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    Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes. Rickels Michael R,Peleckis Amy J,Dalton-Bakes Cornelia,Naji Joseph R,Ran Nina A,Nguyen Huong-Lan,O'Brien Shannon,Chen Sanjian,Lee Insup,Schutta Mark H The Journal of clinical endocrinology and metabolism Context:Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia. Objective:To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness. Design, Setting, Participants, and Intervention:Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants. Main Outcome Measure:Endogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose. Results:In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg-1·min-1) but improved after 18 months (0.84 ± 0.15 mg·kg-1·min-1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg-1·min-1; P ≤ 0.01 vs all). Conclusions:Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose. 10.1210/jc.2017-01516
    Hybrid Closed-Loop Control Is Safe and Effective for People with Type 1 Diabetes Who Are at Moderate to High Risk for Hypoglycemia. Anderson Stacey M,Buckingham Bruce A,Breton Marc D,Robic Jessica L,Barnett Charlotte L,Wakeman Christian A,Oliveri Mary C,Brown Sue A,Ly Trang T,Clinton Paula K,Hsu Liana J,Kingman Ryan S,Norlander Lisa M,Loebner Sarah E,Reuschel-DiVirglio Suzette,Kovatchev Boris P Diabetes technology & therapeutics Typically, closed-loop control (CLC) studies excluded patients with significant hypoglycemia. We evaluated the effectiveness of hybrid CLC (HCLC) versus sensor-augmented pump (SAP) in reducing hypoglycemia in this high-risk population. Forty-four subjects with type 1 diabetes, 25 women, 37 ± 2 years old, HbA1c 7.4% ± 0.2% (57 ± 1.5 mmol/mol), diabetes duration 19 ± 2 years, on insulin pump, were enrolled at the University of Virginia ( = 33) and Stanford University ( = 11). Eligibility: increased risk of hypoglycemia confirmed by 1 week of blinded continuous glucose monitor (CGM); randomized to 4 weeks of home use of either HCLC or SAP. Primary/secondary outcomes: risk for hypoglycemia measured by the low blood glucose index (LBGI)/CGM-based time in ranges. Values reported: mean ± standard deviation. From baseline to the final week of study: LBGI decreased more on HCLC (2.51 ± 1.17 to 1.28 ± 0.5) than on SAP (2.1 ± 1.05 to 1.79 ± 0.98),  < 0.001; percent time below 70 mg/dL (3.9 mmol/L) decreased on HCLC (7.2% ± 5.3% to 2.0% ± 1.4%) but not on SAP (5.8% ± 4.7% to 4.8% ± 4.5%),  = 0.001; percent time within the target range 70-180 mg/dL (3.9-10 mmol/L) increased on HCLC (67.8% ± 13.5% to 78.2% ± 10%) but decreased on SAP (65.6% ± 12.9% to 59.6% ± 16.5%),  < 0.001; percent time above 180 mg/dL (10 mmol/L) decreased on HCLC (25.1% ± 15.3% to 19.8% ± 10.1%) but increased on SAP (28.6% ± 14.6% to 35.6% ± 17.6%),  = 0.009. Mean glucose did not change significantly on HCLC (144.9 ± 27.9 to 143.8 ± 14.4 mg/dL [8.1 ± 1.6 to 8.0 ± 0.8 mmol/L]) or SAP (152.5 ± 24.3 to 162.4 ± 28.2 [8.5 ± 1.4 to 9.0 ± 1.6]),  = ns. Compared with SAP therapy, HCLC reduced the risk and frequency of hypoglycemia, while improving time in target range and reducing hyperglycemia in people at moderate to high risk of hypoglycemia. 10.1089/dia.2019.0018
    Diverse causes of hypoglycemia-associated autonomic failure in diabetes. Cryer Philip E The New England journal of medicine 10.1056/NEJMra031354
    International Consensus on Use of Continuous Glucose Monitoring. Danne Thomas,Nimri Revital,Battelino Tadej,Bergenstal Richard M,Close Kelly L,DeVries J Hans,Garg Satish,Heinemann Lutz,Hirsch Irl,Amiel Stephanie A,Beck Roy,Bosi Emanuele,Buckingham Bruce,Cobelli Claudio,Dassau Eyal,Doyle Francis J,Heller Simon,Hovorka Roman,Jia Weiping,Jones Tim,Kordonouri Olga,Kovatchev Boris,Kowalski Aaron,Laffel Lori,Maahs David,Murphy Helen R,Nørgaard Kirsten,Parkin Christopher G,Renard Eric,Saboo Banshi,Scharf Mauro,Tamborlane William V,Weinzimer Stuart A,Phillip Moshe Diabetes care Measurement of glycated hemoglobin (HbA) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, 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 these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes. 10.2337/dc17-1600
    6. Glycemic Targets: . Diabetes care The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 10.2337/dc19-S006
    Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Clarke W L,Cox D J,Gonder-Frederick L A,Julian D,Schlundt D,Polonsky W Diabetes care OBJECTIVE:To prospectively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia, to validate their self-designations in their natural environment, and to determine objectively the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose (BG) levels. RESEARCH DESIGN AND METHODS:A total of 78 insulin-dependent diabetes mellitus (IDDM) subjects (mean age 38.3 +/- 9.2 years; duration of diabetes 19.3 +/- 10.4 years) completed two sets of assessments separated by 6 months. The assessments included reports of frequency and severity of low BG, symptoms associated with low BG, and a BG symptom/estimation trial using a hand-held computer (HHC). Diaries of hypoglycemic episodes were kept for the intervening 6 months. HbA1 levels were determined at each assessment. RESULTS:Of the subjects, 39 declared themselves as having reduced awareness of hypoglycemia (reduced-awareness subjects). There were no differences between these reduced-awareness subjects and aware subjects with regard to age, sex, disease duration, insulin dose, or HbA1. During the HHC trials, reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l (33.2 +/- 47 vs. 47.6 +/- 50% detection, P = 0.001) and had significantly fewer autonomic (0.41 +/- 0.82 vs. 1.08 +/- 1.22, P = 0.006, reduced-awareness vs. aware) and neuroglycopenic (0.44 +/- 0.85 vs. 1.18 +/- 1.32, P = 0.004, reduced-awareness vs. aware) symptoms per subject. Prospective diary records revealed that reduced-awareness subjects experienced more moderate (351 vs. 238, P = 0.026) and severe (50 vs. 17, P = 0.0062) hypoglycemic events. The second assessment results were similar to the first and verified the reliability of the data. CONCLUSIONS:IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct. They have a history of more moderate and severe hypoglycemia, are less accurate at detecting BG < 3.9 mmol/l, and prospectively experience more moderate and severe hypoglycemia than do aware subjects. Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia. Reduced-awareness individuals may benefit from interventions designed to teach them to recognize all of their potential early warning symptoms. 10.2337/diacare.18.4.517
    Standardizing Clinically Meaningful Outcome Measures Beyond HbA for Type 1 Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Agiostratidou Gina,Anhalt Henry,Ball Dana,Blonde Lawrence,Gourgari Evgenia,Harriman Karen N,Kowalski Aaron J,Madden Paul,McAuliffe-Fogarty Alicia H,McElwee-Malloy Molly,Peters Anne,Raman Sripriya,Reifschneider Kent,Rubin Karen,Weinzimer Stuart A Diabetes care OBJECTIVE:To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A (HbA) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS:A Steering Committee-comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange-was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS:The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome's short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes-specific development is needed. CONCLUSIONS:The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA in the research, development, and evaluation of type 1 diabetes therapies. 10.2337/dc17-1624
    Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Battelino Tadej,Danne Thomas,Bergenstal Richard M,Amiel Stephanie A,Beck Roy,Biester Torben,Bosi Emanuele,Buckingham Bruce A,Cefalu William T,Close Kelly L,Cobelli Claudio,Dassau Eyal,DeVries J Hans,Donaghue Kim C,Dovc Klemen,Doyle Francis J,Garg Satish,Grunberger George,Heller Simon,Heinemann Lutz,Hirsch Irl B,Hovorka Roman,Jia Weiping,Kordonouri Olga,Kovatchev Boris,Kowalski Aaron,Laffel Lori,Levine Brian,Mayorov Alexander,Mathieu Chantal,Murphy Helen R,Nimri Revital,Nørgaard Kirsten,Parkin Christopher G,Renard Eric,Rodbard David,Saboo Banshi,Schatz Desmond,Stoner Keaton,Urakami Tatsuiko,Weinzimer Stuart A,Phillip Moshe Diabetes care 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. 10.2337/dci19-0028
    Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. Beck Roy W,Riddlesworth Tonya,Ruedy Katrina,Ahmann Andrew,Bergenstal Richard,Haller Stacie,Kollman Craig,Kruger Davida,McGill Janet B,Polonsky William,Toschi Elena,Wolpert Howard,Price David, JAMA Importance:Previous clinical trials showing the benefit of continuous glucose monitoring (CGM) in the management of type 1 diabetes predominantly have included adults using insulin pumps, even though the majority of adults with type 1 diabetes administer insulin by injection. Objective:To determine the effectiveness of CGM in adults with type 1 diabetes treated with insulin injections. Design, Setting, and Participants:Randomized clinical trial conducted between October 2014 and May 2016 at 24 endocrinology practices in the United States that included 158 adults with type 1 diabetes who were using multiple daily insulin injections and had hemoglobin A1c (HbA1c) levels of 7.5% to 9.9%. Interventions:Random assignment 2:1 to CGM (n = 105) or usual care (control group; n = 53). Main Outcomes and Measures:Primary outcome measure was the difference in change in central-laboratory-measured HbA1c level from baseline to 24 weeks. There were 18 secondary or exploratory end points, of which 15 are reported in this article, including duration of hypoglycemia at less than 70 mg/dL, measured with CGM for 7 days at 12 and 24 weeks. Results:Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10-31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was -0.6% (95% CI, -0.8% to -0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27-69) in the CGM group vs 80 min/d (IQR, 36-111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group. Conclusions and Relevance:Among adults with type 1 diabetes who used multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA1c level during 24 weeks. Further research is needed to assess longer-term effectiveness, as well as clinical outcomes and adverse effects. Trial Registration:clinicaltrials.gov Identifier: NCT02282397. 10.1001/jama.2016.19975
    Continuous glucose monitoring and intensive treatment of type 1 diabetes. ,Tamborlane William V,Beck Roy W,Bode Bruce W,Buckingham Bruce,Chase H Peter,Clemons Robert,Fiallo-Scharer Rosanna,Fox Larry A,Gilliam Lisa K,Hirsch Irl B,Huang Elbert S,Kollman Craig,Kowalski Aaron J,Laffel Lori,Lawrence Jean M,Lee Joyce,Mauras Nelly,O'Grady Michael,Ruedy Katrina J,Tansey Michael,Tsalikian Eva,Weinzimer Stuart,Wilson Darrell M,Wolpert Howard,Wysocki Tim,Xing Dongyuan The New England journal of medicine BACKGROUND:The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS:In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS:The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS:Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.) 10.1056/NEJMoa0805017
    The Fallacy of Average: How Using HbA Alone to Assess Glycemic Control Can Be Misleading. Beck Roy W,Connor Crystal G,Mullen Deborah M,Wesley David M,Bergenstal Richard M Diabetes care HbA is a v 10.2337/dc17-0636
    Treatment of Diabetes in Older Adults: An Endocrine Society* Clinical Practice Guideline. LeRoith Derek,Biessels Geert Jan,Braithwaite Susan S,Casanueva Felipe F,Draznin Boris,Halter Jeffrey B,Hirsch Irl B,McDonnell Marie E,Molitch Mark E,Murad M Hassan,Sinclair Alan J The Journal of clinical endocrinology and metabolism OBJECTIVE:The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults. CONCLUSIONS:Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects. 10.1210/jc.2019-00198
