Anders Frid

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 ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤40 kg/m2. 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 (∼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.

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.

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 raXe wash-out technique. Plasma glucose was determined intermittently. The rate constant for 125l-insulin increased during exercise from 0.46 ± 0.08 to 1.17 ± 0.14%/min after intramuscular injection (P < 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 ∼80% greater, and the decrease in plasma glucose was ∼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. Because accidental intramuscular injection of insulin may occur frequently, these findings highlight a previously unobserved risk for an unexpected decrease in plasma glucose levels in connection with leg exercise in IDDM patients. This risk could be minimized by injection into a skin fold or by use of shorter needles for thigh injection.

Predictive factors of developing diabetes mellitus in women with gestational diabetes

Background.  To investigate which factors during gestational diabetes pregnancies correlate with the risk of developing impaired glucose tolerance or diabetes 1 year postpartum and to compare this risk in women with gestational diabetes and women with a normal oral glucose tolerance test during pregnancy.

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 m2 body surface. RESULTS Patients with eGFR >60, 30–60, and <30 ml/min/1.73 m2 had median trough metformin concentrations of 4.5 μmol/l (range 0.1–20.7, n = 107), 7.71 μmol/l (0.12–15.15, n = 21), and 8.88 μmol/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 μmol/l. Metformin measurement is less suitable for dose titration.

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

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.

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 >180 min, respectively (P < .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.

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.

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.