Eficacia y Seguridad del uso de la insulina análoga de acción corta Lispro en comparación con insulina regular humana (NPH) en pacientes niños, adolescentes y adultos con Diabetes Mellitus tipo 1 / Efficacy and Safety of Using Analog Insulin of action cuts Lispro in comparison with insulin regular human function (NPH) in child patients, adolescents and adults with type 1 Diabetes Mellitus

INTRODUCCIÓN: La Diabetes Mellitus tipo (DM1) es una enfermedad que se caracteriza por una hiperglicemia persistente debido a una disminución o ausencia de células beta pancreáticas por destrucción de las mismas. Esta hiperglicemia persistente aumenta luego de cada comida, debido a la falta de insulina. Por lo tanto, como parte de la insulinoterapia, es prioritario conocer los valores previos de glicemia para poder optimizar la dosis de insulina de cada paciente, tanto para poder detectar valores elevados como valores bajos. TECNOLOGÍA SANITARIA: La insulina Lispro es un análogo de acción corta de insulina producidas mediante tecnología de ADN recombinante, que regula el metabolismo de la glucosa a través de la estimulación de la captación de glucosa en el tejido esquelético y la grasa, así como la inhibición de la producción de glucosa hepática. OBJETIVO: Evaluar la eficacia y seguridad, de la insulina Lispro en comparación de la insulina NPH en las personas con Diabetes Mellitus Tipo 1 para el desarrollo de la hipoglicemia severa, mejorar la calidad de vida y la adherencia. METODOLOGÍA: Se realizó una búsqueda sistemática en las bases de datos bibliográficas: MEDLINE (PubMed), LILACS, Cochrane Library, así́como en buscadores genéricos de Internet incluyendo Google Scholar. Así también, se hizo una búsqueda en agencias que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se seleccionó una revisión sistemática, cinco guías de práctica clínica, una evaluación de tecnologías sanitarias y un ensayo clínico aleatorizado para responder la pregunta PICO formulada. CONCLUSIONES: En pacientes con DM1, el uso de la insulina Lispro en comparación de la insulina NPH, no tuvo diferencias en el riesgo de hipoglicemia severa y la calidad de vida de los pacientes. Las cinco GPC recomiendan preferentemente usar análogos de insulina, como Lispro para pacientes que con alto riesgo de hipoglucemia se definen como aquellos con antecedentes de hipoglucemia grave (que requieren asistencia para su manejo), alteración de la conciencia de la hipoglucemia (IAH) y/o condiciones médicas que los predisponen a la hipoglucemia grave incluida la disfunción renal y hepática. El informe de ETS de Canadá concluye que no hay diferencia en los episodios de hipoglicemia entre la insulina Lispro y la insulina NPH, más que solo un grupo en riesgo de hipoglicemia severa se beneficiaria de la intervención.

ISPAD Clinical Practice Consensus Guideline: Diabetic ketoacidosis in the time of COVID-19 and resource-limited settings-role of subcutaneous insulin.

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.

Urinary detection of rapid-acting insulin analogs in healthy humans.

Human insulin and its synthetic analogs are considered as life-saving drugs for people suffering from diabetes mellitus. Next to the therapeutic use, scientific and non-scientific literature (e.g. bodybuilding forums; antidoping intelligence and investigation reports) indicate that these prohibited substances are used as performance enhancing agents. In the present report, the development and validation of a sensitive analytical strategy is described for the urinary detection of three rapid-acting insulin analogs (Lispro, Aspart, Glulisine). The method is based on sample purification by the combination of ultrafiltration and immunoaffinity purification and subsequent analysis by nano-flow liquid chromatography coupled to high resolution mass spectrometry. Next to the results on different validation parameters (LOD: 10 pg/mL; recovery: 25-48%; matrix effect: -3-(-8) %), data on urinary elimination times, which were obtained in the frame of an administration study with the participation of healthy volunteers, are presented. The determined detection windows (~9 hours) are expected to help to evaluate current routine analytical methods and aim to aid doping authorities to set appropriate target windows for efficient testing.

Precision Dosing of Rapid-Acting Insulin Matters.

