A Randomized Comparison of Postprandial Glucose Excursion Using Inhaled Insulin Versus Rapid-Acting Analog Insulin in Adults With Type 1 Diabetes Using Multiple Daily Injections of Insulin or Automated Insulin Delivery.

OBJECTIVE: To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin. RESEARCH DESIGN AND METHODS: A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61). RESULTS: The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference -12 mg/dL, 95% CI -22 to -2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group. CONCLUSIONS: Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users.

Converting Short-Acting Insulin into Thermo-Stable Longer-Acting Insulin Using Multi-Layer Detachable Microneedles.

The detachable dissolving microneedles (DDMNs) feature an array of needles capable of being separated from the base sheet during administration. Here they were fabricated to address delivery efficiency and storage stability of insulin. The constructed insulin-DDMN is multi-layered, with 1) a hard tip cover layer; 2) a layer of regular short-acting insulin (RI) mixed with hyaluronic acid (HA) and sorbitol (Sor) which occupies the taper tip region of the needles; 3) a barrier layer situated above the RI layer; and 4) a fast-dissolving layer connecting the barrier layer to the base sheet. RI entrapped in DDMNs exhibited enhanced thermal stability; it could be stored at 40 °C for 35 days without losing significant biological activity. Differential scanning calorimetric analysis revealed that the HA-Sor matrix could improve the denaturation temperature of the RI from lower than room temperature to 186 °C. Tests in ex vivo porcine skin demonstrated RI delivery efficiency of 91±1.59 %. Experiments with diabetic rats revealed sustained release of RI, i.e., when compared to subcutaneous injection with the same RI dose, RI-DDMNs produced slower absorption of insulin into blood circulation, delayed onset of hypoglycemic effect, longer serum insulin half-life, and longer hypoglycemic duration.

Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P < 0.001; I2 = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P < 0.001; I2 = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P < 0.001; I2 = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P = 0.019; I2 = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P < 0.001; I2 = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.

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.

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.

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.

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.

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.