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Lecture - MMHDC
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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, MD 1 JOHN B. BUSE, MD, PHD 2 MAYER B. DAVIDSON, MD 3 ELE FERRANNINI, MD 4 RURY R. HOLMAN, FRCP 5 ROBERT SHERWIN, MD 6 BERNARD ZINMAN, MD 7 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 updatetotheconsensusalgorithmpublishedinJanuary2008specificallyaddressedsafetyissues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. Diabetes Care 31:1?11, 2008 T he epidemic of type 2 diabetes and the recognition that achieving spe- cificglycemicgoalscansubstantially reduce morbidity have made the effective treatment of hyperglycemia a top priority (1?3). While the management of hyper- glycemia, the hallmark metabolic abnor- malityassociatedwithtype2diabetes,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 hasbeendemonstratedtohaveapowerful 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 intensivediabetestherapyonCVDintype 2 diabetes (11?13). The development of new classes of blood glucose?lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has in- creased the number of treatment options available for type 2 diabetes. Whether used alone or in combination with other blood glucose?lowering interventions, the increased number of choices available to practitioners and patients has height- ened uncertainty regarding the most appropriate means of treating this wide- spreaddisease(14).Althoughnumerousre- viewsonthemanagementoftype2diabetes 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 nonpregnantadulttohelpguidehealthcare 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- entdiabetestreatmentregimensremainsa major impediment to recommending one classofdrugs,oraparticularcombination of therapies, over another. The second source of material that in- formed our recommendations wasclinical 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 ????????????????????????????????????????????????? Fromthe 1 DiabetesCenter,MassachusettsGeneralHospital,Boston,Massachusetts;the 2 UniversityofNorth Carolina School of Medicine, Chapel Hill, North Carolina; the 3 Clinical Center for Research Excellence, Charles R. Drew University, Los Angeles, California; the 4 Department of Internal Medicine, University of Pisa, Pisa, Italy; the 5 Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, U.K.; the 6 Department of Internal Medicine and Yale Center for Clinical Investigation, Yale University School of Medicine, New Haven, Connecticut; and the 7 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Corresponding author: David. M. Nathan, firstname.lastname@example.org.. This article is being simultaneously published in 2008 by Diabetes Care and Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes. An American Diabetes Association consensus statement represents the authors? collective analysis, evalua- tion, and opinion at the time of publication and does not represent official association opinion. DOI: 10.2337/dc08-9025 © 2008 by the American Diabetes Association and Springer. Copying with attribution allowed for any non-commercial use of the work. Reviews/Commentaries/ADA Statements CONSENSUS STATEMENT DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 1 the literature must also be supplemented by value judgements, where the benefits oftreatmentareweighedagainstrisksand 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-termmicrovascularandneuropathic complications. The most appropriate tar- get levels for blood glucose, on a day-to- daybasis,andA1C,asanindexofchronic glycemia, have not been systematically studied.However,boththeDCCT(4)and the UKPDS (6,7) had as their goals the achievement of glycemic levels in the nondiabeticrange.Neitherstudywasable to maintain A1C levels in the nondiabetic range in their intensive treatment groups, achieving mean levels over time of H110117%, which is 4 SDs above the nondiabetic mean. Themostrecentglycemicgoalrecom- 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 ofH110217% (1). The most recent glycemic goal set by the International Di- abetes Federation is an A1C level of H110216.5%. The upper limit of the nondia- betic range is 6.1% (mean H11006 SD. A1C level of 5H110062%) with the DCCT/UKPDS- standardized assay, which has been pro- mulgated through the National Glycohemoglobin Standardization Pro- gram(NGSP)andadoptedbythevastma- jority of commercially available assays (20). Several recent clinical trials have aimed for A1C levels H113496.5% with a vari- etyofinterventions(11,12).Theresultsof theActiontoControlCardiovascularRisk in Diabetes (ACCORD) study, which had the primary objective of decreasing CVD with interventions aimed at achieving an A1C level of H110216.0% vs. interventions aimed at achieving an A1C level of H110217.9%, 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.OurconsensusisthatanA1Clevel ofH113507% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level of H110217%. We are mindful