12). The
`glycemic benefits of sulfonylureas are
`nearly fully realized at half-maximal
`doses, and higher doses should generally
`be avoided.
`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 levels by
`⬃1.5 percentage points. Nateglinide is
`somewhat less effective in lowering A1C
`than repaglinide when used as mono-
`therapy or in combination therapy
`(57,58). The risk of weight gain is similar
`to that for the sulfonylureas, but hypogly-
`cemia may be less frequent, at least with
`nateglinide, than with some sulfonylureas
`(58,59).
`␣-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 levels by
`0.5– 0.8 percentage points (29). Since
`carbohydrate is absorbed more distally,
`malabsorption and weight loss do not oc-
`cur; however, increased delivery of carbo-
`hydrate to the colon commonly results in
`increased gas production and gastrointes-
`tinal symptoms. In clinical trials, 25– 45%
`of participants have discontinued ␣-glu-
`cosidase inhibitor use as a result of this
`side effect (29,60).
`One clinical trial examining acarbose as
`a means of preventing the development of
`diabetes in high-risk individuals with im-
`paired glucose tolerance showed an unex-
`pected reduction in severe CVD outcomes
`
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`(60). This potential benefit of ␣-glucosidase
`inhibitors 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 data regarding the blood glu-
`cose–lowering effectiveness of TZDs
`when used as monotherapy have dem-
`onstrated a 0.5–1.4 percentage point
`decrease in A1C. The TZDs appear to
`have a more durable effect on glycemic
`control, particularly compared with
`sulfonylureas (55). The most common
`adverse effects with TZDs are weight
`gain and fluid retention, with peripheral
`edema and a twofold increased risk for
`congestive heart failure (61,62). There
`is an increase in adiposity, largely sub-
`cutaneous, with some reduction in vis-
`ceral fat shown in some studies. The
`TZDs either have a beneficial (pioglita-
`zone) or neutral (rosiglitazone) effect
`on atherogenic lipid profiles (63,64).
`Several meta-analyses have suggested a
`30 – 40% relative increase in risk for
`myocardial infarction (65,66) with rosi-
`glitazone. On the other hand, the Pro-
`spective Pioglitazone Clinical Trial in
`macrovascular events (PROactive) dem-
`onstrated no significant effects of pio-
`glitazone compared with placebo on the
`primary CVD outcome (a composite of
`all-cause mortality, nonfatal and silent
`myocardial infarction, stroke, major leg
`amputation, acute coronary syndrome,
`coronary artery bypass graft or percuta-
`neous coronary intervention, and leg re-
`vascularization) after 3 years of follow-up
`(67). Pioglitazone was associated with a
`16% reduction in death, myocardial in-
`farction, and stroke—a controversial sec-
`ondary end point reported to have
`marginal statistical significance (67).
`Meta-analyses have supported a possible
`beneficial effect of pioglitazone on CVD
`risk (68). Although the data are less than
`conclusive for a CVD risk with rosiglita-
`zone or a CVD benefit with pioglitazone,
`we have previously advised (69) caution
`in using either TZD on the basis that they
`are both associated with increased risks of
`fluid retention and congestive heart fail-
`ure and an increased incidence of frac-
`tures in women and perhaps in men
`(55,61,62,70). Although the meta-
`analyses discussed above are not conclu-
`sive regarding the potential cardiovascular
`risk associated with rosiglitazone, given
`that other options are now recom-
`
`mended, the consensus group members
`unanimously advised against using rosi-
`glitazone. Currently, in the U.S., the
`TZDs are approved for use in combina-
`tion with metformin, sulfonylureas,
`glinides, and insulin.
`Insulin. Insulin is the oldest of the cur-
`rently available medications and, there-
`fore, the treatment with which we have
`the most clinical experience. It is also the
`most effective at lowering glycemia. Insu-
`lin 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
`the target level. Although initial therapy is
`aimed at increasing basal insulin supply,
`usually with intermediate- or long-acting-
`insulins, patients may also require pran-
`dial therapy with short- or rapid-acting
`insulins (Fig. 1). The very rapid-acting
`and long-acting insulin analogues have
`not been shown to lower A1C levels more
`effectively than the older, rapid-acting or
`intermediate-acting formulations (71–
`73). Insulin therapy has beneficial effects
`on triacylglycerol and HDL cholesterol
`levels, especially in patients with poor
`glycemic control (74), but is associated
`with weight gain of ⬃2– 4 kg, which is
`probably proportional to the correction of
`glycemia and predominantly the result of
`the reduction of glycosuria. Insulin ther-
`apy is also associated with hypoglycemia,
`albeit much less frequently than in type 1
`diabetes. In clinical trials aimed at normo-
`glycemia and achieving a mean A1C of
`⬃7%, severe hypoglycemic episodes (de-
`fined as requiring help from another per-
`son to treat) occurred at a rate of between
`one and three per 100 patient-years
`(8,75–77), compared with 61 per 100 pa-
`tient-years in the DCCT intensive therapy
`group (4). Insulin analogues with longer,
`nonpeaking profiles decrease the risk of
`hypoglycemia modestly compared with
`NPH, and analogues with very short du-
`rations of action reduce the risk of hypo-
`glycemia compared with regular insulin
`(76,77).