    State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Foster Nicole C,Beck Roy W,Miller Kellee M,Clements Mark A,Rickels Michael R,DiMeglio Linda A,Maahs David M,Tamborlane William V,Bergenstal Richard,Smith Elizabeth,Olson Beth A,Garg Satish K Diabetes technology & therapeutics OBJECTIVE:To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. RESEARCH DESIGN AND METHODS:Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants. RESULTS:Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of <58 mmol/mol for youth was achieved by only 17% and the goal of <53 mmol/mol for adults by only 21%. Mean HbA1c levels changed little between 2010-2012 and 2016-2018, except in adolescents who had a higher mean HbA1c in 2016-2018. Insulin pump use increased from 57% in 2010-2012 to 63% in 2016-2018. Continuous glucose monitoring (CGM) increased from 7% in 2010-2012 to 30% in 2016-2018, rising >10-fold in children <12 years old. HbA1c levels were lower in CGM users than nonusers. Severe hypoglycemia was most frequent in participants ≥50 years old and diabetic ketoacidosis was most common in adolescents and young adults. Racial differences were evident in use of pumps and CGM and HbA1c levels. CONCLUSIONS:Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c. 10.1089/dia.2018.0384
    Evaluation of an intensified insulin treatment and teaching programme as routine management of type 1 (insulin-dependent) diabetes. The Bucharest-Düsseldorf Study. Mühlhauser I,Bruckner I,Berger M,Cheţa D,Jörgens V,Ionescu-Tîrgovişte C,Scholz V,Mincu I Diabetologia It has been questioned whether aiming at near-normoglycaemia by intensified insulin treatment regimens is feasible and safe for the majority of patients with insulin-dependent diabetes. In this study, intensified insulin injection therapy (including blood glucose self-monitoring and multiple insulin injections) based upon a 5-day inpatient group teaching programme was evaluated in Type 1 (insulin-dependent) diabetes mellitus in the centralised health care system of Bucharest. One hundred patients (group A, initial HbA1 12.5%) were followed for 1 year on their standard therapy (individual teaching, no metabolic self-monitoring), and thereafter for 1 year on intensified therapy. Another 100 patients (group B, HbA1 12.3%) were followed for 2 years on intensified therapy. A third 100 patients (group C, HbA1 11.7%) were assigned to a basic 4-day inpatient group teaching programme with conventional insulin therapy (including self-monitoring of glucosuria and acetonuria) and followed for 1 year. Mean HbA1 remained unchanged after standard treatment (group A: 12.8% at 12 months), but decreased during intensified therapy (group A: 10.1% at 24 months; group B: 9.3% at 12 months, 9.5% at 24 months; p less than 0.0001). In group C, no change was found compared to standard treatment (i.e. group A at 12 months). Incidence rates of ketoacidosis were 0.16 episodes per patient per year during standard treatment, 0.01 during intensified treatment (p less than 0.01) and 0.04 in group C (p less than 0.025). Hospitalisation rates were reduced by 60% during intensified therapy and by 40% in group C. Frequency of severe hypoglycaemia was not significantly different between the three treatment regimens. Thus, under the condition that insulin treatment is based upon a structured and comprehensive training of the patient, intensified insulin injection therapy performed as routine treatment of Type 1 diabetes significantly lowers HbA1 levels without increasing the risk of severe hypoglycaemia.
    Approaches to rapid acting insulin intensification in patients with type 2 diabetes mellitus not achieving glycemic targets. Migdal Alexandra,Abrahamson Martin,Peters Anne,Vint Nan Annals of medicine Type 2 diabetes mellitus (T2DM) is a growing problem in the USA, affecting 30.3 million Americans, or 9.4% of the US population. Given that T2DM is a progressive disease, intensification of rapid acting insulin (RAI) to address hyperglycaemia is often required. The American Diabetes Association and the European Association for the Study of Diabetes recommend individualizing the treatment approach to glucose control, considering factors such as age, health behaviours, comorbidities and life expectancy. There are several validated treatment algorithms in the literature, which can be helpful for providing guidance on initiation of RAI while simultaneously considering patient preferences and clinical needs during treatment intensification. This paper provides expert recommendations on prandial insulin regimens and how to use treatment algorithms to promote better glucose control through best practice guidelines. To help patients reach HbA1c targets through treatment intensification, the FullSTEP, SimpleSTEP, ExtraSTEP and AUTONOMY algorithms are discussed in this paper. KEY MESSAGES Clinical inertia should be prevented with timely intensification of therapy when HbA1c levels are greater than 7% (or rising above a patient's individual target) according to national guidelines. Increased personalization in the intensification of T2D treatment is necessary to improve HbA1c targets while addressing risk of hypoglycaemia, concern about weight gain, and overall health goals. Healthcare providers are encouraged to address glycaemic control with a variety of strategies, including prandial insulin, while developing evidence-based treatment plans on the basis of algorithms discussed in the literature. 10.1080/07853890.2018.1493216
    Severe hypoglycemia is associated with high risk for falls in adults with type 1 diabetes. Shah Viral N,Wu Mengdi,Foster Nicole,Dhaliwal Ruban,Al Mukaddam Mona Archives of osteoporosis We evaluated fall frequency and factors affecting falls among middle-aged and older adults with type 1 diabetes (T1D) from T1D Exchange Registry. Twenty-nine percent of T1D participants reported falls within the past 12 months. Severe hypoglycemia, diabetic peripheral neuropathy, and depression were associated with falls in adults with T1D. PURPOSE:Fall is an important risk factor for osteoporotic fracture; we evaluated fall frequency and factors affecting falls among middle-aged and older adults with type 1 diabetes (T1D). METHODS:Participants aged ≥ 55 years with T1D completed an email-based questionnaire on falls in the prior 12 months. Demographic, clinical, and fall-related information were gathered from the questionnaire; HbA1c was recorded from medical record data extraction. RESULTS:Four hundred and thirty five adults with T1D completed the fall questionnaire (mean age 64 ± 7 years, 57% females, and 97% were non-Hispanic whites). The mean diabetes duration was 36 years with mean HbA1c of 7.3%. Among the 435 participants, 126 reported at least one fall in the prior 12 months (29%). The fall frequency values in adults (55-64 years) with T1D and older adults (> 65 years) were 26 and 32%, respectively (p = 0.16). There was no significant difference in frequency of fall between female and male participants (31 vs. 26%, p = 0.33). Of 126 participants who had a fall, 44% had injuries due to fall, 24% required medical attention, and 13 participants reported fracture (10%). Severe hypoglycemia (odds ratio (OR) 3.6), diabetic peripheral neuropathy (OR 2.2), and depression (OR 1.7) were associated with falls in adults with T1D. Forty-one percent of participants were fearful of falls. CONCLUSIONS:This is the first study on prevalence and risk factors for falls suggesting that falls are common in T1D and severe hypoglycemia is a unique diabetes-related factor associated with threefold higher risk for falls. 10.1007/s11657-018-0475-z
    Determinants of fracture in adults with type 1 diabetes in the USA: Results from the T1D Exchange Clinic Registry. Dhaliwal Ruban,Foster Nicole C,Boyle Claire,Al Mukaddam Mona,Weinstock Ruth S,Rickels Michael R,Shah Viral N,DiMeglio Linda A Journal of diabetes and its complications AIMS:To examine the prevalence/determinants of fracture in the T1D Exchange Clinic Registry. RESEARCH DESIGN/METHODS:Adults (≥18 years) with T1D duration ≥5 years, diagnosed before age 45 years completed a fracture questionnaire. Additional characteristics were collected from registry data. Only fractures reported as occurring after T1D diagnosis were included. Characteristics were compared between those with and without fractures. RESULTS:Respondents included 756 adults (mean age 39 ± 16 years, 28% ≥50 years, 63% female, 90% non-Hispanic White, diabetes duration 24 ± 14 years); 48% reported ≥1 fracture since diagnosis. Of the 659 reported fractures, 24% involved metatarsal/toe, 21% metacarpal/fingers, 14% fibula/tibia, 5% hip/pelvis/femur and 3% vertebrae. Those with fracture were more likely to be older (43 ± 16 vs. 36 ± 14 years), have longer T1D duration (28 ± 14 vs. 20 ± 12 years), been diagnosed with T1D before age 20 years (79% vs. 71%) compared to those without fracture (all p-values < 0.01). CONCLUSIONS:Data from this national sample suggest fractures in adults with T1D are common at young age and frequently involve peripheral sites. Age, longer diabetes duration, and T1D diagnosis prior to peak bone mass accrual are notable risk factors. Further research is needed to examine the impact of these determinants on fracture risk in T1D. 10.1016/j.jdiacomp.2018.08.016
    Risk Factors Associated With Severe Hypoglycemia in Older Adults With Type 1 Diabetes. Weinstock Ruth S,DuBose Stephanie N,Bergenstal Richard M,Chaytor Naomi S,Peterson Christina,Olson Beth A,Munshi Medha N,Perrin Alysa J S,Miller Kellee M,Beck Roy W,Liljenquist David R,Aleppo Grazia,Buse John B,Kruger Davida,Bhargava Anuj,Goland Robin S,Edelen Rachel C,Pratley Richard E,Peters Anne L,Rodriguez Henry,Ahmann Andrew J,Lock John-Paul,Garg Satish K,Rickels Michael R,Hirsch Irl B, Diabetes care OBJECTIVE:Severe hypoglycemia is common in older adults with long-standing type 1 diabetes, but little is known about factors associated with its occurrence. RESEARCH DESIGN AND METHODS:A case-control study was conducted at 18 diabetes centers in the T1D Exchange Clinic Network. Participants were ≥60 years old with type 1 diabetes for ≥20 years. Case subjects (n = 101) had at least one severe hypoglycemic event in the prior 12 months. Control subjects (n = 100), frequency-matched to case subjects by age, had no severe hypoglycemia in the prior 3 years. Data were analyzed for cognitive and functional abilities, social support, depression, hypoglycemia unawareness, various aspects of diabetes management, C-peptide level, glycated hemoglobin level, and blinded continuous glucose monitoring (CGM) metrics. RESULTS:Glycated hemoglobin (mean 7.8% vs. 7.7%) and CGM-measured mean glucose (175 vs. 175 mg/dL) were similar between case and control subjects. More case than control subjects had hypoglycemia unawareness: only 11% of case subjects compared with 43% of control subjects reported always having symptoms associated with low blood glucose levels (P < 0.001). Case subjects had greater glucose variability than control subjects (P = 0.008) and experienced CGM glucose levels <60 mg/dL for ≥20 min on 46% of days compared with 33% of days in control subjects (P = 0.10). On certain cognitive tests, case subjects scored worse than control subjects. CONCLUSIONS:In older adults with long-standing type 1 diabetes, greater hypoglycemia unawareness and glucose variability are associated with an increased risk of severe hypoglycemia. A study to assess interventions to prevent severe hypoglycemia in high-risk individuals is needed. 10.2337/dc15-1426
