Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study.

AIMS: To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2 years in patients with type 2 diabetes. METHODS: In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n = 1091) were randomized (2 : 2 : 2 : 1: 2) to liraglutide (0.6, 1.2 or 1.8 mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80 years old with HbA1c 7.0-11.0% (previous monotherapy ≥3 months), or 7.0-10.0% (previous combination therapy ≥3 months), and body mass index ≤40 kg/m(2) . Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. RESULTS: HbA1c decreased significantly with liraglutide (0.4% with 0.6 mg, 0.6% with 1.2 and 1.8 mg) versus 0.3% increase with metformin monotherapy (p < 0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9 kg with 0.6, 1.2 and 1.8 mg, respectively) compared to weight gain (0.7 kg) with glimepiride (p < 0.0001). Weight loss with liraglutide 1.2 and 1.8 mg was significantly greater than with metformin monotherapy (1.8 kg; p = 0.0185 and p = 0.0378 for 1.2 and 1.8 mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p < 0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. CONCLUSIONS: Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia.

Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled Type 1 diabetes; a randomized controlled trial.

AIMS: To investigate the efficacy of sensor-augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled Type 1 diabetes. METHODS: In this investigator-initiated multi-centre trial (the Eurythmics Trial) in eight outpatient centres in Europe, we randomized 83 patients with Type 1 diabetes (40 women) currently treated with multiple daily injections, age 18-65 years and HbA(1c) ≥ 8.2% (≥ 66 mmol/mol) to 26 weeks of treatment with either a sensor-augmented insulin pump (n = 44) (Paradigm(®) REAL-Time) or continued with multiple daily injections (n = 39). Change in HbA(1c) between baseline and 26 weeks, sensor-derived endpoints and patient-reported outcomes were assessed. RESULTS: The trial was completed by 43/44 (98%) patients in the sensor-augmented insulin pump group and 35/39 (90%) patients in the multiple daily injections group. Mean HbA(1c) at baseline and at 26 weeks changed from 8.46% (SD 0.95) (69 mmol/mol) to 7.23% (SD 0.65) (56 mmol/mol) in the sensor-augmented insulin pump group and from 8.59% (SD 0.82) (70 mmol/mol) to 8.46% (SD 1.04) (69 mmol/mol) in the multiple daily injections group. Mean difference in change in HbA(1c) after 26 weeks was -1.21% (95% confidence interval -1.52 to -0.90, P < 0.001) in favour of the sensor-augmented insulin pump group. This was achieved without an increase in percentage of time spent in hypoglycaemia: between-group difference 0.0% (95% confidence interval -1.6 to 1.7, P = 0.96). There were four episodes of severe hypoglycaemia in the sensor-augmented insulin pump group and one episode in the multiple daily injections group (P = 0.21). Problem Areas in Diabetes and Diabetes Treatment Satisfaction Questionnaire scores improved in the sensor-augmented insulin pump group. CONCLUSIONS: Sensor augmented pump therapy effectively lowers HbA(1c) in patients with Type 1 diabetes suboptimally controlled with multiple daily injections.

Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue.

AIM: The effect on body composition of liraglutide, a once-daily human glucagon-like peptide-1 analogue, as monotherapy or added to metformin was examined in patients with type 2 diabetes (T2D). METHODS: These were randomized, double-blind, parallel-group trials of 26 [Liraglutide Effect and Action in Diabetes-2 (LEAD-2)] and 52 weeks (LEAD-3). Patients with T2D, aged 18-80 years, body mass index (BMI) < or =40 kg/m(2) (LEAD-2), < or =45 kg/m(2) (LEAD-3) and HbA1c 7.0-11.0% were included. Patients were randomized to liraglutide 1.8, 1.2 or 0.6 mg/day, placebo or glimepiride 4 mg/day, all combined with metformin 1.5-2 g/day in LEAD-2 and to liraglutide 1.8, 1.2 or glimepiride 8 mg/day in LEAD-3. LEAD-2/3: total lean body tissue, fat tissue and fat percentage were measured. LEAD-2: adipose tissue area and hepatic steatosis were assessed. RESULTS: LEAD-2: fat percentage with liraglutide 1.2 and 1.8 mg/metformin was significantly reduced vs. glimepiride/metformin (p < 0.05) but not vs. placebo. Visceral and subcutaneous adipose tissue areas were reduced from baseline in all liraglutide/metformin arms. Except with liraglutide 0.6 mg/metformin, reductions were significantly different vs. changes seen with glimepiride (p < 0.05) but not with placebo. Liver-to-spleen attenuation ratio increased with liraglutide 1.8 mg/metformin possibly indicating reduced hepatic steatosis. LEAD-3: reductions in fat mass and fat percentage with liraglutide monotherapy were significantly different vs. increases with glimepiride (p < 0.01). CONCLUSION: Liraglutide (monotherapy or added to metformin) significantly reduced fat mass and fat percentage vs. glimepiride in patients with T2D.

