Correction to: Pediatric Insulin Injection Technique: A Multi-Country Survey and Clinical Practice Implications.

In the original publication, fourth author name was incorrectly published as Asthma Deeb in author group.

Pediatric Insulin Injection Technique: A Multi-Country Survey and Clinical Practice Implications.

INTRODUCTION: The 2015 Insulin Injection Technique Questionnaire survey involving 13,289 patients included 898 (6.8%) patients in the pediatric age range (≤ 18 years). METHODS: The younger patients included in the questionnaire survey were grouped according to age: Group 1 (G1), 0-6 years, n = 85; Group 2(G2), 7-13, n = 423; Group 3 (G3), 14-18, n = 390. The injection technique was evaluated by means of a questionnaire and nurse assessment. RESULTS: Nurses found lipohypertrophy at injection sites in 41.3, 45.2, and 47.3% of patients in G1, G2, and G3, respectively. Unexpected hypoglycemia was common, ranging from 23.8 to 48.1% of patients, and glucose variability was even more common (61.0% in G1, 45.9% in G2, and 52.5% in G3); both conditions were associated with lipohypertrophy. While increasing numbers of patients were using the recommended 4-mm needles, large percentages still used longer ones (33.3% in G1, 45.9% in G2, and 61.5% in G3). The reuse of needles was also common, ranging from 21.1 to 32.5% in the three age groups. Excessive reuse, defined as using a single needle more than five times, was reported by 9.4-21.8% of patients in the three age group. The percentages of patients who had not received any injection training in the last 12 months ranged from 21.2 to 26.8% in the three groups. CONCLUSION: Implications of our study are as follows: (1) pediatric patients should use 4-mm pen needles or 6-mm syringes (inserted at a 45° angle); (2) patients aged ≤ 6 years should always inject into a raised skin fold regardless of which device is used; (3) all patients should rotate sites and use needles only once to avoid lipohypertrophy. FUNDING: Becton-Dickinson (BD) diabetes care.

Preventing contrast medium-induced acute kidney injury : Side-by-side comparison of Swedish-ESUR guidelines.

A side-by-side comparison of updated guidelines regarding contrast medium-induced acute kidney injury (CI-AKI) from the Swedish Society of Uroradiology (SSUR) and the European Society of Urogenital Radiology (ESUR) is presented. The major discrepancies include a higher glomerular filtration rate (GFR) threshold as a risk factor for CI-AKI and for discontinuation of metformin by SSUR, i.e., < 45 ml/min versus < 30 ml/min/1.73 m2 by ESUR, when intravenous or intra-arterial contrast media (CM) with second-pass renal exposure is administered. SSUR also continues to recommend consideration of traditional non-renal risk factors such as diabetes and congestive heart failure, while ESUR considers these factors as non-specific for CI-AKI and does not recommend any consideration. Contrary to ESUR, SSUR also recommends discontinuation of NSAID and nephrotoxic medication if possible. Insufficient evidence at the present time motivates the more cautionary attitude taken by SSUR. Furthermore, SSUR expresses GFR thresholds in absolute values in ml/min as recommended by the National Kidney Foundation for drugs excreted by glomerular filtration, while ESUR uses the relative GFR normalised to body surface area in ml/min/1.73 m2. CM dose/GFR ratio thresholds established for coronary angiography/interventions are also applied as recommendations for CM-enhanced CT by SSUR, since SSUR regards coronary procedures as a second-pass renal exposure of CM with no obvious difference in the incidence of AKI compared with IV CM administration. Finally, SSUR recommends reducing the gram-iodine dose/GFR ratio from < 1.0 in patients not at risk to < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation. KEY POINTS: • The more cautionary attitude taken by SSUR compared with that of ESUR is motivated by insufficient evidence regarding risk for contrast medium-induced acute kidney injuries (CI-AKI). • SSUR recommends that absolute and not relative GFR should be used when dosing drugs eliminated by the kidneys such as contrast media. • According to SSUR the gram-iodine dose/GFR ratio should be < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation.

