Search

Aims/introduction: To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real-world clinical setting., Materials and Methods: A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain., Results: HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately -0.3% and -0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors., Conclusions: The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: Treatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia., Materials and Methods: Outcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia., Results: Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (-0.72% difference between groups; P < 0.0001)., Conclusions: New data from this post-hoc analysis of the JP-L trial show that treatment with the fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin vs similar doses of iGlar alone., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Recent evidence suggests a potentially protective effect of increasing ketone body availability via accepting low macronutrient intake early after onset of critical illness. The impact of blood glucose control with insulin on circulating ketones is unclear. Whereas lowering blood glucose may activate ketogenesis, high insulin concentrations may have the opposite effect. We hypothesized that the previously reported protective effects of tight glucose control in critically ill patients receiving early parenteral nutrition may have been mediated in part by activation of ketogenesis., Methods: This is a secondary analysis of 3 randomized controlled trials on tight versus liberal blood glucose control in the intensive care unit, including 700 critically ill children and 2748 critically ill adults. All patients received early parenteral nutrition as part of the contemporary standard of care. Before studying a potential mediator role of circulating ketones in improving outcome, we performed a time course analysis to investigate whether tight glucose control significantly affected ketogenesis and to identify a day of maximal effect, if any. We quantified plasma/serum 3-hydroxybutyrate concentrations from intensive care unit admission until day 3 in 2 matched subsets of 100 critically ill children and 100 critically ill adults. Univariable differences between groups were investigated by Kruskal-Wallis test. Differences in 3-hydroxybutyrate concentrations between study days were investigated by Wilcoxon signed-rank test., Results: In critically ill children and adults receiving early parenteral nutrition, tight glucose control, as compared with liberal glucose control, lowered mean morning blood glucose on days 1-3 (P < 0.0001) via infusing insulin at a higher dose (P < 0.0001). Throughout the study period, caloric intake was not different between groups. In both children and adults, tight glucose control did not affect 3-hydroxybutyrate concentrations, which were suppressed on ICU days 1-3 and significantly lower than the ICU admission values for both groups (P < 0.0001)., Conclusion: Tight versus liberal glucose control in the context of early parenteral nutrition did not affect 3-hydroxybutyrate concentrations in critically ill patients. Hence, the protective effects of tight glucose control in this context cannot be attributed to increased ketone body availability., (© 2021. The Author(s).)

Despite innovations in insulin therapy since its discovery, most patients living with type 1 diabetes do not achieve sufficient glycemic control to prevent complications, and they experience hypoglycemia, weight gain, and major self-care burden. Promising pharmacological advances in insulin therapy include the refinement of extremely rapid insulin analogs, alternate insulin-delivery routes, liver-selective insulins, add-on drugs that enhance insulin effect, and glucose-responsive insulin molecules. The greatest future impact will come from combining these pharmacological solutions with existing automated insulin delivery methods that integrate insulin pumps and glucose sensors. These systems will use algorithms enhanced by machine learning, supplemented by technologies that include activity monitors and sensors for other key metabolites such as ketones. The future challenges facing clinicians and researchers will be those of access and broad clinical implementation., (Copyright © 2021, American Association for the Advancement of Science.)

Abstract: The aim of this research is to observe the effect of insulin pump combined with Ulinastatin on the levels of procalcitonin (PCT), triglycerides (TG), pentraxin-3(PTX-3), and C-X3-C motif chemokine ligand 1 (CX3CL1) in patients with diabetic ketoacidosis and pancreatitis.A total of 72 patients with diabetic ketoacidosis and pancreatitis who were admitted to our hospital from February 2016 to February 2020 were selected as the research subjects. They were divided into study groups (36 cases, given insulin pump combined Ulinastatin treatment) and control group (36 cases, given insulin pump treatment). Statistics of changes in blood amylase (AMS), blood glucose, blood ketones, glycosylated hemoglobin (HbA1c), PCT, TG, PTX-3, and chemokine CX3CL in pancreatic tissue before and after treatment.After treatment, the clinical efficacy of the study group was significantly higher than that of the control group (94.44% vs 75.00%), the difference was significant (P < .05). After treatment, the clinical symptoms (abdominal distension, abdominal pain, body temperature, blood sugar, HbA1c and blood amylase) in the study group were significantly less time-to-normal than in the control group, and the difference was significant (P < .05). After treatment, the AMS, blood sugar, HbA1c, and blood ketones of the 2 groups were all lower than before treatment, and the study group's AMS, blood sugar, HbA1c, and blood ketones were all lower In the control group, the difference was significant (P < .05). After treatment, the 2 groups of PCT, TG, PTX-3, and CX3CL were all lower than before treatment, among which the study group PCT, TG, PTX-3, and CX3CL1 were lower than the control group, the difference was significant (P < .05). After treatment, the total adverse reaction rate of the 2 groups was not significantly different (P > .05), but the total adverse reaction rate of the study group was lower than that of the control group.The combination of insulin pump and ulinastatin in the treatment of patients with diabetic ketoacidosis complicated with acute pancreatitis has a effect, which can shorten the recovery time of clinical symptoms, reduce the levels of PCT, TG, PTX-3, and CX3CL1, and has fewer adverse reactions. It is worthy of clinical application., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction : The aim of insulin replacement in insulin-deficient people (type 1 diabetes, pancreatic causes of diabetes, long-standing type 2 diabetes) is to approximate the physiologic insulin action profile as closely as possible. However, short-acting human insulins start too slow and act too long, causing postprandial hyperglycemia and delayed hypoglycemia, while the insulin action profile of long-acting human insulins is too variable in duration and strength of action, leading to insufficient basal insulin covering and peak insulin levels after injection causing early nocturnal hypoglycemia. Insulin analogues were designed to overcome these shortcomings. In insulin-resistant people (type 2 diabetes), insulin analogues contribute to more efficient and safer insulin supplementation. Areas covered : In this review, we describe the unmet needs for insulin therapy, the currently available short- and long-acting insulin analogues and some considerations on cardiovascular outcomes, use in special populations, and cost-effectiveness. Finally, we discuss what is new in the field of insulin analogues. Expert opinion : The development of insulin analogues is an important step in diabetes treatment. Despite many patients meeting their glycemic targets with the newest analogues, hypoglycemic episodes remain a major problem. More physiologic insulin regimens, with glucose-sensitive or organ-targeting insulin analogues may be the answer to these issues.