A dietary exchange of common bread for tailored bread of low glycaemic index and rich in dietary fibre improved insulin economy in young women with impaired glucose tolerance.

OBJECTIVE: To study the possibility of improving blood lipids, glucose tolerance and insulin sensitivity in women with impaired glucose tolerance and a history of gestational diabetes by merely changing the glycaemic index (GI) and dietary fibre (DF) content of their bread. DESIGN: Randomized crossover study where test subjects were given either low GI/high DF or high GI/low DF bread products during two consecutive 3-week periods, separated by a 3-week washout period. An intravenous glucose tolerance test followed by a euglycaemic-hyperinsulinaemic clamp was performed on days 1 and 21 in both the high- and low-GI periods, to assess insulin secretion and insulin sensitivity. Blood samples were also collected on days 1 and 21 for analysis of fasting levels of glucose, insulin, HDL-cholesterol and triacylglycerols (TG). SETTING: Lund University, Sweden. SUBJECTS: Seven women with impaired glucose tolerance. RESULTS: The study shows that a modest dietary modification, confined to a lowering of the GI character and increasing cereal DF of the bread products, improved insulin economy as judged from the fact that all women lowered their insulin responses to the intravenous glucose challenge on average by 35% (0-60 min), in the absence of effect on glycaemia. No changes were found in fasting levels of glucose, insulin, HDL-cholesterol or TG. CONCLUSION: It is concluded that a combination of low GI and a high content of cereal DF has a beneficial effect on insulin economy in women at risk of developing type II diabetes. This is in accordance with epidemiological data, suggesting that a low dietary GI and/or increased intake of whole grain prevent against development of type II diabetes. SPONSORSHIP: Supported by grants from Cerealia Research Foundation.

Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM.

The influence of bicycle exercise (60% of W170 [working capacity at a pulse rate of 170 beats/min]; 40 min) on the absorption of 125I-labeled fast-acting insulin (10 U; Actrapid human insulin) after intramuscular compared with subcutaneous injection in the thigh was studied on 2 consecutive days in 10 insulin-dependent diabetes mellitus (IDDM) patients. Insulin absorption was measured as disappearance of radioactivity (1st-order elimination rate constants) by continuous external monitoring and as appearance of plasma free immunoreactive insulin (IRI). Subcutaneous adipose tissue blood flow (ATBF) and skeletal muscle blood flow (MF) were measured concomitantly in the contralateral thigh with the 133Xe wash-out technique. Plasma glucose was determined intermittently. The rate constant for 125I-insulin increased during exercise from 0.46 +/- 0.08 to 1.17 +/- 0.14%/min after intramuscular injection (P less than 0.001) and from 0.31 +/- 0.05 to 0.45 +/- 0.09%/min (NS) after subcutaneous injection. The rate constant of 125I-insulin from muscle remained elevated during the 80-min recovery period. The peak plasma free-IRI value was 39 mU/L higher, the area under the IRI curve was approximately 80% greater, and the decrease in plasma glucose was approximately 2 mM greater after intramuscular injection. Whereas MF increased fivefold, ATBF did not rise significantly during exercise. The results demonstrate that intramuscular compared with subcutaneous thigh injection of insulin followed by bicycle exercise induces a marked increase in insulin absorption and a substantial fall in plasma glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of accidental intramuscular injection on insulin absorption in IDDM.

