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Beck R.W.,Jaeb Center for Health Research | Tamborlane W.V.,Yale University | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Miller K.M.,Jaeb Center for Health Research | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: The T1D Exchange includes a clinic-based registry, a patient-centric web site called Glu, and a biobank. Objective: The aim of the study was to describe the T1D Exchange clinic registry and provide an overview of participant characteristics. Design: Data obtained through participant completion of a questionnaire and chart extraction include diabetes history, management, and monitoring; general health; lifestyle; family history; socioeconomic factors; medications; acute and chronic diabetic complications; other medical conditions; and laboratory results. Setting: Data were collected from 67 endocrinology centers throughout the United States. Patients: We studied 25,833 adults and children with presumed autoimmune type 1 diabetes (T1D). Results: Participants ranged in age from less than 1 to 93 yr, 50% were female, 82% were Caucasian, 50% used an insulin pump, 6% used continuous glucose monitoring, and 16% had a first-degree family member with T1D. Glycosylated hemoglobin at enrollment averaged 8.3% and was highest in 13 to 25 yr olds. The prevalence of renal disease was ≤4% until T1D was present for at least 10 yr, and retinopathy treatment was ≤2% until T1D was present for at least 20 yr. A severe hypoglycemic event (seizure or coma) in the prior 12 months was reported by 7% of participants and diabetic ketoacidosis in the prior 12 months by 8%. Conclusions: The T1D Exchange clinic registry provides a database of important information on individuals with T1D in the United States. The rich dataset of the registry provides an opportunity to address numerous issues of relevance to clinicians and patients, including assessments of associations between patient characteristics and diabetes management factors with outcomes. Copyright © 2012 by The Endocrine Society.


Bergensta R.M.,International Diabetes Center at Park Nicollet | Klonoff D.C.,Diabetes Research Institute | Garg S.K.,University of Colorado at Denver | Bode B.W.,Atlanta Diabetes Associates | And 6 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia. METHODS: We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold-suspend events were analyzed with respect to subsequent sensor glucose values. RESULTS: A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980±1200 mg per deciliter [54.4±66.6 mmol per liter] x minutes vs. 1568±1995 mg per deciliter [87.0±110.7 mmol per liter] x minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5±1.0 vs. 2.2±1.3 per patient-week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6±40.7 mg per deciliter (5.1±2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis. CONCLUSIONS: This study showed that over a 3-month period the use of sensor-augmented insulin-pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values. Copyright © 2013 Massachusetts Medical Society.


Buse J.B.,University of North Carolina at Chapel Hill | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Glass L.C.,Eli Lilly and Company | Heilmann C.R.,Eli Lilly and Company | And 4 more authors.
Annals of Internal Medicine | Year: 2011

Background: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1c (HbA1c) targets. Objective: To test whether twice-daily exenatide injections reduce HbA1c levels more than placebo in people receiving insulin glargine. Design: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1c level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) Setting: 59 centers in 5 countries. Patients: Adults with type 2 diabetes and an HbA1c level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). Intervention: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 μg twice daily, or placebo for 30 weeks. Measurements: The primary outcome was change in HbA1c level. Secondary outcomes included the percentage of participants with HbA1c values of 7.0% or less and 6.5% or less, 7-point selfmonitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. Results: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1c level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. Limitations: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1c levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. Conclusion: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. Primary Funding Source: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals. © 2011 American College of Physicians.


Yki-Jarvinen H.,University of Helsinki | Bergenstal R.,International Diabetes Center at Park Nicollet | Ziemen M.,Sanofi S.A. | Wardecki M.,Sanofi S.A. | And 3 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: To compare the efficacy and safety of new insulin glargine 300 units/mL (Gla-300) with glargine 100 units/mL (Gla-100) in people with type 2 diabetes using basal insulin (≥42 units/day) plus oral antihyperglycemic drugs (OADs). RESEARCH DESIGN AND METHODS: EDITION 2 was a multicenter, open-label, two-arm study. Adults receiving basal insulin plus OADs were randomized to Gla-300 or Gla-100 once daily for 6 months. The primary end point was change in HbA1c. The main secondary end point was percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemic events from week 9 to month 6. RESULTS: Randomized participants ( n = 811) had amean (SD) HbA1c of 8.24% (0.82) and BMI of 34.8 kg/m2 (6.4). Glycemic control improved similarly with both basal insulins; least squares mean (SD) reduction from baseline was -0.57% (0.09) for Gla-300 and -0.56% (0.09) for Gla-100 (mean difference -0.01% [95% CI -0.14 to 0.12]), with 10% higher dose of Gla-300. Less nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemia was observed with Gla-300 from week 9 to month 6 (relative risk 0.77 [95% CI 0.61-0.99]; P = 0.038) and during the first 8 weeks. Fewer nocturnal and any time (24 h) hypoglycemic events were reported during the entire 6-month period. Weight gain was lower with Gla-300 than with Gla-100 ( P = 0.015). No between-treatment differences in safety parameters were identified. CONCLUSIONS: Gla-300 was as effective as Gla-100 and associated with a lower risk of hypoglycemia during the night and at any time of the day. © 2014 by the American Diabetes Association.