    Associations between recent severe hypoglycemia, retinal vessel diameters, and cognition in adults with type 1 diabetes. Ryan Christopher M,Klein Barbara E K,Lee Kristine E,Cruickshanks Karen J,Klein Ronald Journal of diabetes and its complications AIMS:Mild cognitive dysfunction has been identified in children and adults with type 1 diabetes, but most studies have failed to find a relationship between severe hypoglycemia and cognition, despite reports of such associations in older adults with type 2 diabetes. Focusing on older adults with type 1 diabetes, we examined the associations between cognitive performance and recent episodes of severe hypoglycemia, retinal vessel diameters and the presence of micro- and macrovascular complications. METHODS:Cognitive functioning was assessed in 244 participants enrolled in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The mean (SD; range) age at assessment in 2012-14 was 55.2 (8.3; 37-82) years and the mean (SD) duration of diabetes was 41.1 (5.6) years. Three cognitive domains were assessed in this cross-sectional study: mental efficiency and executive function, nonverbal memory, and verbal memory. RESULTS:Multivariate modeling demonstrated that although age and/or education are most strongly associated with performance on measures of mental efficiency, three diabetes-related variables were also associated with poorer test scores: an episode of severe hypoglycemia in the past year (β=-0.360 [95% CI, -0.672, -0.047]), retinal arteriolar and venular diameters (β=0.140 [95% CI, 0.062, 0.219]; β=-0.127 [95% CI -0.207, -0.047]), and carotid artery plaque (β=-0.372 [95% CI -0.741, -0.003]). In addition, recent severe hypoglycemia was associated with poorer nonverbal memory (β=-0.522 [95% CI, -0.849, -0.194]). CONCLUSIONS:For middle-aged and older adults with long-duration type 1 diabetes, poorer cognition was associated with a recent episode of severe hypoglycemia as well as with the presence of micro- and/or macrovascular conditions. Given the increasing numbers of aging adults with type 1 diabetes, future longitudinal studies are needed to identify causality and to determine whether diabetes management techniques that reduce the onset or severity of vascular complications and hypoglycemia can also reduce the risk of cognitive dysfunction in this population. 10.1016/j.jdiacomp.2016.08.010
    Severe hypoglycemia and risks of vascular events and death. Zoungas Sophia,Patel Anushka,Chalmers John,de Galan Bastiaan E,Li Qiang,Billot Laurent,Woodward Mark,Ninomiya Toshiharu,Neal Bruce,MacMahon Stephen,Grobbee Diederick E,Kengne Andre Pascal,Marre Michel,Heller Simon, The New England journal of medicine BACKGROUND:Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS:We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS:During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS:Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.). 10.1056/NEJMoa1003795
    Response to Comment on Weber et al. Type 1 Diabetes is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN). Diabetes Care 2015;38:1913-1920. Weber David R,Haynes Kevin,Leonard Mary B,Willi Steven M,Denburg Michelle R Diabetes care 10.2337/dci15-0019
    Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases: silent hypoglycemias and silent arrhythmias. Stahn Annett,Pistrosch Frank,Ganz Xenia,Teige Madlen,Koehler Carsta,Bornstein Stefan,Hanefeld Markolf Diabetes care OBJECTIVE:In patients with type 2 diabetes and cardiovascular diseases (CVDs), intensive treatment with insulin and/or sulfonylurea (SU) may be associated with excessive increased risk of hypoglycemic episodes. To evaluate the risk of critical arrhythmias related to glycemic variability, we carried out an observational study in type 2 diabetes patients with CVD. RESEARCH DESIGN AND METHODS:Thirty patients with type 2 diabetes and documented CVD who had been treated with insulin and/or SU underwent 5 days of monitoring with a continuous glucose measurement system along with parallel electrocardiogram recording for monitoring of ventricular arrhythmias. Twelve age-matched patients with documented CVD who received treatment with metformin and/or dipeptidyl peptidase-4 inhibitor served as the control group. Patients were receiving stable treatment, and were instructed to notice symptoms of arrhythmias and hypoglycemia, respectively. RESULTS:We observed a high incidence of asymptomatic severe episodes of hypoglycemia (<3.1 mmol/L) in patients receiving treatment with insulin and/or SU, whereas severe hypoglycemia did not develop in any of the control subjects. Patients with severe hypoglycemia (n = 12) had a higher number of severe ventricular arrhythmias (patients with versus without severe hypoglycemia, respectively: ventricular couplets 41.7 ± 81.8 vs. 5.5 ± 16.7; ventricular tachycardia 1.0 ± 1.9 vs. 0.1 ± 0.3). No direct correlation could be found among different variables of glucose profile, corrected QT interval, and ventricular arrhythmias. CONCLUSIONS:Our results suggest that severe episodes of hypoglycemia are associated with an increased risk of severe ventricular arrhythmias. 10.2337/dc13-0600
    Oxygenation of frog gastric mucosa in vitro. Kidder G W,Montgomery C W The American journal of physiology We have recently shown that 5% CO2/95% O2 in the serosal bathing solution, with 100% O2 in the mucosal solution, results in CO2-diffusion limitation of acid secretion in bullfrog gastric mucosa. Changing to 10% CO2/90% 02 on both surfaces doubles the acid secretory rate. We calculate that, were the rate of oxygen consumption to increase significantly as a result of secretory stimulation, the tissue would now be oxygen limited. This prediction is tested by raising the P02 by increasing the total pressure in a hyperbaric chamber. Since no change in acid secretory rate or potential difference was observed upon changing from PO2 = 0.9 to PO2 = 1.9 atm, we conclude that the tissue is not O2 limited at normal pressure. Decreasing PO2 below 0.9 atm, by contrast, decreases the acid secretory rate and raises both PD and resistance. We infer that the rate of oxygen consumption did not rise significantly when acid secretion was increased by supplying sufficient CO2. 10.1152/ajplegacy.1975.229.6.1510
    Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange clinic registry. Weinstock Ruth S,Xing Dongyuan,Maahs David M,Michels Aaron,Rickels Michael R,Peters Anne L,Bergenstal Richard M,Harris Breanne,Dubose Stephanie N,Miller Kellee M,Beck Roy W, The Journal of clinical endocrinology and metabolism CONTEXT:Few studies have assessed factors associated with severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D). OBJECTIVE:Our objective was to determine frequency of and factors associated with the occurrence of SH and DKA in adults with T1D. DESIGN AND SETTING:We conducted a cross-sectional analysis from the T1D Exchange clinic registry at 70 U.S. endocrinology centers. PATIENTS:Analysis included 7012 participants in the T1D Exchange clinic registry aged 26 to 93 years old with T1D for ≥2 years. RESULTS:Higher frequencies of SH and DKA were associated with lower socioeconomic status (P < .001). SH was strongly associated with diabetes duration (P < .001), with 18.6% of those with diabetes ≥40 years having an event in the past 12 months. SH frequency was lowest in those with hemoglobin A1c (HbA1c) levels of 7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), being higher in those with HbA1c levels <7.0% (<53 mmol/mol) or >7.5% (>58 mmol/mol). DKA frequency increased with higher HbA1c levels (P < .001), with 21.0% of those with HbA1c ≥10.0% (≥86 mmol/mol) having an event in the past 12 months. CONCLUSIONS:SH and DKA are more common in those with lower socioeconomic status. DKA, most common in those with HbA1c ≥10.0% (≥86 mmol/mol), should be largely preventable. In contrast, SH, most frequent with diabetes ≥40 years duration, cannot be abolished given the limitation of current therapies. To reduce SH in adults with longstanding diabetes, consideration should be given to modifying HbA1c goals, particularly in patients with very low HbA1c levels. 10.1210/jc.2013-1589
    Increased mortality of patients with diabetes reporting severe hypoglycemia. McCoy Rozalina G,Van Houten Holly K,Ziegenfuss Jeanette Y,Shah Nilay D,Wermers Robert A,Smith Steven A Diabetes care OBJECTIVE:Hypoglycemia is a cause of significant morbidity among patients with diabetes and may be associated with greater risk of death. We conducted a retrospective study to determine whether patient self-report of severe hypoglycemia is associated with increased mortality. RESEARCH DESIGN AND METHODS:Adult patients (N = 1,020) seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned about frequency of hypoglycemia during a preencounter interview; 7 were lost to follow-up and excluded from analysis. Mild hypoglycemia was defined as symptoms managed without assistance, and severe hypoglycemia was defined as symptoms requiring external assistance. Mortality data, demographics, clinical characteristics, and Charlson comorbidity index (CCI) were obtained from the electronic medical record after 5 years. Patients were stratified by self-report of hypoglycemia at baseline, demographics were compared using the two-sample t test, and risk of death was expressed as odds ratio (95% CI). Associations were controlled for age, sex, diabetes type and duration, CCI, HbA(1c), and report of severe hypoglycemia. RESULTS:In total, 1,013 patients with type 1 (21.3%) and type 2 (78.7%) diabetes were questioned about hypoglycemia. Among these, 625 (61.7%) reported any hypoglycemia, and 76 (7.5%) reported severe hypoglycemia. After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5-7.4; P = 0.005) compared with those who reported mild/no hypoglycemia. CONCLUSIONS:Self-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes. 10.2337/dc11-2054
    Cost-effectiveness of Initiating an Insulin Pump in T1D Adults Using Continuous Glucose Monitoring Compared with Multiple Daily Insulin Injections: The DIAMOND Randomized Trial. Wan Wen,Skandari M Reza,Minc Alexa,Nathan Aviva G,Zarei Parmida,Winn Aaron N,O'Grady Michael,Huang Elbert S Medical decision making : an international journal of the Society for Medical Decision Making BACKGROUND:The economic impact of both continuous glucose monitoring (CGM) and insulin pumps (continuous subcutaneous insulin infusion [CSII]) in type 1 diabetes (T1D) have been evaluated separately. However, the cost-effectiveness of adding CSII to existing CGM users has not yet been assessed. OBJECTIVE:The aim of this study was to evaluate the societal cost-effectiveness of CSII versus continuing multiple daily injections (MDI) in adults with T1D already using CGM. METHODS:In the second phase of the DIAMOND trial, 75 adults using CGM were randomized to either CGM+CSII or CGM+MDI (control) and surveyed at baseline and 28 weeks. We performed within-trial and lifetime cost-effectiveness analyses (CEAs) and estimated lifetime costs and quality-adjusted life-years (QALYs) via a modified Sheffield T1D model. RESULTS:Within the trial, the CGM+CSII group had a significant reduction in quality of life from baseline (-0.02 ± 0.05 difference in difference [DiD]) compared with controls. Total per-person 28-week costs were $8,272 (CGM+CSII) versus $5,623 (CGM+MDI); the difference in costs was primarily attributable to pump use ($2,644). Pump users reduced insulin intake (-12.8 units DiD) but increased the use of daily number of test strips (+1.2 DiD). Pump users also increased time with glucose in range of 70 to 180 mg/dL but had a higher HbA1c (+0.13 DiD) and more nonsevere hypoglycemic events. In the lifetime CEA, CGM+CSII would increase total costs by $112,045 DiD, decrease QALYs by 0.71, and decrease life expectancy by 0.48 years. CONCLUSIONS:Based on this single trial, initiating an insulin pump in adults with T1D already using CGM was associated with higher costs and reduced quality of life. Additional evidence regarding the clinical effects of adopting combinations of new technologies from trials and real-world populations is needed to confirm these findings. 10.1177/0272989X18803109