Background/aim: Several studies have reported that DM is closely associated with an increased incidence of hepatocellular carcinoma (HCC). To clarify the effects of diabetes mellitus (DM) and antidiabetic medications on the prognosis of patients with non-B non-C (NBNC) HCC following curative initial hepatectomy., Patients and Methods: HCC patients (n=156) were divided into three groups according to the presence or absence of chronic viral hepatitis: hepatitis B virus (HBV) group, hepatitis C virus (HCV) group, and NBNC group. The clinical characteristics and survival outcomes were compared. In the NBNC group, univariate and multivariate analyses were conducted to determine prognostic factors., Results: The NBNC group had a higher incidence of DM, ethanol intake, and large nodules than the other groups. Disease-free survival (DFS) was significantly worse in the NBNC group than in the HBV group. In the NBNC group, insulin treatment was an independent prognostic factor for DFS and overall survival (OS)., Conclusion: Medications for DM that affect insulin resistance might be appropriate prognostic factors for NBNC-HCC., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 65-year-old woman with known breast cancer presented with lower back pain over 1 month. Multiple sclerotic foci of increased tracer uptake in the bones were noted on the Tc-MDP bone scintigraphy and SPECT/CT images, suggesting osteoblastic metastasis. Unexpectedly, symmetric Tc-MDP activity was visualized in the soft tissue near the umbilical area, corresponding to the sites of insulin injection.

The International Society for Pediatric and Adolescent Diabetes Clinical Practice Consensus Guideline 2018 for management of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state provide comprehensive guidance for management of DKA in young people. Intravenous (IV) infusion of insulin remains the treatment of choice for treating DKA; however, the policy of many hospitals around the world requires admission to an intensive care unit (ICU) for IV insulin infusion. During the coronavirus 2019 (COVID-19) pandemic or other settings where intensive care resources are limited, ICU services may need to be prioritized or may not be appropriate due to risk of transmission of infection to young people with type 1 or type 2 diabetes. The aim of this guideline, which should be used in conjunction with the ISPAD 2018 guidelines, is to ensure that young individuals with DKA receive management according to best evidence in the context of limited ICU resources. Specifically, this guideline summarizes evidence for the role of subcutaneous insulin in treatment of uncomplicated mild to moderate DKA in young people and may be implemented if administration of IV insulin is not an option., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

The purpose of this study was to investigate stigmatization, sociodemographic/diabetes-related characteristics and parents-related characteristics as predictors of a negative perception of insulin treatment in adolescents with type 1 diabetes in Turkey. The study was carried out using a cross-sectional correlation design. The research sample included 80 adolescents with type 1 diabetes who volunteered to take part. A positive perception of insulin treatment (β = -.38, p < .001), stigmatization (β = -.24, p = .013), informing others about one's type 1 diabetes (β = .24, p = .017) and only using insulin when alone in public places (β = .19, p = .042) were significant predictors of a negative perception of insulin treatment, and these variables explained 35% of the common variance. Diabetes' nurses should take stigmatization into account during their training and plan appropriate measures. Entrepreneurial, randomized, and controlled studies should be conducted to decrease the negative influence of stigmatization on the perception of insulin treatment in individuals with type 1 diabetes.

Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the 125 I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The design and development of insulin pumps and various glucose sensor systems has an enormous impact on life quality of diabetic patients. Surveillance and therapy of diabetes has improved due to the new diabetic devices, which are affixed to the patients' skin for several days. Since their introduction, irritant and allergic contact dermatitis have been frequently reported. Patients often acquire contact sensitization to isobornyl acrylate, N,N-dimethylacrylamide or formerly to 2‑ethyl-cyanoacrylate. These contact allergens were found in the patch, in the glue to affix the box on the patch or in the casing of the system itself. Development of contact allergy to substances of these systems may result in the need to abandon modern diabetic devices.