Despite several molecular and technological advances in insulin therapy and insulin delivery, global evidence highlights inadequate glycemic control in populations with type 1 diabetes (T1D) and type 2 diabetes (T2D). In this review, we discuss the importance of more precise dosing of insulin as one of the approaches to improve glycemic control while reducing hypoglycemic events. This report is based on the expert opinion of authors and literature search of articles relevant to the past and present insulin delivery devices in diabetes management, especially half-unit insulin pens. We describe the various factors that facilitate better glycemic control, focusing on the impact of appropriate insulin delivery device selection on diabetes management. Precision dosing of insulin is a lesser-studied factor that contributes toward better glycemic control. Insulin pens have consistently outperformed syringes as delivery devices due to their greater accuracy and precision of dosing, ease-of-use, and patient preference. These advantages make them better suited to administer insulin in hypoglycemia-prone insulin-sensitive people with T1D, particularly younger children and geriatric patients. Half-unit insulin pens further extend this benefit by delivering half-unit doses of insulin accurately. They may contribute to better management of diabetes by allowing flexible dosing for mealtimes and physical activities even in erratic diet situations or illnesses by offering corrective doses in small increments. They are ideal delivery devices for insulin-sensitive people with T1D who require greater accuracy and precision in insulin delivery to achieve more stringent glycemic control.

Addition of a single short-acting insulin bolus to basal insulin-supported oral therapy: a systematic review of data on the basal-plus regimen.

We summarize here clinical and trial data on a once-daily administration of a single bolus to the meal with the largest expected postprandial glucose excursion (basal-plus), and comment on its clinical utility in the treatment of type 2 diabetes. A PubMed search of data published until September 2018 was taken into consideration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Eighteen reports representing 15 studies were identified (age: 18-80 years; 50-890 patients; follow-up: 8 days to 60 weeks). Data suggest basal-plus is efficacious for improving glycemic control, with a low incidence of (severe) hypoglycemia and minor increases in bodyweight. The timing of short-acting insulin administration and use of different monitoring/titration approaches appear to have minimal impact. When compared with premixed insulin, basal-plus results in largely comparable outcomes. Compared with basal-bolus, it may result in non-inferior glycemic improvements with less weight gain, less hypoglycemia and fewer daily injections. A basal insulin/glucagon-like peptide-1 receptor agonist fixed ratio combination may offer several advantages over the basal-plus regimen, at the cost of gastrointestinal side effects. We conclude that the stepwise introduction of short-acting insulin via the basal-plus strategy represents a viable alternative to a full basal-bolus regimen and may help to overcome barriers associated with multiple injections and anticipated complexity of the insulin regimen.

Descriptive Analysis of Long- and Intermediate-Acting Insulin and Key Safety Outcomes in Adults with Type 2 Diabetes Mellitus.