[Treatment with metformin in type 2 diabetes mellitus - new routines when renal function is reduced and in connection with administration of iodine contrast media]. / GFR-gränsen har sänkts för metformin vid typ 2-diabetes - Nya rekommendationer vid nedsatt njurfunktion och undersökning med jodkontrastmedel.

Metformin is eliminated through glomerular filtration and tubular secretion in the kidneys. New guidelines recommend use of metformin down to a GFR of 30 mL/min under the condition that the dose is adjusted. As the risk of inducing lactic acidosis is very low in connection with administration of iodine contrast media, new recommendations in Sweden say that metformin must be stopped only when GFR is below 45 mL/min. Determination of metformin levels in serum is useful to guide therapeutic dose when GFR is low but also to confirm that lactic acidosis is caused by metformin.

Effect of Oral Pre-Meal Administration of Betaglucans on Glycaemic Control and Variability in Subjects with Type 1 Diabetes.

We conducted a double-blind placebo-controlled crossover pilot study to investigate the effect of oat betaglucans (ß-glucan) on glycaemic control and variability in adults with type 1 diabetes (T1D; n = 14). Stomacol® tablets (1.53 g of ß-glucan) or placebo (Plac) were administered three times daily before meals for two weeks. Glucose levels were monitored during the second week by continuous glucose monitoring (CGM). There was an increase in basic measures of glycaemic control (maximal glucose value 341 ± 15 vs. 378 ± 13 mg/dL for Plac and ß-glucan, p = 0.004), and average daily risk range (62 ± 5 vs. 79 ± 4 mg/dL for Plac and ß-glucan, p = 0.003) favouring Plac over ß-glucan, but no increase in the M-value (the weighted average of the glucose values) or other more complex measures. Basic measures of glucose variability were also slightly increased during ß-glucan treatment, with no difference in more complex measures. However, glycaemic variability increased between the first and last two CGM days on Plac, but remained unchanged on ß-glucan. In conclusion, in this pilot study we were unable to demonstrate a general positive effect of ß-glucan before meals on glucose control or variability in T1D.

Continuous Glucose Monitoring vs Conventional Therapy for Glycemic Control in Adults With Type 1 Diabetes Treated With Multiple Daily Insulin Injections: The GOLD Randomized Clinical Trial.

Importance: The majority of individuals with type 1 diabetes do not meet recommended glycemic targets. Objective: To evaluate the effects of continuous glucose monitoring in adults with type 1 diabetes treated with multiple daily insulin injections. Design, Setting, and Participants: Open-label crossover randomized clinical trial conducted in 15 diabetes outpatient clinics in Sweden between February 24, 2014, and June 1, 2016 that included 161 individuals with type 1 diabetes and hemoglobin A1c (HbA1c) of at least 7.5% (58 mmol/mol) treated with multiple daily insulin injections. Interventions: Participants were randomized to receive treatment using a continuous glucose monitoring system or conventional treatment for 26 weeks, separated by a washout period of 17 weeks. Main Outcomes and Measures: Difference in HbA1c between weeks 26 and 69 for the 2 treatments. Adverse events including severe hypoglycemia were also studied. Results: Among 161 randomized participants, mean age was 43.7 years, 45.3% were women, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, -0.43% [95% CI, -0.57% to -0.29%] or -4.7 [-6.3 to -3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia. Conclusions and Relevance: Among patients with inadequately controlled type 1 diabetes treated with multiple daily insulin injections, the use of continuous glucose monitoring compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT02092051.

Worldwide Injection Technique Questionnaire Study: Population Parameters and Injection Practices.

