2008糖尿病诊治新指南

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes DAVID M. NATHAN, MD1 JOHN B. BUSE, MD, PHD2 MAYER B. DAVIDSON, MD3 ELE FERRANNINI, MD4 RURY R. HOLMAN, FRCP5 ROBERT SHERWIN, MD6 BERNARD ZINMAN, MD7 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. Diabetes Care 31:1–11, 2008 The epidemic of type 2 diabetes andthe 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 associatedwith 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 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 onCVD in type 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).Althoughnumerous re- views on themanagement of type2diabetes 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 themanagement 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 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 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 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. 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 DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008 1 Diabetes Care Publish Ahead of Print, published online October 22, 2008 Copyright American Diabetes Association, Inc., 2008 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-termmicrovascular 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 theDCCT (4) and the UKPDS (6,7) had as their goals the achievement of glycemic levels in the nondiabetic range. Neither studywas 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. Themost recent glycemic goal recom- mended by the American Diabetes Asso- ciat ion, selected on the basis of practicality and the projected reduction in complications over time, is, in general, an A1C level of�7% (1). Themost 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- mulga t ed through the Nat iona l Glycohemoglobin Standardization Pro- gram (NGSP) and adopted by the vastma- jority of commercially available assays (20). Several recent clinical trials have aimed for A1C levels �6.5% 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 CVDmortality 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�7% 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 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 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- 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 �-Glucosidase inhibitor 0.5–0.8 Weight neutral Frequent GI side effects, three times/day dosing, expensive Glinide 0.5–1.5a Rapidly effective Weight gain, three times/day dosing, hypoglycemia, expensive Pramlintide 0.5–1.0 Weight loss Three injections daily, frequent GI side effects, long-term safety not established, expensive DPP-4 inhibitor 0.5–0.8 Weight neutral Long-term safety not established, expensive aRepaglinide 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- 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 themost 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 diabetesmanagement.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. Amajor 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 themedications. 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 a