Diabetes Care Volume 40, December 2017 1 Gina Agiostratidou,1 Henry Anhalt,2 Standardizing Clinically Dana Ball,2 Lawrence Blonde,3 Evgenia Gourgari,4 Karen N. Harriman,5 Meaningful Outcome Measures Aaron J. Kowalski,6 Paul Madden,7 Alicia H. McAuliffe-Fogarty,7 Beyond HbA1c for Type 1 Diabetes: Molly McElwee-Malloy,5 Anne Peters,4 Sripriya Raman,3 Kent Reifschneider,8 A Consensus Statement of the Karen Rubin,8 and Stuart A. Weinzimer8 American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, CONSENSUS REPORTS the Endocrine Society, JDRF International, The Leona M. and HarryB.HelmsleyCharitable Trust, the Pediatric Endocrine Society, and the T1D Exchange Diabetes Care 2017;40:1–9 | https://doi.org/10.2337/dc17-1624 OBJECTIVE To identify and define clinically meaningful type 1 diabetes outcomes beyond he- 1The Leona M. and Harry B. Helmsley Charitable moglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical Trust, New York, NY experts, and input from researchers, people with type 1 diabetes, and industry. 2T1D Exchange, Boston, MA Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic 3American Association of Clinical Endocrinolo- ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes gists, Jacksonville, FL 4Endocrine Society, Washington, DC for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this 5American Association of Diabetes Educators, work. Chicago, IL 6JDRF International, New York, NY RESEARCH AND METHODS 7American Diabetes Association, Arlington, VA 8 ASteeringCommitteedcomprising representatives from the American Association Pediatric Endocrine Society, McLean, VA of Clinical Endocrinologists, the American Association of Diabetes Educators, the Corresponding author: Aaron J. Kowalski, akowalski@ jdrf.org. American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. This article contains Supplementary Data online and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the at http://care.diabetesjournals.org/lookup/ T1D Exchangedwas the decision-making body for the Type 1 Diabetes Outcomes suppl/doi:10.2337/dc17-1624/-/DC1. Program. Their work was informed by input from researchers, industry, and people © 2017 by the American Diabetes Association. with diabetes through Advisory Committees representing each stakeholder group. Readers may use this article as long as the work Stakeholder surveys were used to identify priority outcomes. The outcomes priori- is properly cited, the use is educational and not for profit, and the work is not altered. More infor- tized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and mation is available at http://www.diabetesjournals PROs. To develop consensus on the definitions of these outcomes, the Steering .org/content/license. Committee relied on published evidence, their clinical expertise, and feedback from See accompanying articles, pp. XXX, the Advisory Committees. XXX, XXX, XXX, XXX, XXX, and XXX. 2 Consensus Report Diabetes Care Volume 40, December 2017 RESULTS definition of population health outcomes, and surveys of Advisory Committee mem- The Steering Committee developed defi- defined as a population’s dynamic state bers also informed discussions of outcome nitions for hypoglycemia, hyperglycemia, of physical, mental, and social well-being definitions. JDRF paid the expenses for this time in range, and DKA in type 1 diabetes. (7). While HbA1c is used as a primary out- group, including teleconferences, travel The definitions reflect their assessment come to assess glycemic control and as a expenses, and consulting services to facil- surrogate for risk of developing complica- itate group discussion, funded in part by a of the outcome’s short- and long-term tions, it has limitations. As a measure of grant from The Leona M. and Harry B. clinical impact on people with type 1 di- mean blood glucose over 2 or 3 months, Helmsley Charitable Trust. A draft consen- abetes. Knowledge gaps to be addressed HbA does not capture short-term va- sus statement was posted on JDRF’s web- fi 1c by future research were identi ed. The riations in blood glucose or exposure to site for 30 days in March 2017 to allow for Steering Committee discussed PROs and hypoglycemia and hyperglycemia in indi- public comments. concluded that further type 1 diabetes– viduals with type 1 diabetes; HbA1c also The outcomes prioritized under the specific development is needed. does not capture the impact of blood glu- program include hypoglycemia, hypergly- cose variations on individuals’ quality of cemia, time in range, diabetic ketoacido- CONCLUSIONS life. Recent advances in type 1 diabetes sis (DKA), and patient-reported outcomes The Steering Committee recommends technologies have made it