Recent studies have shown that with the injection technique presently recommended to diabetic patients, accidental intramuscular injection of insulin is liable to occur quite frequently. In this study, the simultaneous absorption of 125I-labeled soluble human insulin (5 U) from subcutaneous and intramuscular injection sites in the thigh and abdomen was measured for 3 h in 10 insulin-dependent diabetic subjects to evaluate the importance of accidental intramuscular injection for insulin absorption in the resting state. Injection sites were located with computed tomography of the thigh and abdomen. From a superficial part of the thigh musculature, the absorption rate was at least 50% higher than from the adjacent subcutaneous tissue, the time until 50% of the initial activity remained (t1/2) being 123 +/- 14 and greater than 180 min, respectively (P less than .001). No difference in absorption rates was found between the two tissues in the abdomen (t1/2 84 +/- 6 vs. 93 +/- 7 min, NS). The results suggest that in the thigh, accidental intramuscular injections will considerably increase the variability of insulin absorption and may impair glycemic control in insulin-dependent diabetic patients. Furthermore, the influence of accidental intramuscular injection on insulin absorption seems to vary among injection regions.

Unchanged insulin absorption after 4 days' use of subcutaneous indwelling catheters for insulin injections.

OBJECTIVE: Since 1985, we have used indwelling catheters (Insuflon, Maersk Medical, Lynge, Denmark; Chronimed, Minnetonka, MN) to lessen pain when injecting insulin. However, some patients experience a rise in blood glucose after using indwelling catheters for a few days. We therefore studied the absorption of 125I-labeled insulin when using indwelling catheters. RESEARCH DESIGN AND METHODS: Five men and five women participated (age 18-25 years, C-peptide negative, HbA1c 9.0 +/- 1.0% [mean +/- SD, DCA-2000 method], diabetes duration 5-21 [median 9.5] years). After thyroid blockage with potassium iodide, we injected 5IU of 125I-labeled short-acting insulin subcutaneously in the abdomen ("ordinary injection") and 5 IU on the contralateral side through an indwelling catheter ("catheter injection"). The injection/insertion area was free of lipohyper- and lipohypotrophies. Disappearance rate was measured for 180 min with a gamma camera. The patients injected all premeal injections of short-acting insulin through the same indwelling catheter in the following 4 days. The investigation procedure was repeated day 3 and 5. RESULTS: We found no statistically or clinically (95% CI) significant difference in residual activity of 125I-insulin after 60 min or in time for 50% of the injected depot to disappear (T-50%) among catheter injections on day 1, 3, and 5; ordinary injections on days 1, 3, and 5; or catheter and ordinary injections on days 1, 3, and 5, respectively. HbA1c correlated both to T-50% (r = 0.73, P = 0.016) and residual activity of 125I-insulin after 60 min (r = 0.69, P = 0.028), indicating that patients with a slower absorption will have a less ideal metabolic control when using premeal bolus injections. CONCLUSIONS: We conclude that using indwelling subcutaneous catheters for insulin injections for up to 4 days does not affect the absorption of short-acting insulin.

[On possible approach to characterizing the buffering capacity of landscape with respect to radiocesium contamination].

It is shown that migration (equally with decay) is a mechanism responsible for the buffering capacity of landscape with respect to radiocesium contamination. An approach is offered to determine the gradation of the buffering capacity and corresponding parameters of the migration models.

The thigh may not be suitable as an injection site for patients self-injecting sumatriptan.