    The burden of severe hypoglycemia in type 1 diabetes. Liu Jieruo,Wang Rosa,Ganz Michael L,Paprocki Yurek,Schneider Doron,Weatherall James Current medical research and opinion AIMS:Approximately 1.25 million people in the US have type 1 diabetes mellitus (T1DM), a chronic metabolic disease that develops from the body's inability to produce insulin, and requires life-long insulin therapy. Poor insulin adherence may cause severe hypoglycemia (SHO), leading to hospitalization and long-term complications; these, in turn, drive up costs of SHO and T1DM overall. This study's objective was to estimate the prevalence and costs of SHO-related hospitalizations and their additional longer-term impacts on patients with T1DM using basal-bolus insulin. METHODS:Using Truven MarketScan claims, we identified adult T1DM patients using basal-bolus insulin regimens who were hospitalized for SHO (inpatient SHO patients) during 2010-2015. Two comparison groups were defined: those with outpatient SHO-related encounters only, including emergency department (ED) visits without hospitalization (outpatient SHO patients), and those with no SHO- or acute hyperglycemia-related events (comparison patients). Lengths of stay and SHO-related hospitalization costs were estimated and propensity score and inverse probability weighting methods were used to adjust for baseline differences across the groups to evaluate longer-term impacts. RESULTS:We identified 8,734 patients, of which 4.2% experienced at least one SHO-related hospitalization. Among those who experienced SHO (i.e. of those in the inpatient and outpatient SHO groups), 31% experienced at least one SHO-related hospitalization, while 9% were treated in the ED without subsequent hospitalization. Approximately 79% of patients were admitted directly to the hospital; the remainder were first assessed or treated in the ED. The inpatient SHO patients stayed in the hospital, including time in the ED, for 1.7 days and incurred $3551 in costs. About one-third of patients were hospitalized again for SHO. Inpatient SHO patients incurred significantly higher monthly costs after their initial SHO-related hospitalization than patients in the two other groups ($2084 vs $1313 and $1372), corresponding to 59% or 52% higher monthly costs for inpatient SHO patients. LIMITATIONS:These analyses excluded patients who did not seek ED or hospital care when faced with SHO; events may have been miscoded; and we were not able to account for clinical characteristics associated with SHO, such as insulin dose and duration of diabetes, or unmeasured confounders. CONCLUSIONS:The burden associated with SHO is not negligible. About 4% of T1DM patients using basal-bolus insulin regimens are hospitalized at least once due to SHO. Not only did those patients incur the costs of their SHO hospitalization, but they also incur red at least $712 (52%) more in costs per month after their hospitalization than outpatient SHO or comparison patients. Reducing SHO events can help decrease the burden associated with SHO among patients with T1DM. 10.1080/03007995.2017.1391079
    National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. Lipska Kasia J,Ross Joseph S,Wang Yun,Inzucchi Silvio E,Minges Karl,Karter Andrew J,Huang Elbert S,Desai Mayur M,Gill Thomas M,Krumholz Harlan M JAMA internal medicine IMPORTANCE:The increasing intensity of diabetes mellitus management over the past decade may have resulted in lower rates of hyperglycemic emergencies but higher rates of hospital admissions for hypoglycemia among older adults. Trends in these hospitalizations and subsequent outcomes are not known. OBJECTIVE:To characterize changes in hyperglycemia and hypoglycemia hospitalization rates and subsequent mortality and readmission rates among older adults in the United States over a 12-year period, and to compare these results according to age, sex, and race. DESIGN, SETTING, AND PATIENTS:Retrospective observational study using data from 33,952,331 Medicare fee-for-service beneficiaries 65 years or older from 1999 to 2011. MAIN OUTCOMES AND MEASURES:Hospitalization rates for hyperglycemia and hypoglycemia, 30-day and 1-year mortality rates, and 30-day readmission rates. RESULTS:A total of 279,937 patients experienced 302,095 hospitalizations for hyperglycemia, and 404,467 patients experienced 429,850 hospitalizations for hypoglycemia between 1999 and 2011. During this time, rates of admissions for hyperglycemia declined by 38.6% (from 114 to 70 admissions per 100,000 person-years), while admissions for hypoglycemia increased by 11.7% (from 94 to 105 admissions per 100,000 person-years). In analyses designed to account for changing diabetes mellitus prevalence, admissions for hyperglycemia and hypoglycemia declined by 55.2% and 9.5%, respectively. Trends were similar across age, sex, and racial subgroups, but hypoglycemia rates were 2-fold higher for older patients (≥75 years) when compared with younger patients (65-74 years), and admission rates for both hyperglycemia and hypoglycemia were 4-fold higher for black patients compared with white patients. The 30-day and 1-year mortality and 30-day readmission rates improved during the study period and were similar after an index hospitalization for either hyperglycemia or hypoglycemia (5.4%, 17.1%, and 15.3%, respectively, after hyperglycemia hospitalizations in 2010; 4.4%, 19.9%, and 16.3% after hypoglycemia hospitalizations). CONCLUSIONS AND RELEVANCE:Hospital admission rates for hypoglycemia now exceed those for hyperglycemia among older adults. Although admissions for hypoglycemia have declined modestly since 2007, rates among black Medicare beneficiaries and those older than 75 years remain high. Hospital admissions for severe hypoglycemia seem to pose a greater health threat than those for hyperglycemia, suggesting new opportunities for improvement in care of persons with diabetes mellitus. 10.1001/jamainternmed.2014.1824
    Cardiovascular Risk in Type 1 Diabetes Mellitus. Schofield Jonathan,Ho Jan,Soran Handrean Diabetes therapy : research, treatment and education of diabetes and related disorders Type 1 diabetes mellitus (T1DM) is associated with premature cardiovascular disease (CVD), but the underlying mechanisms remain poorly understood. The American Diabetes Association and the European Association for the Study of Diabetes recently updated their position statement on the management of type 2 diabetes mellitus (T2DM) to include additional focus on cardiovascular risk; improved management of risk factors in T1DM is also needed. There are important differences in the pathophysiology of CVD in T1DM and T2DM. Hyperglycaemia appears to have a more profound effect on cardiovascular risk in T1DM than T2DM, and other risk factors appear to cause a synergistic rather than additive effect, so achievement of treatment targets for all recognized risk factors is crucial to reducing cardiovascular risk. Here we discuss the evidence for addressing established cardiovascular risk factors, candidate biomarkers and surrogate measurements, and possible interventions. 10.1007/s13300-019-0612-8
    Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. You Wen-Peng,Henneberg Maciej BMJ open diabetes research & care OBJECTIVE:Prevalence of type 1 diabetes (T1D) disease is increasing worldwide. We aim to test correlation of T1D prevalence to the reduced natural selection measured by Biological State Index (Ibs). RESEARCH DESIGN AND METHODS:Country-specific estimates of T1D prevalence, life expectancy, obesity prevalence rate, urbanization rates, per capita sugars consumption and per capita gross domestic product (GDP) were obtained. Ibs and country-specific longevity (e50) increase for each country were self-calculated. These data were then matched to T1D prevalence by country for our ecological study among 118 countries. Countries were also grouped to study the associations in different regions. SPSS V.22 was used for correlation analysis. RESULTS:Worldwide, both Ibs and life expectancy at birth (Ibs proxy) were significantly correlated to T1D prevalence in Pearson r (r=0.713, p<0.001 and r=0.722, p<0.001, respectively) and Spearman's r (r=0.724, p<0.001 and r=0.689, p<0.001, respectively). T1D prevalence was not correlated to longevity increase measured as life expectancy at 50 years old. T1D prevalence was significantly associated with I bs (r=0.307, p<0.001) and newborn life expectancy (r=0.349, p<0.001) independent of per capita total sugar consumption, per capita GDP, urbanization and obesity prevalence in partial correlation. Globally, both life expectancy at birth and Ibs exponentially correlated to T1D prevalence. Pearson correlations generally existed in different country categorizations by geographic region, culture background and economic status. CONCLUSIONS:Reduced natural selection may have contributed to the increasing T1D prevalence worldwide. T1D epidemiology study in total population may be the practical solution to identify the causes of increasing T1D prevalence. 10.1136/bmjdrc-2015-000161
    Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Chiang Jane L,Kirkman M Sue,Laffel Lori M B,Peters Anne L, Diabetes care 10.2337/dc14-1140
    Retention Among Participants in the National Diabetes Prevention Program Lifestyle Change Program, 2012-2017. Cannon Michael J,Masalovich Svetlana,Ng Boon Peng,Soler Robin E,Jabrah Rajai,Ely Elizabeth K,Smith Bryce D Diabetes care OBJECTIVE:To assess retention in the National Diabetes Prevention Program (DPP) lifestyle change program, which seeks to prevent type 2 diabetes in adults at high risk. RESEARCH DESIGN AND METHODS:We analyzed retention among 41,203 individuals who enrolled in Centers for Disease Control and Prevention (CDC)-recognized in-person lifestyle change programs at organizations that submitted data to CDC's Diabetes Prevention Recognition Program during January 2012-February 2017. RESULTS:Weekly attrition rates were typically <1-2% but were between 3.5% and 5% at week 2 and at weeks 17 and 18, where session frequency typically transitions from weekly to monthly. The percentage of participants retained through 18 weeks varied by age (45.9% for 18-29 year olds, 53.4% for 30-44 year olds, 60.2% for 45-54 year olds, 66.7% for 55-64 year olds, and 67.6% for ≥65 year olds), race/ethnicity (70.5% for non-Hispanic whites, 60.5% for non-Hispanic blacks, 52.6% for Hispanics, and 50.6% for other), mean weekly percentage of body weight lost (41.0% for ≤0% lost, 66.2% for >0% to <0.25% lost, 72.9% for 0.25% to <0.5% lost, and 73.9% for ≥0.5% lost), and mean weekly physical activity minutes (12.8% for 0 min, 56.1% for >0 to <60 min, 74.8% for 60 to <150 min, and 82.8% for ≥150 min) but not by sex (63.0% for men and 63.1% for women). CONCLUSIONS:Our results demonstrate the need to identify strategies to improve retention, especially among individuals who are younger or are members of racial/ethnic minority populations and among those who report less physical activity or less early weight loss. Strategies that address retention after the first session and during the transition from weekly to monthly sessions offer the greatest opportunity for impact. 10.2337/dc19-2366
    Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. Cannon Christopher P,Blazing Michael A,Giugliano Robert P,McCagg Amy,White Jennifer A,Theroux Pierre,Darius Harald,Lewis Basil S,Ophuis Ton Oude,Jukema J Wouter,De Ferrari Gaetano M,Ruzyllo Witold,De Lucca Paul,Im KyungAh,Bohula Erin A,Reist Craig,Wiviott Stephen D,Tershakovec Andrew M,Musliner Thomas A,Braunwald Eugene,Califf Robert M, The New England journal of medicine BACKGROUND:Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS:We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS:The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS:When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.). 10.1056/NEJMoa1410489
    Intensive versus moderate lipid lowering with statins after acute coronary syndromes. Cannon Christopher P,Braunwald Eugene,McCabe Carolyn H,Rader Daniel J,Rouleau Jean L,Belder Rene,Joyal Steven V,Hill Karen A,Pfeffer Marc A,Skene Allan M, The New England journal of medicine BACKGROUND:Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. METHODS:We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). RESULTS:The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. CONCLUSIONS:Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels. 10.1056/NEJMoa040583
    Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. Schwartz G G,Olsson A G,Ezekowitz M D,Ganz P,Oliver M F,Waters D,Zeiher A,Chaitman B R,Leslie S,Stern T, JAMA CONTEXT:Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. OBJECTIVE:To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. DESIGN AND SETTING:A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. PATIENTS:A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. INTERVENTIONS:Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. MAIN OUTCOME MEASURES:Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. RESULTS:A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). CONCLUSION:For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization. 10.1001/jama.285.13.1711
    Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Fox K A A,Goodman S G,Klein W,Brieger D,Steg P G,Dabbous O,Avezum A European heart journal AIMS:Despite advances in the treatment of acute coronary syndromes based on randomized trial data and published guidelines, the extent to which such treatments are applied in practice remains uncertain. Data from clinical trials derive from selected geographical areas and in highly selected populations of patients, and hence may not reflect the overall population. The aim of the study was to investigate variations in hospital management and outcome using unselected data collected in the prospective Global Registry of Acute Coronary Events (GRACE). METHODS AND RESULTS:The 95 hospitals in GRACE were organized into 18 population-based clusters in 14 countries. Information was recorded about patient management and outcome during hospitalization and after discharge. Data on treatments administered were analysed by baseline condition, hospital type, by the presence or absence of a catheterization laboratory, and by geographical region. Of 11543 patients, 44% had an admission diagnosis of unstable angina, 36% presented with myocardial infarction, 9% were admitted to rule out a myocardial infarction, 7% had chest pain and 4% were hospitalized for 'other cardiac' and 'non-cardiac' diagnoses. Of the total GRACE population 38% had a final diagnosis of unstable angina, 30% ST-segment elevation myocardial infarction, 25% non-ST-segment elevation myocardial infarction, and 7% of 'other cardiac' and 'non-cardiac' final diagnoses. The event rates for hospital death or reinfarction were six and 2% for non-ST-segment elevation myocardial infarction, seven and 3% for ST-segment elevation myocardial infarction, and 3% hospital death for unstable angina. The use of aspirin was similar across all hospital types and geographical regions. In contrast, the use of percutaneous coronary intervention and glycoprotein IIb/IIIa inhibitors was higher (P<0.0001) in teaching hospitals and hospitals with catheterization laboratories and was also higher in the United States. At discharge a higher percentage (P<0.0001) of patients received angiotensin-converting enzyme inhibitors in hospitals without catheterization laboratories. The use of statins was lower in non-teaching hospitals and in centres without a catheterization laboratory. CONCLUSIONS:The GRACE study reveals substantial differences in the management of patients based on hospital type and geographical location. Further analyses will determine whether such variations translate into differences in longer term outcomes. GRACE provides a multinational reference for the implementation of therapies of proven efficacy. 10.1053/euhj.2001.3081
    6. Glycemic Targets: . Diabetes care The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 10.2337/dc20-S006
    Empowering patients during insulin initiation: a real-world approach. LaSalle James R The Journal of the American Osteopathic Association Glycemic control is suboptimal in many patients with type 2 diabetes mellitus (T2DM). Despite documented benefits of insulin therapy, initiation of insulin is delayed in many cases because of the reluctance of patients and physicians to use this important treatment. A review of the literature revealed that educating patients about the role of insulin in managing T2DM and the advantages of using insulin analogs and insulin delivery devices may help alleviate some patients' concerns regarding insulin therapy. Compared with standard clinic-directed approaches, patient-driven algorithms that empower patients to initiate and titrate basal insulin therapy have been shown to improve glycemic control. Additional research is needed to confirm the importance of patient empowerment programs in T2DM management.
    Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Husain Mansoor,Birkenfeld Andreas L,Donsmark Morten,Dungan Kathleen,Eliaschewitz Freddy G,Franco Denise R,Jeppesen Ole K,Lingvay Ildiko,Mosenzon Ofri,Pedersen Sue D,Tack Cees J,Thomsen Mette,Vilsbøll Tina,Warren Mark L,Bain Stephen C, The New England journal of medicine BACKGROUND:Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS:We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS:A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS:In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.). 10.1056/NEJMoa1901118
    Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis. Min Se Hee,Yoon Jeong-Hwa,Hahn Seokyung,Cho Young Min Diabetes/metabolism research and reviews BACKGROUND:Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors. METHODS:We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through June 2015. Randomized controlled trials published in English that compare SGLT2 inhibitor plus insulin (SGLT2i/INS) with placebo plus insulin or DPP4 inhibitor plus insulin (DPP4i/INS) with placebo plus insulin in patients with T2DM were selected. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between SGLT2i/INS and DPP4i/INS indirectly with covariates adjustment. Risk of potential bias was assessed. RESULTS:Fourteen eligible randomized controlled trials comprising 6980 patients were included (five SGLT2 inhibitor studies and nine DPP4 inhibitor studies). Covariate-adjusted indirect comparison using meta-regression analyses revealed that SGLT2i/INS achieved greater reduction in HbA [weighted mean difference (WMD) -0.24%, 95% confidence interval (CI) -0.43 to -0.05%], fasting plasma glucose (WMD -18.0 mg/dL, 95% CI -28.5 to -7.6 mg/dL) and body weight (WMD -2.38 kg, 95% CI -3.18 to -1.58 kg) from baseline than DPP4i/INS without increasing the risk of hypoglycaemia (relative risks 1.19, 95% CI 0.78 to 1.82). CONCLUSIONS:Sodium glucose cotransporter 2 inhibitors achieved better glycaemic control and greater weight reduction than DPP4 inhibitors without increasing the risk of hypoglycaemia in patients with T2DM that is inadequately controlled with insulin. There has been no direct comparison of SGLT2 inhibitors and DPP4 inhibitors in patients with T2DM inadequately controlled with insulin therapy. In this study, we performed indirect meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy. Without increasing hypoglycaemia, SGLT2 inhibitors showed better glycaemic control and greater weight reduction than DPP4 inhibitors in patients with T2DM inadequately controlled with insulin. The results of the current study could serve as the best available evidence in selecting oral agents to improve glycaemic control in insulin-treated T2DM patients. Copyright © 2016 John Wiley & Sons, Ltd. 10.1002/dmrr.2818
    BeAM value: an indicator of the need to initiate and intensify prandial therapy in patients with type 2 diabetes mellitus receiving basal insulin. Zisman Ariel,Morales Francienid,Stewart John,Stuhr Andreas,Vlajnic Aleksandra,Zhou Rong BMJ open diabetes research & care INTRODUCTION:In patients with type 2 diabetes mellitus (T2DM) with uncontrolled glycemia despite ongoing upward titration of basal insulin, targeting postprandial hyperglycemia may be required. Nevertheless, the point at which basal insulin is fully optimized and postprandial glucose (PPG) should be targeted with additional treatment remains unclear. We report here on the BeAM value (difference between bedtime and morning blood glucose values) as an indicator of the need to target PPG. METHODS:This study had 3 stages: exploratory, main, and proof-of-concept analyses. For the exploratory and main analyses, data were pooled from phase 3 trials in adults with T2DM adding basal insulin to oral antidiabetic drugs (OADs). The main analysis included only patients who did not reach A1C ≤7.0% (53 mmol/mol) at week 24. The proof-of-concept analysis used pooled data from phase 3 trials in adults with T2DM adding insulin glargine and a single insulin glulisine injection to OADs. RESULTS:In patients undergoing basal insulin titration, BeAM value increased over 24 weeks (27.8-61.7 mg/dL, n=1188; 32.6-71.2 mg/dL, n=553; exploratory and main analyses, respectively). There were significant correlations between week 24 BeAM value and postprandial contribution to hyperglycemia (Pearson's correlation coefficient (r)=0.375, p<0.001; r=0.396, p<0.001; exploratory and main analyses, respectively). When PPG was targeted (proof-of-concept analysis), the BeAM value reduced from 77.0 to 40.4 mg/dL (n=299). CONCLUSIONS:The BeAM value described in this study is a simple, easy-to-calculate value that may identify patients with T2DM using basal insulin that need targeting of postprandial control rather than advancing basal insulin dose. 10.1136/bmjdrc-2015-000171
    Bedtime-to-Morning Glucose Difference and iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of LixiLan-L. Zisman Ariel,Dex Terry,Roberts Michelle,Saremi Aramesh,Chao Jason,Aroda Vanita R Diabetes therapy : research, treatment and education of diabetes and related disorders INTRODUCTION:A difference of ≥ 50-55 mg/dL between bedtime and morning glucose (BeAM) values in patients with type 2 diabetes (T2D) on basal insulin is an indicator of poor postprandial glucose control. This analysis compared the effect of treatment with a fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs insulin glargine (iGlar) on BeAM values, and evaluated the impact of BeAM values on glycemic and safety endpoints. METHODS:In this post hoc analysis of 517 participants from the LixiLan-L trial, change in BeAM values and composite efficacy and safety endpoints stratified by BeAM value < 55 mg/dL or ≥ 55 mg/dL were evaluated in patients with T2D uncontrolled on basal insulin randomized to iGlarLixi or iGlar over 30 weeks (LixiLan-L). RESULTS:Greater reductions in BeAM values were seen with iGlarLixi vs iGlar, and a higher proportion of patients reached a BeAM value < 55 mg/dL in the iGlarLixi arm. A BeAM value < 55 mg/dL was associated with improved glycemic control, lower risk of hypoglycemia, and a greater proportion of patients achieving glycemic targets without hypoglycemia or weight gain. Greater reductions in BeAM values were seen with iGlarLixi vs iGlar, irrespective of stratification by glycated hemoglobin A or glycemic endpoints. CONCLUSIONS:Greater reductions in bedtime-to-morning glucose differential, or BeAM, were observed with iGlarLixi vs iGlar in patients with T2D uncontrolled on basal insulin, reflecting better overall control of both fasting and prandial glucose and more appropriate matching of therapy to physiologic needs. TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT02058160. FUNDING:Sanofi US, Inc. 10.1007/s13300-018-0507-0
    Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis. Dagenais Gilles R,Rydén Lars,Leiter Lawrence A,Lakshmanan Mark,Dyal Leanne,Probstfield Jeffrey L,Atisso Charles Messan,Shaw Jonathan E,Conget Ignacio,Cushman William C,Lopez-Jaramillo Patricio,Lanas Fernando,Munoz Ernesto German Cordona,Pirags Valdis,Pogosova Nana,Basile Jan,Sheu Wayne H H,Temelkova-Kurktschiev Theodora,Raubenheimer Peter J,Keltai Matyas,Hall Stephanie,Pais Prem,Colhoun Helen M,Riddle Matthew C,Gerstein Hertzel C Cardiovascular diabetology BACKGROUND:The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants METHODS: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. RESULTS:Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028]. CONCLUSIONS:These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. CLINICAL TRIAL REGISTRATION:https://www.clinicaltrials.gouv . Unique Identifier NCT01394952). 10.1186/s12933-020-01179-1
    Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Marso Steven P,Bain Stephen C,Consoli Agostino,Eliaschewitz Freddy G,Jódar Esteban,Leiter Lawrence A,Lingvay Ildiko,Rosenstock Julio,Seufert Jochen,Warren Mark L,Woo Vincent,Hansen Oluf,Holst Anders G,Pettersson Jonas,Vilsbøll Tina, The New England journal of medicine BACKGROUND:Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS:We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS:At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS:In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .). 10.1056/NEJMoa1607141
    Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine BACKGROUND:The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS:In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS:A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS:In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.). 10.1056/NEJMoa1603827
    Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research. Levin Philip A,Nguyen Hiep,Wittbrodt Eric T,Kim Seoyoung C Diabetes, metabolic syndrome and obesity : targets and therapy BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) act by increasing insulin secretion, decreasing glucagon secretion, slowing gastric emptying, and increasing satiety. OBJECTIVE:Published evidence directly comparing GLP-1RAs with other approved treatments for type 2 diabetes (T2D) was systematically reviewed. METHODS:A literature search was performed using MEDLINE and Embase databases to identify papers comparing GLP-1RAs with other classes of glucose-lowering therapy in patients with T2D. RESULTS:Of the 1303 papers identified, 57 met the prespecified criteria for a high-quality clinical trial or retrospective study. The efficacy and tolerability of approved GLP-1RAs (exenatide twice daily or once weekly, dulaglutide, liraglutide, lixisenatide, and albiglutide) were compared with insulin products (23 prospective studies + seven retrospective studies), dipeptidyl peptidase-4 inhibitors (11 prospective studies + three retrospective studies), sulfonylureas (nine prospective studies + one retrospective study), thiazolidinediones (five prospective studies), and metformin (two prospective studies). GLP-1RAs are effective as a second-line therapy in improving glycemic parameters in patients with T2D. Reductions in glycated hemoglobin from baseline with GLP-1RAs tended to be greater or similar compared with insulin therapy. GLP-1RAs were consistently more effective in reducing body weight than most oral glucose-lowering drugs and insulin and were associated with lower hypoglycemia risk versus insulin or sulfonylureas. GLP-1RAs improved cardiovascular risk factors, and preliminary data suggest they improve cardiovascular outcomes in patients with T2D compared with oral glucose-lowering drugs. However, results from ongoing studies are awaited to confirm these early findings. CONCLUSION:This systematic review found that GLP-1RAs are an effective class of glucose-lowering drugs for T2D. 10.2147/DMSO.S130834
    Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Janka Hans U,Plewe Gerd,Riddle Matthew C,Kliebe-Frisch Christine,Schweitzer Matthias A,Yki-Järvinen Hannele Diabetes care OBJECTIVE:To compare the efficacy and safety of adding once-daily basal insulin versus switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS:In a 24-week, multinational, multicenter, open, parallel group clinical trial, 371 insulin-naive patients with poor glycemic control (fasting blood glucose [FBG] >/=120 mg/dl, HbA(1c) 7.5-10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without OADs. Insulin dosage was titrated to target FBG </=100 mg/dl (both insulins) and predinner blood glucose </=100 mg/dl (70/30 only) using a weekly forced-titration algorithm. RESULTS:Mean HbA(1c) decrease from baseline was significantly more pronounced (-1.64 vs. -1.31%, P = 0.0003), and more patients reached HbA(1c) </=7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, P = 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference -17 mg/dl [-0.9 mmol/l], P < 0.0001), and more patients reached target FBG </=100 mg/dl with glargine plus OAD than with 70/30 (31.6 vs. 15.0%, P = 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P < 0.0001). CONCLUSIONS:Initiating insulin treatment by adding basal insulin glargine once daily to glimepiride plus metformin treatment was safer and more effective than beginning twice-daily injections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled with OADs. 10.2337/diacare.28.2.254
    Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin. Heinemann Lutz,Baughman Robert,Boss Anders,Hompesch Marcus Journal of diabetes science and technology Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time-action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time-action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control. 10.1177/1932296816658055
    A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes. Heise Tim,Pieber Thomas R,Danne Thomas,Erichsen Lars,Haahr Hanne Clinical pharmacokinetics BACKGROUND:Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared. METHODS:The analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme. Subjects received subcutaneous dosing (0.2 U/kg) of faster aspart and IAsp. In three trials, a 12-h euglycaemic clamp was performed (target 5.5 mmol/L; 100 mg/dL) to assess pharmacodynamics. RESULTS:The pharmacokinetic and pharmacodynamic profiles were left-shifted for faster aspart versus IAsp. Onset of appearance occurred 4.9 min earlier (95% confidence interval [CI] faster aspart-IAsp: [-5.3 to -4.4], p < 0.001), early exposure (AUC) was two times greater (estimated ratio faster aspart/IAsp 2.01 [1.87-2.17], p < 0.001) and offset of exposure (t ) occurred 12.2 min earlier [-17.9 to -6.5] (p < 0.001) for faster aspart versus IAsp. Accordingly, onset of action occurred 4.9 min earlier [-6.9 to -3.0] (p < 0.001), early glucose-lowering effect (AUC) was 74% greater (1.74 [1.47-2.10], p < 0.001) and offset of glucose-lowering effect (t ) occurred 14.3 min earlier [-22.1 to -6.5] (p < 0.001) for faster aspart versus IAsp. Total exposure and total glucose-lowering effect did not differ significantly between treatments. CONCLUSIONS:Faster aspart has the potential to better mimic the physiologic prandial insulin secretion and thereby to improve postprandial glucose control compared with IAsp. ClinicalTrials.gov identifiers: NCT02035371, NCT01924637, NCT02131246, NCT02033239, NCT02003677, NCT01618188. 10.1007/s40262-017-0514-8
    The use of glucose-lowering medications for the treatment of type 2 diabetes mellitus during pregnancy in the United States. Endocrinology, diabetes & metabolism INTRODUCTION:Some guidelines allow for the use of either insulin or noninsulin antidiabetic agents for gestational diabetes, but only insulin is recommended for pregnant women with preexisting type 2 diabetes mellitus (T2DM). We aimed to document treatment patterns in routine care for women with preexisting T2DM. METHODS:We identified pregnancy cohorts within 2 US claims databases for publicly and privately insured individuals: the Medicaid Analytical eXtract (2000-2014) and OptumClinformatics (2004-2014). T2DM was classified with a validated algorithm using ICD-9-CM and CPT codes. We assessed medication usage over the years of the study, and changes in medication use before and after the beginning of pregnancy, using prescription fills as a proxy for the use of insulin, metformin, sulphonylureas and other noninsulin antidiabetic agents before pregnancy and during each trimester. RESULTS:Among 12,631 women with T2DM, insulin use in pregnancy was stable over the study years (55%-60% in the 2nd trimester), but 2nd trimester use of metformin increased from <5% to 20%. Over the study period, 41% of women filled a prescription for metformin before pregnancy, 37% in the 1st trimester and 17% in the 2nd trimester. By the 2nd trimester, few women used sulphonylureas (11%) or other noninsulin antidiabetic agents (1%). Of the women on metformin only before pregnancy, 36% switched to insulin only by 2nd trimester, 11% added insulin and 16% continued on metformin only. Of the women on metformin and insulin before pregnancy, 61% switched to insulin only by 2nd trimester, 22% continued with metformin and insulin and <5% used only metformin. CONCLUSION:The use of insulin-metformin combinations and other noninsulin antidiabetic drugs during pregnancy has increased. Safety studies for these medication regimens are needed. 10.1002/edm2.319
    Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers. Home P D,Barriocanal L,Lindholm A European journal of clinical pharmacology OBJECTIVE:The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. METHODS:Either insulin aspart or human insulin, 0.1 U x kg-body-weight(-1), was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. RESULTS:The absorption of insulin aspart was, on average, more than twice as fast and reached levels more than twice as high compared with human insulin [tmax(ins) of 52 (23) vs 145 (93) min, P < 0.0001; and Cmax(ins) of 41 (11) vs 18 (4) mU x l(-1), P < 0.0001; mean with (SD)]. However, total bioavailability did not differ between the insulins, and thus the mean residence time was significantly shorter for insulin aspart [MRT(ins) of 149 (26) vs 217 (30) min, P < 0.0001]. Plasma glucose (PG) fell more than twice as rapidly [tmin(PG) of 94 (45) vs 226 (120) min, P < 0.0001], to a greater extent [Cmin(PG) 2.1 (0.6) vs 1.4 (0.4) mmol x l(-1), P < 0.0001], and for a shorter duration with insulin aspart than with human insulin. CONCLUSION:With improved subcutaneous absorption characteristics, the insulin aspart concentration-time profile resembles physiological meal-stimulated insulin release more closely than that of unmodified human insulin. This significantly alters the pharmacodynamic response in an advantageous manner in the meal-related treatment of diabetes mellitus.
