Showing papers in "Diabetes Care in 2018"

Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Abstract: The American Diabetes Association and the European Association for the Study of Diabetes have briefly updated their 2018 recommendations on management of hyperglycemia, based on important research findings from large cardiovascular outcomes trials published in 2019. Important changes include: 1) the decision to treat high-risk individuals with a glucagon-like peptide 1 (GLP-1) receptor agonist or sodium-glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), cardiovascular death, or chronic kidney disease (CKD) progression should be considered independently of baseline HbA1c or individualized HbA1c target; 2) GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established cardiovascular disease (CVD) but with the presence of specific indicators of high risk; and 3) SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE, and CVD death, as well as in patients with type 2 diabetes with CKD (estimated glomerular filtration rate 30 to ≤60 mL min-1 [1.73 m]-2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE, and cardiovascular death.

Global Economic Burden of Diabetes in Adults: Projections From 2015 to 2030

Abstract: OBJECTIVE Despite the importance of diabetes for global health, the future economic consequences of the disease remain opaque. We forecast the full global costs of diabetes in adults through the year 2030 and predict the economic consequences of diabetes if global targets under the Sustainable Development Goals (SDG) and World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 are met. RESEARCH DESIGN AND METHODS We modeled the absolute and gross domestic product (GDP)-relative economic burden of diabetes in individuals aged 20–79 years using epidemiological and demographic data, as well as recent GDP forecasts for 180 countries. We assumed three scenarios: prevalence and mortality 1 ) increased only with urbanization and population aging (baseline scenario), 2 ) increased in line with previous trends (past trends scenario), and 3 ) achieved global targets (target scenario). RESULTS The absolute global economic burden will increase from U.S. $1.3 trillion (95% CI 1.3–1.4) in 2015 to $2.2 trillion (2.2–2.3) in the baseline, $2.5 trillion (2.4–2.6) in the past trends, and $2.1 trillion (2.1–2.2) in the target scenarios by 2030. This translates to an increase in costs as a share of global GDP from 1.8% (1.7–1.9) in 2015 to a maximum of 2.2% (2.1–2.2). CONCLUSIONS The global costs of diabetes and its consequences are large and will substantially increase by 2030. Even if countries meet international targets, the global economic burden will not decrease. Policy makers need to take urgent action to prepare health and social security systems to mitigate the effects of diabetes.

Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis

Abstract: Objective Several studies have explored the impact of nonalcoholic fatty liver disease (NAFLD) on risk of incident type 2 diabetes. However, the extent to which NAFLD may confer risk of incident diabetes remains uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes. Research design and methods We collected data using PubMed, Scopus, and Web of Science from January 2000 to July 2017. We included only large (n ≥500) observational studies with a follow-up duration of at least 1 year in which NAFLD was diagnosed on imaging methods. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling. Results A total of 19 observational studies with 296,439 individuals (30.1% with NAFLD) and nearly 16,000 cases of incident diabetes over a median of 5 years were included in the final analysis. Patients with NAFLD had a greater risk of incident diabetes than those without NAFLD (random-effects hazard ratio [HR] 2.22, 95% CI 1.84-2.60; I2 = 79.2%). Patients with more "severe" NAFLD were also more likely to develop incident diabetes; this risk increased across the ultrasonographic scores of steatosis (n = 3 studies), but it appeared to be even greater among NAFLD patients with advanced high NAFLD fibrosis score (n = 1 study; random-effects HR 4.74, 95% CI 3.54-5.94). Sensitivity analyses did not alter these findings. Funnel plot and Egger test did not reveal significant publication bias. Study limitations included high heterogeneity, varying degrees of confounder adjustment across individual studies, and lack of studies using liver biopsy. Conclusions NAFLD is significantly associated with a twofold increased risk of incident diabetes. However, the observational design of the eligible studies does not allow for proving causality.

Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)

Abstract: OBJECTIVE Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to reduce liver fat in rodent models. Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce. This study examined the effect of empagliflozin (an SGLT-2 inhibitor) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) by using MRI-derived proton density fat fraction (MRI-PDFF). RESEARCH DESIGN AND METHODS Fifty patients with type 2 diabetes and NAFLD were randomly assigned to either the empagliflozin group (standard treatment for type 2 diabetes plus empagliflozin 10 mg daily) or the control group (standard treatment without empagliflozin) for 20 weeks. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels. RESULTS When included in the standard treatment for type 2 diabetes, empagliflozin was significantly better at reducing liver fat (mean MRI-PDFF difference between the empagliflozin and control groups −4.0%; P P P = 0.057). The two groups showed a significant difference for change in serum ALT level ( P = 0.005) and nonsignificant differences for AST ( P = 0.212) and GGT ( P = 0.057) levels. CONCLUSIONS When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

Risk of Infection in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study.

Abstract: OBJECTIVE We describe in detail the burden of infections in adults with diabetes within a large national population cohort. We also compare infection rates between patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). RESEARCH DESIGN AND METHODS A retrospective cohort study compared 102,493 English primary care patients aged 40–89 years with a diabetes diagnosis by 2008 ( n = 5,863 T1DM and n = 96,630 T2DM) with 203,518 age-sex-practice–matched control subjects without diabetes. Infection rates during 2008–2015, compiled from primary care and linked hospital and mortality records, were compared across 19 individual infection categories. These were further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate incidence rate ratios (IRRs) between 1 ) people with diabetes and control subjects and 2 ) T1DM and T2DM adjusted for age, sex, smoking, BMI, and deprivation. RESULTS Compared with control subjects without diabetes, patients with diabetes had higher rates for all infections, with the highest IRRs seen for bone and joint infections, sepsis, and cellulitis. IRRs for infection-related hospitalizations were 3.71 (95% CI 3.27–4.21) for T1DM and 1.88 (95% CI 1.83–1.92) for T2DM. A direct comparison of types confirmed higher adjusted risks for T1DM versus T2DM (death from infection IRR 2.19 [95% CI 1.75–2.74]). We estimate that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes. CONCLUSIONS People with diabetes, particularly T1DM, are at increased risk of serious infection, representing an important population burden. Strategies that reduce the risk of developing severe infections and poor treatment outcomes are under-researched and should be explored.

Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring

Abstract: 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.

Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes

Abstract: OBJECTIVE Continuous glucose monitoring (CGM) has provided new measures of glycemic control that link to diabetes complications. This study investigated the association between the time in range (TIR) assessed by CGM and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS A total of 3,262 patients with type 2 diabetes were recruited. TIR was defined as the percentage of time spent within the glucose range of 3.9–10.0 mmol/L during a 24-h period. Measures of glycemic variability (GV) were assessed as well. DR was determined by using fundus photography and graded as 1 ) non-DR; 2 ) mild nonproliferative DR (NPDR); 3 ) moderate NPDR; or 4 ) vision-threatening DR (VTDR). RESULTS The overall prevalence of DR was 23.9% (mild NPDR 10.9%, moderate NPDR 6.1%, VTDR 6.9%). Patients with more advanced DR had significantly less TIR and higher measures of GV (all P for trend P for trend r = −0.147; P P = 0.018; moderate NPDR, P = 0.014; VTDR, P = 0.019) after controlling for age, sex, BMI, diabetes duration, blood pressure, lipid profile, and HbA 1c . Further adjustment of GV metrics partially attenuated these associations, although the link between TIR and the presence of any DR remained significant. CONCLUSIONS TIR assessed by CGM is associated with DR in type 2 diabetes.

Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum

Abstract: 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.

Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers

Abstract: Diabetic foot ulcers remain a major health care problem. They are common, result in considerable suffering, frequently recur, and are associated with high mortality, as well as considerable health care costs. While national and international guidance exists, the evidence base for much of routine clinical care is thin. It follows that many aspects of the structure and delivery of care are susceptible to the beliefs and opinion of individuals. It is probable that this contributes to the geographic variation in outcome that has been documented in a number of countries. This article considers these issues in depth and emphasizes the urgent need to improve the design and conduct of clinical trials in this field, as well as to undertake systematic comparison of the results of routine care in different health economies. There is strong suggestive evidence to indicate that appropriate changes in the relevant care pathways can result in a prompt improvement in clinical outcomes.

Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association

Abstract: Since the American Diabetes Association (ADA) published the Position Statement “Care of Children and Adolescents With Type 1 Diabetes” (1) in 2005, innovations have transformed the landscape and management of type 1 diabetes: novel autoantibodies, sophisticated devices for delivering insulin and measuring glucose, and diabetes registries. However, strategies to prevent or delay type 1 diabetes in youth remain elusive, and meanwhile the number of affected children continues to grow. The SEARCH for Diabetes in Youth (SEARCH) study found a 21.1% rise in the prevalence of type 1 diabetes from 2001 to 2009 in youth aged 0 through 19 years, with increases observed in all sex, age, and race/ethnic subgroups except those with the lowest prevalence (0–4 years old and American Indians) (2). Incidence has also increased; the adjusted risk for developing type 1 diabetes increased 1.4% annually between 2002 and 2012, with significant increases in all age-groups except those 0–4 years old (3). One theme of this Position Statement is that “children are not little adults”—pediatric-onset diabetes is different from adult diabetes because of its distinct epidemiology, pathophysiology, developmental considerations, and response to therapy (4,5). Diabetes management for children must not be extrapolated from adult diabetes care. In caring for children and adolescents, clinicians need to be mindful of the child’s evolving developmental stages and must adapt care to the child’s needs and circumstances. Timely anticipatory guidance and care coordination will enable a seamless child/adolescent/young adult transition for both the developing patient and his or her family. Although the ADA stopped developing new position statements in 2018 (6), this Position Statement was developed under the 2017 criteria (7) and provides recommendations for current standards of care for youth (children and adolescents) with type 1 diabetes. It is not intended to be an exhaustive compendium on all aspects …

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

Abstract: OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia, insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study.

Abstract: OBJECTIVE Diabetes mellitus (DM) increases the risk of infections, but the effect of better control has not been thoroughly investigated. RESEARCH DESIGN AND METHODS With the use of English primary care data, average glycated hemoglobin (HbA1c) during 2008–2009 was estimated for 85,312 patients with DM ages 40–89 years. Infection rates during 2010–2015 compiled from primary care, linked hospital, and mortality records were estimated across 18 infection categories and further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) by HbA1c categories across all DM, and type 1 and type 2 DM separately. IRRs also were compared with 153,341 age-sex-practice–matched controls without DM. Attributable fractions (AF%) among patients with DM were estimated for an optimal control scenario (HbA1c 6–7% [42–53 mmol/mol]). RESULTS Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6–7% [42–53 mmol/mol], IRR 1.41 [95% CI 1.36–1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24–5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86–12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43–3.00]) after adjustment for duration and other confounders. AF% of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%). CONCLUSIONS Poor glycemic control is powerfully associated with serious infections and should be a high priority.

Effect of a Lifestyle Intervention Program With Energy-Restricted Mediterranean Diet and Exercise on Weight Loss and Cardiovascular Risk Factors: One-Year Results of the PREDIMED-Plus Trial