The objective of our study was to evaluate the differences between injection sites in the midthigh and the upper lateral quadrant of the gluteal area regarding the effect, depth of subcutaneous tissue, side effects, and patient preference in patients with cluster headache who self-inject 6 mg (0.5 ml) of sumatriptan. Our open, prospective clinical study was performed at the outpatient department of a Swedish university clinic. There were 19 male and one female subjects, 34 to 68 years old, suffering from cluster headache. We measured the subcutaneous tissue depth by ultrasound. Subjects performed four self-injections of sumatriptan, two in the thigh and two in the gluteal area. We evaluated the subcutaneous tissue depth from the skin surface to the muscle fascia, the effect on headache, side effects, and patient preference regarding the injection site. Subcutaneous tissue depth laterally in the thigh was 2 to 12 mm (median, 4 mm) and in the gluteal area was 34 to 68 mm (median, 45 mm). The needle of the self-injector protrudes 5 to 6 mm. Forty thigh and 39 gluteal injections were recorded. The effect on headache was equal. Following injection in thigh the patients experienced more bleeding (p < 0.001, chi 2); local pain (p < 0.05, chi 2); and a feeling of oppression in the head, neck, and chest area (p < 0.05, chi 2); compared with injections in the gluteal area. Fifteen patients preferred the gluteal area as the injection site after the study, two patients had no preference, and three preferred the thigh. When using the self-injector in the lateral aspect of the thigh, intramuscular injection is liable to occur frequently in male patients. This may explain the differences in local and general side effects observed in this study. The upper lateral quadrant of the gluteal area is a more suitable injection site for male, and some female, patients when using the sumatriptan self-injector.

Clinically important differences in insulin absorption from abdomen in IDDM.

The absorption of radiolabeled soluble insulin ([125I]Actrapid Human; 10 U) from subcutaneous injection sites above (120 mm) and below (40 mm) the umbilicus was studied on 2 consecutive days in nine IDDM patients during 180 min. Insulin absorption was measured as disappearance of radioactivity by continuous external monitoring and as appearance of plasma immunoreactive free insulin (IRI). Adipose tissue blood flow (ATBF) was measured concomitantly by the 133Xe-washout technique. Plasma glucose was determined. Prior to the injections the depth of the subcutaneous fat tissue was determined using ultrasound. Significantly less radioactivity remained at the upper site, 42 +/- 5 vs. 60 +/- 6% after 180 min (P < 0.001). In accordance with this, injection into the site above vs. below the umbilicus resulted in a greater area under curve for plasma insulin, 3306 +/- 493 vs. 2357 +/- 466 mU/l per min (0-180 min; P < 0.01), and a more pronounced plasma glucose-lowering effect (P < 0.05). However, ATBF did not differ significantly between the two sites. These data suggest that there are clinically relevant differences in insulin absorption within the abdomen. Thus, insulin injection into the epigastric area causes more rapid insulin absorption resulting in an enhanced plasma glucose-lowering effect than injection into the more conventional site close beneath the umbilicus.

Effects of chronic hypoxia on the secretory responses of rat salivary glands.

Female Wistar rats were placed for 3 weeks in a simulated chamber evacuated by a vacuum pump and maintained at 40.5 kPa (7100 m). Dose-response curves were obtained through the sequential injection, via the femoral vein, of increasing doses of methacholine, methoxamine, isoprenaline and substance P. The secretory activity in the parotid gland after exposure to chronic hypoxia was significantly decreased for all agonists studied, and the submaxillary gland showed the same behaviour except in relation to isoprenaline, which did not show a significant difference compared to controls. These data suggest that changes in the number or sensitivity of autonomic receptors and/or alterations in the intracellular signals caused by hypoxia may be involved in the reduction in salivary secretory responses.

[Mechanisms and models of 137Cs migration in soils]. / Mekhanizmy i modeli migratsii 137Cs v pochvakh.

The most spread mechanisms and models of 137Cs migration in soil were considered and the advantage of the models, which take into account the kinetics of sorption-desorption above the models with two components were presented.

[Dynamic characteristics of growth of the root system of a plant and methods of determining it]. / Dinamicheskaia kharakteristika rosta kornevoi sistemy rasteniia i metody ikh opredeleniia

A method of description for the dynamics of growth of the plant root system is considered. The methods are proposed for the qualitative analysis of the dynamics of growth and the quantitative determination of such a value as the time of active consumption of substances by an individual root region until its suberification. The corresponding calculation was performed for the oat and the barley.