Background: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related., Objective: We conducted a narrative review of low-cost OHMs., Methods: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications., Results: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment., Conclusion: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

At any given moment, behavior is controlled by a combination of external stimuli and an animal's internal state. As physiological conditions change, vastly different behaviors might result from the same stimuli. For example, the motivation to hunt and hunting strategy are influenced by satiety. Here, we describe how sensory responsiveness and motor activity of a praying mantis ( Tenodera sinensis ) change as the insect feeds, leading to an altered hunting strategy. We further show that these changes can be induced by injection of insulin, which likely functions as a metabotropic indicator. Praying mantises directed their attention toward real and simulated prey less often as they fed and became sated. The range of distance and azimuth at which prey was detected decreased as did pursuit of prey, while opportunistic close-range attacks persisted. Together, these sensorimotor changes are indicative of a behavioral paradigm shift from 'pursuit' to 'ambush'. A similar effect was induced in starved praying mantises injected with 0.05 ml of 200 μg ml -1 bovine insulin. These experiments showed that insulin injection into the circulating hemolymph is sufficient to decrease prey orientation as well as in prey-directed locomotor behaviors (tracking and pursuit). The effects of prey consumption and insulin injection were similarly dose dependent. These results suggest that insulin is a signal of internal, physiological conditions that can modify responses to external stimuli. A change in hunting strategy thus results from coordinated effects of a neurohormone on a set of independent sensorimotor processes and the overall activity level of the animal., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Introduction: Closed-loop systems titrate insulin based on sensor glucose levels, providing novel means to reduce the risk of hypoglycaemia while improving glycaemic control. We will assess effectiveness of 6-month day-and-night closed-loop insulin delivery compared with usual care (conventional or sensor-augmented pump therapy) in children and adolescents with type 1 diabetes., Methods and Analysis: The trial adopts an open-label, multicentre, multinational (UK and USA), randomised, single-period, parallel design. Participants (n=130) are children and adolescents (aged ≥6 and <19 years) with type 1 diabetes for at least 1 year, and insulin pump use for at least 3 months with suboptimal glycaemic control (glycated haemoglobin ≥58 mmol/mol (7.5%) and ≤86 mmol/mol (10%)). After a 2-3 week run-in period, participants will be randomised to 6-month use of hybrid closed-loop insulin delivery, or to usual care. Analyses will be conducted on an intention-to-treat basis. The primary outcome is glycated haemoglobin at 6 months. Other key endpoints include time in the target glucose range (3.9-10 mmol/L, 70-180 mg/dL), mean sensor glucose and time spent above and below target. Secondary outcomes include SD and coefficient of variation of sensor glucose levels, time with sensor glucose levels <3.5 mmol/L (63 mg/dL) and <3.0 mmol/L (54 mg/dL), area under the curve of glucose <3.5 mmol/L (63 mg/dL), time with glucose levels >16.7 mmol/L (300 mg/dL), area under the curve of glucose >10.0 mmol/L (180 mg/dL), total, basal and bolus insulin dose, body mass index z-score and blood pressure. Cognitive, emotional and behavioural characteristics of participants and caregivers and their responses to the closed-loop and clinical trial will be assessed. An incremental cost-effectiveness ratio for closed-loop will be estimated., Ethics and Dissemination: Cambridge South Research Ethics Committee and Jaeb Center for Health Research Institutional Review Office approved the study. The findings will be disseminated by peer-review publications and conference presentations., Trial Registration Number: NCT02925299; Pre-results., Competing Interests: Competing interests: RH reports having received speaker honoraria from Eli Lilly and Novo Nordisk, serving on advisory panel for Eli Lilly and Novo Nordisk, receiving licence fees from BBraun and Medtronic. RH and MEW report patent patents and patent applications. MT has received speaker honoraria from Medtronic and NovoNordisk. PW reports receiving speaker honoraria from Dexcom and serving on advisory panels for Eli Lilly and Novo Nordisk and research support from Bigfoot Biomedical, Dexcom, Lexicon, Mannkind and Novo Nordisk. BAB is on Advisory Boards for Novo Nordisk and Convatec, has received research support from Medtronic Diabetes, Tandem Diabetes, Insulet, Convatec and Dexcom. SW has received speaker honoraria from Medtronic, Insulet and Tandem, and has received consultant honoraria from Sanofi and Zealand Pharmaceuticals. KH has received research support from Dexcom for an investigator-initiated project; he has received consultant fees from Lilly Innovation Center, Bigfoot Biomedical and Insulet. LDM reports grants from Medtronic., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: The expanding variety of insulins, including biosynthetic human insulin and rapid and long-acting insulin analogs, have dramatically transformed the management of type 1 diabetes (T1D) over the past 25 years. Moreover, increasing interest in the use of novel drugs developed for the treatment of type 2 diabetes (T2D) as adjunctive therapies for T1D remains a work in progress. Areas Covered: We reviewed articles published up to December 2018 in PubMed and ClinicalTrials.gov for recent developments in the pharmacologic treatment of T1D, including inhaled insulin, ultrafast and ultralong-acting insulins and adjunctive therapies including pramlintide, metformin, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2, and SGLT1/2 inhibitors. Expert Opinion: With the creation of ultrafast-acting insulin analogs and very prolonged duration of action of basal insulins, it is possible to more closely mimic physiologic insulin secretion. Adjunctive therapies, likewise, may also overcome some of the abnormal physiology that is a hallmark of T1D. Therefore, individualized consideration of the efficacy of these agents must be measured alongside the potential adverse effects when choosing an adjunctive therapy.

