Are newer insulins always the better option?

PURPOSE OF REVIEW: Since its discovery almost a century ago, there have been numerous advancements in the formulations of insulin. The newer insulin analogs have structural modifications with the goal of altering pharmacokinetics to achieve either quick onset and offset of action (mealtime bolus analogs), or a prolonged steady action (basal analogs). These analogs offer many advantages over older human insulins but are several-fold more expensive. The aim of this review is to evaluate reasons for the exorbitant price of the newer insulins, to examine the evidence regarding their clinical advantages and to make value-based prescribing recommendations. RECENT FINDINGS: The higher cost of newer insulins cannot be justified based on drug development or manufacturing costs. Compared with older insulins, newer analogs do not offer significant advantage in achieving hemoglobin A1c targets, but they reduce risk of hypoglycemia. The reductions in hypoglycemia are relatively modest and most apparent in those with type 1 diabetes, possibly because these individuals are more prone to hypoglycemia. SUMMARY: When cost considerations are important, the older insulins (regular and NPH insulin) can be used safely and effectively for most individuals with type 2 diabetes who have a low risk of hypoglycemia.

A Natural Language Processing System That Links Medical Terms in Electronic Health Record Notes to Lay Definitions: System Development Using Physician Reviews.

BACKGROUND: Many health care systems now allow patients to access their electronic health record (EHR) notes online through patient portals. Medical jargon in EHR notes can confuse patients, which may interfere with potential benefits of patient access to EHR notes. OBJECTIVE: The aim of this study was to develop and evaluate the usability and content quality of NoteAid, a Web-based natural language processing system that links medical terms in EHR notes to lay definitions, that is, definitions easily understood by lay people. METHODS: NoteAid incorporates two core components: CoDeMed, a lexical resource of lay definitions for medical terms, and MedLink, a computational unit that links medical terms to lay definitions. We developed innovative computational methods, including an adapted distant supervision algorithm to prioritize medical terms important for EHR comprehension to facilitate the effort of building CoDeMed. Ten physician domain experts evaluated the user interface and content quality of NoteAid. The evaluation protocol included a cognitive walkthrough session and a postsession questionnaire. Physician feedback sessions were audio-recorded. We used standard content analysis methods to analyze qualitative data from these sessions. RESULTS: Physician feedback was mixed. Positive feedback on NoteAid included (1) Easy to use, (2) Good visual display, (3) Satisfactory system speed, and (4) Adequate lay definitions. Opportunities for improvement arising from evaluation sessions and feedback included (1) improving the display of definitions for partially matched terms, (2) including more medical terms in CoDeMed, (3) improving the handling of terms whose definitions vary depending on different contexts, and (4) standardizing the scope of definitions for medicines. On the basis of these results, we have improved NoteAid's user interface and a number of definitions, and added 4502 more definitions in CoDeMed. CONCLUSIONS: Physician evaluation yielded useful feedback for content validation and refinement of this innovative tool that has the potential to improve patient EHR comprehension and experience using patient portals. Future ongoing work will develop algorithms to handle ambiguous medical terms and test and evaluate NoteAid with patients.

Frequency and Predictors of Self-Reported Hypoglycemia in Insulin-Treated Diabetes.

AIMS: Hypoglycemia is a limiting factor for achieving stringent glycemic control in diabetes. This study analyzes the frequency and predictors of hypoglycemia in insulin-treated diabetes in an ambulatory setting. METHODS: A retrospective chart review was performed to study self-monitored blood glucose (SMBG) data for 3 months prior to a patient's HbA1c test. RESULTS: Hypoglycemia occurred more frequently in type 1 than in type 2 diabetes; however, 19% of type 2 diabetes patients did experience at least one episode of severe hypoglycemia. For type 1 diabetes, hypoglycemia had a positive association with glycemic variability and duration of diabetes and a negative association with HbA1c and lowest blood glucose (BG). For type 2 diabetes, a positive association was noted with glycemic variability and a negative association with age and lowest BG. CONCLUSIONS: Delineating factors predisposing to hypoglycemia in type 2 diabetes is difficult. Lower HbA1c is a potential predictor of hypoglycemia in type 1 but not in type 2 diabetes. Longer duration of diabetes for type 1 and younger age for type 2 are associated with more hypoglycemia. Glycemic variability portends increased risk for hypoglycemia and should be a focus of further research.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Redesigning Diabetes Care: Defining the Role of Endocrinologists Among Alternative Providers.