that this goal is not appropriate or practical for some patients, and clinical judgementbasedonthepotentialbenefits 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 topublishedguidelinesforadiscussionof 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 withregardtoeffectsoncomplications.In other words, the salutary effects of ther- apyonlong-termcomplicationsappearto 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.TheUKPDScomparedthreeclasses of glucose-lowering medications (sulfo- nylurea, metformin, or insulin) but was unabletodemonstrateclearsuperiorityof any one drug over the others with regard todiabetescomplications(6,7).However, the different classes do have variable ef- fectiveness in decreasing glycemic levels (Table 1), and the overarching principle in selecting a particular intervention will be its ability to achieve and maintain gly- cemic goals. In addition to their inten- tion-to-treat analyses demonstrating the superiority of intensive versus conven- tional interventions, the DCCT and UKPDS demonstrated a strong correla- tion between mean A1C levels over time and the development and progression of retinopathy and nephropathy (23,24). Therefore, we think it is reasonable to judge and compare blood glucose? lowering medications, as well as combi- nations of such agents, primarily on the basis of their capacity to decrease and maintain A1C levels and according to their safety, specific side effects, tolerabil- ity, ease of use, and expense. Nonglycemic effects of medications In addition to variable effects on glyce- mia, specific effects of individual thera- pies on CVD risk factors, such as hypertension or dyslipidemia, were also considered important. We also included the effects of interventions that may ben- efit or worsen the prospects for long-term glycemic control in our recommenda- tions. Examples of these would be changes in body mass, insulin resistance, or insulin secretory capacity in type 2 di- abetic patients. Choosing specific diabetes interventions and their roles in treating type 2 diabetes Numerous reviews have focused on the characteristics of the specific diabetes in- terventions listed below (25?34). In addi- tion, meta-analyses and reviews have summarized and compared the glucose- lowering effectiveness and other charac- teristics of the medications (35?37). The aim here is to provide enough informa- tion to justify the choices of medications, the order in which they are recom- mended, and the use of combinations of therapies. Unfortunately, there is a dearth of high-quality studies that provide head- to-head comparisons of the ability of the medications to achieve the currently rec- ommended glycemic levels. The authors Nathan and Associates 2 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 highly recommend that such studies be conducted. However, even in the absence of rigorous, comprehensive studies that directly compare the efficacy of all avail- able glucose-lowering treatments and their combinations, we feel that there are enough data regarding the characteristics of the individual interventions to provide the guidelines below. An important intervention that is likely to improve the probability that a patient will have better long-term control of diabetes is to make the diagnosis early, when the metabolic abnormalities of dia- betes are usually less severe. Lower levels of glycemia at the time of initial therapy are associated with lower A1C levels over time and decreased long-term complica- tions (38). Lifestyle interventions The major environmental factors that in- crease the risk of type 2 diabetes are over- nutrition and a sedentary lifestyle, with consequent overweight and obesity (39,40). Not surprisingly, interventions that reverse or improve these factors have been demonstrated to have a beneficial effect on control of glycemia in estab- lished type 2 diabetes (41). Unfortu- nately, the high rate of weight regain has limited the role of lifestyle interventions as an effective means of controlling glyce- mia in the long term. The most convinc- ing long-term data indicating that weight loss effectively lowers glycemia have been generated in the follow-up of type 2 dia- betic patients who have had bariatric sur- gery. In this setting, with a mean sustained weight loss ofH1102220 kg, diabetes is virtually eliminated (42?45). In addi- tion to the beneficial effects of weight loss on glycemia, weight loss and exercise im- prove coincident CVD risk factors, such as blood pressure and atherogenic lipid profiles, and ameliorate other conse- quences of obesity (41,46,47). There are few adverse consequences of such life- Table 1?Summary of glucose-lowering interventions Intervention Expected decrease in A1C with monotherapy (%) Advantages Disadvantages Tier 1: well-validated core Step 1: initial therapy Lifestyle to decrease weight and increase activity 1.0?2.0 Broad benefits Insufficient for most within first year Metformin 1.0?2.0 Weight neutral GI side effects, contraindicated