    A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Prasad-Reddy Lalita,Isaacs Diana Drugs in context The prevalence of type 2 diabetes is increasing at an astounding rate. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists represent a unique approach to the treatment of diabetes, with benefits extending outside glucose control, including positive effects on weight, blood pressure, cholesterol levels, and beta-cell function. They mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. Their effects include increasing insulin secretion, decreasing glucagon release, increasing satiety, and slowing gastric emptying. There are currently four approved GLP-1 receptor agonists in the United States: exenatide, liraglutide, albiglutide, and dulaglutide. A fifth agent, lixisenatide, is available in Europe. There are important pharmacodynamic, pharmacokinetic, and clinical differences of each agent. The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Other warnings and precautions include pancreatitis and thyroid cell carcinomas. GLP-1 receptor agonists are an innovative and effective option to improve blood glucose control, with other potential benefits of preserving beta-cell function, weight loss, and increasing insulin sensitivity. Once-weekly formulations may also improve patient adherence. Overall, these are effective agents for patients with type 2 diabetes, who are either uncontrolled on metformin or intolerant to metformin. 10.7573/dic.212283
    Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Rosenstock Julio,Fonseca Vivian A,Gross Jorge L,Ratner Robert E,Ahrén Bo,Chow Francis C C,Yang Fred,Miller Diane,Johnson Susan L,Stewart Murray W,Leiter Lawrence A, Diabetes care OBJECTIVE:GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODS:Patients taking basal insulin (with or without oral agents) with HbA1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA1c change from baseline at week 26. RESULTS:At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (-0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). CONCLUSIONS:Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk. 10.2337/dc14-0001
    Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Balena R,Hensley I E,Miller S,Barnett A H Diabetes, obesity & metabolism Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from 'real-world' use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly reported. 10.1111/dom.12025
    How much is too much? Outcomes in patients using high-dose insulin glargine. Reid T,Gao L,Gill J,Stuhr A,Traylor L,Vlajnic A,Rhinehart A International journal of clinical practice BACKGROUND AND OBJECTIVES:Many patients with type 2 diabetes mellitus (T2DM) do not achieve glycaemic control targets on basal insulin regimens. This analysis investigated characteristics, clinical outcomes and impact of concomitant oral antidiabetes drugs (OADs) in patients with T2DM treated with high-dose insulin glargine. METHODS:Patient-level data were pooled from 15 randomised, treat-to-target trials in patients with T2DM treated with insulin glargine ± OADs for ≥ 24 weeks. Data were stratified according to whether patients exceeded three insulin dose cut-off levels (> 0.5, > 0.7 and > 1.0 IU/kg). End-points included glycated haemoglobin A1c (A1C), fasting plasma glucose, body weight, and overall, nocturnal and severe hypoglycaemia. RESULTS:Data from 2837 insulin-naïve patients were analysed. Patients with insulin titrated beyond the three doses investigated had significantly higher baseline A1C levels and were younger, with shorter diabetes duration than those at/below cut-offs (p < 0.05 for all cut-offs); they also had greater weight gain (p < 0.001 for the > 0.5 and > 0.7 IU/kg cut-offs) than those who did not exceed the cut-offs, regardless of concomitant OAD. Patients on concomitant metformin alone had higher insulin doses at Week 24, but achieved greater reductions in A1C, less weight gain and lower hypoglycaemia rates than patients on a concomitant sulfonylurea or metformin plus a sulfonylurea, regardless of whether cut-offs were exceeded. CONCLUSION:In patients with T2DM, increasing basal insulin doses above 0.5 IU/kg may not improve glycaemic control; treatment strategies targeting postprandial glucose control should be considered for such patients. 10.1111/ijcp.12747
    Dose-response effects of insulin glargine in type 2 diabetes. Diabetes care OBJECTIVE:To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS:Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal. CONCLUSION:A single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes. 10.2337/dc09-2011
    When basal insulin is not enough: A dose-response relationship between insulin glargine 100 units/mL and glycaemic control. Umpierrez Guillermo E,Skolnik Neil,Dex Terry,Traylor Louise,Chao Jason,Shaefer Charles Diabetes, obesity & metabolism AIMS:A post-hoc analysis to assess the impact in people with type 2 diabetes, of increasing doses of basal insulin on glycaemic measures, body weight and hypoglycaemia. RESEARCH DESIGN AND METHODS:We included data from prospective, randomized controlled treat-to-target trials of ≥24 weeks' duration in people with type 2 diabetes, uncontrolled on metformin and sulphonylureas, and treated with insulin glargine 100 units/mL (U100), who had at least six fasting plasma glucose (FPG) measurements. The impact of insulin dose on glycated haemoglobin (HbA1c) values, FPG, hypoglycaemia incidence (<3.9 mmol/L [70 mg/dL]), and body weight was analysed. A total of 458 participants from three eligible trials were included. RESULTS:The observed relationship between higher basal insulin doses and glycaemic control was non-linear, with increasing insulin dose leading to smaller reductions in FPG and HbA1c for doses >0.3 IU/kg/d, with a plateauing effect at 0.5 IU/kg/d. Total daily dose of insulin >0.5 IU/kg/d resulted in greater weight gain, but without higher rates of hypoglycaemia, compared with insulin doses ≤0.5 IU/kg/d. CONCLUSIONS:This analysis indicates that basal insulin doses >0.5 IU/kg/d have diminishing additional impact on improving glycaemic measures, with the disadvantage of additional weight gain. Clinicians should consider anti-hyperglycaemic treatment intensification at doses approaching 0.5 IU/kg/d. 10.1111/dom.13653
    When basal insulin is not enough: response to M Davidson. Umpierrez Guillermo E,Skolnik Neil,Dex Terry,Traylor Louise,Chao Jason,Shaefer Charles Diabetes, obesity & metabolism 10.1111/dom.13916
    Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review. Meece Jerry Diabetes therapy : research, treatment and education of diabetes and related disorders As the number of people living with type 2 diabetes (T2D) continues to rise, managing their complex needs presents an increasing challenge to physicians. While treatment guidelines provide evidence-based guidance, they are not prescriptive-rather they emphasize individualization of management based on a patient's clinical needs and preferences. Physicians, therefore, need to be fully aware of the advantages and disadvantages of the multiple and increasing treatment options available to them at each stage of the disease. The progressive nature of T2D means that treatment with basal insulin will become inevitable for many patients, while for some patients basal insulin alone will eventually be insufficient for maintaining glycemic targets. Recent guidelines recommend two basic approaches for intensifying basal insulin: the use of rapid-acting insulin, either as additional prandial injections or as part of premix (biphasic) insulin; and the addition of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to the insulin therapy, which can be administered via subcutaneous injection once or twice daily, or weekly depending on formulation. More recently, two fixed-ratio combinations of basal insulin and a GLP-1 RA that allow for once-daily dosing have been approved. Each of these approaches has potential benefits and drawbacks, particularly in terms of risk for hypoglycemia, weight change, convenience, and side effects. Understanding these differences is central to guiding patient and physician choice. This article discusses the rationale, advantages, disadvantages, and implementation of currently available strategies for basal insulin treatment intensification in patients with T2D. FUNDING:Sanofi US, Inc. 10.1007/s13300-018-0395-3
    Mechanisms of disposal of acid and alkali in rabbit duodenum. Fiddian-Green R G,Silen W The American journal of physiology Stripped duodenal mucosa of rabbits was mounted in Ussing chambers containing a Ringer solution gassed with 100% O2. The disappearance of acid or alkali from the mucosal solution of short-circuited tissue was measured with a pH stat while the serosal pH was kept at 7.4. The duodenum rapidly disposed of both acid and alkali; neither property was altered by gassing with N2 while iodoacetate was in the perfusing solutions. Prevention of release of CO2 from the mucosal chamber obliterated the early rapid phase of acid disposal by the mucosa while a similar maneuver in the serosal chamber increased the appearance of serosal acid without altering the rate of acid disposal. Gut sacs of rabbit duodenum in vitro and in vivo showed a positive correlation between acid disposal and the rate of luminal CO2 production. While acid disposal progressively decreased with time for the in vitro gut sacs, the in vivo gut sac showed no fatigue in this respect. Luminal acidification in the Ussing chamber was associated with a profound reduction in short-circuit current (Isc), partially reversible by elevation of the mucosal pH but not by luminal glucose. Our data suggest that acid disposal occurs in part by intraluminal neutralization and in part by diffusion into the mucosa. 10.1152/ajplegacy.1975.229.6.1641
    Appropriate Titration of Basal Insulin in Type 2 Diabetes and the Potential Role of the Pharmacist. Patel Dhiren,Triplitt Curtis,Trujillo Jennifer Advances in therapy A substantial proportion of patients with suboptimal control of their type 2 diabetes experience delays in treatment intensification. Additionally, patients often experience overuse of basal insulin, commonly referred to as "over-basalization," whereby basal insulin continues to be uptitrated in order to meet targets, when addition of a mealtime bolus insulin dose may be a more appropriate option. In order to overcome these challenges, there is a need to develop the capacity of allied healthcare professionals to provide appropriate support to these patients, such as during initiation or titration of basal insulin. Pharmacists play an integral role in healthcare delivery, with patients seeing their pharmacist, on average, seven times more often than their primary care physician. This places pharmacists in a unique position to provide diabetes education and care, which may help patients avoid clinical inertia. Nevertheless, the management of the disease with basal insulin is becoming increasingly complex, with growing numbers of treatment options (such as recent second-generation longer-acting basal insulin formulations) and frequently updated titration algorithms. The two most common titration schedules specify either increasing doses by a set amount every 2-3 days or a treat-to-target strategy. Neither schedule has been shown to be superior, and the decision to use one or the other should be based on a discussion between the clinician and patient after assessment of mental and physical acumen, comfort of both parties, and follow-up plans. This review article discusses basal insulin therapy options and titration algorithms from the unique perspective of the pharmacist in order to help ensure that optimal antidiabetes therapy is initiated, appropriately titrated, and maintained.Funding: Sanofi US, Inc. 10.1007/s12325-019-00907-8
    Insulin for type 2 diabetes: How and when to get started. Shubrook Jay H The Journal of family practice With guidelines now calling for initiation of basal insulin for patients who are not at goal a year after diagnosis, familiarity with optimal timing, dosing, and titration is critical for family physicians.
    Addendum. 9. Pharmacologic Approaches to Glycemic Treatment: . Diabetes Care 2020;43(Suppl. 1):S98-S110. Diabetes care 10.2337/dc20-ad08a
    Common standards of basal insulin titration in type 2 diabetes. Arnolds Sabine,Heise Tim,Flacke Frank,Sieber Jochen Journal of diabetes science and technology Type 2 diabetes mellitus has become a worldwide major health problem, and the number of people affected is steadily increasing. Thus, not all patients suffering from the disease can be treated by specialized diabetes centers or outpatient clinics, but by primary care physicians. The latter, however, might have time constraints and have to deal with many kinds of diseases or with multimorbid patients, so their focus is not so much on lowering high blood glucose values. Thus, the physicians, as well as the patients themselves, are often reluctant to initiate and adjust insulin therapy, although basal insulin therapy is considered the appropriate strategy after oral antidiabetic drug failure, according to the latest international guidelines. A substantial number of clinical studies have shown that insulin initiation and optimization can be managed successfully by using titration algorithms-even in cases where patients themselves are the drivers of insulin titration. Nevertheless, tools and strategies are needed to facilitate this process in the daily life of both primary health care professionals and patients with diabetes. 10.1177/193229681300700323
    Erratum. Basal Glucose Can Be Controlled, but the Prandial Problem Persists-It's the Next Target! Diabetes Care 2017;40:291-300. Riddle Matthew C Diabetes care 10.2337/dc17-er08b
    Contributions of fasting and postprandial glucose to hemoglobin A1c. Monnier Louis,Colette Claude Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists OBJECTIVE:To define the respective contributions of fasting and postprandial plasma glucose to hemoglobin A1c (HbA1c) in patients with non-insulin-treated type 2 diabetes. METHODS:Previous studies of diurnal glycemic profiles are reviewed, and glucose values for predicting successful treatment of diabetes are suggested. RESULTS:By analyzing the results from prior studies of diurnal glycemic profiles, we found that the relative contribution of postprandial plasma glucose was high (70%) in patients with fairly good control of diabetes (HbA1c <7.3%) and decreased progressively (30%) with worsening diabetes (HbA1c >10.2%). In contrast, the contribution of fasting plasma glucose showed a gradual increase with increasing levels of HbA1c. By using the same model (the diurnal glycemic profile), we established that post-meal glycemia was a better predictor of good or satisfactory control of diabetes (HbA1c <7%) than was fasting glucose. The best cutoff values that ensured the optimal balance between high sensitivity and specificity were approximately 200 mg/dL at 11 AM and 160 mg/dL at 2 PM. The cut-point values for predicting treatment success (specificity (3) 90%) were 162 mg/dL at 11 AM and 126 mg/dL at 2 PM. CONCLUSION:Postprandial plasma glucose is the predominant contributor in patients with satisfactory to good control of diabetes, whereas the contribution of fasting plasma glucose increases with worsening diabetes. Postmeal thresholds for predicting good or satisfactory control of diabetes are dependent on the timing of the meals. 10.4158/EP.12.S1.42
    Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care physicians and other health care professionals. LaSalle James R,Berria Rachele The Journal of the American Osteopathic Association The responsibility of diabetes management and insulin therapy has definitively moved to primary care physicians. Within the primary care setting, there is a growing need for clear, evidence-based guidelines related to the management of insulin therapy. Straightforward algorithms regarding insulin initiation, titration, and follow-up management can help physicians effectively treat patients with type 2 diabetes mellitus. Once 2 oral diabetic drugs have failed in a patient whose disease duration is 7 to 10 years, use of insulin therapy with a basal insulin analog should be considered. For patients who receive maximal basal insulin doses without reaching fasting blood glucose and target glycated hemoglobin levels with basal insulin analogs, a mealtime-insulin intensification approach should be considered. The authors discuss how simplified insulin initiation and titration regimens allow primary care physicians and other health care professionals to care for patients with type 2 diabetes mellitus.
    Therapeutic Inertia is a Problem for All of Us. Brunton Stephen Clinical diabetes : a publication of the American Diabetes Association 10.2337/cd19-0090
    Probability of Achieving Glycemic Control with Basal Insulin in Patients with Type 2 Diabetes in Real-World Practice in the USA. Blonde Lawrence,Meneghini Luigi,Peng Xuejun Victor,Boss Anders,Rhee Kyu,Shaunik Alka,Kumar Supriya,Balodi Sidhartha,Brulle-Wohlhueter Claire,McCrimmon Rory J Diabetes therapy : research, treatment and education of diabetes and related disorders INTRODUCTION:Basal insulin (BI) plays an important role in treating type 2 diabetes (T2D), especially when oral antidiabetic (OAD) medications are insufficient for glycemic control. We conducted a retrospective, observational study using electronic medical records (EMR) data from the IBM Explorys database to evaluate the probability of achieving glycemic control over 24 months after BI initiation in patients with T2D in the USA. METHODS:A cohort of 6597 patients with T2D who started BI following OAD(s) and had at least one valid glycated hemoglobin (HbA1c) result recorded both within 90 days before and 720 days after BI initiation were selected. We estimated the changes from baseline in HbA1c every 6 months, the quarterly conditional probabilities of reaching HbA1c < 7% if a patient had not achieved glycemic control prior to each quarter (Q), and the cumulative probability of reaching glycemic control over 24 months. RESULTS:Our cohort was representative of patients with T2D who initiated BI from OADs in the USA. The average HbA1c was 9.1% at BI initiation, and decreased robustly (1.5%) in the first 6 months after initiation with no further reductions thereafter. The conditional probability of reaching glycemic control decreased rapidly in the first year (26.6% in Q2; 17.6% in Q3; 8.6% in Q4), and then remained low (≤ 6.1%) for each quarter in the second year. Cumulatively, about 38% of patients reached HbA1c < 7% in the first year; only approximately 8% more did so in the second year. CONCLUSION:Our study of real-world data from a large US EMR database suggested that among patients with T2D who initiated BI after OADs, the likelihood of reaching glycemic control diminished over time, and remained low from 12 months onwards. Additional treatment options should be considered if patients do not reach glycemic control within 12 months of BI initiation. FUNDING:Sanofi Corporation. 10.1007/s13300-018-0413-5
    Are patients on basal insulin attaining glycemic targets? Characteristics and goal achievement of patients with type 2 diabetes mellitus treated with basal insulin and physician-perceived barriers to achieving glycemic targets. Dalal Mehul R,Grabner Michael,Bonine Nicole,Stephenson Judith J,DiGenio Andres,Bieszk Nella Diabetes research and clinical practice AIMS:To investigate treatment patterns and achievement of glycemic targets in patients with type 2 diabetes mellitus treated with basal insulin in a real-world setting, and to determine physicians' beliefs and practices regarding these patients. METHODS:This study had two components; a retrospective analysis using a US claims database of patient and treatment data, and a survey of physicians' beliefs and practices. RESULTS:A total of 39,074 patients treated with basal insulin were included in this analysis. The proportion of patients achieving HbA1c<7.0% (53mmol/mol) was similar in ongoing basal insulin users at baseline (26%) and at 3months follow-up (27%). The number of new initiators achieving HbA1c<7.0% (53mmol/mol) increased from baseline (11%) to 3months (27%). In the physician survey component, the majority of physicians indicated they would continue to increase basal insulin dose as long as was needed to reach HbA1c/fasting blood glucose goals (85% of physicians treating 'not on-goal' patients, 78% of physicians treating 'on-goal' patients). Physician-perceived barriers to insulin intensification included patient's lifestyle, non-adherence, and concerns about out-of-pocket costs. CONCLUSIONS:A large proportion of patients on insulin-based therapy fail to reach glycemic goals. More education of clinicians may improve insulin intensification rates and increase the proportion of patients reaching glycemic targets. 10.1016/j.diabres.2016.08.004
    Assessing achievement and maintenance of glycemic control by patients initiating basal insulin. Wu Ning,Aagren Mark,Boulanger Luke,Friedman Michelle,Wilkey Kelly Current medical research and opinion OBJECTIVE:Describe characteristics of diabetic patients who initiated basal insulin and assess their glycemic control. RESEARCH DESIGN AND METHODS:Physician encounters in the General Electric EMR Database (2005-2010) were assessed for patients with type II diabetes (T2DM) who initiated basal insulin between February 2006 and August 2009, with initiation defined as no prescription record of insulin in prior 15 months. Patients were followed for an average 2.5 years after insulin initiation. The proportion and time to achieving HbA1c ≤ 7% ('goal') were assessed. Among patients who reached goal, the proportion and time to HbA1c increasing above 7% were analyzed. Cox proportional hazard models were estimated to identify predictors of HbA1c goal achievement and goal sustainability. RESULTS:Basal insulin initiators with T2DM (n = 13,373) were on average 60 years old, 50.5% were females, and 59.5% had HbA1c > 8%; 5840 (44%) patients reached goal within one year and 7699 (58%) reached goal during the ∼2.5-year follow-up. Being older, white or male, lower baseline HbA1c values, and no OAD use before insulin initiation were associated with significantly higher rates of reaching goal. Among patients who reached goal, 57.6% could not sustain the goal. Being Hispanic, higher baseline HbA1c values, and baseline OAD use were associated with significantly lower rates of goal sustainment. CONCLUSION:A high proportion of T2DM patients did not have adequate glycemic control after initiating basal insulin. Various factors existing prior to insulin initiation were related to successful treatment of T2DM. Further research on how to improve glycemic control is encouraged. 10.1185/03007995.2012.722989
    Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA. Mauricio Dídac,Meneghini Luigi,Seufert Jochen,Liao Laura,Wang Hongwei,Tong Liyue,Cali Anna,Stella Peter,Carita Paulo,Khunti Kamlesh Diabetes, obesity & metabolism AIMS:To evaluate short- and long-term glycaemic control and hypoglycaemia incidence in insulin-naïve patients ≥30 years of age with type 2 diabetes (T2DM) initiating basal insulin (BI) with or without oral anti-hyperglycaemic drugs (OADs). METHODS:This was an observational, retrospective longitudinal analysis of electronic medical records from 5 European countries and the USA. A multivariable logistic regression model assessed baseline and short-term (0-3 months post BI initiation) factors associated with long-term (3-24 months) glycaemic control and hypoglycaemia. RESULTS:Overall, 40 627 patients were included; 20.9% and 27.8% achieved the general HbA1c target of ≤7% at 3 and 24 months post BI initiation, respectively. Failure to achieve HbA1c ≤7% at 3 months was associated with increased risk of failing to achieve target at 24 months (odds ratio [OR], 3.70 [95% CI, 3.41-4.00]). Over 24 months, 8.9% of patients experienced a recorded hypoglycaemic event. Hypoglycaemia during the initial 3-month period was associated with longer-term risk of these events over the ensuing 3 to 24 months (OR, 5.71 [95% CI, 4.67-6.99]). CONCLUSIONS:Initiating BI with or without OADs is associated with short- and long-term suboptimal glycaemic control; the majority of patients fail to achieve HbA1c target ≤7% in the first 3 months, or after 2 years of BI treatment. Treatment response and hypoglycaemia incidence by 3 months post BI initiation are associated with longer-term glycaemic control and hypoglycaemic risk, respectively. These results support the need for early anti-hyperglycaemic interventions that more effectively control blood glucose levels without increasing the risk of hypoglycaemia. 10.1111/dom.12927
    The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Stark Casagrande Sarah,Fradkin Judith E,Saydah Sharon H,Rust Keith F,Cowie Catherine C Diabetes care OBJECTIVE:To determine the prevalence of people with diabetes who meet hemoglobin A1c (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010. RESEARCH DESIGN AND METHODS:Data were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988-1994, 1999-2002, 2003-2006, and 2007-2010. Participants were 4,926 adults aged ≥ 20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination (n = 1,558 for valid LDL levels). Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins. RESULTS:In 2007-2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs. These levels of control were significant improvements from 1988 to 1994 (all P < 0.05). Statin use significantly increased between 1988-1994 (4.2%) and 2007-2010 (51.4%, P < 0.01). Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals (P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals (P < 0.02). Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals (P < 0.01). Younger individuals were less likely to meet A1C and LDL goals. CONCLUSIONS:Despite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups. Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality. 10.2337/dc12-2258
    Evaluation of the Cascade of Diabetes Care in the United States, 2005-2016. Kazemian Pooyan,Shebl Fatma M,McCann Nicole,Walensky Rochelle P,Wexler Deborah J JAMA internal medicine Importance:Treatment advances in diabetes can meaningfully improve outcomes only if they effectively reach the populations at risk. Objectives:To evaluate whether the cascade of US diabetes care, defined as diabetes diagnosis, linkage to care, and achievement of individual and combined treatment targets, improved from 2005 to 2016 and to investigate potential disparities in US diabetes care. Design, Setting, and Participants:Nationally representative, serial cross-sectional studies included in the 2005-2016 National Health and Nutrition Examination Survey were evaluated. Data on nonpregnant US adults (age ≥18 years) with diabetes who had reported fasting for 9 or more hours (n = 1742 diagnosed and 746 undiagnosed) were included. Data analysis was performed from August 1, 2018, to May 10, 2019. Exposures:Time period (2005-2008, 2009-2012, and 2013-2016), age, sex, race/ethnicity, health insurance, and educational level incorporated into logistic regression models predicting odds of target achievement. Main Outcomes and Measures:Proportion of participants overall and stratified by age, sex, and race/ethnicity who were linked to diabetes care and met glycemic (hemoglobin A1c <7.0%-8.5%, depending on age and complications), blood pressure (<140/90 mm Hg), cholesterol level (low-density lipoprotein cholesterol <100 mg/dL), and smoking abstinence targets and a composite of all targets. Results:In 2013-2016, of 1742 US adults with diagnosed diabetes, 94% (95% CI, 92%-96%) were linked to diabetes care; 64% (95% CI, 58%-69%) met hemoglobin A1c level, 70% (95% CI, 64%-75%) met blood pressure level, and 57% (95% CI, 51%-62%) met cholesterol level targets; 85% were nonsmokers (95% CI, 82%-88%); and 23% (95% CI, 17%-29%) achieved the composite goal. Results were similar in 2005-2008 (composite 23%) and in 2009-2012 (composite 25%). There was no significant improvement in diagnosis or target achievement during the study period. Compared with middle-aged adults (45-64 years) with diagnosed diabetes, older patients (≥65 years) had higher odds (adjusted odds ratio [aOR], 1.70; 95% CI, 1.17-2.48) and younger adults (18-44 years) had lower odds (aOR, 0.53; 95% CI, 0.29-0.97) of meeting the composite target. Women had lower odds of achieving the composite target than men (aOR, 0.60; 95% CI, 0.45-0.80). Non-Hispanic black individuals vs non-Hispanic white individuals had lower odds of achieving the composite target (aOR, 0.57; 95% CI, 0.39-0.83). Having health insurance was the strongest predictor of linkage to diabetes care (aOR, 3.96; 95% CI, 2.34-6.69). Conclusions and Relevance:It appears that the diabetes care cascade in the United States has not significantly improved between 2005 and 2016. This study's findings suggest that gaps in diabetes care that were present in 2005, particularly among younger adults (18-44 years), women, and nonwhite individuals, persist. 10.1001/jamainternmed.2019.2396