Purpose: To develop a planar, asymmetric, micro-scale oral drug delivery vehicle by i) fabricating microdevice bodies with enteric materials, ii) efficiently and stably loading sensitive drug molecules, and iii) capping microdevices for controlled drug release., Methods: Picoliter-volume inkjet printing was used to fabricate microdevices through additive manufacturing via drop-by-drop deposition of enteric polymer materials. Microdevice bodies with reservoirs are fabricated through deposition of an enteric polymer, Eudragit FS 30 D. A model API, insulin, was loaded into each microdevice and retained its stability during printing and release. Eudragit L 100 and/or S 100 were used to cap microdevices and control the kinetics of insulin release in simulated intestinal conditions., Results: Microdevice morphologies and size can be tuned on the fly based on printing parameters to span from the microscale to the mesoscale. Insulin retained its stability throughout device fabrication and during in vitro release in simulated intestinal conditions. Insulin release kinetics, from burst release to no release, can be tailored by controlling the blend of the Eudragit capping material., Conclusion: This approach represents a uniquely scalable and flexible strategy for microdevice fabrication that overcomes limitations in loading sensitive biologics and in the tuneability of device geometries that are inherent to traditional microfabrication strategies.

The earliest marketed insulins were crude acidic formulations with concentrations of ≤10 units/mL. Since the early 1920s, insulins have improved continually, via bioengineering, process, and chemical modifications. Today, most insulin formulations have a concentration of 100 units/mL (U100). However, more concentrated insulin formulations (200, 300, and 500 units/mL; U200, U300, and U500, respectively) are also available. There is a tendency to assume that concentrated insulins are similar, both to each other and to their U100 counterparts, but this is not always the case: two concentrated insulins, namely insulin degludec U200 and insulin lispro U200, are bioequivalent to their U100 counterparts, whereas regular human insulin U500 and insulin glargine U300 are not. The advent of these concentrated insulins offers greater opportunities to provide tailored therapy for patients; it also introduces potential confusion, and highlights the need for prescriber and patient education. Precise and accurate dedicated insulin delivery devices are also necessary for the safe use of these concentrated insulins. Although some clinicians only use concentrated insulin with obese and severely insulin-resistant patients, other patients would also benefit from the reduced injection volume associated with concentrated insulins, or the modified time-action profile of some concentrated insulins. The aim of this review is to enhance understanding of the historic development and the safe and effective use of concentrated insulins in clinical practice., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

New concentrated insulins (exceeding 100 units/mL) and dedicated devices have recently become available, offering new treatment options for people with diabetes, for basal and prandial insulin supplementation. The concentrated insulin formulations range from 2-fold concentration (insulin lispro 200 units/mL) with rapid-acting prandial action to 5-fold concentration (human regular insulin, 500 units/mL) with basal and short-acting prandial actions. Long-acting basal insulins include degludec 200 units/mL and glargine 300 units/mL. Concentrated insulins have been developed with the goal of easing insulin therapy by reducing the volume and number of injections and in some cases making use of altered pharmacokinetic and pharmacodynamic properties. This review summarizes the unique characteristics of each concentrated insulin to help healthcare providers and people with diabetes understand how to best use them., (Copyright © 2019 Eli Lilly and Company. Published by Elsevier B.V. All rights reserved.)