with renal insufficiency Step 2: additional therapy Insulin 1.5?3.5 No dose limit, rapidly effective, improved lipid profile One to four injections daily, monitoring, weight gain, hypoglycemia, analogues are expensive Sulfonylurea 1.0?2.0 Rapidly effective Weight gain, hypoglycemia (especially with glibenclamide or chlorpropamide) Tier 2: less well validated TZDs 0.5?1.4 Improved lipid profile (pioglitazone), potential decrease in MI (pioglitazone) Fluid retention, CHF, weight gain, bone fractures, expensive, potential increase in MI (rosiglitazone) GLP-1 agonist 0.5?1.0 Weight loss Two injections daily, frequent GI side effects, long-term safety not established, expensive Other therapy H9251-Glucosidase inhibitor 0.5?0.8 Weight neutral Frequent GI side effects, three times/day dosing, expensive Glinide 0.5?1.5 a 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. Consensus Statement DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 3 style interventions other than difficulty in incorporating them into usual lifestyle and sustaining them and the usually mi- nor musculoskeletal injuries and poten- tialproblemsassociatedwithneuropathy, such as foot trauma and ulcers, that may occurasaresultofincreasedactivity.The- oretically, effective weight loss, with its pleiotropic benefits, safety profile, and lowcost,shouldbethemostcost-effective means of controlling diabetes?if it could be achieved and maintained over the long term. Given these beneficial effects, which areusuallyseenrapidly?withinweeksto 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 ofdiabetesmanagement.Weightlossofas little as 4 kg will often ameliorate hyper- glycemia.However,thelimitedlong-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- nessofindividualtherapiesandcombina- 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. Amajorfactorinselectingaclassofdrugs, 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 H110228.5%), 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., A1CH110217.5%),medicationswithlesserpo- 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 characteristicsofregimens,includingside effects, tolerability, ease of use, long-term adherence,expense,andthenonglycemic effectsofthemedications.Type2diabetes is a progressive disease characterized by worseningglycemia;higherdosesandad- 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 H110111.5 percentage points (27,49).Itisgenerallywelltolerated,with the most common adverse effects being gastrointestinal. Metformin monotherapy isnotusuallyaccompaniedbyhypoglyce- mia and has been used safely, without causing hypoglycemia, in patients with prediabetic hyperglycemia (50). Met- formin interferes with vitamin B 12 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 estimatedglomerularfiltrationratefallsto H1102130 ml/min (52). Sulfonylureas. Sulfonylureas lower gly- cemia by enhancing insulin secretion. In termsofefficacy,theyappeartobesimilar to metformin, lowering A1C levels by H110111.5 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 H110112 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 H110111.5 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,thanwithsomesulfonylureas (58,59). H9251-Glucosidase inhibitors. H9251-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,increaseddeliveryofcarbo- hydrate to the colon commonly results in increased gas production and gastrointes- tinalsymptoms.Inclinicaltrials,25?45% of participants have discontinued H9251-glu- cosidase inhibitor use as a result of this side effect (29,60). Oneclinicaltrialexaminingacarboseas 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 Nathan and Associates 4 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 (60).ThispotentialbenefitofH9251-glucosidase inhibitors needs to be confirmed. Thiazolidinediones. Thiazolidinedio- nes (TZDs or glitazones) are peroxisome proliferator?activatedreceptorH9253modula- 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 gainandfluidretention,withperipheral 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 arebothassociatedwithincreasedrisksof 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 notoccur.Relativelylargedosesofinsulin (H113501 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 thetargetlevel.Althoughinitialtherapyis aimed at increasing basal insulin supply, usuallywithintermediate-orlong-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 H110112?4 kg, which is probablyproportionaltothecorrectionof 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.Inclinicaltrialsaimedatnormo- glycemia and achieving a mean A1C of H110117%, 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 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 H9252-cell and augments glucose- mediatedinsulinsecretion(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).Exenatidealsosuppresses 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 H110112?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- lintideisasyntheticanalogueoftheH9252-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 gastrointestinal in nature. H1101130% of 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 isH110111?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. Consensus Statement DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 5 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. a Premixed 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. Nathan and Associates 6 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 Dipeptidyl peptidase four inhibitors. GLP-1 and glucose-dependent insulino- tropic peptide (GIP), the main insulino- tropic peptides of intestinal origin (incretins), are rapidly degraded by dipeptidylpeptidasefour(DPP-4).DPP-4 is a member of a family of cell membrane proteins that are expressed in many tis- sues, including immune cells (34). DPP-4 inhibitors are small molecules that en- hance the effects of GLP-1 and GIP, in- creasing glucose-mediated insulin secretion and suppressing glucagon se- cretion (83,84). The first oral DPP-4 in- hibitor, sitagliptin, was approved by the Food and Drug Administration in Octo- ber 2006 for use as monotherapy or in combination with metformin or TZDs. Another DPP-4 inhibitor, vildagliptin, was approved in Europe in February 2008, and several other compounds are under development. In clinical trials per- formed to date, DPP-4 inhibitors lower A1Clevels by 0.6?0.9 percentage points and are weight neutral and relatively well tolerated (83,84). They do not cause hy- poglycemia when used as monotherapy. A fixed-dose combination pill with met- formin is available. The potential for this class of compounds to interfere with im- mune function is of concern; an increase in upper respiratory infections has been reported (34). How to initiate diabetes therapy and advance interventions Except in rare circumstances, such as dia- betic ketoacidosis or patients who are ex- tremely catabolic or hyperosmolar or who are unable to hydrate themselves ade- quately (see SPECIAL CONSIDERATIONS/PATIENTS below), hospitalization is not required for initiation or adjustment of therapy. The pa- tient is the key player in the diabetes care team and should be trained and empow- ered to adjust medications with the guid- ance of health care professionals to achieve glycemic goals and to prevent and treat hy- poglycemia. Many patients may be man- aged effectively with monotherapy; however, the progressive nature of the dis- ease will require the use of combination therapy in many, if not most, patients 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 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 (85) and are de- pendent on the medications used. Oral glucose-loweringregimensthatdonotin- clude sulfonylureas or glinides, and are therefore not likely to cause hypoglyce- mia, usually do not require SMBG (86). However, SMBG may be used to deter- mine whether therapeutic blood glucose targets are being achieved and for adjust- mentoftreatmentregimenswithoutrequir- ing the patient to have laboratory-based blood glucose testing. Insulin therapy re- quires more frequent monitoring. The levels of plasma or capillary glu- cose (most meters that measure finger- stick capillary samples are adjusted to provide values equivalent to plasma glu- cose) that should result in long-term gly- cemia in the nondiabetic target range, as measured by A1C, are fasting and pre- prandial levels between 3.9 and 7.2 mmol/l (70 and 130 mg/dl). If A1C levels remain above the desired target despite preprandial levels that are in range, post- prandiallevels,usuallymeasured90?120 min after a meal, may be checked. They should be H1102110 mmol/l (180 mg/dl) to achieve A1C levels in the target range. Attempts to achieve target glycemic levels with regimens including sulfonyl- ureas or insulin may be associated with modesthypoglycemia,withglucoselevels in the 3.1?3.9 mmol/l (55?70 mg/dl) range. These episodes are generally well tolerated, easily treated with oral carbo- hydrate such as glucose tablets or 120? 180 ml (4?6 oz) of juice or nondiet soda, and rarely progress to more severe hypo- glycemia, including loss of consciousness or seizures. Algorithm The algorithm (Fig. 2) takes into account the characteristics of the individual inter- ventions, their synergies, and expense. The goal is to achieve and maintain A1C levels of H110217% and to change interven- tions at as rapid a pace as titration of med- icationsallowswhentargetglycemicgoals are not being achieved. Mounting evi- dencesuggeststhataggressiveloweringof glycemia, especially with insulin therapy, in newly diagnosed diabetes can result in sustained remissions, i.e., normoglyce- mia without need for glucose-lowering medications (87,88). Type 2 diabetes is a progressive disease (89), and patients should be informed that they are likely to require the addition of glucose-lowering medications over time. The amylin agonists, H9251-glucosidase inhibitors, glinides, and DPP-4 inhibitors are not included in the two