Predictive modeling of hypoglycemia for clinical decision support in evaluating outpatients with diabetes mellitus.

Objective: Hypoglycemia occurs in 20-60% of patients with diabetes mellitus. Identifying at-risk patients can facilitate interventions to lower risk. We sought to develop a hypoglycemia prediction model. Methods: In this retrospective cohort study, urban adults prescribed a diabetes drug between 2004 and 2013 were identified. Demographic and clinical data were extracted from an electronic medical record (EMR). Laboratory tests, diagnostic codes and natural language processing (NLP) identified hypoglycemia. We compared multiple logistic regression, classification and regression trees (CART), and random forest. Models were evaluated on an independent test set or through cross-validation. Results: The 38,780 patients had mean age 57 years; 56% were female, 40% African-American and 39% uninsured. Hypoglycemia occurred in 8128 (539 identified only by NLP). In logistic regression, factors positively associated with hypoglycemia included infection, non-long-acting insulin, dementia and recent hypoglycemia. Negatively associated factors included long-acting insulin plus sulfonylurea, and age 75 or older. The models' area under curve was similar (logistic regression, 89%; CART, 88%; random forest, 90%, with ten-fold cross-validation). Conclusions: NLP improved identification of hypoglycemia. Non-long-acting insulin was an important risk factor. Decreased risk with age may reflect treatment or diminished awareness of hypoglycemia. More complex models did not improve prediction.

Implementation of Basal-Bolus Therapy in Type 2 Diabetes: A Randomized Controlled Trial Comparing Bolus Insulin Delivery Using an Insulin Patch with an Insulin Pen.

Background: Barriers to mealtime insulin include complexity, fear of injections, and lifestyle interference. This multicenter, randomized controlled trial evaluated efficacy, safety, and self-reported outcomes in adults with type 2 diabetes, inadequately controlled on basal insulin, initiating and managing mealtime insulin with a wearable patch versus an insulin pen. Methods: Adults with type 2 diabetes (n = 278, age: 59.2 ± 8.9 years), were randomized to patch (n = 139) versus pen (n = 139) for 48 weeks, with crossover at week 44. Baseline insulin was divided 1:1 basal: bolus. Using a pattern-control logbook, subjects adjusted basal and bolus insulin weekly using fasting and premeal glucose targets. Results: Glycated hemoglobin (HbA1c) change (least squares mean ± standard error) from baseline to week 24 (primary endpoint) improved (P < 0.0001) in both arms, -1.7% ± 0.1% and -1.6% ± 0.1% for patch and pen (-18.6 ± 1.1 and -17.5 ± 1.1 mmol/mol), and was maintained at 44 weeks. The coefficient of variation of 7-point self-monitoring blood glucose decreased more (P = 0.02) from baseline to week 44 for patch versus pen. There were no differences in adverse events, including hypoglycemia (three severe episodes per arm), and changes in weight and insulin doses. Subject-reported treatment satisfaction, quality of life, experience ratings at week 24, and device preferences at week 48 significantly favored the patch. Most health care providers preferred patch for mealtime insulin. Conclusions: Bolus insulin delivered by patch and pen using an algorithm-based weekly insulin dose titration significantly improved HbA1c in adults with type 2 diabetes, with improved subject and health care provider experience and preference for the patch.

Vitamin D deficiency and coronary artery calcification in subjects with type 1 diabetes.

OBJECTIVE: The objective of this study is to examine the relationship among serum levels of 25-hydroxyvitamin D (25[OH]D), polymorphisms in vitamin D-associated genes, and the presence and progression of coronary artery calcification (CAC) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: This prospective study included 374 non-Hispanic white individuals with type 1 diabetes (mean age 40 ± 9 years; 46% were male). CAC was measured at the baseline and 3- and 6-year follow-up visits were determined by electron beam computed tomography. Serum 25[OH]D levels were measured by liquid chromatography tandem mass spectrometry at the 3-year visit. RESULTS: Normal (>30 ng/mL), insufficient (20-30 ng/mL), and deficient (<20 ng/mL) 25-[OH]D levels were present in 65%, 25%, and 10% of the individuals with type 1 diabetes, respectively. 25[OH]D deficiency was associated with the presence of CAC at the 3-year visit, odds ratio (OR) = 3.3 (95% CI 1.6-7.0), adjusting for age, sex, and hours of daylight. In subjects free of CAC at the 3-year visit, 25[OH]D deficiency predicted the development of CAC over the next 3 years in those with the vitamin D receptor M1T CC genotype (OR = 6.5 [1.1-40.2], P = 0.04) than in those with the CT or TT genotype (OR = 1.6 [0.3-8.6], P = 0.57). CONCLUSIONS: Vitamin D deficiency independently predicts prevalence and development of CAC, a marker of coronary artery plaque burden, in individuals with type 1 diabetes.