Depressed eruption dental rate in rats with hemodynamically-mediated acute renal failure.

The effects of acute renal failure on the impeded (IER) and unimpeded (UER) eruption dental rate and attrition rate (AR) were investigated. Adult female Wistar rats were injected with 125 mg/kg b.w of human methemoglobin (M-Hb) in order to induce a first episode of hemodynamically-mediated acute renal failure (H-ARF). Ten days after the injection of M-Hb, other groups of rats received another equal dose of the drug in order to induce a second episode of H-ARF. A group of six animals was pair-fed daily and individually with rats of M-Hb groups. Evaluation of renal function, histopathology studies, IER, UER, food intake (FI), AR and body weight gains was performed at different times after the first and second injections, of M-Hb. Treatment induced transient increases in plasma urea concentration and urine volume, and significant depression in urine osmolality, body weight gains, IER, UER and AR. In every case, the maximal effect of the first injection of M-Hb on the individual parameters was always greater than that of the second injection. Histologic sections showed interstitial cellular infiltration, desquamation of the proximal tubular epithelium and collapse or dilation of the tubular lumen. The functional values of kidney, histologic findings, IER, UER and AR of the pair-fed rats were not significantly different from control values. The results of the present study indicate that dental eruption rate (IER and UER) is relatively low in uremic rats with kidney tubule lesions and that both parameters are related.

Needlestick injuries in European nurses in diabetes.

AIM: With the June 2010 publication of EU Council Directive 2010/32/EU scrutiny is now being focused on the safety and protection of diabetes nurses. METHODS: We used a questionnaire to study the frequency and risks of Needlestick Injuries (NSI) associated with diabetic injections in European hospitals. 634 nurses participated from 13 western European countries and Russia. RESULTS: When patients with diabetes who self-inject at home are hospitalized injections are given always by the staff in 31% of cases, by the patients themselves where possible in 33%, initially by staff, then the patient takes over in 12% and both staff and patient throughout the stay in 21%. 86% of nurses said their hospitals had a written policy on the prevention of NSI but, where it was available, only 56% were familiar with it. 67% of the nurses had not attended any training on the prevention of NSI and only 13% had attended one in the last year. 7.1% of nurses report recapping needles and 5.9% report storing unprotected needles temporarily on a tray, trolley or cart. 32% of nurses report suffering a NSI while giving a diabetic injection at some point in the past. 29.5% of NSI occurred while recapping a used needle. 57% of nurses unscrew pen needles using their own fingers. In 80% cases the source patient's identity was known and the sharp item was "contaminated" (known previous percutaneous exposure to patient) in almost half the cases (43%). NSIs were reported to the proper authorities in only 2/3 of cases. CONCLUSION: Our study shows that frequent NSI occur in European nurses treating people with diabetes in hospital settings. These injuries are a source of possible infection despite the small size of diabetes needles. The introduction of safety-engineered medical devices has been shown to reduce the risk of injury. A new European Directive that has now come into force specifically stipulates that wherever there is risk of sharps injury, the user and all healthcare workers must be protected by adequate safety precautions, including the use of "medical devices incorporating safety-engineered protection mechanisms".

The Third Injection Technique Workshop in Athens (TITAN).

The first Injection Technique workshop brought together endocrinologists and injection experts from around the world in Strasbourg in 1997. From its work came groundbreaking recommendations which advanced best practices in areas such as the use of a skin fold when injecting. The second Injection Technique workshop, with an expanded format including nurses and diabetes educators, took place in Barcelona in 2000. The initial stimulus to use shorter injecting needles can be said to date from this meeting. The third Injection Technique workshop was held in Athens in September 2009 and involved 127 experts from across the globe. After a comprehensive review of all publications since 2000 as well as several unpublished studies, the attendees divided into smaller groups to debate and draft new injecting recommendations based on the new data and their collective experience. This paper summarizes all the formal presentations given at this practical consensus workshop.

New injection recommendations for patients with diabetes.

AIM: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. METHODS: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. RESULTS: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. CONCLUSION: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections.