2013年ADA低血糖和糖尿病共识

Hypoglycemia and Diabetes: A Report of aWorkgroup of the American Diabetes Association and The Endocrine Society ELIZABETH R. SEAQUIST, MD1 JOHN ANDERSON, MD2 BELINDA CHILDS, ARNP, MN, BC-ADM, CDE3 PHILIP CRYER, MD4 SAMUEL DAGOGO-JACK, MD, MBBS, MSC5 LISA FISH, MD6 SIMON R. HELLER, MD7 HENRY RODRIGUEZ, MD8 JAMES ROSENZWEIG, MD9 ROBERT VIGERSKY, MD10 OBJECTIVEdTo review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTSdFive members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. Theworkgroupmeeting was supported by educational grants to the AmericanDiabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association fromSanofi. The sponsors hadno input into the development of or content of the report. EVIDENCEdThe writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESSdConsensus was achieved by group discussion during confer- ence calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONSdThe workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future re- search. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided. In 2005, the American Diabetes Asso-ciation Workgroup on Hypoglycemiareleased a report entitled “Defining and Reporting Hypoglycemia in Diabetes” (1). In that report, recommendations were primarily made to advise the U.S. Food and Drug Administration (FDA) on how hypoglycemia should be used as an end point in studies of new treatments for di- abetes. In 2009, The Endocrine Society released a clinical practice guideline enti- tled “Evaluation and Management of Adult Hypoglycemic Disorders,” which summarized how clinicians should man- age hypoglycemia in patients with diabe- tes (2). Since then, new evidence has become available that links hypoglycemia with adverse outcomes in older patients with type 2 diabetes (3–6) and in children with type 1 diabetes (7,8). To provide guidance about how this new information should be incorporated into clinical prac- tice, the American Diabetes Association and The Endocrine Society assembled a new Workgroup on Hypoglycemia in April 2012 to address the following ques- tions: 1. How should hypoglycemia in diabetes be defined and reported? 2. What are the implications of hypo- glycemia on both short- and long-term outcomes in people with diabetes? 3. What are the implications of hypo- glycemia on treatment targets for pa- tients with diabetes? c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c From the 1Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 2The Frist Clinic, Nashville, Tennessee; 3Mid-America Di- abetes Associates, Wichita, Kansas; the 4Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, Saint Louis, Missouri; the 5Division of Endocrinology, Diabetes andMetabolism, University of Tennessee Health Science Center, Memphis, Tennessee, 6Diabetes, Metabolism and Endocrinology/ Internal Medicine, Park Nicollet Clinic, Saint Louis Park, Minnesota; the 7Academic Unit of Diabetes, Endocrinology and Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, U.K.; the 8Diabetes Center, University of South Florida College of Medicine, Tampa, Florida; 9Diabetes Services, Boston Med- ical Center, Boston University School of Medicine, Boston, Massachusetts; and the 10Diabetes In- stitute, Walter Reed National Military Medical Center, Bethesda, Maryland. Corresponding author: ElizabethR. Seaquist, seaqu001@ umn.edu. DOI: 10.2337/dc12-2480 This report was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and ap- proved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. This article has been copublished in the Journal of Clinical Endocrinology & Metabolism. A slide set summarizing this article is available online. © 2013 by the American Diabetes Association and The Endocrine Society. Readers may use this ar- ticle as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ licenses/by-nc-nd/3.0/ for details. care.diabetesjournals.org DIABETES CARE 1 C O N S E N S U S R E P O R T Diabetes Care Publish Ahead of Print, published online April 15, 2013 4. What strategies are known to prevent hypoglycemia, and what are the clini- cal recommendations for those at risk for hypoglycemia? 