The current diabetes epidemic threatens to overwhelm the healthcare system unless we redesign how diabetes care is delivered. The number of endocrinologists is grossly inadequate to provide care for all individuals with diabetes, but with the appropriate utilization of the primary care workforce and alternative healthcare providers working together in teams, effective diabetes care can be provided to all. We propose a patient-centered, goal-based approach with resources devoted to care coordination, measurement of outcomes, appropriate use of technology, and measurement of patient satisfaction. Financial incentives to healthcare systems and providers need to be based on defined outcome measures and reducing long-term total medical expenditures, rather than reimbursement based on number of visits and lengthy documentation. Endocrinologists have a responsibility in setting up effective diabetes care delivery systems within their organizations, in addition to delivering diabetes care and serving as a resource for the educational needs for other medical professionals in the community. There are major challenges to implementing such systems, both at the financial and organizational levels. We suggest a stepwise implementation of discrete components based on the local priorities and resources and provide some examples of steps we have taken at our institution.

An update on the role of bariatric surgery in diabetes management.

PURPOSE OF REVIEW: To review the current state of knowledge on the effects of weight loss (bariatric) surgical procedures in individuals with type 2 diabetes. RECENT FINDINGS: Observational and randomized studies provide robust data on the efficacy of bariatric surgery for weight loss and improvement in hyperglycemia. Follow-up information up to 20 years is now available. Surgery offers similar benefits in individuals with BMI 30-35, compared with those with higher BMI. There is a better understanding of the role of gut hormones and nonhormonal factors on weight loss and glucose metabolism. Preoperative factors that predict favorable surgical outcomes have been identified. SUMMARY: Of commonly performed procedures, adjustable gastric banding has the lowest efficacy for weight loss and diabetes remission and a higher complication rate. Roux-en-Y gastric bypass and sleeve gastrectomy are comparable in terms of efficacy and complications. Remission rates for diabetes range between 40 and 80%; randomized trials show slightly lower remission rates compared with observational studies. At 20 years, approximately 50% of remitters have relapse of diabetes. Complex gut hormonal changes, caloric restriction, and other intestinal factors form the basis for metabolic effects of surgery. Better preoperative ß-cell function is the strongest predictor for remission. Long-term follow-up data is still sparse.

Predicting remission of diabetes after RYGB surgery following intensive management to optimize preoperative glucose control.

BACKGROUND: The purpose of the study is to investigate the association of preoperative glucose optimization prior to a Roux-en-Y gastric bypass (RYGB) and diabetes remission. METHODS: The study is a retrospective review of 245 patients with a history of diabetes type II and a RYGB from 2008 to 2012 at UMass Memorial Hospital. RESULTS: Patients that benefited from glucose optimization prior to RYGB were more likely to achieve diabetes remission 1 year after surgery. The preoperative glucose optimization intervention demonstrated that when patients decreased their HbA1c prior to surgery by 1 %, these individuals were 68 % more likely to remit (p = 0.015). Duration of diabetes (p = 0.005) and insulin use (p < 0.001) were also significant predictors of remission, whereas age, race, and gender were not. CONCLUSIONS: Our study results indicate that a greater degree of glycemic improvement in response to presurgical medical intervention is associated with higher rates of diabetes remission post-operatively among obese adults with diabetes type II. Conversely, the lack of favorable glycemic response to intensification of medical management predicts a poor glycemic response to bariatric surgery. Further research is needed to determine if this difference is due to physiological factors or is simply an indicator of patient behavior.

Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4.