Abstract: OBJECTIVE The long-term impact of intentional weight loss on cardiovascular events remains unknown. We describe 12-month changes in body weight and cardiovascular risk factors in PREvencion con DIeta MEDiterranea (PREDIMED)-Plus, a trial designed to evaluate the long-term effectiveness of an intensive weight-loss lifestyle intervention on primary cardiovascular prevention. RESEARCH DESIGN AND METHODS Overweight/obese adults with metabolic syndrome aged 55–75 years ( n = 626) were randomized to an intensive weight-loss lifestyle intervention based on an energy-restricted Mediterranean diet, physical activity promotion, and behavioral support (IG) or a control group (CG). The primary and secondary outcomes were changes in weight and cardiovascular risk markers, respectively. RESULTS Diet and physical activity changes were in the expected direction, with significant improvements in IG versus CG. After 12 months, IG participants lost an average of 3.2 kg vs. 0.7 kg in the CG ( P P P 1c , and circulating levels of leptin, interleukin-18, and MCP-1 were greater in IG than CG participants ( P CONCLUSIONS PREDIMED-Plus intensive lifestyle intervention for 12 months was effective in decreasing adiposity and improving cardiovascular risk factors in overweight/obese older adults with metabolic syndrome, as well as in individuals with or at risk for diabetes.

Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials

Abstract: OBJECTIVE To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program ( N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg ( n = 243), 25 mg ( n = 244), and placebo ( n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg ( n = 241), 10 mg ( n = 248), 25 mg ( n = 245), and placebo ( n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia. RESULTS The observed largest mean placebo-subtracted glycated hemoglobin reductions were −0.28% (95% CI −0.42, −0.15) for 2.5 mg, −0.54% (−0.65, −0.42) for 10 mg, and −0.53% (−0.65, −0.42) for 25 mg (all P P P P P CONCLUSIONS Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.

Insulin Access and Affordability Working Group: Conclusions and Recommendations.

Abstract: 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 …

Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis.

Abstract: OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL−) or with (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with d-[6,6- 2 H 2 ]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assess mitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL−, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. Hepatic maximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association

Abstract: Although all types of diabetes result in hyperglycemia, the pathophysiology of each type of diabetes is different. These guidelines summarize available data specific to the comprehensive care of youth with type 2 diabetes. The objective is to enrich the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology, its management, and the prevention of associated complications. Glucose homeostasis is maintained by a balance between insulin secretion from the pancreatic β-cells and sensitivity to insulin in skeletal muscle, adipose tissue, and liver (1). When insulin sensitivity declines, insulin secretion must increase to maintain glucose tolerance, and, in most youth, decreased insulin sensitivity due to puberty and/or obesity is compensated by increased insulin secretion. However, when β-cells cannot secrete sufficient insulin to compensate for insulin resistance, abnormalities in glucose homeostasis ensue, potentially progressing to prediabetes and type 2 diabetes as β-cell function deteriorates further (2–9). The relationship between β-cell function and insulin sensitivity in adults and youth has been demonstrated to be a hyperbolic function and can be described mathematically as the product of insulin sensitivity and β-cell function, called the disposition index (DI) (1). The DI essentially expresses the amount of insulin being secreted relative to the degree of insulin resistance and is a constant for a given degree of glucose tolerance in any one individual. Overweight and obesity are major acquired contributors to the development of insulin resistance, particularly in the face of the physiologic insulin resistance characteristic of puberty. Robust pancreatic β-cell compensatory insulin secretion maintains normal glucose homeostasis. However, in adolescents with obesity who develop type 2 diabetes, there is severe peripheral and hepatic insulin resistance, with ∼50% lower peripheral insulin sensitivity than peers with obesity without diabetes, along with increased fasting hepatic glucose production and inadequate first- and second-phase insulin secretion, resulting …

Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank.

Abstract: OBJECTIVE To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds. RESEARCH DESIGN AND METHODS In the UK Biobank, we examined associations of current (N = 272,214) and lifetime (N = 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes. RESULTS Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05–1.26]; some nights: OR 1.18 [95% CI 1.05–1.32]; and usual nights: OR 1.44 [95% CI 1.19–1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93–1.27]). Considering a person’s lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds ( 8/month: OR 1.36 [95% CI 1.14–1.62]; Ptrend = 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure. CONCLUSIONS Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication.

Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes.