BACKGROUND: As new biosimilar and follow-on insulins enter the market, more data are needed on safety, effectiveness, and patterns of use for these products to inform prescriber and patient decision-making regarding treatment. Additionally, data are needed regarding real-world patterns of use to inform future studies comparing the safety and effectiveness of bio-similars to already approved agents for diabetes treatment. OBJECTIVE: To analyze the medication use patterns, adverse events, and availability of glycated hemoglobin (A1c) values for adult patients with type 2 diabetes mellitus (T2DM) who use long-acting insulin (LAI) or neutral protamine Hagedorn (NPH), an intermediate-acting insulin. METHODS: We used the Biologics and Biosimilars Collective Intelligence Consortium's (BBCIC) distributed research network (DRN) for this descriptive analysis. The analysis time frame was January 1, 2011, to September 30, 2015, and included patients continuously insured for at least 183 days before the first date of a filled prescription for LAI or NPH insulin alone or with rapid- or short-acting insulin or sulfonylureas, whether newly starting insulin or switching to a different product. Insulin exposure episodes were the unit of analysis, and patients were classified in cohorts according to treatment. We followed patients until end of health plan enrollment or the end of the study period. We used occurrence of a study outcome, switch to another medication regimen, discontinuation of the current medication, or study end date to mark the end of an insulin episode. We describe demographics and availability of A1c values for analysis. Study outcomes included severe hypoglycemic events and major adverse cardiac events (MACE). RESULTS: We identified 103,951 patients with T2DM from a database of 39.1 million patients with commercial or Medicare Advantage pharmacy and medical benefits, who contributed 279,533 unique insulin exposure episodes. Most episodes (89%) included patients using LAI, and 52% of patients contributed data to 2 or more exposure cohorts. Insulin episodes lasted an average of 3.5 months, and patients had an average follow-up of 8.6 months. The unadjusted rate of severe hypoglycemic events requiring medical attention was 96.9 per 10,000 patient-years at risk (10kPYR). The unadjusted incident MACE rate was 676.9 events per 10kPYR. 38,330 T2DM patients in the BBCIC DRN had a baseline A1c available, and of those, less than 50% had a follow-up A1c result. CONCLUSIONS: Among patients with T2DM, our observed insulin patterns of use and rates of severe hypoglycemic outcomes and MACE are consistent with other studies. We noted a paucity of A1c results available, which implies that additional data sources may be needed to augment the BBCIC DRN. DISCLOSURES: This study was coordinated and funded by the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) and represents the independent findings of the BBCIC Insulins Principal Investigator and the BBCIC Insulins Research Team. Lockhart is employed by the BBCIC and the Academy of Managed Care Pharmacy (AMCP). Eichelberger was employed by the BBCIC and AMCP at the time of this study. McMahill-Walraven is employed by Aetna, a CVS Health business. Panozzo, Marshall, and Brown are employed by Harvard Pilgrim Healthcare Institute. Aetna was reimbursed for data and analytic support from Harvard Pilgrim Healthcare Institute and the Reagan Udall Foundation for the U.S. Food and Drug Administration. Aetna receives external funding through research grants and subcontracts with Harvard Pilgrim Healthcare Institute, which are funded by the FDA, NIH, PCORI, BBCIC, Pfizer, and GSK; the Reagan-Udall Foundation for IMEDS; and PCORI for the ADAPTABLE Study. This work was previously presented as a poster at AMCP Nexus 2018; October 22-25, 2018; in Orlando, FL.

Approaches to rapid acting insulin intensification in patients with type 2 diabetes mellitus not achieving glycemic targets.

Type 2 diabetes mellitus (T2DM) is a growing problem in the USA, affecting 30.3 million Americans, or 9.4% of the US population. Given that T2DM is a progressive disease, intensification of rapid acting insulin (RAI) to address hyperglycaemia is often required. The American Diabetes Association and the European Association for the Study of Diabetes recommend individualizing the treatment approach to glucose control, considering factors such as age, health behaviours, comorbidities and life expectancy. There are several validated treatment algorithms in the literature, which can be helpful for providing guidance on initiation of RAI while simultaneously considering patient preferences and clinical needs during treatment intensification. This paper provides expert recommendations on prandial insulin regimens and how to use treatment algorithms to promote better glucose control through best practice guidelines. To help patients reach HbA1c targets through treatment intensification, the FullSTEP, SimpleSTEP, ExtraSTEP and AUTONOMY algorithms are discussed in this paper. KEY MESSAGES Clinical inertia should be prevented with timely intensification of therapy when HbA1c levels are greater than 7% (or rising above a patient's individual target) according to national guidelines. Increased personalization in the intensification of T2D treatment is necessary to improve HbA1c targets while addressing risk of hypoglycaemia, concern about weight gain, and overall health goals. Healthcare providers are encouraged to address glycaemic control with a variety of strategies, including prandial insulin, while developing evidence-based treatment plans on the basis of algorithms discussed in the literature.

Recommendations for Initiating Use of Afrezza Inhaled Insulin in Individuals with Type 1 Diabetes.

Treatment with Afrezza® (insulin human) inhalation powder in individuals with type 1 diabetes (T1D) reduces HbA1c levels similar to rapid-acting insulin analogs, but with significantly less hypoglycemia due to its unique time action profile. Examinations of studies of Afrezza pharmacokinetics/pharmacodynamics, relevant clinical trials, and U.S. Food and Drug Administration (FDA) documentation suggest that current FDA-mandated dosing recommendations for initiating Afrezza treatment may not result in optimal glycemic control for individuals with T1D. Recommendations for initiating Afrezza insulin therapy in T1D patients are presented in this article.

Treating Type 1 Diabetes Mellitus with a Rapid-Acting Analog Insulin Regimen vs. Regular Human Insulin in Germany: A Long-Term Cost-Effectiveness Evaluation.