5. What are the current knowledge gaps in our understanding of hypoglyce- mia, and what research is necessary to fill these gaps? How should hypoglycemia in diabetes be defined and reported?dHypoglycemia puts pa- tients at risk for injury and death. Conse- quently the workgroup defines iatrogenic hypoglycemia in patients with diabetes as all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm. A single threshold value for plasma glucose concen- tration that defines hypoglycemia in diabe- tes cannot be assigned because glycemic thresholds for symptoms of hypoglycemia (among other responses) shift to lower plasma glucose concentrations after recent antecedent hypoglycemia (9–12) and to higher plasma glucose concentrations in pa- tients with poorly controlled diabetes and infrequent hypoglycemia (13). Nonetheless, an alert value can be defined that draws the attention of both patients and caregivers to the potential harm associated with hypoglycemia. The workgroup (1) suggests that patients at risk for hypoglycemia (i.e., those treated with a sulfonylurea, glinide, or insulin) should be alert to the possibility of devel- oping hypoglycemia at a self-monitored plasma glucosedor continuous glucose monitoring subcutaneous glucosed concentration of #70 mg/dL (#3.9 mmol/L). This alert value is data driven and pragmatic (14). Given the limited accuracy of the monitoring devices, it ap- proximates the lower limit of the normal postabsorptive plasma glucose concentra- tion (15), the glycemic thresholds for acti- vation of glucose counterregulatory systems in nondiabetic individuals (15), and the upper limit of plasma glucose level reported to reduce counterregulatory re- sponses to subsequent hypoglycemia (11). Because it is higher than the glycemic threshold for symptoms in both non- diabetic individuals and those with well- controlled diabetes (9,13,14), it generally allows time to prevent a clinical hypoglyce- mic episode and provides some margin for the limited accuracy of monitoring devices at low-glucose levels. People with diabetes need not always self-treat at an estimated glucose concentration of #70 mg/dL (#3.9 mmol/L). Options other than carbohydrate ingestion include repeating the test in the short term, changing behavior (e.g., avoidingdrivingor elective exercise un- til the glucose level is higher), and adjusting the treatment regimen. Although this alert value has been debated (9,13,14), a plas- ma concentration of #70 mg/dL (#3.9 mmol/L) can be used as a cut-off value in the classificationof hypoglycemia indiabetes. Consistent with past recommenda- tions (1), the workgroup suggests the fol- lowing classification of hypoglycemia in diabetes: 1) Severe hypoglycemia. Severe hypo- glycemia is an event requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose con- centrations may not be available during an event, but neurological recovery fol- lowing the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. 2) Documented symptomatic hypogly- cemia. Documented symptomatic hypo- glycemia is an event during which typical symptoms of hypoglycemia are accompa- nied by a measured plasma glucose con- centration #70 mg/dL (#3.9 mmol/L). 3) Asymptomatic hypoglycemia. Asymp- tomatic hypoglycemia is an event not accompanied by typical symptoms of hy- poglycemia but with a measured plasma glucose concentration #70 mg/dL (#3.9 mmol/L). 4) Probable symptomatic hypoglyce- mia. Probable symptomatic hypoglycemia is an event during which symptoms typical of hypoglycemia are not accompanied by a plasma glucose determination but that was presumably caused by a plasma glucose concentration#70mg/dL (#3.9mmol/L). 5) Pseudo-hypoglycemia. Pseudo- hypoglycemia is an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia with a measured plasma glucose concen- tration.70mg/dL (.3.9 mmol/L) but ap- proaching that level. The challenge of measuring glucose accurately Currently, two technologies are available to measure glucose in outpatients: capillary measurement with point-of-care (POC) glucose meters (self-monitored blood glu- cose [SMBG]) and interstitial measure- ment with continuous glucose monitors (CGMs), both retrospective and real time. The International Organization for Stan- dardization (ISO) and FDA standards require that POC meters’ analytical accu- racy be within 20% of the actual value in 95% of samples with glucose levels $75 mg/dL and 615 mg/dL for samples with glucose,75 mg/dL. Despite this rel- atively large permissible variation, Freck- mann et al. (16) found that only 15 of 27 meters on the market in Europe several years ago met the current analytical stand- ards of 615 mg/dL in the hypoglycemia