Aims: To compare real-world antidiabetic treatment outcomes over 12 months in obese people with type 2 diabetes mellitus (T2DM) who previously received oral antidiabetic therapy and then initiated a first injectable therapy with liraglutide or basal insulin., Patients and Methods: This was a retrospective, propensity score-matched, longitudinal cohort study using real-world data (January 2010 to December 2015) from the Dutch PHARMO Database Network. Adult obese (body mass index [BMI] ≥35 kg/m 2 ) patients with T2DM with ≥2 dispensing dates for liraglutide or basal insulin supported oral therapy (BOT) were selected. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline during 12 months of follow-up. The secondary endpoints were the changes in weight, BMI and cardiovascular risk factors from baseline. Clinical data were analysed using descriptive statistics and compared using mixed models for repeated measures., Results: Obese patients with T2DM (N = 1157) in each treatment group were matched (liraglutide cohort, n = 544; BOT cohort, n = 613). From 3 months onwards, glycaemic control improved in both cohorts but improved significantly more with liraglutide than with BOT (12 months: -12.2 mmol/mol vs -8.8 mmol/mol; P = .0053). In addition, weight and BMI were significantly lower for treatments with liraglutide vs BOT (12 months: -6.0 kg vs -1.6 kg and - 2.1 kg/m 2 vs -0.5 kg/m 2 , respectively; P < .0001 for both). No significant differences were seen in changes in cardiovascular risk factors., Conclusions: The results of this real-world study in matched obese patients with T2DM showed that liraglutide was more effective than BOT for HbA1c control and weight/BMI reductions. Patients were more likely to maintain glycaemic control over time after initiating liraglutide than after initiating BOT., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: To compile, analyze, and summarize the literature on concentrated insulins (i.e. concentrations >100 units/mL) from randomized controlled trials and derive guidance on appropriate use of these agents., Methods: Searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, Trialtrove (through April 2016) and ClinicalTrials.gov (through April 2017) for phase 1-4 clinical studies using concentrated insulins. Selected studies included multiple-arm, randomized controlled trials evaluating subcutaneously administered concentrated insulins. Trial registration numbers (selected studies) were searched in Medline, Embase and Google Scholar (through April 2017). Late-phase studies were graded using guidance from the Agency for Healthcare Research and Quality., Results: Thirty-eight completed trials (7900 participants) and 34 qualifying publications were identified. Four marketed concentrated insulins were evaluated: two long-acting basal (insulin glargine 300 units/mL and insulin degludec 200 units/mL [IDeg200]), one rapid-acting prandial (insulin lispro 200 units/mL [ILis200]), and one prandial/basal (human regular insulin 500 units/mL). Early-phase trials established bioequivalence for IDeg200 and ILis200 with the corresponding 100 units/mL formulations. Efficacy studies showed noninferior glycemic control between comparators for long-acting basal and prandial/basal products with generally low severe hypoglycemia. Six additional concentrated insulins with completed early-phase development were also identified., Conclusion: Concentrated-insulin products demonstrated efficacious and safe outcomes in appropriate patients. Clinical findings (HbA1c and hypoglycemia) and methodology (initiation and titration), patient factors (insulin experience and dosing requirements) and treatment characteristics (bioequivalence, potency and device features) are important considerations. This overview of these and other factors provides essential information and guidance for using concentrated insulins in clinical practice.