OBJECTIVE: The aim of the present study was to evaluate the cost effectiveness of rapid-acting analog insulin relative to regular human insulin in adults with type 1 diabetes mellitus in Germany. METHODS: The PRIME Diabetes Model, a patient-level, discrete event simulation model, was used to project long-term clinical and cost outcomes for patients with type 1 diabetes from the perspective of a German healthcare payer. Simulated patients had a mean age of 21.5 years, duration of diabetes of 8.6 years, and baseline glycosylated hemoglobin of 7.39%. Regular human insulin and rapid-acting analog insulin regimens reduced glycosylated hemoglobin by 0.312 and 0.402%, respectively. Compared with human insulin, hypoglycemia rate ratios with rapid-acting analog insulin were 0.51 (non-severe nocturnal) and 0.80 (severe). No differences in non-severe diurnal hypoglycemia were modeled. Discount rates of 3% were applied to future costs and clinical benefits accrued over the 50-year time horizon. RESULTS: In the base-case analysis, rapid-acting analog insulin was associated with an improvement in quality-adjusted life expectancy of 1.01 quality-adjusted life-years per patient (12.54 vs. 11.53 quality-adjusted life-years). Rapid-acting analog insulin was also associated with an increase in direct costs of €4490, resulting in an incremental cost-effectiveness ratio of €4427 per quality-adjusted life-year gained vs. human insulin. Sensitivity analyses showed that the base case was driven predominantly by differences in hypoglycemia; abolishing these differences reduced incremental quality-adjusted life expectancy to 0.07 quality-adjusted life-years, yielding an incremental cost-effectiveness ratio of €74,622 per quality-adjusted life-year gained. CONCLUSIONS: Rapid-acting analog insulin is associated with beneficial outcomes in patients with type 1 diabetes and is likely to be considered cost effective in the German setting vs. regular human insulin.

Persistence with rapid-acting insulin and its association with A1C level and severe hypoglycemia among elderly patients with type 2 diabetes.

OBJECTIVE: To examine the persistence with rapid-acting insulin (RAI) and its association with clinical outcomes among elderly patients with type 2 diabetes (T2D). METHODS: This observational, retrospective cohort study analyzed RAI persistence and its association with change in glycated hemoglobin A1c and risk of severe hypoglycemia among elderly (≥65 years) Medicare beneficiaries with T2D who added RAI to their basal insulin regimen. RESULTS: Among T2D patients with >1 RAI prescriptions (n = 3927), only 21% were persistent. Baseline factors positively associated with RAI persistence (adjusted odds ratio [95% CI]) were: age ≥75 vs. 65-74 years: 1.20 (1.01-1.43); use of ≥3 oral antidiabetes drugs: 1.63 (1.16-2.28); cognitive impairment: 1.34 (1.03-1.73); and A1C >9.0%: 1.58 (1.15-2.17). Elderly T2D patients having emergency department visits (0.73 [0.59-0.91]) and higher RAI out-of-pocket costs (≥$75 vs. $0 - <$6.40: 0.56 [0.44-0.70]) were less likely to be persistent. Persistent RAI users had a significantly higher reduction in A1C (beta coefficient [standard error]): -0.24 (0.10) and lower odds of severe hypoglycemia (adjusted odds ratio [95% CI]): 0.73 (0.53-0.99). CONCLUSION: Among elderly T2D patients, persistence with RAI added to basal insulin was associated with improved glycemic control and lower risk of severe hypoglycemia. Despite treatment effectiveness, RAI persistence was poor and might be improved by reducing RAI out-of-pocket costs.

