Search

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed “remission” as the most appropriate descriptive term, and HbA1c

Chronic metabolic disorders such as diabetes and obesity are major public health issues in the United States. However, significant disparities in their prevalence and incidence place a greater burden on US racial and ethnic minority groups, contributing to worse COVID-19 outcomes in many. Improving treatment and prevention of diabetes and obesity is critical to the NIDDK. In this Perspective, we will review the burden of metabolic diseases in the United States, the observed disparities for metabolic diseases in relation to COVID-19, and research opportunities to address underlying causes of metabolic diseases, their associated health disparities, and COVID-19., Diabetes and obesity are associated with greater COVID-19 severity, and certain racial and ethnic groups bear a disproportionate burden of these metabolic diseases. There is a need to focus on SDOH and truly understand how these factors adversely affect an individual’s health and contribute to increasing prevalence of metabolic diseases.

One hundred years have passed since the discovery of insulin—an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.

The current worldwide pandemic of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause incredible morbidity and mortality on a global level. Presently, there is no effective pharmacologic therapy nor a vaccine to offer. Given the circumstances and mode of transmission, the coronavirus crisis is expected to remain a significant part of our lives for the foreseeable future, continuing to cause economic hardships, straining our health care system, and changing the way we work and live on a daily basis. From this crisis, we have learned, and will continue to learn, new information almost daily. What we did know prior to the pandemic was that past viral pandemics have clearly demonstrated the association of chronic disease comorbidities with increased risk for morbidity and mortality (1–3). This observation is no different with the current crisis, as a number of chronic diseases appear to be important comorbidities in those with COVID-19 infection (3,4). As recently reported, during 1–30 March 2020, 89.3% of hospitalized adults had one or more underlying conditions. The most commonly reported conditions overall were hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes (28.3%), cardiovascular disease (27.8%), and kidney disease (13.1%) (4), several of which fall within National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mission areas. It is important from a medical perspective that we fully understand the clinical characteristics of individuals affected, risk factors for mortality and other outcomes, potential underlying health disparities, and other clinical variables in order to be in the best position as a medical community to inform on mitigation strategies and treatment until a vaccine is found. At present, clinicians managing patients with acute onset of multisystem dysfunction must make urgent decisions with little evidence to guide their practice. …

James L. Januzzi, Jr, MD, FACC, Chair Tariq Ahmad, MD, MPH, FACC Brendan Everett, MD, FACC William Hucker, MD, PHD Dharam J. Kumbhani, MD, SM, FACC Joseph E. Marine, MD, FACC Pamela B. Morris, MD, FACC Robert N. Piana, MD, FACC Sunil V. Rao, MD, FACC Marielle Scherrer-Crosbie, MD, PhD

In the recent past we have been fortunate to find new treatments based on entirely new mechanisms . . . or is that really so? The sodium–glucose cotransporter inhibitors (SGLTi) offer an instructive case in point. These apparently “ new” agents were preceded by phlorizin, a naturally occurring compound that has been used for physiologic studies for over 100 years (1). Given orally it interferes with intestinal absorption of carbohydrates and causes glucosuria. Studies in animal models of diabetes have provided useful insights, such as evidence that reduction of hyperglycemia can restore insulin sensitivity toward normal (2). However, phlorizin was considered unsuited for use by humans due to undesirable side effects. Recently its mechanism of action has been traced to effects on sodium–glucose cotransporters (SGLT) in the intestinal mucosa and the renal proximal tubule (3), and drugs with more nuanced effects on these transporters have been developed (4,5). These newer agents have greater affinity for SGLT2, which is expressed mainly in the kidney, and less for SGLT1, which facilitates intestinal absorption of glucose. Clinical effects of the newer SGLTi drugs in type 2 diabetes (T2D) include modest reductions of plasma glucose and A1C, weight, and blood pressure and are mediated in large part by glucosuria and sodium diuresis. These agents are taken once daily by mouth and do not require dose titration. Symptomatic side effects—mostly urinary or genital irritation or infections—are common but tolerated by most patients. Importantly, the new SGLTi drugs have highly desirable—and somewhat unexpected—cardiac and renal protective effects, as least in selected cohorts. Large trials of empagliflozin and canagliflozin, aiming to demonstrate safety in patients with T2D and high cardiovascular risk, have shown favorable effects on heart failure, cardiovascular death, and progression of albuminuria (6–9). Unwanted effects have been reported as well, including …

In their article, Tsapas and colleagues reported a network meta-analysis of randomized controlled trials to generate evidence for guiding the pharmacologic management of type 2 diabetes. The editor...