Aims: To evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care., Materials and Methods: This was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI]., Results: T1DM (n = 1717): HbA1c decreased by -2.2 [-2.6; -2.0] mmol/mol (-0.20 [-0.24; -0.17]%) at 6 months vs baseline (P < .001). Rate ratio of overall (0.79 [0.69; 0.89]), non-severe nocturnal (0.54 [0.42; 0.69]) and severe (0.15 [0.09; 0.24]) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period (P < .001 for all). Total daily insulin dose decreased by -4.88 [-5.52; -4.24] U (-11%) at 6 months vs baseline (P < .001). T2DM (n = 833): HbA1c decreased by -5.6 [-6.3; -4.7] mmol/mol (-0.51 [-0.58; -0.43] %) at 6 months vs baseline (P < .001). Rate ratio of overall (0.39 [0.27; 0.58], P < .001), non-severe nocturnal (0.10 [0.06; 0.16], P < .001) and severe (0.075 [0.01; 0.43], P = .004) hypoglycaemia was significantly lower in the 6-month post-switch period vs the pre-switch period. Total daily insulin dose decreased by -2.48 [-4.24; -0.71] U (-3%) at 6 months vs baseline (P = .006). Clinical outcomes for T1DM and T2DM at 12 months were consistent with results at 6 months., Conclusions: This study demonstrates that switching patients to IDeg from other basal insulins improves glycaemic control and significantly reduces the risk of hypoglycaemia in routine clinical practice., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The inability to achieve optimal diabetes glucose control in people with diabetes is multifactorial, but one contributor may be inadequate control of postprandial glucose. In patients treated with multiple daily injections of insulin, both the dose and timing of meal-related rapid-acting insulin are key factors in this. There are conflicting opinions and evidence on the optimal time to administer mealtime insulin. We performed a comprehensive literature search to review the published data, focusing on the use of rapid-acting insulin analogues in patients with Type 1 diabetes. Pharmacokinetic and pharmacodynamic studies of rapid-acting insulin analogues, together with postprandial glucose excursion data, suggest that administering these 15-20 min before food would provide optimal postprandial glucose control. Data from clinical studies involving people with Type 1 diabetes receiving structured meals and rapid-acting insulin analogues support this, showing a reduction in post-meal glucose levels of ~30% and less hypoglycaemia when meal insulin was taken 15-20 min before a meal compared with immediately before the meal. Importantly, there was also a greater risk of postprandial hypoglycaemia when patients took rapid-acting analogues after eating compared with before eating., (© 2017 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objectives: This study tested hypotheses drawn from a risk model positing that psychosocial risk plus disease-related and treatment factors contribute to bulimic symptoms in youth with type 1 diabetes (T1D) transitioning to an insulin pump. The goal of this study was to examine whether disease-related factors, particularly disease- and treatment-based disruption in hunger and satiety, contribute to report of bulimic symptoms in youth with T1D after accounting for psychosocial risk factors., Methods: 43 youth (ages 10-17, 54% female) with established T1D were recruited before transition from multiple daily injections to insulin-pump therapy from three tertiary pediatric diabetes centers. Participants completed measures of bulimic symptoms, depressive symptoms dietary restraint, and the Diabetes Treatment and Satiety Scale, a diabetes-specific questionnaire assessing hunger and satiety cues and eating behavior in response to blood glucose levels and treatment., Results: Hierarchical multiple regression was used to assess contributions of psychosocial and disease-based risk to report of bulimic symptoms. After assessing the contributions of body mass index, body image dissatisfaction, and dietary restraint, a significant 2-way interaction emerged between depression and diabetes-related uncontrollable hunger related to bulimic symptoms (β = 1.82, p < .01)., Conclusions: In addition to psychosocial risk, disease- and treatment-based hunger and satiety dysregulation appear to be important factors contributing to report of bulimic symptoms in youth with T1D. These preliminary findings have significant treatment implications for bulimic symptoms in youth with T1D., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Insulin pharmacokinetics following subcutaneous administration were modeled, simulated, and displayed through an interactive and user-friendly interface to illustrate the time course of administered insulins frequently prescribed, providing a simple tool for clinicians through a straightforward visualization of insulin regimens. Pharmacokinetic data of insulin formulations with different onset and duration of action from several clinical studies, including insulin glargine, regular insulin, neutral protamine Hagedorn (NPH), insulin lispro, and premixed preparations of NPH with regular insulin (Mix 70/30), and insulin lispro protamine suspension with insulin lispro (Mix 50/50, Mix 75/25), were used to develop a predictive population pharmacokinetic model of insulins with consideration of factors such as insulin formulation, weight-based dosing, body-weight effect on volume of distribution, and administration time relative to meals, on the insulin time-action profile. The model-predicted insulin profile of each insulin was validated and confirmed to be comparable to observed data via an external validation method. Model-based simulations of clinically relevant insulin-dosing scenarios to cater to specific initial patient and prescribing conditions were then implemented with differential equations using the R statistical program (version 3.2.2). The R package Shiny was subsequently applied to build a web browser interface to execute and visualize the model simulation outputs. The application of insulin pharmacokinetic modeling enabled informative visualization of insulin time-action profiles and provided an efficient and intuitive educational tool to quickly convey and interactively explore many insulin time-action profiles to ease the understanding of insulin formulations in clinical practice., (© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Three higher concentration insulin products (insulin lispro 200 units/mL, insulin degludec 200 units/mL, and insulin glargine 300 units/mL) received US Food and Drug Administration (FDA) approval in 2015. Although human regular insulin 500 units/mL (U-500) was approved in 1997, a pen and dedicated U-500 syringe became available in 2016. These products offer more treatment options for the increasing numbers of patients requiring insulin to achieve and maintain glycemic targets. Higher concentration insulins have some unique safety and efficacy considerations. Important considerations when transitioning patients from the 100 unit/mL concentration (U-100) to the higher concentration include bioequivalence, pen dose increments, and pen appearance. Bioequivalent insulins have similar pharmacokinetic properties and no dose adjustments are expected when transitioning from the U-100 to the higher concentration. In contrast, higher concentration insulins with different pharmacokinetic and pharmacodynamic properties compared with the U-100 formulation may require dose adjustments. In order to provide safe and effective therapy to patients with higher daily insulin dose requirements, it is important for healthcare professionals to become very familiar with the characteristics of and differences between each of the higher concentration insulins. This paper highlights differences between the U-100 and higher concentration insulins and focuses on practical aspects of use.

We present clinical, electroencephalographic and low-resolution electromagnetic tomography data that support combined treatment with insulin and a monoamine oxidase inhibitor in a patient with type 1 diabetes. We suggest that brain imaging data can identify a subgroup of patients who are likely to benefit from an insulin regimen and monoamine oxidase inhibition to improve glycaemic control, cardiovascular function, normalize the circadian rhythm and restore perception of glycaemic awareness.

Background: Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required., Objective: Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)., Methods: We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines., Results: Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses., Conclusion: Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin (HbA 1c ).

Newer insulin products have advanced the evolution of insulin replacement options to more accurately mimic natural insulin action. There are new, modified, and concentrated insulins; administration devices calibrated for both increased concentrations and administration accuracy to improve adherence and safety; and inhaled insulin. There are new combinations of longer-acting basal insulin and rapid-acting insulin or glucagon like protein-1 receptor agonists. Existing insulin replacement designs and methods can be updated using these tools to improve efficacy and safety. Individualized decisions to use them should be based on patient physiologic needs, self-care ability, comorbidities, and cost considerations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Once-daily insulin degludec/liraglutide (IDegLira) is the first basal insulin and glucagon like peptide-1 receptor agonist combined in one delivery device. Our aim was to investigate the cost effectiveness of IDegLira vs. basal insulin intensification therapies for patients with type 2 diabetes mellitus uncontrolled on basal insulin (glycosylated haemoglobin; HbA1c >7.5 %; 58 mmol/mol) in a UK setting., Research Design and Methods: Baseline cohort and clinical parameters were sourced from a pooled analysis comparing IDegLira with basal insulin plus liraglutide and basal-bolus therapy, and from the DUAL™ V trial comparing IDegLira with up-titrated insulin glargine (IGlar; Lantus(®)). The CORE Diabetes Model simulated lifetime costs and outcomes with IDegLira vs. these comparators from a UK healthcare payers' perspective. All costs were expressed in 2015 GBP. Sensitivity analyses were performed to assess the impact of key parameters in the model., Results: Treatment with IDegLira resulted in mean increases in quality-adjusted life-years (QALYs) of 0.12, 0.41 and 0.24 vs. basal insulin plus liraglutide, basal-bolus therapy and up-titrated IGlar, respectively. IDegLira was associated with lower costs of £971 and £1698 vs. basal insulin plus liraglutide and basal-bolus therapy, respectively, and increased costs of £1441 vs. up-titrated IGlar. IDegLira was dominant, i.e., both more effective and less costly vs. basal insulin plus liraglutide and basal-bolus therapy, and highly cost effective vs. up-titrated IGlar with an incremental cost-effectiveness ratio of £6090/QALY gained., Conclusions: Once-daily IDegLira may be considered a cost-effective treatment option for prescribers, to improve glycaemic control for type 2 diabetes patients uncontrolled on basal insulin without an increased risk of hypoglycaemia or weight gain, and without adding to their injection burden.

Introduction: Diabetes during pregnancy may lead to maternal, fetal and neonatal complications. In order to limit unwarranted outcomes, strict glycemic control is essential. In the past, human insulin was the only insulin formulation administered in pregnancy. However, insulin analogues have also been used for this indication in recent years., Areas Covered: This article reviews the published data regarding the safety of insulin analogue use during pregnancy. We present the qualities, advantages and pitfalls of insulin analogue use in pregnancy compared with human insulin. Insulins lispro, aspart and detemir are safe in pregnant women with type 1 diabetes. Correspondingly, they were reclassified for the treatment of pregnant women with diabetes from category C to category B. For insulin glargine use in pregnancy, most studies are small and retrospective. Yet, no major safety concerns were reported. Insulin glulisine and degludec have not been studied in pregnancy., Expert Opinion: Insulin analogues are viable therapeutic options for diabetes in pregnancy, specifically lispro, aspart and detemir. Though data in limited, their safety and efficacy are comparable with human insulin. Remarkably, the analogues are superior to human insulin regarding hypoglycaemia risk. More data, specifically for their use in pregnancies complicated by gestational diabetes or type 2 diabetes, is needed.

Aims: To assess the performance and safety of an integrated bihormonal artificial pancreas system consisting of one wearable device and two wireless glucose sensor transmitters during short-term daily use at home., Methods: Adult patients with type 1 diabetes using an insulin pump were invited to enrol in this randomized crossover study. Treatment with the artificial pancreas started with a day and night in the clinical research centre, followed by 3 days at home. The control period consisted of 4 days of insulin pump therapy at home with blinded continuous glucose monitoring for data collection. Days 2-4 were predefined as the analysis period, with median glucose as the primary outcome., Results: A total of 10 patients completed the study. The median [interquartile range (IQR)] glucose level was similar for the two treatments [7.3 (7.0-7.6) mmol/l for the artificial pancreas vs. 7.7 (7.0-9.0) mmol/l for the control; p = 0.123]. The median (IQR) percentage of time spent in euglycaemia (3.9-10 mmol/l) was longer during use of the artificial pancreas [84.7 (82.2-87.8)% for the artificial pancreas vs. 68.5 (57.9-83.6)% for the control; p = 0.007]. Time in hypoglycaemia was 1.3 (0.2-3.2)% for the artificial pancreas and 2.4 (0.4-10.3)% for the control treatment (p = 0.139). Separate analysis of daytime and night-time showed that the improvements were mainly achieved during the night., Conclusions: The results of this pilot study suggest that our integrated artificial pancreas provides better glucose control than insulin pump therapy in patients with type 1 diabetes at home and that the treatment is safe., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Safe and effective insulin therapy for diabetes mellitus requires initial dose titration and regular adjustments based on blood glucose (BG) monitoring. Our objective was to explore the use of BG measurement in phase-III clinical studies of insulin analogs. These studies provide safety and efficacy information for regulatory authorities and are the basis for insulin analog regulatory approval., Methods: A systematic review of phase-III studies of rapid-acting insulin analogs (insulin lispro, insulin aspart and insulin glulisine) and pre-mixed insulin analogs (biphasic insulin aspart and insulin lispro mix) was conducted. Studies were identified using manufacturers' databases. Search for reports was performed in Medline and registry of clinical trials (clinicaltrials.gov). The European Medicines Agency was contacted to provide Clinical Study Reports., Results: Forty-five studies were included. Regular BG measurements were reported in 100 % of the studies and were performed by either self-monitoring of blood glucose (SMBG) alone in 84 %, laboratory alone in 7 %, and both SMBG and laboratory in 9 % of studies. In total, 93 % of the studies reported SMBG. Most studies (91 %) reported insulin therapy adjustments based on BG measurements., Conclusions: The findings suggest that BG monitoring and specifically SMBG are co-dependent technologies with insulin analogs. BG measurement is used in most phase-III registration studies for establishing safe and efficacious insulin administration and is recommended in the insulin labels. The indispensable role of SMBG in treatment of insulin-dependent patients should receive attention from health care payers to assess and reimburse SMBG along with insulin to avoid adverse events from inappropriate insulin administration and associated costs.