A Comparison of Pharmacokinetic and Pharmacodynamic Properties Between Faster-Acting Insulin Aspart and Insulin Aspart in Elderly Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: Due to population aging, an increasing number of elderly patients with diabetes use insulin. It is therefore important to investigate the characteristics of new insulins in this population. Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with faster absorption. This study investigated the pharmacological properties of faster aspart in elderly subjects with type 1 diabetes mellitus (T1DM). METHODS: In a randomised, double-blind, two-period crossover trial, 30 elderly (≥65 years) and 37 younger adults (18-35 years) with T1DM received single subcutaneous faster aspart or IAsp dosing (0.2 U/kg) and underwent an euglycaemic clamp (target 5.5 mmol/L) for up to 12 h. RESULTS: The pharmacokinetic and pharmacodynamic time profiles were left-shifted for faster aspart versus IAsp. In each age group, onset of appearance occurred approximately twice as fast (~3 min earlier) and early exposure (area under the concentration-time curve [AUC] for serum IAsp from time zero to 30 min [AUCIAsp,0-30 min]) was greater (by 86% in elderly and 67% in younger adults) for faster aspart than for IAsp. Likewise, onset of action occurred 10 min faster in the elderly and 9 min faster in younger adults, and early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 30 min [AUCGIR,0-30 min]) was greater (by 109%) for faster aspart than for IAsp in both age groups. Total exposure (AUCIAsp,0-t) and the maximum concentration (C max) for faster aspart were greater (by 30 and 28%, respectively) in elderly than in younger adults. No age group differences were seen for the total (AUCGIR,0-t) or maximum (GIRmax) glucose-lowering effect. CONCLUSION: This study demonstrated that the ultra-fast pharmacological properties of faster aspart are similar in elderly subjects and younger adults with T1DM. ClinicalTrials.gov Identifier: NCT02003677.

A novel option for prandial insulin therapy: inhaled insulin.

Many adults with type 2 diabetes (T2D) do not achieve or maintain glycemic targets on oral antidiabetes drugs (OADs) alone and require insulin therapy. Although initiating basal insulin is common when treatment needs to be intensified, individualization of therapy (in line with current guidelines) may lead more health care professionals (HCPs) to add rapid-acting insulin (RAI) to OAD regimens for treatment of postprandial hyperglycemia to achieve glycated hemoglobin (A1C) targets. HCPs and patients are concerned about the burden associated with injections. Inhaled Technosphere® insulin (inhaled TI) - as an alternative to injectable bolus doses of prandial insulin - may increase patient and HCP willingness to intensify therapy and improve compliance with more complex regimens. Clinical studies have shown that inhaled TI is effective and well tolerated as a prandial insulin, and has the potential to improve treatment satisfaction and quality of life in adults with T2D. The favorable pharmacokinetic profile of inhaled TI (i.e., a very rapid onset of action and a short duration of anti-hyperglycemic effect) may reduce the risk of insulin stacking (overlapping effects of RAI injections taken < 4 hours apart) and postprandial hypoglycemia. In this review, we present inhaled TI as an alternative to OADs or injected insulin as adjunctive therapy, for consideration by HCPs striving to achieve glycemic targets for their patients.

Accuracy of Continuous Glucose Monitoring (CGM) during Continuous and High-Intensity Interval Exercise in Patients with Type 1 Diabetes Mellitus.

Continuous exercise (CON) and high-intensity interval exercise (HIIE) can be safely performed with type 1 diabetes mellitus (T1DM). Additionally, continuous glucose monitoring (CGM) systems may serve as a tool to reduce the risk of exercise-induced hypoglycemia. It is unclear if CGM is accurate during CON and HIIE at different mean workloads. Seven T1DM patients performed CON and HIIE at 5% below (L) and above (M) the first lactate turn point (LTP1), and 5% below the second lactate turn point (LTP2) (H) on a cycle ergometer. Glucose was measured via CGM and in capillary blood (BG). Differences were found in comparison of CGM vs. BG in three out of the six tests (p < 0.05). In CON, bias and levels of agreement for L, M, and H were found at: 0.85 (-3.44, 5.15) mmol·L(-1), -0.45 (-3.95, 3.05) mmol·L(-1), -0.31 (-8.83, 8.20) mmol·L(-1) and at 1.17 (-2.06, 4.40) mmol·L(-1), 0.11 (-5.79, 6.01) mmol·L(-1), 1.48 (-2.60, 5.57) mmol·L(-1) in HIIE for the same intensities. Clinically-acceptable results (except for CON H) were found. CGM estimated BG to be clinically acceptable, except for CON H. Additionally, using CGM may increase avoidance of exercise-induced hypoglycemia, but usual BG control should be performed during intense exercise.

Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review.