Abstract: OJBECTIVE To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes aged 18–80 years, who initiated any ADD, were selected ( n = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, n = 357,482); the third-line therapy choices were further explored. RESULTS From 2005 to 2016, first-line use increased for metformin (60–77%) and decreased for sulfonylureas (20–8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA 1c of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60–46%), it remained the most popular second ADD choice. Use increased for insulin (7–17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4–21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, P CONCLUSIONS Most patients initiate second-line therapy at elevated HbA 1c levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas.

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial.

Abstract: OBJECTIVE This 24-week, double-blinded, phase 3 clinical trial (DEPICT-2; ClinicalTrials.gov, NCT02460978) evaluated efficacy and safety of dapagliflozin as adjunct therapy to adjustable insulin in patients with inadequately controlled type 1 diabetes (HbA 1c 7.5–10.5%). RESEARCH DESIGN AND METHODS Patients were randomized 1:1:1 to dapagliflozin 5 mg ( n = 271), dapagliflozin 10 mg ( n = 270), or placebo ( n = 272) plus insulin. Insulin dose was adjusted by investigators according to self-monitored glucose readings, local guidance, and individual circumstances. RESULTS Baseline characteristics were balanced between treatment groups. At week 24, dapagliflozin significantly decreased HbA 1c (primary outcome; difference vs. placebo: dapagliflozin 5 mg −0.37% [95% CI −0.49, −0.26], dapagliflozin 10 mg –0.42% [−0.53, −0.30]), total daily insulin dose (−10.78% [−13.73, −7.72] and −11.08% [−14.04, −8.02], respectively), and body weight (−3.21% [−3.96, −2.45] and −3.74% [−4.49, −2.99], respectively) ( P 70 to ≤180 mg/dL) versus placebo were significantly improved. More patients receiving dapagliflozin achieved a reduction in HbA 1c ≥0.5% without severe hypoglycemia compared with placebo. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events with dapagliflozin: 2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. CONCLUSIONS Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events.

Predictive Low-Glucose Suspend Reduces Hypoglycemia in Adults, Adolescents, and Children With Type 1 Diabetes in an At-Home Randomized Crossover Study: Results of the PROLOG Trial.

Abstract: OBJECTIVE This study evaluated a new insulin delivery system designed to reduce insulin delivery when trends in continuous glucose monitoring (CGM) glucose concentrations predict future hypoglycemia. RESEARCH DESIGN AND METHODS Individuals with type 1 diabetes ( n = 103, age 6–72 years, mean HbA 1c 7.3% [56 mmol/mol]) participated in a 6-week randomized crossover trial to evaluate the efficacy and safety of a Tandem Diabetes Care t:slim X2 pump with Basal-IQ integrated with a Dexcom G5 sensor and a predictive low-glucose suspend algorithm (PLGS) compared with sensor-augmented pump (SAP) therapy. The primary outcome was CGM-measured time RESULTS Both study periods were completed by 99% of participants; median CGM usage exceeded 90% in both arms. Median time P P = 0.40) or percentage of time spent >180 mg/dL (32% vs. 33%, P = 0.12). One severe hypoglycemic event occurred in the SAP arm and none in the PLGS arm. Mean pump suspension time was 104 min/day. CONCLUSIONS The Tandem Diabetes Care Basal-IQ PLGS system significantly reduced hypoglycemia without rebound hyperglycemia, indicating that the system can benefit adults and youth with type 1 diabetes in improving glycemic control.

Gut Microbiota Differs in Composition and Functionality Between Children With Type 1 Diabetes and MODY2 and Healthy Control Subjects: A Case-Control Study.