From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries took part in one of the largest surveys ever performed in diabetes. The goal was to assess patient characteristics, as well as historical and practical aspects of their injection technique. Results show that 4- and 8-mm needle lengths are each used by nearly 30% of patients and 5- and 6-mm needles each by approximately 20%. Higher consumption of insulin (as measured by total daily dose) is associated with having lipohypertrophy (LH), injecting into LH, leakage from the injection site, and failing to reconstitute cloudy insulin. Glycated hemoglobin values are, on average, 0.5% higher in patients with LH and are significantly higher with incorrect rotation of sites and with needle reuse. Glycated hemoglobin values are lower in patients who distribute their injections over larger injection areas and whose sites are inspected routinely. The frequencies of unexpected hypoglycemia and glucose variability are significantly higher in those with LH, those injecting into LH, those who incorrectly rotate sites, and those who reuse needles. Needles associated with diabetes treatment are the most commonly used medical sharps in the world. However, correct disposal of sharps after use is critically suboptimal. Many used sharps end up in public trash and constitute a major accidental needlestick risk. Use of these data should stimulate renewed interest in and commitment to optimizing injection practices in patients with diabetes.

Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional.

From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries participated in one of the largest surveys ever performed in diabetes. The first results of this survey are published elsewhere in this issue. Herein we report that the most common complication of injecting insulin is lipohypertrophy (LH), which was self-reported by 29.0% of patients and found by physical examination in 30.8% by health care professionals (HCPs). Patients with LH consumed a mean of 10.1 IU more insulin daily than patients without LH. Glycated hemoglobin levels averaged 0.55% higher in patients with vs without LH. Lipohypertrophy was associated with higher rates of unexplained hypoglycemia and glycemic variability as well as more frequent diabetic ketoacidosis, incorrect rotation of injection sites, use of smaller injection zones, longer duration of insulin use, and reuse of pen needles (each P<.05). Routine inspection of injection sites by the HCP was associated with lower glycated hemoglobin levels, less LH, and more correct injection site rotation. Patients were also more likely to rotate correctly if they received injection instructions from their HCP in the past 6 months. Fewer than 40% of patients claimed to have gotten such instructions in the past 6 months, and 10% said that they have never received training on how to inject correctly despite injecting for a mean of nearly 9 years. Use of these data should stimulate renewed commitment to optimizing insulin injection practices.

New Insulin Delivery Recommendations.

Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.

Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy.

BACKGROUND: Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings. RESULTS: Thirty-nine consecutive patients with diabetes mellitus were included in the study after clinical examination and examination by esophageal manometry and gastric emptying scintigraphy. Serum was analyzed for the presence of antibodies against GnRH using an ELISA, and values are expressed as relative units (RU). Two age- and gender-matched healthy subjects per each patient served as controls. The prevalence of IgM GnRH antibodies in patients was 33% compared to 14% in controls (p = 0.027), with a higher antibody titer; 1.2 (0.6-5.0) and 0.2 (0.1-0.3) RU, respectively (p = 0.000). The expression of IgG antibodies was 15% in patients and none in controls (p = 0.000). Lower body mass index was associated with the presence of IgM antibodies (OR = 0.835, 95% CI = 0.699-0.998), and autonomic neuropathy with the presence IgG antibodies (OR = 9.000, 95% CI = 1.327-61.025). Esophageal dysmotility (69%) or gastroparesis (18%) were not associated with the presence of IgM antibodies (OR = 0.589, 95% CI = 0.143-2.424 and OR = 3.407, 95% CI = 0.633-18.350, respectively). Neither was esophageal dysmotility associated with IgG antibodies (OR = 2.500, 95% CI = 0.259-24.096). CONCLUSIONS: Antibodies against GnRH are more common in patients with diabetes mellitus compared with healthy controls. IgM antibodies are associated with lower body mass index and IgG antibodies are associated with autonomic neuropathy.

Esophageal dysmotility is more common than gastroparesis in diabetes mellitus and is associated with retinopathy.