Inpatient hyperglycemia is common and is associated with an increased risk of hospital complications, higher healthcare resource utilization, and higher in-hospital mortality rates. Appropriate glycemic control strategies can reduce these risks, although hypoglycemia is a concern. In critically ill patients, intravenous (IV) insulin is most appropriate, with a starting threshold no higher than 180 mg/dL. Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL. In noncritically ill patients, basal-bolus regimens with basal, prandial, and correction components are preferred for those with good nutritional intake. In contrast, a single dose of long-acting insulin plus correction insulin is preferred for patients with poor or no oral intake. Measuring hemoglobin A1c at admission is important to assess glycemic control and to tailor the treatment regimen at discharge., (Copyright © 2016 Cleveland Clinic.)

Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced.

Introduction: Diabetes mellitus, the prevalence of which has increased dramatically worldwide, may put patients at a higher risk of cancer. The aim of our study is the clarification of the possible mechanisms linking diabetes mellitus and gynecological cancer and their epidemiological relationship., Materials and Methods: This is a narrative review of the current literature, following a search on MEDLINE and the Cochrane Library, from their inception until January 2012. Articles investigating gynecologic cancer (endometrial, ovarian, and breast) incidence in diabetic patients were extracted., Results: The strong evidence for a positive association between diabetes mellitus and the risk for cancer indicates that energy intake in excess to energy expenditure, or the sequelae thereof, is involved in gynecological carcinogenesis. This risk may be further heightened by glucose which can directly promote the production of tumor cells by functioning as a source of energy. Insulin resistance accompanied by secondary hyperinsulinemia is hypothezised to have a mitogenic effect. Steroid hormones are in addition potent regulators of the balance between cellular differentiation, proliferation, and apoptosis. Inflammatory pathways may also be implicated, as a correlation seems to exist between diabetes mellitus and breast or endometrial carcinoma pathogenesis, although an analogous correlation with ovarian carcinoma is still under investigation. Antidiabetic agents have been correlated with elevated cancer risk, while metformin seems to lower the risk., Conclusion: Diabetes mellitus is associated with an elevation in gynecologic cancer risk. Moreover, there are many studies exploring the prognosis of patients with diabetes and gynecological cancer, the outcome and the overall survival in well-regulated patients.

Background: Overseeing proper insulin initiation and titration remains a challenging task in diabetes care. Recent advances in mobile technology have enabled new models of collaborative care between patients and healthcare providers (HCPs). We hypothesized that the adoption of such technology could help individuals starting basal insulin achieve better glycemic control compared with standard clinical practice., Materials and Methods: This was a 12 ± 2-week randomized controlled study with 40 individuals with type 2 diabetes who were starting basal insulin due to poor glycemic control. The control group (n = 20) received standard face-to-face care and phone follow-up as needed in a tertiary center, whereas the intervention group (n = 20) received care through the cloud-based diabetes management program where regular communications about glycemic control and insulin doses were conducted via patient self-tracking tools, shared decision-making interfaces, secure text messages, and virtual visits (audio, video, and shared screen control) instead of office visits., Results: By intention-to-treat analysis, the intervention group achieved a greater hemoglobin A1c decline compared with the control group (3.2 ± 1.5% vs. 2.0% ± 2.0%; P = 0.048). The Diabetes Treatment Satisfaction Questionnaire showed a significant improvement in the intervention group compared with the control group (an increase of 10.1 ± 11.7 vs. 2.1 ± 6.5 points; P = 0.01). HCPs spent less time with patients in the intervention group compared with those in the control group (65.9 min per subject vs. 81.6 min per subject). However, the intervention group required additional training time to use the mobile device., Conclusions: Mobile health technology could be an effective tool in sharing data, enhancing communication, and improving glycemic control while enabling collaborative decision making in diabetes care.

The year 2015 was punctuated by numerous events in diabetology. First, the ADA/EASD guidelines have been updated. The pharmacological panel for type 2 diabetes treatment saw the arrival of different new molecules. Two new basal insulins were also approved. Also, cardiovascular safety trials have been published regarding recent antidiabetic drugs. A new insulin pump than can be coupled with a glucosensor was released. Finally, a new unexpected complication of SGLT2 inhibitors treatment was reported, the euglycemic keto-acidosis.

The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients' health-related quality of life; reviews relevant pharmacoeconomic data; and discusses recent advances in pump technology, including the development of closed-loop 'artificial pancreas' systems. © 2015 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd., (© 2015 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.)