The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as “diabetes.” Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.

Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise. This randomized, double-blind, Phase 3 study included a placebo-controlled, 26-week core period (canagliflozin 100 or 300 mg vs placebo) and an active-controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]). ClinicalTrials.gov identifier: NCT01081834. Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin. Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA1c of −0.81% and −1.11%. Canagliflozin 100 and 300 mg decreased FPG (−1.5 and −2.2 mmol/L [−27.4 and −39.1 mg/dL]), body weight (−3.3% and −4.4%), and systolic BP (−1.4 and −3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE-related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups. Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.

While A1C is well established as an important risk marker for diabetes complications, with the increasing use of continuous glucose monitoring (CGM) to help facilitate safe and effective diabetes management, it is important to understand how CGM metrics, such as mean glucose, and A1C correlate. Estimated A1C (eA1C) is a measure converting the mean glucose from CGM or self-monitored blood glucose readings, using a formula derived from glucose readings from a population of individuals, into an estimate of a simultaneously measured laboratory A1C. Many patients and clinicians find the eA1C to be a helpful educational tool, but others are often confused or even frustrated if the eA1C and laboratory-measured A1C do not agree. In the U.S., the Food and Drug Administration determined that the nomenclature of eA1C needed to change. This led the authors to work toward a multipart solution to facilitate the retention of such a metric, which includes renaming the eA1C the glucose management indicator (GMI) and generating a new formula for converting CGM-derived mean glucose to GMI based on recent clinical trials using the most accurate CGM systems available. The final aspect of ensuring a smooth transition from the old eA1C to the new GMI is providing new CGM analyses and explanations to further understand how to interpret GMI and use it most effectively in clinical practice. This Perspective will address why a new name for eA1C was needed, why GMI was selected as the new name, how GMI is calculated, and how to understand and explain GMI if one chooses to use GMI as a tool in diabetes education or management.

There are more than 30 million Americans with diabetes, a disease that costs the U.S. more than $327 billion per year (1,2). Achieving glycemic control and controlling cardiovascular risk factors have been conclusively shown to reduce diabetes complications, comorbidities, and mortality. To achieve these desired outcomes, the medical community now has available many classes of medications and many formulations of insulin to effectively manage the metabolic abnormalities for people with diabetes. However, the affordability of medications in general, and for insulin specifically, is currently of great concern to people with diabetes, their families, health care providers, insurers, and employers. For millions of people living with diabetes, including all individuals with type 1 diabetes, access to insulin is literally a matter of life and death. The average list price of insulin has skyrocketed in recent years, nearly tripling between 2002 and 2013 (3). The reasons for this increase are not entirely clear but are due in part to the complexity of drug pricing in general and of insulin pricing in particular. As the price of insulin continues to rise, individuals with diabetes are often forced to choose between purchasing their medications or paying for other necessities, exposing them to serious short- and long-term health consequences (4–9). To find solutions to the issue of insulin affordability, there must be a better understanding of the transactions throughout the insulin supply chain, the impact each stakeholder has on what people with diabetes pay for insulin, and the relative efficacy of therapeutic options. Thus, as the nation’s leading voluntary health organization whose mission is “to prevent and cure diabetes and to improve the lives of all people affected by diabetes,” the American Diabetes Association (ADA) is committed to finding ways to provide relief for individuals and families who lack affordable access …

A noninvasive method to estimate muscle mass based on creatine ( methyl-d3) (D3-creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58–76 yr old) fasted overnight and then received an oral 30-mg dose of D3-creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3–4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography–tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D3-creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = −3.00 ± 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 ± 3.7 kg). However, intraindividual variability was high with the D3-creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D3-creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d3) (D3-creatine) and D3-creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D3-creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less bias than DXA. However, intraindividual variability is high with the D3-creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted.

OBJECTIVE We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). RESEARCH DESIGN AND METHODS During the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs). RESULTS During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD −4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD −1.03 cases/100 person-years with baseline HbA1c

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors’ Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association’s Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.