Adipose tissue expansion requires growth and proliferation of adipocytes and the concomitant expansion of their stromovascular network. We have used an ex vivo angiogenesis assay to study the mechanisms involved in adipose tissue expansion. In this assay, adipose tissue fragments placed under pro-angiogenic conditions form sprouts composed of endothelial, perivascular, and other proliferative cells. We find that sprouting was directly stimulated by insulin and was enhanced by prior treatment of mice with the insulin sensitizer rosiglitazone. Moreover, basal and insulin-stimulated sprouting increased progressively over 30 weeks of high fat diet feeding, correlating with tissue expansion during this period. cDNA microarrays analyzed to identify genes correlating with insulin-stimulated sprouting surprisingly revealed only four positively correlating (Fads3, Tmsb10, Depdc6, and Rasl12) and four negatively correlating (Asph, IGFbp4, Ppm1b, and Adcyap1r1) genes. Among the proteins encoded by these genes, IGFbp4, which suppresses IGF-1 signaling, has been previously implicated in angiogenesis, suggesting a role for IGF-1 in adipose tissue expandability. Indeed, IGF-1 potently stimulated sprouting, and the presence of activated IGF-1 receptors in the vasculature was revealed by immunostaining. Recombinant IGFbp4 blocked the effects of insulin and IGF-1 on mouse adipose tissue sprouting and also suppressed sprouting from human subcutaneous adipose tissue. These results reveal an important role of IGF-1/IGFbp4 signaling in post-developmental adipose tissue expansion.

Reducing analytical variation between point-of-care and laboratory HbA1c testing.

BACKGROUND: Point-of-care (POC) HbA1c testing allows for timely treatment changes, improved glycemic control, and patient and provider satisfaction. Substantial variation between POC and laboratory HbA1c results has been reported. At our university hospital diabetes clinic, we observed significant negative bias in HbA1c with the DCA Vantage (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) compared with the Tosoh G8 HPLC laboratory analyzer (Tosoh Bioscience, San Francisco, CA, USA). This led us to systematically analyze the bias with the goal of recalibrating the DCA to minimize bias. METHODS: We analyzed 45 patient samples, with HbA1c ranging between 5% and 10.8%, concurrently on two DCA analyzers and on the Tosoh G8 machine. The bias for each sample was the difference between the value on the DCA and the Tosoh G8 analyzer. Based on regression equations derived from the data, a correction factor for each DCA analyzer was calculated. The analyzers were recalibrated and retested for bias. RESULTS: At baseline, the mean bias (range) was -0.5229 (+0.1 to -1.3) for Analyzer 1 and -0.5348 (0.0 to -1.6) for Analyzer 2. After recalibration, the mean bias (range) was 0.000 (+0.6 to -0.6) and 0.0003 (+0.5 to -0.5) for Analyzers 1 and 2, respectively, and the systematic negative bias seen prior to the calibration was almost eliminated. CONCLUSIONS: We recommend periodic recalibration of POC analyzers to eliminate systematic unidirectional bias and to harmonize results between the POC and central laboratory analyzers within a healthcare system. Calibration may need to be repeated with any change in the reagent lot.

Spontaneous coronary artery dissection during cabergoline therapy.

Although spontaneous coronary artery dissection is a rare cause of acute coronary syndrome, it should be considered during the evaluation of patients who have chest pain. Coronary vasospasm can lead to spontaneous dissection. The dopamine agonist cabergoline is known to cause digital vasospasm. Herein, we report a case of spontaneous right coronary artery dissection in a 43-year-old woman who was taking cabergoline as therapy for prolactinoma. To our knowledge, this is the first report of an apparent relationship between cabergoline therapy and spontaneous coronary artery dissection. The possible association of cabergoline with coronary artery spasm and dissection should be considered in patients who present with chest pain while taking this medication.

Controversies on how diabetes is diagnosed.

PURPOSE OF REVIEW: To evaluate the controversial aspects of diabetes diagnosis. RECENT FINDINGS: Within the past 2 years, revised guidelines for the diagnosis of diabetes have been issued which endorse the use of the hemoglobin A1C as a diagnostic test, in addition to the previously recommended tests. Updated diagnostic criteria for gestational diabetes were also published in the same period. Recent publications on the current role of oral glucose tolerance tests and diagnosis of diabetes in the acutely ill are sparse. There are new recommendations regarding the use of genetic testing and antibody testing in establishing the cause of diabetes. SUMMARY: The inclusion of A1C as a diagnostic test has many advantages including reproducibility of the test and convenience, but there are situations where the test is unreliable and it misses many individuals who would have been diagnosed by plasma glucose testing. The diagnostic threshold of 6.5% for the A1C remains controversial. There is still no consensus on the best approach to diagnose gestational diabetes. The role of the oral glucose tolerance test seems to be diminishing. Diagnosis of diabetes in acute illness is aided by A1C testing. Genetic and autoantibody testing in specific situations offer diagnostic and therapeutic utility.