range, 2 of 27 met 610 mg/dL, and none were capable of measuring 65 mg/dL. The need for accurate meters in the ,75 mg/dL range is essential in insulin- treated patients, whether they are outpa- tients or inpatients, but it is less important in those outpatients who are on medica- tions that rarely cause hypoglycemia. In critical care units, where the accuracy of POC meters is particularly crucial, their performance may be compromised by medications (vasopressors, acetamino- phen), treatments (oxygen), and clinical states (hypotension, anemia) (17). Karon et al. (18) translated these measurement errors into potential insulin-dosing errors using simulation modeling and found that if there were a total measurement error of 20%, 1- and 2-step errors in in- sulin dose would occur 45% and 6% of the time, respectively, in a tight glycemic control protocol. Such imprecision may affect the safe implementation of insulin infusion protocols in critical care units and may account in part for the high hy- poglycemia rates in most trials of inpa- tient intensive glycemic control. Retrospective and real-time CGMs represent an evolving technology that has made considerable progress in overall (point1 rate) accuracy. However, the ac- curacy of CGMs in the hypoglycemic range is poor as demonstrated by error grid analysis (19,20). With existing real- time CGMs, accuracy can be achieved in only 60–73% of samples in the range of 40–80 mg/dL (21,22). Because the ac- curacy of CGMs, like POC meters, is neg- atively affected by multiple factors in hospitalized patients and they are cali- brated with POC meters affected by those same factors, CGMs are not recommended for glycemic management in hospitalized patients at this time (17). What are the implications of hypoglycemia on both short- and long-term outcomes in people with diabetes?dIatrogenic hypoglycemia is more frequent in patients with profound endogenous insulin deficiencydtype 2 DIABETES CARE care.diabetesjournals.org Consensus Report 1 diabetes and advanced type 2 diabe- tesdand its incidence increases with the duration of diabetes (23). It is caused by treatment with a sulfonylurea, glinide, or insulin and occurs about two to three times more frequently in type 1 diabetes than in type 2 diabetes (23,24). Event rates for severe hypoglycemia for patients with type 1 diabetes range from 115 (24) to 320 (23) per 100 patient-years. Severe hypo- glycemia in patients with type 2 diabetes has been shown to occur at rates of 35 (24) to 70 (23) per 100 patient-years. However, because type 2 diabetes is much more prevalent than type 1 diabetes, most epi- sodes of hypoglycemia, including severe hypoglycemia, occur in people with type 2 diabetes (25). There is no doubt that hypoglycemia can be fatal (26). In addition to case re- ports of hypoglycemic deaths in patients with type 1 and type 2 diabetes, four re- cent reports of mortality rates in series of patients indicate that 4% (27), 6% (28), 7% (29), and 10% (30) of deaths of pa- tients with type 1 diabetes were caused by hypoglycemia. A temporal relationship between extremely low subcutaneous glucose concentrations and death in a patient with type 1 diabetes who was wearing a CGM device and was found dead in bed has been reported (31). Al- though profound and prolonged hypo- glycemia can cause brain death, most episodes of fatal hypoglycemia are prob- ably the result of other mechanisms, such as ventricular arrhythmias (26). In this section, we will consider the effects of hypoglycemia on the development of hy- poglycemia unawareness and how iatro- genic hypoglycemia may affect outcomes in specific patient groups. Hypoglycemia unawareness and hypoglycemia-associated autonomic failure Acute hypoglycemia in patients with di- abetes can lead to confusion, loss of consciousness, seizures, and even death, but how a particular patient responds to a drop in glucose appears to depend on how frequently that patient experiences hypoglycemia. Recurrent hypoglycemia has been shown to reduce the glucose level that precipitates the counterregulatory response necessary to restore euglycemia during a subsequent episode of hypogly- cemia (10–12). As a result, patients with frequent hypoglycemia do not experience the symptoms from the adrenergic re- sponse to a fall in glucose until the blood glucose reaches lower and lower levels. For some individuals, the level that