Diabetes in older adults is a growing public health burden. The unprecedented aging of the world's population is a major contributor to the diabetes epidemic, and older adults represent one of the fastest growing segments of the diabetes population. Of impending concern is that these numbers are projected to grow dramatically over the next few decades (1,2). Almost one-third of U.S. adults over the age of 65 years have diabetes. Approximately half of those are undiagnosed, and an additional one-third of older adults have prediabetes (3). Persons with diabetes today are living much longer compared with those in the past. We also recognize that management of older adults with diabetes is clearly more complicated given the observation that they commonly have multiple coexisting medical conditions that can impact clinical management. While rates of diabetes-related complications have declined overall in the general population, the incidence rates of macrovascular complications such as acute myocardial infarction and stroke continue to be the highest in older age-groups. These individuals also have the highest rate of diabetes-related end-stage renal disease (4). Heterogeneity in the health status of older adults (ranging from robust and otherwise healthy individuals to those with frailty and multiple comorbid conditions) and the paucity of evidence from clinical trials represent a challenge to making generalized treatment recommendations for older adults. Although many more individuals with type 1 diabetes are living longer (5), type 2 diabetes remains the most common type in older age-groups. Furthermore, older adults with diabetes may either have elderly onset disease (diagnosed at age 65 years or older) or long-standing diabetes with onset in middle age or earlier years (6), adding to the complexity of managing diabetes in older adults. Consequently, the American Diabetes Association (ADA) organized a Consensus Development Conference on Diabetes and Older Adults …

With this January 2017 issue, our editorial team celebrates its 5-year anniversary at the helm of Diabetes Care . In 2012, when we accepted the assignment to oversee the scientific aspects of the journal, we envisioned that the editorial for this January 2017 issue would be our opportunity to thank the American Diabetes Association (ADA) for allowing us to lead this effort, to thank our reviewers and associate editors for their tireless efforts, and to thank the readers for their valuable suggestions and ideas. However, we are now writing to inform you that those plans have been put on hold. Our editorial team has been given the opportunity to continue to guide Diabetes Care for another 2-year period. We have accepted the invitation primarily because our “team” (including the editorial committee, editorial office, and publications staff) feels we still have creative ideas to make the journal better and considerable energy to bring these ideas to fruition. Therefore, suffice it to say, we remain honored to continue to lead Diabetes Care for this extended period. It has been our custom to summarize our productivity and achievements in both the January and June issues of each year. This year we believe the trajectory of quality continues to rise. We hope you will also agree when reading the summary presented in this narrative. We feel each year’s monthly issues have surpassed the prior year’s work, and year 2016 is no exception! As we described in July of 2016, we aim to provide the readers with lagniappe—“a little something extra”! (1). This past year the editorial team took our initiative to another level devoting several monthly issues to specific clinical or research topics. A current summary of all thematic monthly issues can be found in our Diabetes Care Online Collections (http://care.diabetesjournals.org/content/diabetes-care-online-collections). In the …

The philosophers of antiquity and others through the ages recognized the connection of human emotion and thought with physiological processes and behavior (1). The relatively recent increases in the human life span and the prevalence of significant chronic illnesses have generated a greater appreciation of the relationship between human emotional, social, cognitive, and behavioral processes and health and wellness. However, understanding human behavior remains challenging, and in the presence of a significant chronic illness such as diabetes, that challenge becomes even more daunting. Specifically, the interaction of individual differences in emotional responses, attitudes, thought processes, preferences, beliefs, and social situations appear amplified with the increased complexities of new diabetes treatments. With the realization that other factors such as quality of life are equally important as physiological outcomes, the necessity of understanding behavioral and psychosocial processes is evident (2,3). Thus, the era of simply outlining a broad plan and sending it home for the patient to implement, if that era ever existed, is over. The era of placing the person with diabetes and family in the center of health care decisions and understanding their individual challenges and barriers has begun. Given the emerging concepts in the psychosocial aspects of diabetes, the editorial committee of Diabetes Care wanted to highlight this area in this issue. This special issue of Diabetes Care presents nine articles that represent a broad spectrum of behavioral and psychosocial issues that can influence treatment success and quality of life for those living with diabetes. Central to this topic and serving as the cornerstone of the special issue is the publication of the first Position Statement from the American Diabetes Association (ADA) for the psychosocial care of people with diabetes (4). This is followed by the presentation of a collection of articles that represent important aspects of …