`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, potentiates glucose-stimulated
`
`Nathan and Associates
`
`insulin secretion. Exendin-4 has homol-
`ogy with the human GLP-1 sequence but
`has a longer circulating half-life. It binds
`avidly to the GLP-1 receptor on the pan-
`creatic ␤-cell and augments glucose-
`mediated insulin secretion (32). Synthetic
`exendin-4 (exenatide) was approved for
`use in the U.S. in 2005 and is adminis-
`tered twice per day by subcutaneous in-
`jection. Although there are less published
`data on this new compound than the
`other blood glucose–lowering medica-
`tions, exendin-4 appears to lower A1C
`levels by 0.5–1 percentage points, mainly
`by lowering postprandial blood glucose
`levels (78 – 81). Exenatide also suppresses
`glucagon secretion and slows gastric mo-
`tility. It is not associated with hypoglyce-
`mia but causes a relatively high frequency
`of gastrointestinal disturbances, with 30 –
`45% of treated patients experiencing one
`or more episodes of nausea, vomiting, or
`diarrhea (78 – 81). These side effects tend
`to abate over time. In published trials, ex-
`enatide is associated with weight loss of
`⬃2–3 kg over 6 months, some of which
`may be a result of its gastrointestinal side
`effects. Recent reports have suggested a
`risk for pancreatitis associated with use of
`GLP agonists; however, the number of
`cases is very small and whether the rela-
`tionship is causal or coincidental is not
`clear at this time. Currently, exenatide
`is approved for use in the U.S. with sul-
`fonylurea, metformin, and/or a TZD.
`Several other GLP-1 agonists and for-
`mulations are under development.
`Amylin agonists (pramlintide). Pram-
`lintide is a synthetic analogue of the ␤-cell
`hormone amylin. It is administered sub-
`cutaneously before meals and slows gas-
`tric emptying,
`inhibits glucagon
`production in a glucose-dependent fash-
`ion, and predominantly decreases post-
`prandial glucose excursions (33). In
`clinical studies, A1C has been decreased
`by 0.5– 0.7 percentage points (82). The
`major clinical side effects of this drug are
`in nature. ⬃30% of
`gastrointestinal
`treated participants in the clinical trials
`have developed nausea, but this side ef-
`fect tends to abate with time on therapy.
`Weight loss associated with this medica-
`tion is ⬃1–1.5 kg over 6 months; as with
`exenatide, some of the weight loss may be
`the result of gastrointestinal side effects.
`Currently, pramlintide is approved for
`use in the U.S. only as adjunctive therapy
`with regular insulin or rapid-acting insu-
`lin analogues.
`
`DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009
`
`197
`
`Boehringer Ex. 2008
`Mylan v. Boehringer Ingelheim
`IPR2016-01563
`Page 5
`
`

`
`Consensus Statement
`
`Start with bedtime intermediate-acting insulin
`or bedtime or morning long-acting insulin (can
`initiate with 10 units or 0.2 units per kg)
`
`1
`
`Check fasting glucose (fingerstick) usually daily and increase
`dose, typically by 2 units every 3 days until fasting levels are
`consistently in target range (3.9-7.2 mmol/1 [70-130 mg/dl]). Can
`increase dose in larger increments, e.g., by 4 units every 3 days, if
`fasting glucose is> 10 mmol/1 ( 180 mg/dl)
`
`------~----------
`
`l
`
`A1C ?.7% after 2-3 months
`
`I
`
`I
`
`If hypoglycemia
`occurs, or fasting
`glucose level <3. 9
`mmol/1 (70 mg/dl),
`reduce bedtime dose by
`4 units or 1 0%(cid:173)
`whichever is greater
`
`No
`
`~~es-------,
`
`"lj If fasting bg is in target
`range (3.9-7.2 mmol/1 [70-
`130 mg/dl]), check bg
`before lunch, dinner, and
`bed. Depending on bg
`results, add second
`injection as below. C