OBJECTIVES: Gastroparesis is a well-known complication of diabetes mellitus, both in symptomatic and asymptomatic patients. Esophageal dysmotility has also been described, but is not as well-characterized. The etiology and effect of these complications need to be clarified. The aim of the present study was to evaluate esophageal and gastric motility, complications, gastrointestinal symptoms, and plasma biomarkers in a cross-sectional study comprising patients with diabetes mellitus. METHODS: Patients with diabetes were consecutively asked to participate, and eventually 84 volunteers were included in the study. Esophageal manometry and the gastric emptying test were performed in all patients. Type of diabetes, symptoms, diabetic complications, body mass index (BMI), and biomarkers were recorded. Patients were interviewed about gastrointestinal symptoms. RESULTS: Esophageal dysmotility was present in 63% of patients and gastroparesis in 13% of patients. There was no difference in dysmotility between patients with type 1 and type 2 diabetes or between genders. Gastrointestinal symptoms did not correlate to objective findings. Age correlated negatively with gastric emptying rate (p = 0.004). Patients with esophageal dysmotility had longer duration of diabetes compared to those without dysmotility (p = 0.043). In logistic regression analysis, retinopathy was strongly associated with esophageal dysmotility, independent of duration (p = 0.003). CONCLUSIONS: Esophageal dysmotility is more common than gastroparesis in diabetes mellitus independent of gender, symptoms, and type of diabetes. There is a strong association between retinopathy and esophageal dysmotility.

Prevalence of impaired glucose tolerance and diabetes after gestational diabetes mellitus comparing different cut-off criteria for abnormal glucose tolerance during pregnancy.

OBJECTIVE: To determine the prevalence of diabetes and impaired glucose tolerance after gestational diabetes mellitus in relation to different categories of glucose tolerance during pregnancy. DESIGN: Prospective study. SETTING: Four delivery departments and three hospitals in southern Sweden took part in recruitment and follow-up. POPULATION: Women undergoing a 75g oral glucose tolerance test during pregnancy delivering in 2003-2005. METHODS: At first follow-up, one to two years after delivery, 29% of eligible women with abnormal glucose tolerance during pregnancy had an oral glucose tolerance test - 160 with gestational diabetes and 309 with gestational impaired glucose tolerance - in addition to 167 control women. Cut-off levels defining gestational diabetes and impaired glucose tolerance were two-hour capillary blood glucose levels of 9.0 and 7.8mmol/l or plasma glucose 10.0 and 8.6mmol/l, respectively. MAIN OUTCOME MEASURES: Frequency of abnormal test results at follow-up. RESULTS: Diabetes was diagnosed in 11% and impaired glucose tolerance in 24% of women with gestational diabetes vs. 4 and 23% in those with gestational impaired glucose tolerance, respectively. Combining women with abnormal test results during pregnancy revealed diabetes or impaired glucose tolerance in 29% as compared to 10% among controls; the odds ratio (95% confidence interval) for having abnormal test results was 3.3 (1.8-5.9) in a multivariate logistic regression analysis. CONCLUSIONS: Lowering the cut-off level for gestational diabetes to include the category of impaired glucose tolerance would identify a high percentage of women with diabetes and impaired glucose tolerance postpartum, who constitute target groups for intervention and/or diabetes prevention.

Extreme lactic acidosis type B associated with metformin treatment.

The elimination of metformin is exclusively through the kidneys and elevated plasma concentrations can cause lactic acidosis. We report a case of severe lactic acidosis (pH 6.60) occuring with ostensibly normal therapeutic doses of metformin in the setting of acute renal failure. Continuous veno-venous haemodiafiltration decreased plasma metformin concentrations from 266 lmol/L at presentation to 68 lmol/L, 21 h later. The patient improved rapidly.

Results and analysis of the 2008-2009 Insulin Injection Technique Questionnaire survey.