BACKGROUND AND OBJECTIVES: Hyperkalemia is a common electrolyte disorder that can result in fatal cardiac arrhythmias. Despite the importance of insulin as a lifesaving intervention in the treatment of hyperkalemia in an emergency setting, there is no consensus on the dose or the method (bolus or infusion) of its administration. Our aim was to review data in the literature to determine the optimal dose and route of administration of insulin in the management of emergency hyperkalemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched several databases from their date of inception through February 2015 for eligible articles published in any language. We included any study that reported on the use of insulin in the management of hyperkalemia. RESULTS: We identified eleven studies. In seven studies, 10 units of regular insulin was administered (bolus in five studies, infusion in two studies), in one study 12 units of regular insulin was infused over 30 minutes, and in three studies 20 units of regular insulin was infused over 60 minutes. The majority of included studies were biased. There was no statistically significant difference in mean decrease in serum potassium (K+) concentration at 60 minutes between studies in which insulin was administered as an infusion of 20 units over 60 minutes and studies in which 10 units of insulin was administered as a bolus (0.79±0.25 mmol/L versus 0.78±0.25 mmol/L, P = 0.98) or studies in which 10 units of insulin was administered as an infusion (0.79±0.25 mmol/L versus 0.39±0.09 mmol/L, P = 0.1). Almost one fifth of the study population experienced an episode of hypoglycemia. CONCLUSION: The limited data available in the literature shows no statistically significant difference between the different regimens of insulin used to acutely lower serum K+ concentration. Accordingly, 10 units of short acting insulin given intravenously may be used in cases of hyperkalemia. Alternatively, 20 units of short acting insulin may be given as a continuous intravenous infusion over 60 minutes in patients with severe hyperkalemia (i.e., serum K+ concentration > 6.5 mmol/L) and those with marked EKG changes related to hyperkalemia (e.g., prolonged PR interval, wide QRS complex) as an alternative to 10 units of short acting insulin. Because the risk of hypoglycemia is increased with using large insulin doses, sufficient glucose (60 grams with the administration of 20 units of insulin and 50 grams with the administration of 10 units) should be given to prevent hypoglycemia, and plasma glucose should be frequently monitored.

Predisposing Factors for Any and Major Hypoglycemia With Saxagliptin Versus Placebo and Overall: Analysis From the SAVOR-TIMI 53 Trial.

OBJECTIVE: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied. RESULTS: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.

Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12-month data from the OpT2mise randomized trial.

AIMS: To compare insulin pump therapy and multiple daily injections (MDI) in patients with type 2 diabetes receiving basal and prandial insulin analogues. METHODS: After a 2-month dose-optimization period, 331 patients with glycated haemoglobin (HbA1c) levels ≥8.0% and ≤12% were randomized to pump therapy or continued MDI for 6 months [randomization phase (RP)]. The MDI group was subsequently switched to pump therapy during a 6-month continuation phase (CP). The primary endpoint was the between-group difference in change in mean HbA1c from baseline to the end of the RP. RESULTS: The mean HbA1c at baseline was 9% in both groups. At the end of the RP, the reduction in HbA1c was significantly greater with pump therapy than with MDI (-1.1 ± 1.2% vs -0.4 ± 1.1%; p < 0.001). The pump therapy group maintained this improvement to 12 months while the MDI group, which was switched to pump therapy, showed a 0.8% reduction: the final HbA1c level was identical in both arms. In the RP, total daily insulin dose (TDD) was 20.4% lower with pump therapy than with MDI and remained stable in the CP. The MDI-pump group showed a 19% decline in TDD, such that by 12 months TDD was equivalent in both groups. There were no differences in weight gain or ketoacidosis between groups. In the CP, one patient in each group experienced severe hypoglycaemia. CONCLUSIONS: Pump therapy has a sustained durable effect on glycaemic control in uncontrolled type 2 diabetes.

Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial.

Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.

Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics.

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.

[Ketosis prone type 2 diabetes (KPD)]. / Diabetes Mellitus tipo 2 con tendencia a la cetosis: Caso clínico.

Ketosis prone type 2 diabetes (KPD) is presently a well-defined clinical entity, characterized by a debut with severe hyperglycemia and ketoacidosis similar to the presenting form of Type 1 diabetes mellitus (DM1). However, it appears in subjects with Type 2 diabetes mellitus (DM2) phenotype. This situation is caused by an acute, reversible dysfunction of the beta cell in individuals with insulin resistance. Once the acute stage subsides, patients behave as having a DM2 and do not require insulin treatment. They should be kept on a diet and oral hypoglycemic drugs due to their susceptibility to have recurrent acute ketotic decompensations.