Abstract: OBJECTIVE Type 1 diabetes is associated with compositional differences in gut microbiota To date, no microbiome studies have been performed in maturity-onset diabetes of the young 2 (MODY2), a monogenic cause of diabetes Gut microbiota of type 1 diabetes, MODY2, and healthy control subjects was compared RESEARCH DESIGN AND METHODS This was a case-control study in 15 children with type 1 diabetes, 15 children with MODY2, and 13 healthy children Metabolic control and potential factors modifying gut microbiota were controlled Microbiome composition was determined by 16S rRNA pyrosequencing RESULTS Compared with healthy control subjects, type 1 diabetes was associated with a significantly lower microbiota diversity, a significantly higher relative abundance of Bacteroides , Ruminococcus , Veillonella , Blautia , and Streptococcus genera, and a lower relative abundance of Bifidobacterium , Roseburia , Faecalibacterium , and Lachnospira Children with MODY2 showed a significantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance Proinflammatory cytokines and lipopolysaccharides were increased in type 1 diabetes, and gut permeability (determined by zonulin levels) was significantly increased in type 1 diabetes and MODY2 The PICRUSt analysis found an increment of genes related to lipid and amino acid metabolism, ABC transport, lipopolysaccharide biosynthesis, arachidonic acid metabolism, antigen processing and presentation, and chemokine signaling pathways in type 1 diabetes CONCLUSIONS Gut microbiota in type 1 diabetes differs at taxonomic and functional levels not only in comparison with healthy subjects but fundamentally with regard to a model of nonautoimmune diabetes Future longitudinal studies should be aimed at evaluating if the modulation of gut microbiota in patients with a high risk of type 1 diabetes could modify the natural history of this autoimmune disease

Diabetes Technology Update: Use of Insulin Pumps and Continuous Glucose Monitoring in the Hospital

Abstract: The use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems has gained wide acceptance in diabetes care. These devices have been demonstrated to be clinically valuable, improving glycemic control and reducing risks of hypoglycemia in ambulatory patients with type 1 diabetes and type 2 diabetes. Approximately 30–40% of patients with type 1 diabetes and an increasing number of insulin-requiring patients with type 2 diabetes are using pump and sensor technology. As the popularity of these devices increases, it becomes very likely that hospital health care providers will face the need to manage the inpatient care of patients under insulin pump therapy and CGM. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized. Health care institutions must have clear policies and procedures to allow the patient to continue to receive CSII treatment to maximize safety and to comply with existing regulations related to self-management of medication. Randomized controlled trials are needed to determine whether CSII therapy and CGM systems in the hospital are associated with improved clinical outcomes compared with intermittent monitoring and conventional insulin treatment or with a favorable cost-benefit ratio.

Gestational Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal Birth Weight

Abstract: OBJECTIVE Medical nutrition therapy is a mainstay of gestational diabetes mellitus (GDM) treatment. However, data are limited regarding the optimal diet for achieving euglycemia and improved perinatal outcomes. This study aims to investigate whether modified dietary interventions are associated with improved glycemia and/or improved birth weight outcomes in women with GDM when compared with control dietary interventions. RESEARCH DESIGN AND METHODS Data from published randomized controlled trials that reported on dietary components, maternal glycemia, and birth weight were gathered from 12 databases. Data were extracted in duplicate using prespecified forms. RESULTS From 2,269 records screened, 18 randomized controlled trials involving 1,151 women were included. Pooled analysis demonstrated that for modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (−4.07 mg/dL [95% CI −7.58, −0.57]; P = 0.02 and −7.78 mg/dL [95% CI −12.27, −3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (−170.62 g [95% CI −333.64, −7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02). The quality of evidence for these outcomes was low to very low. Baseline differences between groups in postprandial glucose may have influenced glucose-related outcomes. As well, relatively small numbers of study participants limit between-diet comparison. CONCLUSIONS Modified dietary interventions favorably influenced outcomes related to maternal glycemia and birth weight. This indicates that there is room for improvement in usual dietary advice for women with GDM.