Giovannucci E.,Harvard University | Harlan D.M.,University of Massachusetts Medical School | Archer M.C.,University of Toronto | Bergenstal R.M.,International Diabetes Center at Park Nicollet | And 5 more authors.
CA Cancer Journal for Clinicians | Year: 2010

Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis; 2) risk factors common to both diabetes and cancer; 3) possible biologic links between diabetes and cancer risk; and 4) whether diabetes treatments influence the risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed. © 2010 by the American Diabetes Association and the American Cancer Society, Inc.


Gough S.C.L.,Oxford Center for Diabetes | Bhargava A.,Iowa Diabetes and Endocrinology Center | Jain R.,Aurora Advanced Healthcare | Mersebach H.,Novo Nordisk AS | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS-In this 26-week, open-label, treat-to-target trial, subjects (n = 457;mean HbA1c 8.3% [67 mmol/mol], BMI 32.4 kg/m2, and fasting plasma glucose [FPG] 9.6mmol/L [173.2mg/dL]) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of <5 mmol/L (<90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days. RESULTS-By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (-3.7 vs. -3.4 mmol/L [-67 vs. -61 mg/dL]; estimated treatment difference: -0.42 [95% CI -0.78 to -0.06], P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups. CONCLUSIONS-In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia. © 2013 by the American Diabetes Association.


Heinemann L.,Science and Co | Fleming G.A.,Kinexum | Petrie J.R.,University of Glasgow | Holl R.W.,University of Ulm | And 2 more authors.
Diabetes Care | Year: 2015

Insulin pump therapy, also known as continuous subcutaneous insulin infusion (CSII), is an important and evolving form of insulin delivery, which is mainly used for people with type 1 diabetes. However, even with modern insulin pumps, errors of insulin infusion can occur due to pump failure, insulin infusion set (IIS) blockage, infusion site problems, insulin stability issues, user error, or a combination of these. Users are therefore exposed to significant and potentially fatal hazards: interruption of insulin infusion can result in hyperglycemia and ketoacidosis; conversely, delivery of excessive insulin can cause severe hypoglycemia. Nevertheless, the available evidence on the safety and efficacy of CSII remains limited. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have therefore joined forces to review the systems in place for evaluating the safety of pumps from a clinical perspective. We found that useful information held by the manufacturing companies is not currently shared in a sufficiently transparent manner. Public availability of adverse event (AE) reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is potentially a rich source of safety information but is insufficiently utilized due to the current configuration of the system; the comparable database in Europe (European Databank on Medical Devices [EUDAMED]) is not publicly accessible. Many AEs appear to be attributable to human factors and/or user error, but the extent to which manufacturing companies are required by regulators to consider the interactions of users with the technical features of their products is limited. The clinical studies required by regulators prior to marketing are small and overreliant on bench testing in relation to "predicate" products. Once a pump is available on the market, insufficient data are made publicly available on its long-term use in a real-world setting; such data could provide vital information to help health care teams to educate and support users and thereby prevent AEs. As well as requiring more from the manufacturing companies, we call for public funding of more research addressing clinically important questions in relation to pump therapy: both observational studies and clinical trials. At present, there are significant differences in the regulatory systems between the US and European Union at both pre- and postmarketing stages; improvements in the European system are more urgently required. This statement concludes with a series of recommended specific actions for "meknovigilance" (i.e., a standardized safety approach to technology) that could be implemented to address the shortcomings we highlight. © 2015 by the American Diabetes Association.


Powers M.A.,International Diabetes Center at Park Nicollet
Journal of the American Dietetic Association | Year: 2010

This single-center, meal-intervention, crossover study was conducted to determine the glycemic response to fixed meals with varying carbohydrate content. Continuous glucose monitoring was used to document the glycemic response. Participants were 14 people with type 2 diabetes on metformin only. On 4 consecutive days in March or July 2008, study participants consumed a fixed breakfast and one of two test meals (lunch) provided in random order. The two lunch types varied only in carbohydrate content; the protein, fat, fiber, and glycemic index were similar. They consumed no caloric food or beverages for 4 hours after each meal. Consuming double the carbohydrate content did not double the glycemic response variables, yet most were substantially different in glucose value (mg/dL) or minutes. General linear model analyses revealed substantial differences for peak glucose, change from baseline glucose to peak, time to return to preprandial glucose, 4-hour glucose area under the curve, and 4-hour mean glucose. Continuous glucose monitoring data provided a robust description of the glycemic response to the two meals. Such data can help improve postprandial glucose levels through more informed nutrition recommendations and synchronization of food intake, diabetes medication, and/or physical activity. Copyright © 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.


Bergenstal R.M.,International Diabetes Center at Park Nicollet
Diabetes Care | Year: 2015

There is no argument that improvingmean levels of glycemic control as judged by assays for glycated hemoglobin (HbA1c) reduces the risks of microvascular complications and cardiovascular disease events in patients with type 1 and type 2 diabetes. However, observations in some trials have suggested that targeting HbA1c to suggested targets may not always result in improved outcomes for people with long-standing type 2 diabetes. The reasons why the glycemic control strategies that primarily use HbA1c in these studies did not have predicted outcomes are not clear. Thus, controversy remains as to whether there are glycemic metrics beyond HbA1c that can be defined as effective measures that can be used in addition to HbA1c to help in assessing the risk of an individual developing diabetes complications. In this regard, the concept of "glycemic variability" (GV) is onemetric that has attracted a lot of attention. GV can be simply defined as the degree to which a patient's blood glucose level fluctuates between high (peaks) and low (nadir) levels. The best andmost precise way to assess GV is also one that is still debated. Thus, while there is universal agreement that HbA1c is the current gold standard for the primary clinical target, there is no consensus as to whether other proposed glycemic metrics hold promise to provide additional clinical data or whether there should be additional targets beyond HbA1c. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the preceding point narrative, Dr. Hirsch provides his argument that fluctuations in blood glucose as assessed by GV metrics are deleterious and control of GV should be a primary treatment target. In the counterpoint narrative below, Dr. Bergenstal argues that there are better markers to assess the risk of diabetes than GV and provides his consideration of other concepts. ©2015 by the American Diabetes Association.


Bergenstal R.M.,International Diabetes Center at Park Nicollet | Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical | Bastyr III E.J.,Eli Lilly and Company | Prince M.J.,Eli Lilly and Company | And 2 more authors.
Diabetes Care | Year: 2014

OBJECTIVE To use continuous glucose monitoring (CGM) to evaluate the impact of the novel, long-acting basal insulin analog LY2605541 on hypoglycemia and glycemic variability in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Hypoglycemia and glucose variability were assessed with CGM of interstitial glucose (IG) in a subset of patients with type 2 diabetes from a phase II, randomized, open-label, parallel study of LY2605541 (n = 51) or insulin glargine (GL) (n = 25). CGM was conducted on 3 consecutive days (72-84 h) during theweek beforeweek 0, 6, and 12 study visits. RESULTS Measured by CGM for 3 days prior to the 12-week visit, fewer LY2605541-treated patients experienced hypoglycemic events overall (50.0 vs. 78.3%, P = 0.036) and nocturnally (20.5 vs. 47.8%, P = 0.027) and spent less time with IG 70 mg/dL than GL-treated patients during the 24-h (25 6 6 vs. 83 6 16 min, P = 0.012) and nocturnal periods (11 6 5 vs. 38 6 13 min, P = 0.024). These observations were detected without associated differences in the average duration of individual hypoglycemic episodes (LY2605541 compared with GL 57.2 6 5.4 vs. 69.9 6 10.2 min per episode, P = NS). Additionally, LY2605541-treated patients had lower within-day glucose SD for both 24-h and nocturnal periods. CONCLUSIONS By CGM, LY2605541 treatment compared with GL resulted in fewer patients with hypoglycemic events and less time in the hypoglycemic range and was not associated with protracted hypoglycemia. © 2014 by the American Diabetes Association.

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