Implications of using hemoglobin A1C for diagnosing diabetes mellitus.

Until 2010, the diagnosis of diabetes mellitus was based solely on glucose concentration, but the American Diabetes Association (ADA) recommendations now include a new criterion: hemoglobin A1C ≥6.5%. Because this change may have significant implications for diabetes diagnosis, we conducted a comprehensive literature review including peer-reviewed articles not referenced in the ADA report. We conclude that A1C and plasma glucose tests are frequently discordant for diagnosing diabetes. A1C ≥6.5% identifies fewer individuals as having diabetes than glucose-based criteria. Convenience of A1C test might increase the number of patients diagnosed, but this is unproven. Diagnostic cut-points for both glucose and A1C are based on consensus judgments regarding optimal sensitivity and specificity for the complications of hyperglycemia. A1C may not accurately reflect levels of glycemia in some situations, but in comparison with glucose measurements, it has greater analytic stability and less temporal variability. When choosing a diagnostic test for diabetes, the limitations of each choice must be understood. Clinical judgment and consideration of patient preference are required to appropriately select among the diagnostic alternatives.

Remission of type 2 diabetes mellitus following bariatric surgery: review of mechanisms and presentation of the concept of 'reversibility'.

PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) leads to remission of type 2 diabetes mellitus (T2DM) in a majority of patients. This is prompting investigation of RYGB, and other bariatric operations as interventional therapies for T2DM. RECENT FINDINGS: The impact of RYGB is due to an increase in the release of gastrointestinal hormones in response to a meal [glucagon-like peptide, peptide YY, oxyntomodulin]. This effect involves the parasympathetic nervous system. These same hormones are responsible for an early increase in ß-cell secretion of insulin, leading to early remission of T2DM following RYGB. Progressive weight loss leads to a later improvement in peripheral insulin sensitivity, which is required for later remissions, and is responsible for re-emergence of T2DM in individuals who regain weight in long-term follow-up. As the success of bariatric surgery has prompted the emergence of the concept that T2DM is reversible, we offer a theory to predict reversibility of diabetes after bariatric surgery that is based on baseline beta cell function. SUMMARY: This review will improve the understanding of the physiology of bariatric surgery and its impact on T2DM, stimulate investigations into new avenues to treat T2DM, and allow better selection of nonobese individuals for interventional therapy of T2DM.

Utility of HbA(1c) levels for diabetes case finding in hospitalized patients with hyperglycemia.

OBJECTIVE: We evaluated the role of a single measurement of HbA(1c) in a diabetes case finding in hospitalized patients with random hyperglycemia at admission. RESEARCH DESIGN AND METHODS: From 20 March to 31 July 2000, 508 patients admitted through the emergency department of one hospital were tested for random hyperglycemia (plasma glucose [PG] >125 mg/dl). Consenting patients with hyperglycemia (without preexisting diabetes or on corticosteroids) underwent testing for HbA(1c) levels, two fasting PG levels, and an outpatient oral glucose tolerance test (OGTT) if necessary. RESULTS: Of the patients, 50 (9.8%) met the inclusion criteria. Of these, 70% (n = 35) completed the study, and 60% (n = 21) were diagnosed with diabetes. Patients with diabetes had higher HbA(1c) levels than subjects without diabetes (6.8 +/- 0.4 vs. 5.3 +/- 0.1%, P = 0.002). An HbA(1c) level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. When a lower cutoff value of HbA(1c) at 5.2% was used, specificity was 50% (10/21) and sensitivity was 100% (7/14). CONCLUSIONS: In acutely ill patients with random hyperglycemia at hospital admission, an HbA(1c) >6.0% reliably diagnoses diabetes, and an HbA(1c) level <5.2% reliably excludes it (paralleling the operating characteristics of the standard fasting glucose measurements); however, the rapidity of the HbA(1c) level can be useful for diabetes case finding and treatment initiation early in the hospital course.