tiers of pre- ferred agents in this algorithm, owing to their lower or equivalent overall glucose- lowering effectiveness compared with the first- and second-tier agents and/or to their limited clinical data or relative ex- pense (Table 1). However, they may be appropriate choices in selected patients. Tier 1: well-validated core therapies These interventions represent the best es- tablished and most effective and cost- effective therapeutic strategy for achieving the target glycemic goals. The tier one algo- rithm is the preferred route of therapy for most patients with type 2 diabetes. Step 1: lifestyle intervention and met- formin. Based on the numerous demon- strated short- and long-term benefits that accrue when weight loss and increased levels of activity are achieved and main- tained, as well as the cost-effectiveness of lifestyle interventions when they succeed, TITRATION OF METFORMIN 1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day. 2. After 5?7 days, if gastrointestinal side effects have not occurred, advance dose to 850, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner). 3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time. 4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used. 5. Based on cost considerations, generic metformin is the first choice of therapy. A longer-acting formulation is available in some countries and can be given once per day. Consensus Statement DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 7 the consensus is that lifestyle interven- tionsshouldbeinitiatedasthefirststepin treating new-onset type 2 diabetes (Fig. 2). These interventions should be imple- mented by health care professionals with appropriate training?usually registered dietitians experienced in behavioral mod- ification?and be sensitive to ethnic and cultural differences among populations. Moreover, lifestyle interventions to im- prove glucose, blood pressure, and lipid levels, and to promote weight loss or at least avoid weight gain, should remain an underlying theme throughout the man- agement of type 2 diabetes, even after medications are used. For the 10?20% of patients with type 2 diabetes who are not obese or overweight, modification of di- etary composition and activity levels may play a supporting role, but medications are still generally required early in the course of diabetes (see SPECIAL CONSIDER- ATIONS/PATIENTS below). The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain the metabolic goals either because of fail- uretoloseweight,weightregain,progres- sive disease, or a combination of factors. Therefore, our consensus is that met- formin therapy should be initiated con- currently with lifestyle intervention at diagnosis. Metformin is recommended as theinitialpharmacologicaltherapy,inthe absence of specific contraindications, for its effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost. Metformin treat- ment should be titrated to its maximally effective dose over 1?2 months, as toler- ated (see text box, entitled Titration of Metformin). Rapid addition of other glu- cose-lowering medications should be considered in the setting of persistent symptomatic hyperglycemia. Step 2: addition of a second medica- tion. If lifestyle intervention and the maximal tolerated dose of metformin fail to achieve or sustain the glycemic goals, another medication should be added within 2?3 months of the initiation of therapy or at any time when the target A1C level is not achieved. Another medi- cation may also be necessary if metformin is contraindicated or not tolerated. The consensus regarding the second medica- tion added to metformin was to choose eitherinsulinorasulfonylurea(Fig.2).As discussed above, the A1C level will deter- mine in part which agent is selected next, with consideration given to the more ef- fective glycemia-lowering agent, insulin, for patients with an A1C level of H110228.5% or with symptoms secondary to ehyper- glycemia. Insulin can be initiated with a basal (intermediate- or long-acting) insu- lin (see Fig. 1 for suggested initial insulin regimens)(90).However,manynewlydi- agnosed type 2 diabetic patients will usu- 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,orintensify,insulintherapy(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 can be considered, especially if the A1C level is close to target (A1C H110218.0%), this approach is usually not preferred, as it is no more effective in lowering glycemia, and is more costly, than initiating or in- tensifying insulin (91). Tier 2: less well-validated therapies In selected clinical settings, this second- tier algorithm may be considered. Specif- ically, when hypoglycemia is particularly undesirable (e.g., in patients who have hazardousjobs),theadditionofexenatide or pioglitazone may be considered. Rosi- glitazone is not recommended. If promo- tion of weight loss is a major consideration andtheA1Clevelisclosetotarget(H110218.0%), exenatideisanoption.Iftheseinterventions are not effective in achieving target A1C, or