feasible to as- (PROs). The Steering Committee, with in- fi use of the de ned clinically meaningful sess the efficacy of therapies and technol- put from the Advisory Committees, came outcomes beyond HbA1c in the research, ogies using a set of outcomes beyond to consensus on standardized definitions development, and evaluation of type 1 HbA1c and to expand definitions of out- for each outcome based on published ev- diabetes therapies. comes such as hypoglycemia. While defi- idence and their expert opinion (or, in the nitions for hypoglycemia in clinical care case of PROs, a consensus that further type – fi Type 1 diabetes is a life-threatening, au- exist, they have not been standardized 1diabetesspeci cPROdevelopment toimmune disease that strikes children among organizations and there is incon- was needed). The focus for this program fi and adults and can be fatal. People with sistency in the de nitions used in differ- was type 1 diabetes, although the litera- Q:4 type 1 diabetes have to test their blood ent research studies. The lack of standard ture reviewed included data from people fi glucose multiple times each day and dose de nitions impedes and can confuse their without diabetes and with type 2 diabe- insulin via injections or an infusion pump use in clinical practice, impedes devel- tes to support the consensus statement. opment processes for new therapies, 24 h a day every day. Too much insulin A parallel article published in this issue of makes comparison of studies in the liter- Diabetes Care focuses more broadly on di- canresultinhypoglycemia,seizures, ature challenging, and may lead to regu- abetes, and it is notable that the definitions coma, or death. Hyperglycemia over time latory and reimbursement decisions that reached are the same for both groups (8). leads to kidney, heart, nerve, and eye fail to meet the needs of people with The immediate goal of the Type 1 Di- damage. Even with diligent monitoring, diabetes. abetes Outcomes Program was to identify the majority of people with type 1 diabe- Toaddressthisvitalissue,thetype1 and provide standardized definitions for tes do not achieve recommended target diabetes–stakeholder community launched an expanded set of clinical outcomes for glucose levels. In the U.S., approximately theType1DiabetesOutcomesProgram research aimed at the development and one in five children and one in three adults to develop consensus definitions for a set evaluation of new diabetes therapies and meet hemoglobin A (HbA ) targets and 1c 1c of priority outcomes for type 1 diabetes. A technologies. It is not our expectation for the average patient spends 7 h a day hy- Steering Committeedcomprising repre- any of the outcomes defined in this doc- perglycemic and over 90 min hypoglyce- sentatives from the American Association ument to replace HbA , as it remains an – 1c mic (1 3). The disease burden of type 1 of Clinical Endocrinologists (AACE), the important outcome measure, but rather diabetes can negatively impact quality of American Association of Diabetes Educa- that they supplement its utility and to al- fi Q:1 life, including nances and careers. Inad- tors (AADE), the American Diabetes Asso- low for the capture of a more comprehen- dition, the stress on and amount of time ciation (ADA), the Endocrine Society, JDRF sive understanding of how interventions required of caregivers, including parents International, The Leona M. and Harry B. might influence people with diabetes. The Q:5 and children caring for aging parents liv- Helmsley Charitable Trust, the Pediat- goal of the program is to ensure that de- ing with type 1 diabetes, also burdens the ric Endocrine Society (PES), and the fined outcomes are included as primary entire family. There remains significant T1D Exchangedwas the decision-making and secondary end points in type 1 diabe- roomfor furtherimprovementinthether- body for the Type 1 Diabetes Outcomes tes research for development and evalu- apies and technologies designed to treat Program. The work of the Steering Com- ation of future therapies. Q:2 and assist in the management of this dis- mittee was informed by diabetes re- For each outcome, the Steering Commit- ease and prevent its life-threatening searchers, industry, and people with tee was asked to ensure that the consensus complications. diabetes through Advisory Committees definition met the following criteria: HbA1c is a well-accepted surrogate out- representing each stakeholder group come measure for evaluating the efficacy (Supplementary Data). The Steering Com- c Clinically meaningful Q:3 of diabetes therapies and technologies in mittee met for distinct in-person meet- c Applicable to the nonpregnant popula-