An Automated Grading System for Detection of Vision-Threatening Referable Diabetic Retinopathy on the Basis of Color Fundus Photographs

Abstract: OBJECTIVE The goal of this study was to describe the development and validation of an artificial intelligence–based, deep learning algorithm (DLA) for the detection of referable diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS A DLA using a convolutional neural network was developed for automated detection of vision-threatening referable DR (preproliferative DR or worse, diabetic macular edema, or both). The DLA was tested by using a set of 106,244 nonstereoscopic retinal images. A panel of ophthalmologists graded DR severity in retinal photographs included in the development and internal validation data sets (n = 71,043); a reference standard grading was assigned once three graders achieved consistent grading outcomes. For external validation, we tested our DLA using 35,201 images of 14,520 eyes (904 eyes with any DR; 401 eyes with vision-threatening referable DR) from population-based cohorts of Malays, Caucasian Australians, and Indigenous Australians. RESULTS Among the 71,043 retinal images in the training and validation data sets, 12,329 showed vision-threatening referable DR. In the internal validation data set, the area under the curve (AUC), sensitivity, and specificity of the DLA for vision-threatening referable DR were 0.989, 97.0%, and 91.4%, respectively. Testing against the independent, multiethnic data set achieved an AUC, sensitivity, and specificity of 0.955, 92.5%, and 98.5%, respectively. Among false-positive cases, 85.6% were due to a misclassification of mild or moderate DR. Undetected intraretinal microvascular abnormalities accounted for 77.3% of all false-negative cases. CONCLUSIONS This artificial intelligence–based DLA can be used with high accuracy in the detection of vision-threatening referable DR in retinal images. This technology offers potential to increase the efficiency and accessibility of DR screening programs.

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study

Abstract: OBJECTIVE This study evaluated the long-term safety and efficacy of dapagliflozin as an adjunct to adjustable insulin in patients with type 1 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS DEPICT-1 (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) was a randomized (1:1:1), double-blind, placebo-controlled Phase 3 study of dapagliflozin 5 mg and 10 mg in patients with type 1 diabetes (HbA 1c , 7.5–10.5% [58–91 mmol/mol]) (NCT02268214). The results of the 52-week study, consisting of the 24-week short-term and 28-week extension period, are reported here. RESULTS Of the 833 patients randomized into the study, 708 (85%) completed the 52-week study. Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA 1c (difference vs. placebo [95% CI] −0.33% [−0.49, −0.17] [−3.6 mmol/mol (−5.4, −1.9)] and −0.36% [−0.53, −0.20] [3.9 mmol/mol (−5.8, −2.2)], respectively) and body weight (difference vs. placebo [95% CI] −2.95% [−3.83, −2.06] and −4.54% [−5.40, −3.66], respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite diabetic ketoacidosis (DKA; 4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively). CONCLUSIONS Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in patients with type 1 diabetes, while increasing the risk of DKA.

More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial

Abstract: OBJECTIVE To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec 100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial. RESEARCH DESIGN AND METHODS BRIGHT (NCT02738151) was a multicenter, open-label, active-controlled, two-arm, parallel-group, 24-week, noninferiority study in insulin-naive patients with uncontrolled type 2 diabetes. Participants were randomized 1:1 to evening dosing with Gla-300 ( N = 466) or IDeg-100 ( N = 463), titrated to fasting self-monitored plasma glucose of 80–100 mg/dL. The primary end point was HbA 1c change from baseline to week 24. Safety end points included incidence and event rates of hypoglycemia. RESULTS At week 24, HbA 1c improved similarly from baseline values of 8.7% (72 mmol/mol) in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0% (53 mmol/mol)—least squares mean difference −0.05% (95% CI −0.15 to 0.05) (−0.6 mmol/mol [−1.7 to 0.6])—demonstrating noninferiority of Gla-300 versus IDeg-100 ( P CONCLUSIONS Gla-300 and IDeg-100 provided similar glycemic control improvements with relatively low hypoglycemia risk. Hypoglycemia incidence and rates were comparable with both insulins during the full study period but lower in favor of Gla-300 during the titration period. The choice between these longer-acting basal insulins may be determined by factors such as access and cost, alongside clinical considerations.