BACKGROUND: The efficacy of injection therapy in diabetes depends on correct injection technique and, to provide patients with guidance in this area, we must understand how they currently inject. METHODS: From September 2008 to June 2009, 4352 insulin-injecting Type 1 and Type 2 diabetic patients from 171 centers in 16 countries were surveyed regarding their injection practices. RESULTS: Overall, 3.6% of patients use the 12.7-mm needle, 1.8% use the 12-mm needle, 1.6% use the 10-mm needle, 48.6% use the 8-mm needle, 15.8% use the 6-mm needle, and 21.6% use the 5-mm needle; 7% of patients do not know what length of needle they use. Twenty-one percent of patients admitted injecting into the same site for an entire day, or even a few days, a practice associated with lipohypertrophy. Approximately 50% of patients have or have had symptoms suggestive of lipohypertrophy. Abdominal lipohypertrophy seems to be more frequent in those using the two smaller injection size areas, and less frequent in those using larger areas. Nearly 3% of patients reported always injecting into lipohypertrophic lesions and 26% inject into them sometimes. Of the 65% of patients using cloudy insulins (e.g. NPH), 35% do not remix it before use. CONCLUSIONS: It is clear from the latest survey that we have improved in certain areas, but that, in others, we have either not moved at all or our efforts have not yielded the results we expected. The results of the present survey are available online on a country-by-country and question-by-question basis at http://www.titan-workshop.org.

Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations.

OBJECTIVE: To study trough levels of metformin in serum and its intra-individual variation in patients using a newly developed assay. RESEARCH DESIGN AND METHODS: Trough serum levels of metformin were measured once using liquid chromatography-tandem mass spectrometry (LCMSMS) in 137 type 2 diabetic patients with varying renal function (99 men) and followed repeatedly during 2 months in 20 patients (16 men) with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) body surface. RESULTS: Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m(2) had median trough metformin concentrations of 4.5 micromol/l (range 0.1-20.7, n = 107), 7.71 micromol/l (0.12-15.15, n = 21), and 8.88 micromol/l (5.99-18.60, n = 9), respectively. The median intra-individual overall coefficient of variation was 29.4% (range 9.8-74.2). CONCLUSIONS: Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values >20 micromol/l. Metformin measurement is less suitable for dose titration.

Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study.

OBJECTIVE: The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS: In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2). RESULTS: A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS: In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

Differences in effects of insulin glargine or pioglitazone added to oral anti-diabetic therapy in patients with type 2 diabetes: what to add--insulin glargine or pioglitazone?

BACKGROUND: While metformin is the first line treatment in type 2 diabetes, the best way to escalate therapy is not always clear, particularly whether to add one or two oral agents or to introduce insulin. METHODS: Thirty-six patients inadequately controlled on metformin and sulfonylurea/meglitinide were randomized to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Insulin was up-titrated to achieve fasting plasma glucose <6 mmol/l. Pioglitazone was increased to 45 mg/day after 16 weeks if HbA1c>6.2%. beta-Cell function and insulin sensitivity were assessed by measuring insulin, proinsulin and adiponectin, and in a subgroup using a combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). Lipids and natriuretic peptides were measured at start and end of study. RESULTS: The reduction in HbA1c was slightly greater in the insulin glargine group and used as co-variate when analysing other variables. The effect on beta-cell function was more favourable with insulin glargine measured by proinsulin (42+/-48 to 19+/-16, p=0.01 vs. 36+/-26 to 27+/-16 p=0.04) while the improvement in insulin sensitivity measured by adiponectin (7.5+/-3.7 to 15+/-10, p<0.01 vs. 8.7+/-4 to 7.6+/-3, p=0.04) and HDL cholesterol (1.10+/-0.24 to 1.24+/-0.3, p<0.01 vs. 1.08+/-0.35 to 1.04+/-0.33, ns) (all p between groups <0.01) was more favourable in pioglitazone group. Pioglitazone caused significant increase in natriuretic peptides (BNP pmol/l 6.6+/-5.2 to 13.7+/-16.1, p=0.04 vs. 8.8+/-11.6 to 8.6+/-10.6, ns, p between groups 0.028). CONCLUSIONS: The results demonstrate characteristic differences in the effects of insulin glargine vs. pioglitazone on measures of beta-cell function and insulin sensitivity as well as cardiac load.