In his State of the Union address on 20 January 2015, President Barack Obama announced the Precision Medicine Initiative. Although the concept of “precision medicine” has been present for nearly a decade, many interpretations of precision medicine exist. At its core, precision medicine is a model that proposes the custom delivery of health care, with medical practices, testing, decisions, and treatments tailored to the individual patient level (1). Diagnostic tests and therapies are selected on the basis of not only the specific ‘omics signature (e.g., genomics, transcriptomics, methylomics, proteomics, methylomics) but also the specific risk factor profile and health history obtained from the electronic health record. In March 2015, National Institutes of Health (NIH) Director Collins established a working group to develop a plan for creating and managing a collection of 1 million volunteers to comprise a precision medicine research cohort. On 17 September 2015, Dr. Collins accepted the framework that would establish the Precision Medicine Initiative, which includes providing the support to build the infrastructure for recruitment of the cohort, collection of the health data, banking of specimens, and launching research. This initial effort for precision medicine represents a major commitment of funds from the NIH. In this regard, President Obama allocated $215 million in fiscal year 2016 to support the initiative, and $130 million alone was targeted for the research participant cohort. Clearly, the Precision Medicine Initiative ushers in a paradigm change in the way we approach patient care. Specifically, it launches a new era of research, technology, and policy in this area, one in which the participant, the health care practitioner, and research merge into an individual-level relationship focused on the maintenance of health and the prevention and treatment of common human diseases. But, given that the editorial team at Diabetes Care desires to provide the most …

Technological progress in the past half century has greatly increased our ability to collect, store, and transmit vast quantities of information, giving rise to the term “big data.” This term refers to very large data sets that can be analyzed to identify patterns, trends, and associations. In medicine—including diabetes care and research—big data come from three main sources: electronic medical records (EMRs), surveys and registries, and randomized controlled trials (RCTs). These systems have evolved in different ways, each with strengths and limitations. EMRs continuously accumulate information about patients and make it readily accessible but are limited by missing data or data that are not quality assured. Because EMRs vary in structure and management, comparisons of data between health systems may be difficult. Registries and surveys provide data that are consistently collected and representative of broad populations but are limited in scope and may be updated only intermittently. RCT databases excel in the specificity, completeness, and accuracy of their data, but rarely include a fully representative sample of the general population. Also, they are costly to build and seldom maintained after a trial’s end. To consider these issues, and the challenges and opportunities they present, the editors of Diabetes Care convened a group of experts in management of diabetes-related data on 21 June 2018, in conjunction with the American Diabetes Association’s 78th Scientific Sessions in Orlando, FL. This article summarizes the discussion and conclusions of that forum, offering a vision of benefits that might be realized from prospectively designed and unified data-management systems to support the collective needs of clinical, surveillance, and research activities related to diabetes.

International audience; Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.

Periodically, a new idea, method, or tool leads to a turning point in the management of diabetes. We believe such a moment is now upon us, brought by development of reliable devices for continuous glucose monitoring (CGM). Obtaining profiles of glucose levels continuously, day and night, is likely to bring new scientific insights and greater ability to individualize treatments for patients with both type 1 diabetes (T1D) and type 2 diabetes (T2D). Notably, such profiles provide the opportunity to develop measures of glycemic control that provide clinically helpful information beyond that provided by an HbA1c value and periodic self-testing of capillary glucose. Several articles in this issue of Diabetes Care summarize recent progress in CGM measurements and their interpretation. The editorial committee of Diabetes Care is proud to present a Scientific Statement developed jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes titled “Improving the Clinical Value and Utility of CGM Systems: Issues and Recommendations” (1). This statement reviews clinical evidence regarding use of CGM and describes the properties and limitations of available CGM systems. It also addresses some practical issues regarding instruction of potential users of these devices and concerns about safety. In addition, we present two other Consensus Reports. In one, experts representing various groups with a strong interest in T1D define measures of glycemic control other than HbA1c, including categories of hypoglycemia and proportions of time in glucose target ranges during CGM, and also consider how best to use patient-reported outcomes in T1D (2). A strong consensus reached by these groups provides an important step forward from previously differing approaches to these issues. In the other, an international group of experts reviews current evidence on how best to use CGM information for improving patient care and research, …

We thank Pluchino et al. (1) from the U.S. Food and Drug Administration (FDA) Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, for their thoughtful and detailed commentary. They conclude that our proposed continuous glucose monitoring (CGM)–derived measure called glucose management indicator (GMI) (2) is appropriate for inclusion in CGM software to generate a metric conveying extended glucose exposure that may also prove to be a helpful additional tool to personalize diabetes management. In our estimation, this example of Dr. Lias and her colleagues from the FDA being willing to engage in a dialogue with the authors and the diabetes community focused on finding a solution to a clinical and regulatory quandary (in this case, the use of the potentially confusing term estimated A1C) is worthy of highlighting as a model for future productive …

George as a child. Who would have known then the impact he would make on the world of the science of obesity? George at the end of his tenure as executive director of Pennington Biomedical Research Center. As Mitzi watches, George receives a commemorative plaque from Dr. Claude Bouchard (executive director after George) during a 20th anniversary celebration event for Pennington Biomedical Research Center. In gratitude and acknowledgment for his work and contributions, and for always doing things the “George Bray way,” Pennington Biomedical named the walkway between the basic and clinical research buildings Bray’s “Weigh” in his honor on the occasion of his retirement from the center on 10 December 2014. George A. Bray was born 25 July 1931 in Winnetka, IL, during the peak of the Depression. He was the first child of George August and Mary H. Bray. His only sibling, Mary Elizabeth (Betsy) Bray, died secondary to rheumatic heart disease. Influenced by his mother, George developed a natural interest in education at a young age, even though one of his teachers at Hubbard Woods School in Winnetka reported that 11-year-old “George is doing good average work in all subjects” (1). Despite this inauspicious assessment, high school marked the emergence of a lifelong interest in and aptitude for science. This is clearly evidenced by his own writing in 1949 in an application for a national college scholarship program when he wrote: “Ever since I took my first science course in high school, I’ve been interested in the infinite possibilities of science.” When it came time to choose a college, George’s choice between Harvard and Brown University was based on the desire to attend one for college and the other for medical school. Choosing Brown University for undergraduate school was to have lifelong implications, as it was at …

Type 2 diabetes is a progressive disorder characterized by increasing hyperglycemia and the need to gradually intensify therapy in order to achieve and maintain glycemic control. Early initiation of combination therapy has been proposed as an approach to achieve glycemic goals earlier and delay the deterioration of glycemic control and with possible better preservation of β-cell function. We discuss in this article the pros and cons of this approach, focusing on individuals with HbA1c at diagnosis of 7.5–9.0%, where difference of opinion still exists on management. Initial combination therapy is proposed to lead to better and faster achievement of glycemic targets versus monotherapy and to impede clinical inertia and may possibly slow the deterioration of β-cell function. However, treating patients with sequential therapy is proposed to allow one to fully assess the efficacy and risk-to-benefit ratio of each drug as it is added. Furthermore, there is no evidence to support that rapid addition and titration of medications according to the glycemic profile achieved are inferior to initial combination therapy if glycemic targets are attained in a timely manner. Initial combination therapy is argued to postpone clinical inertia to the next decision point but does not eliminate it. Additionally, it may have been the agents chosen and not the timing of their initiation that led to improved β-cell function in the studies of initial combination therapy, and there are no data currently comparing use of the same drugs initiated simultaneously or sequentially. Heightened awareness of providers, individualization of therapy and setting, and reaching glycemic targets remain the mainstays of care.

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

The accelerating pandemic of diabetes is recognized as one of the greatest global public health threats of our time (1). When one reviews the latest estimates for diabetes prevalence and projections worldwide, it is easy to appreciate the magnitude of the problem facing us not only today but also for generations to come. Given the microvascular and macrovascular complications associated with this disease, as well as the resulting morbidity and mortality, the personal, medical, and societal costs are enormous (2,3). In addition, despite continuing advances in diabetes pharmacotherapy, fewer than half of adults with type 2 diabetes mellitus (T2D) attain therapeutic goals designed to reduce long-term risks of complications, especially for glycemic control (4–6), and lifestyle interventions are disappointing in the long term (7). In facing these challenges, it is imperative that interventions that may interdict the disease process and complement existing therapies be expeditiously advanced into clinical practice while also balancing the costs attributed to each intervention. This month’s issue of Diabetes Care includes 11 articles that report the latest data supporting bariatric/metabolic surgery as a new treatment option in the management of T2D. In the centerpiece of this collection, Rubino et al. (8) report new evidence-based guidelines for surgical treatment of T2D, writing on behalf of 48 voting delegates (75% are nonsurgeons) of the 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference organized in collaboration with major diabetes organizations. These recommendations, endorsed thus far by 45 international professional societies [see Table 1, Rubino et al. (8)], reflect a large body of evidence demonstrating that several gastrointestinal (GI) operations initially designed to promote weight loss (bariatric surgery) can improve glucose homeostasis more effectively than any known pharmaceutical or behavioral approach (9–24), causing durable remission in many patients with T2D (25,26 …