are not tolerated, addition of a sulfonylurea could be considered. Alternatively, the tier two interventions should be stopped and basal insulin started. Rationale for selecting specific combinations More than one medication will be neces- sary for the majority of patients over time. Selection of the individual agents should be made on the basis of their glucose- lowering effectiveness and other charac- teristics listed in Table 1. However, when adding second antihyperglycemic medi- cations, the synergy of particular combi- nations and other interactions should be considered. In general, antihyperglyce- mic drugs with different mechanisms of action will have the greatest synergy. In- sulin plus metformin (92) is a particularly effective means of lowering glycemia while limiting weight gain. Figure 2?Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle inter- ventions at every visit and check A1C every 3 months until A1C isH110217% and then at least every 6 months. The interventions should be changed if A1C is H113507%. a Sulfonylureas other than glyben- clamide (glyburide) or chlorpropamide. b Insufficient clinical use to be confident regarding safety. See text box, entitled TITRATION OF METFORMIN. See Fig. 1 for initiation and adjustment of insulin. CHF, congestive heart failure. Nathan and Associates 8 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 Special considerations/patients In the setting of severely uncontrolled di- abetes with catabolism, defined as fasting plasma glucose levelsH1102213.9 mmol/l (250 mg/dl), random glucose levels consis- tently above 16.7 mmol/l (300 mg/dl), A1C above 10%, or the presence of keto- nuria, or as symptomatic diabetes with polyuria, polydipsia and weight loss, in- sulin therapy in combination with life- style intervention is the treatment of choice. Some patients with these charac- teristics will have unrecognized type 1 di- abetes; others will have type 2 diabetes withsevereinsulindeficiency.Insulincan be titrated rapidly and is associated with the greatest likelihood of returning glu- cose levels rapidly to target levels. After symptoms are relieved and glucose levels decreased, oral agents can often be added and it may be possible to withdraw insu- lin, if preferred. Conclusions Type 2 diabetes is epidemic. Its long-term consequences translate into enormous human suffering and economic costs; however, much of the morbidity associ- ated with long-term microvascular and neuropathic complications can be sub- stantially reduced by interventions that achieve glucose levels close to the nondi- abetic range. Although new classes of medications and numerous combinations have been demonstrated to lower glyce- mia, current-day management has failed to achieve and maintain the glycemic lev- els most likely to provide optimal health- care status for people with diabetes. Summary The guidelines and treatment algorithm presented here emphasize the following: ? Achievement and maintenance of near normoglycaemia (A1C H110217.0%) ? Initial therapy with lifestyle interven- tion and metformin ? Rapid addition of medications, and transitiontonewregimens,whentarget glycemic goals are not achieved or sus- tained ? Early addition of insulin therapy in pa- tients who do not meet target goals Duality of interest D.M.N. has received a research grant for investigator-initiatedresearchfromsanofi aventis and support for educational pro- grams from GlaxoSmithKline. J.B.B. has conducted research and/or served on ad- visory boards under contract between the University of North Carolina and Amylin, Becton Dickinson, Bristol-Myers Squibb, Hoffman-LaRoche, Eli Lilly, GlaxoSmith- Kline, Novo Nordisk, Merck, Novartis, Pfizer, and sanofi aventis. M.B.D. has re- ceived research support from Eli Lilly, Merck, and Pfizer; has served on advisory boards for Amylin, GlaxoSmithKline, Merck, and sanofi aventis; and has been on speakers bureaus for Amylin, Eli Lilly, GlaxoSmithKline, and Pfizer. E.F. has received research support from Astra Zeneca,MerckSharpe&Dohme,andNo- vartis and serves on scientific advisory boards for Amylin, AstraZeneca, Glaxo- SmithKline, Roche, Merck Sharpe & Dohme, Novartis, Servier, sanofi aventis, Boehringer Ingelheim, and Takeda. R.R.H. has received research support from Bristol-Myers Squibb, GlaxoSmith- Kline,MerckSante,NovoNordisk,Pfizer, and Pronova and has served on advisory boards and/or received honoraria for speaking engagements from Amylin, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, and sanofi aventis. R.S. hasservedonadvisoryboardsforAmylin, Astra Zeneca, Boehringer Ingelheim, Di- Obex, Eli Lilly, Insulet, Merck, Mann- Kind, and Novartis. B.Z. has received research support from GlaxoSmithKline, Merck, Novartis, and Novo Nordisk and has been a member of scientific advisory boards and/or received honoraria for speaking engagements from Amylin, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, sanofi aventis, and Servier. 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