triggers the response is below the glucose level associ- atedwith neuroglycopenia. The first sign of hypoglycemia in these patients is confu- sion, and they often must rely on the assis- tance of others to recognize and treat low blood glucose. Such individuals are said to have developed hypoglycemia unaware- ness. Defective glucose counterregulation (the result of loss of a decrease in insulin production and an increase in glucagon re- lease along with an attenuated increase in epinephrine) and hypoglycemia unaware- ness (the result of an attenuated increase in sympathoadrenal activity) are the compo- nents of hypoglycemia-associated auto- nomic failure (HAAF) in patients with diabetes.HAAF is a form of functional sym- pathoadrenal failure that is most often caused by recent antecedent iatrogenic hypoglycemia (25) and is at least partly re- versible by scrupulous avoidance of hypo- glycemia (32–34). Indeed, HAAF has been shown to be maintained by recurrent iatro- genic hypoglycemia (33,34). The develop- ment of HAAF is associated with a 25-fold (35) or greater (36) increased risk of severe hypoglycemia during intensive glycemic therapy. It is important to distinguish HAAF from classical autonomic neuro- pathy, which may occur as one form of diabetic neuropathy. Impaired sympathoa- drenal activation is generally confined to the response to hypoglycemia, and auto- nomic activities in organs such as the heart, gastrointestinal tract, and bladder appear to be unaffected. Clinically, HAAF can be viewed as both adaptive and maladaptive. On the one hand, patients with hypoglycemia unawareness and type 1 diabetes appear to perform better on tests of cognitive function during hypoglycemia than do patients who are able to detect hypogly- cemia normally (37). In addition, the time necessary for full cognitive recovery after restoration of euglycemia appears to be faster in patients who have hypoglycemia unawareness than in patients with normal detection of hypoglycemia (37). The HAAF habituation of the sympathoadre- nal response to recurrent hypoglycemic stress in humans (38) may be analogous to the phenomenon of habituation of the hypothalamic-pituitary-adrenocortical response to recurrent restraint stress in rats (39). Rats subjected to recurrent moderate hypoglycemia had less brain cell death (40) and less mortality (41) during or following marked hypoglyce- mia than those not subjected to recurrent hypoglycemia. On the other hand, HAAF is clearly maladaptive since defective glucose coun- terregulation and hypoglycemia un- awareness substantially increase the risk of severe hypoglycemia with its morbidity and potential mortality (26). A particu- larly low plasma glucose concentra- tion might trigger a robust, potentially fatal sympathoadrenal discharge. Life- threatening episodes of hypoglycemia need not be frequent to be devastating. Impact of hypoglycemia on children with diabetes Hypoglycemia is a common problem in children with type 1 diabetes because of the challenges presented by insulin dosing, variable eating patterns, erratic activity, and the limited ability of small children to detect hypoglycemia. The infant, young child, and even the adolescent typically exhibit unpredictable feedingdnot eat- ing all the anticipated food at a meal and snacking unpredictably between mealsdand have prolonged periods of fasting overnight that increase the risk of hypoglycemia. Selecting the correct pran- dial dose of insulin is therefore often diffi- cult. Very low insulin requirements for basal and mealtime dosing in the infant and young child frequently require use of miniscule basal rates in pump therapy and one-half unit dosing increments with injections. Management rarely requires the use of diluted insulin, e.g., 10 units per mL. Infants and toddlers may not rec- ognize the symptoms of hypoglycemia and lack the ability to effectively commu- nicate their distress. Caregivers must be particularly aware that changes in behav- ior such as a loss of tempermay be a sign of hypoglycemia. Puberty is associated with insulin resistance, while at the same time the normal developmental stages of adoles- cence may lead to inattention to diabetes and increased risk for hypoglycemia. As children grow, they often have widely fluctuating levels of activity during the day, which puts them at risk for hypo- glycemia. Minimizing the impact of hy- poglycemia on