Despite improved understanding of the pathogenesis of diabetes and the release of impressive new medications to control the condition, there remains a significant global diabetes burden. The latest International Diabetes Federation estimates indicate that 415 million (1 in 11 persons) have diabetes, and this will increase to 642 million or almost 10% of the general population by 2040 (1). Indeed, there are great individual, societal, and economic costs associated with diabetes. These costs clearly relate to the microvascular complications, which include retinopathy, nephropathy, and neuropathy, that have been attenuated by better glycemic control and macrovascular complications that are relatively abated by better lipid and blood pressure control. However, for individuals with diabetes, cardiovascular disease (CVD) remains the main problem. Diabetes and CVD are closely linked, and CVD remains the most prevalent cause of morbidity and mortality in both men and women with diabetes (2). Specifically, the relative risk for CVD morbidity and mortality in adults with diabetes ranges from 1 to 3 in men and from 2 to 5 in women compared with those without diabetes (3). Given the issues facing individuals with both diabetes and CVD, we urgently need effective evidence-based interventional strategies to reduce cardiovascular risk and improve outcomes. With the aim of advancing toward this challenging goal, our editorial team is featuring in the present issue of Diabetes Care a collection of articles that may help to clarify the mechanisms linking diabetes to CVD. These articles comment on the control of risk factors and biomarkers for CVD and provide new updates on outcomes of landmark studies. In addition, we have included commentaries on cardiovascular safety of newer diabetes drugs and provide insights on mechanisms of action for cardioprotection observed with some new agents (4–13). The need to control risk factors for CVD (lipids, blood …

With the increasing availability of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII), the artificial pancreas (AP) (the commonly accepted term for closed-loop control [CLC] of blood glucose [BG] levels in diabetes) has become a hot area in translational research and industrial development. After a prolonged period of inpatient, clinical research center trials using cumbersome systems, the field has progressed rapidly over the past 2 years to long-term, free-living studies running AP algorithms on smartphones. Although it is still not a cure, the AP is the most promising advance in the treatment of diabetes at this time. This issue of Diabetes Care presents today’s AP state of the art, including reports on multinational home-use AP trials, studies in young children, the use of multihormonal approaches to mitigate meal-related hyperglycemia, and discussions of AP study designs and outcome measures. This collection of articles establishes the AP as a new diabetes treatment paradigm—not a single-function CGM or CSII device but an adaptable wearable network encompassing the patient in a digital treatment ecosystem. In its May 2014 issue, Diabetes Care featured the progress in the AP field in a series of articles labeled “Advances in Artificial Pancreas Development.” In addition to an editorial discussing the state of the art of AP development in 2014 (1), the issue included original articles that covered a broad range of topics including analyses of the possible physiological inputs to CLC (2), real-time estimation of insulin sensitivity from CGM and insulin pump data (3), engineering of the AP algorithms (4), reports of predictive low-glucose suspend (LGS) systems (5), studies of overnight CLC at home (6), feasibility of the AP in type 2 diabetes (7), and the first around-the-clock outpatient CLC running a model predictive control (MPC) algorithm on a portable AP system (8). Since then, …

On 1 July 2011, I began my initial duties as Editor in Chief of Diabetes Care . In my initial Editor’s Commentary titled “ Diabetes Care : Change Is Constant” (1), I outlined the current status of the journal and what I had learned from the outstanding editors and associate editors who came before me. I described how, as an editorial team, we had prepared to take on the enormous duties that lay before us by studying the strategies that former editorial teams used to advance the journal. We evaluated what had worked, what didn’t work, and provided a narrative on our anticipated challenges. We initiated actions to address and keep abreast of changing times, increased competition from other journals now focused on diabetes, and the issues related to alterations in research funding and health care delivery that would likely drive the content for the journal. During my tenure as Editor in Chief, our editorial team kept you, our readers, well informed with regular updates on our progress, format changes, and views on controversial topics. With dedication and vision, as well as the expertise from the editorial office, the editorial team, and the American Diabetes Association (ADA) Publishing office, we were successful in sustaining the upward trajectory of the journal. The journal's latest impact factor for 2016 is 11.857—its highest impact factor ever—which is an increase from 8.934 in 2015. Diabetes Care , without question, is at its highest level in relevance and remains the world’s premier journal focused solely on diabetes care and clinical research. Given the success of the journal as outlined above and the fact that our “team” (i.e., editorial committee, editorial office, and publications staff) felt we still had “creative ideas to make the journal better and considerable energy to bring these ideas to fruition,” we …

Background Insulin resistance underlies metabolic syndrome and is associated with excess adiposity and visceral fat accumulation, which is more frequently observed in males than females. However, in young females, the prevalence of metabolic syndrome is rising, mainly driven by accumulation of abdominal visceral fat. The degree to which sex-related differences could influence the development of insulin resistance remains unclear, and studies of potential therapeutic strategies to combat metabolic syndrome using rodent models have focused predominantly on males. We therefore evaluated the effects of two nutritional supplements derived from botanical sources, an extract of Artemisia dracunculus L. (termed PMI5011) and Momordica charantia (commonly known as bitter melon), on female mice challenged with a high-fat diet in order to determine if dietary intake of these supplements could ameliorate obesity-induced insulin resistance and metabolic inflexibility in skeletal muscle. Methods Body composition, physical activity and energy expenditure, fatty acid oxidation, insulin signaling, and gene and protein expression of factors controlling lipid metabolism and ectopic lipid accumulation were evaluated in female mice fed a high-fat diet supplemented with either PMI5011 or bitter melon. Statistical significance was assessed by unpaired two-tailed t test and repeated measures ANOVA. Results PMI5011 supplementation resulted in increased body weight and adiposity, while bitter melon did not induce changes in these parameters. Pyruvate tolerance testing indicated that both supplements increased hepatic glucose production. Both supplements induced a significant suppression in fatty acid oxidation in skeletal muscle homogenates treated with pyruvate, indicating enhanced metabolic flexibility. PMI5011 reduced lipid accumulation in skeletal muscle, while bitter melon induced a downward trend in lipid accumulation in the skeletal muscle and liver. This was accompanied by transcriptional regulation of autophagic genes by bitter melon in the liver. Conclusions Data from the current study indicates that dietary supplementation with PMI5011 and bitter melon evokes a divergent, and generally less favorable, set of metabolic responses in female mice compared to effects previously observed in males. Our findings underscore the importance of considering sex-related variations in responses to dietary supplementation aimed at combating metabolic syndrome. Electronic supplementary material The online version of this article (10.1186/s13293-018-0199-1) contains supplementary material, which is available to authorized users.

Medication persistence is imperative for successful treatment of type 2 diabetes (T2D). Prior research has shown that discontinuation of prescribed medication within the first year is common for number of chronic disease treatments and that this is associated with poor clinical outcomes. We performed a retrospective, observational study using claims data from the Truven Health MarketScan® Commercial and Medicare Supplemental Databases (2013-2016) to identify T2D patients initiating T2D therapy. Patients with at least one diagnosis for T2D and one outpatient pharmacy claim for a T2D medication preceded by 12 months without such medications were included. Patients were required to have at least 12 months of continuous enrollment in the database before and after the therapy initiation date. The primary outcome was initial treatment regimen discontinuation, defined as a gap of at least 45 days with no T2D medications on hand. Re-starting therapy with any T2D medication from the discontinuation date through the end of the 12-month follow-up was also assessed. Those with continuous treatment were censored at the end of the 12-month follow-up period. A total of 324,136 patients initiating therapy were identified. The sample was 46% female and had an average age of 55 years. Following initiation, 31% of patients discontinued within the first 3 months, 44% within 6 months and 58% within 12 months. Among those who discontinued within the 12-month follow-up, 27% restarted therapy within 60 days, and 39% re-started therapy anytime during the 12-month follow-up. Those who discontinued and re-started therapy spent a mean of 107 days without treatment on hand. This study provides real-world evidence that a majority of T2D medication patients discontinue within one year of initiation. Interventions aimed at improving treatment persistence should be targeted early after initiation to avoid gaps in therapy and associated clinical consequences. Disclosure W.T. Cefalu: None. T. Darsow: None. M. Petersen: None. L. Palmer: None. E. Thiel: None. L. Latts: Other Relationship; Self; Medtronic, Novo Nordisk Inc., Sanofi.

Data from placebo controlled, randomized clinical trials (RCTs) have demonstrated cardio-protective effects of certain diabetes therapy classes, including sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon receptor agonists (GLP-1RA). However, the majority of these trials made comparisons to placebo and there is limited data on head to head comparisons between specific classes. We performed an observational cohort study using the Truven Health MarketScan® Research Databases (2013-2016) to compare the risk of cardiovascular events between patients initiating treatment with SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP-4is) and GLP-1-RAs vs. sulfonylureas (SUs) in a real-world setting. Propensity score weighting and doubly robust methods (boosting and Poisson regression) were used to control for differences in baseline characteristics. The primary study outcomes were hospitalization for congestive heart failure, acute myocardial infarction, stroke and a composite of all three. Lower extremity amputations were also examined. The relative risks of events in the 12 months before and after treatment initiation were compared to generate relative risk ratios. Protective effects of SGLT2is compared to SUs were observed (Table). Interestingly, there was also a protective effect of DPP-4is on individual outcomes compared to SUs in contrast to DPP-4i vs. placebo in RCTs. Disclosure E. Thiel: None. W.D. Marder: Employee; Self; IBM. W.T. Cefalu: None. T. Darsow: None. M. Petersen: None. L. Latts: Other Relationship; Self; Medtronic, Novo Nordisk Inc., Sanofi.