Global Diabetes Prevention Interventions: A Systematic Review and Network Meta-analysis of the Real-World Impact on Incidence, Weight, and Glucose

Abstract: OBJECTIVE Understanding the real-world impacts of lifestyle modification (LSM) for diabetes prevention is imperative to inform resource allocation. The purpose of this study was to synthetize global evidence on the impact of LSM strategies on diabetes incidence and risk factors in one parsimonious model. RESEARCH DESIGN AND METHODS PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for studies published between January 1990 and April 2015. Effectiveness/translation studies of any design testing LSM strategies, targeting high-risk populations (with prediabetes or diabetes risk factors), and reporting diabetes incidence, weight, or glucose outcomes were included. We extracted number of diabetes cases/incidence rates and mean changes in weight (kg), fasting blood glucose (FBG, mmol/L), 2-h postload glucose (mmol/L), and hemoglobin A 1c (%). Pairwise random-effects and frequentist random-effects network meta-analyses were used to obtain pooled effects. RESULTS Sixty-three studies were pooled in the meta-analysis ( n = 17,272, mean age 49.7 years, 28.8% male, 60.8% white/European). In analyses restricted to controlled studies ( n = 7), diabetes cumulative incidence was 9% among intervention participants and 12% among control participants (absolute risk reduction 3%; relative risk 0.71 [95% CI 0.58, 0.88]). In analyses combining controlled and uncontrolled studies ( n = 14), participants receiving group education by health care professionals had 33% lower diabetes odds than control participants (odds ratio 0.67 [0.49, 0.92]). Intervention participants lost 1.5 kg more weight [−2.2, −0.8] and achieved a 0.09 mmol/L greater FBG decrease [−0.15, −0.03] than control participants. Every additional kilogram lost by participants was associated with 43% lower diabetes odds (β = 0.57 [0.41, 0.78]). CONCLUSIONS Real-world LSM strategies can reduce diabetes risk, even with small weight reductions.

Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study

Abstract: OBJECTIVE Evaluate the efficacy and safety of the dual sodium–glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo ( n = 268), sotagliflozin 200 mg ( n = 263), or sotagliflozin 400 mg ( n = 262) after 6 weeks of insulin optimization. The primary end point was HbA 1c change from baseline at 24 weeks. HbA 1c , weight, and safety were also assessed through 52 weeks. RESULTS From a mean baseline of 7.57%, placebo-adjusted HbA 1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P 1c ≥7.0%, an HbA 1c P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were −1.08 mmol/L for fasting plasma glucose, −4.32 kg for weight, and −15.63% for bolus insulin dose and −11.87% for basal insulin dose (all P P CONCLUSIONS In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA 1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (NCT02384941).

Disparities in Environmental Exposures to Endocrine-Disrupting Chemicals and Diabetes Risk in Vulnerable Populations.

Abstract: Burgeoning epidemiological, animal, and cellular data link environmental endocrine-disrupting chemicals (EDCs) to metabolic dysfunction. Disproportionate exposure to diabetes-associated EDCs may be an underappreciated contributor to disparities in metabolic disease risk. The burden of diabetes is not uniformly borne by American society; rather, this disease disproportionately affects certain populations, including African Americans, Latinos, and low-income individuals. The purpose of this study was to review the evidence linking unequal exposures to EDCs with racial, ethnic, and socioeconomic diabetes disparities in the U.S.; discuss social forces promoting these disparities; and explore potential interventions. Articles examining the links between chemical exposures and metabolic disease were extracted from the U.S. National Library of Medicine for the period of 1966 to 3 December 2016. EDCs associated with diabetes in the literature were then searched for evidence of racial, ethnic, and socioeconomic exposure disparities. Among Latinos, African Americans, and low-income individuals, numerous studies have reported significantly higher exposures to diabetogenic EDCs, including polychlorinated biphenyls, organochlorine pesticides, multiple chemical constituents of air pollution, bisphenol A, and phthalates. This review reveals that unequal exposure to EDCs may be a novel contributor to diabetes disparities. Efforts to reduce the individual and societal burden of diabetes should include educating clinicians on environmental exposures that may increase disease risk, strategies to reduce those exposures, and social policies to address environmental inequality as a novel source of diabetes disparities.