Latent autoimmune diabetes in adults.

CONTEXT: Autoantibodies that are reactive to islet antigens are present at the time of diagnosis in most patients with type 1 diabetes. Additionally, approximately 10% of phenotypic type 2 diabetic patients are positive for at least one of the islet autoantibodies, and this group is often referred to as "latent autoimmune diabetes in adults (LADA)." These patients share many genetic and immunological similarities with type 1 diabetes, suggesting that LADA, like type 1 diabetes, is an autoimmune disease. However, there are differences in autoantibody clustering, T cell reactivity, and genetic susceptibility and protection between type 1 diabetes and LADA, implying important differences in the underlying disease processes. EVIDENCE ACQUISITION AND SYNTHESIS: In this clinical review, we will summarize the current understanding of LADA based on the MEDLINE search of all peer-reviewed publications (original articles and reviews) on this topic between 1974 and 2009. CONCLUSIONS: In LADA, diabetes occurs earlier in the beta-cell-destructive process because of the greater insulin resistance. Complexities arise also because of variable definitions of LADA and type 1 diabetes in adults. As immunomodulatory therapies that slow or halt the type 1 diabetes disease process are discovered, testing these therapies in LADA will be essential.

Use of continuous glucose monitoring in patients with type 1 diabetes.

The prevalence of type 1 diabetes continues to increase worldwide at a rate higher than previously projected, while the number of patients achieving American Diabetes Association (ADA) glycated hemoglobin (A1c) goals remains suboptimal. There are numerous barriers to patients achieving A1c targets including increased frequency of severe hypoglycemia associated with lowering plasma glucose as measured by lower A1c values. Continuous glucose monitoring (CGM) was first approved for retrospective analysis and now has advanced to the next step in diabetes management with the approval of real-time glucose sensing. Real-time CGM, in short term studies, has been shown to decrease A1c values, improve glucose variability (GV), and minimize the time and number of hypoglycemic events in patients with type 1 diabetes. These products are approved for adjunctive use to self-monitoring of blood glucose (SMBG), but future long-term studies are needed to document their safety, efficacy, ability to replace SMBG as a tool of monitoring, and ultimately utility into closed-loop insulin delivery systems. New algorithms will need to be developed that account for rapid changes in the glucose values, so that accuracy of the sensor data can be maintained. In addition, for better clinical care and usage, algorithms also need to be developed for both patients and the providers to guide them for their ongoing diabetes care.

Precursor frequencies of T-cells reactive to insulin in recent onset type 1 diabetes mellitus.

T-cell mediated autoimmune beta-cell destruction is an important component of type 1 diabetes (T1D) and insulin is a critical antigen recognized by autoreactive T-cells. The aim of this study was to investigate the precursor frequency of insulin reactive T-cells in type 1 diabetes. We studied 19 T1D patients, 12 age-matching non-diabetic healthy siblings and 12 non-diabetic healthy parents. Limiting dilution analysis (LDA) was performed to insulin and tetanus toxoid (TT). A progressive decrease in the number of negative cultures at increasing cell concentrations that is represented by a low goodness-of-fit (GoF, low Chi-square), was seen with the TT response in all three groups; precursor frequencies and GoF were similar in patients, siblings, and parents. Reactivity to insulin, however, showed low precursor frequencies in patients and siblings and the LDA to insulin demonstrated dramatic decreases in the number of positive cultures at higher cell concentrations leading to a high GoF in patients and siblings compared to parents. This saw-toothed pattern of reactivity to insulin is indicative of multiple hit kinetics and implies that the response is regulated. Consequently the precursor frequency of insulin autoreactive cells in patients and their siblings is probably much higher than calculated.