Hall et al. (1) write concerning our summary of the future potential and current limitations of analyses based on big data in populations of people with diabetes, published as the proceedings of an Expert Forum (2). They commented specifically on three aspects of this question. They call attention to collection of data from reimbursement claims and newer sources such as physiologic measurements obtained by personal devices used or worn by individual patients. We briefly referred to these sources of information in our article, but we agree they will be increasingly useful in the future. Second, they comment on the role of analytic approaches to …

On page 1302 of the article cited above, the wording of the following sentence was incorrect: “In contrast, net prices received by the …

Expert clinicians counter some of the recommendations regarding hemoglobin A1c targets for type 2 diabetes that were proposed in a recent American College of Physicians guideline.

A set of guidance statements recently published by the American College of Physicians (ACP) advocates relaxation of goals for control of glycated hemoglobin (A1C) by people with type 2 diabetes (T2D) (1). This publication advises that “clinicians should reevaluate HbA1c levels and revise treatment strategies on the basis of changes in the balance of benefits and harms.” Specifically, it proposes reducing pharmacotherapy for any person when A1C is

Summary Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism. Men with prediabetes were randomized to eTRF (6-hr feeding period, with dinner before 3 p.m.) or a control schedule (12-hr feeding period) for 5 weeks and later crossed over to the other schedule. eTRF improved insulin sensitivity, β cell responsiveness, blood pressure, oxidative stress, and appetite. We demonstrate for the first time in humans that eTRF improves some aspects of cardiometabolic health and that IF's effects are not solely due to weight loss.

It is well understood that diabetes is a complex, chronic illness in which glycemic control reduces the development and progression of macrovascular and microvascular complications. Achieving risk reduction requires continuous medical care and self-management, with multifactorial risk-management strategies beyond just glycemic control, including lifestyle changes and cardiovascular risk reduction. Given the current knowledge of what is required to reduce complications, improve quality of life, and prevent progression to overt disease states, it is important that providers caring for people with diabetes have the latest and most updated clinical translation of the evidence as they consider the day-to-day management of their patients. In this regard, the American Diabetes Association (ADA) has been actively involved in the development and dissemination of diabetes care standards, guidelines, and related documents to support and improve patient care for over 25 years. Specifically, the ADA’s “Standards of Medical Care in Diabetes,” referred to as the Standards of Care, has always been intended to provide clinicians, patients, researchers, payers, and other interested individuals with evidence-based information on all aspects of diabetes care, general treatment goals, and tools to evaluate the quality of care (1). The recent acceleration of the pace of new information being released regarding diabetes care and research has been startling. To put this in perspective, the first ADA Standards of Care, published in 1989, provided recommendations based on the available evidence at that time and filled only four pages in Diabetes Care (2). In the most recent update, 28 years later, the document is well over 170 pages! Over 40 new type 2 diabetes treatment options have been approved since 2005 (3), not even counting advances in technology, such as continuous glucose monitoring. In the last year alone, there have been many significant changes to the Standards of Care, and the 2018 version …

Scope The primary disorder underlying metabolic syndrome is insulin resistance due to excess body weight and abdominal visceral fat accumulation. In this study, it is asked if dietary intake of an ethanolic extract from Russian tarragon (Artemisia dracunculus L., termed PMI5011), shown to improve glucose utilization by enhancing insulin signaling in skeletal muscle, could prevent obesity-induced insulin resistance, skeletal muscle metabolic inflexibility, and ectopic lipid accumulation in the skeletal muscle and liver. Methods and results Male wild-type mice are fed a high-fat diet alone or supplemented with PMI5011 (1% w/w) over 3 months. Dietary intake of PMI5011 improved fatty acid oxidation and metabolic flexibility in the skeletal muscle, reduced insulin levels, and enhanced insulin signaling in the skeletal muscle and liver independent of robust changes in expression of factors that control fatty acid oxidation. This corresponds with significantly reduced lipid accumulation in the skeletal muscle and liver, although body weight gain is comparable to a high-fat diet alone. Conclusion Previous studies showed that PMI5011 enhances insulin sensitivity in the setting of established obesity-induced insulin resistance. The current study demonstrates that dietary intake of PMI5011 prevents high-fat diet-induced insulin resistance, metabolic dysfunction, and ectopic lipid accumulation in the skeletal muscle and liver without reducing body weight.

Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression.