Insulin degludec and glutamine dipeptide modify glucose homeostasis and liver metabolism in diabetic mice undergoing insulin-induced hypoglycemia.

This study investigated whether a 30-day co-treatment with 1 g/kg glutamine dipeptide (GdiP) and 1 U/kg regular (rapid acting) or 5 U/kg degludec (long acting) insulins modifies glucose homeostasis and liver metabolism of alloxan-induced type 1 diabetic (T1D) male Swiss mice undergoing insulin-induced hypoglycemia (IIH). Glycemic curves were measured in fasted mice after IIH with 1 U/kg regular insulin. One hour after IIH, the lipid profile and AST and ALT activities were assayed in the serum. Morphometric analysis was assessed in the liver sections stained with hematoxylin-eosin and glycolysis, glycogenolysis, gluconeogenesis and ureagenesis were evaluated in perfused livers. T1D mice receiving GdiP or the insulins had a smaller blood glucose drop at 60 minutes after IIH, which was not sustained during the subsequent period up to 300 minutes. The 30-day treatment of T1D mice with insulin degludec, but not with regular insulin, improved fasting glycemia, body weight gain and serum activity of AST and ALT. Treatments with insulin degludec, GdiP and insulin degludec + GdiP decreased the liver capacity in synthesizing glucose from alanine. GdiP, in combination with both insulins, was associated with increases in the serum triglycerides and, in addition, regular insulin and GdiP increased AST and ALT activities, which could be the consequence of hepatic glycogen overload. GdiP and the insulins improved the IIH, although to a small extent. Caution is recommended, however, with respect to the use of GdiP because of its increasing effects on serum triglycerides and AST plus ALT activities.

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats.

PURPOSE: Long-acting insulin analogues are known to be a major player in the management of glucose levels in type I diabetic patients. However, highly frequent hypo- and hyperglycemic incidences of current long-acting insulins are the important factor to limit stable management of glucose level for clinical benefits. To further optimize the properties for steadily controlling glucose level, a novel long-acting insulin INS061 was designed and its efficacy, pharmacokinetics, biodistribution and excretion profiles were investigated in rats. METHODS: The glucose-lowering effects were evaluated in a streptozocin-induced diabetic rats compared to commercial insulins via subcutaneous administration. The pharmacokinetics, biodistribution, and excretion were examined by validated analytical methods including radioactivity assay and radioactivity assay after the precipitation with TCA and the separation by HPLC. RESULTS: INS061 exhibited favorable blood glucose lowering effects up to 24 h compared to Degludec. Pharmacokinetic study revealed that the concentration-time curves of INS061 between two administration routes were remarkably different. Following intravenous administration, INS061 was quickly distributed to various organs and tissues and slowly eliminated over time with urinary excretion being the major route for elimination, and the maximum plasma concentrations (Cmax) and systemic exposures (AUC) increased in a linear manner. CONCLUSION: The present structural modifications of human insulin possessed a long-acting profile and glucose-lowering function along with favorable in vivo properties in rats, which establish a foundation for further preclinical and clinical evaluation.

Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin.

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Effectiveness of Insulin Degludec in Thai Patients with Diabetes Mellitus: Real-World Evidence From a Specialized Diabetes Center.

BACKGROUND: Insulin degludec, an ultra-long-acting insulin analogue, has been available in Thailand since October 2016. Although clinical trial results revealed less hypoglycemia, data from real-world settings is limited especially in Asian patients. This study aimed to evaluate prospectively the real-world effectiveness, safety, quality of life (QOL) and patient satisfaction with insulin degludec among Thai patients with diabetes mellitus (DM). METHODS: From October 2016 to September 2017, all patients who had started insulin degludec for at least 3 months were observed and evaluated at baseline, 3, 6, and 12 months. QOL was assessed using WHOQOL-BREF-THAI and level of satisfaction was measured by 7-point Likert scale. Glycemic fluctuation from paired iPro2 continuous glucose monitoring (CGM) obtained 4-6 weeks apart were also evaluated from a subset of patients with T1DM who switched from insulin glargine to insulin degludec. RESULTS: A total of 55 patients (T2DM 76.4%, females 54.5%, mean age 57.1±16.1 years, duration of diabetes 16.7±8.8 years, BMI 27.3±5.5 kg/m2, baseline A1C 9.3±2.3%, median duration of treatment 8 months) were included in the study. In T1DM patients (n=13), the overall mean A1C reduction at 12 months was 0.5% with minimal weight gain of 0.9 kgs at 12 months. In T2DM patients (n=42), the overall mean A1C reduction at 12 months was 0.8% with minimal weight loss of 0.4 kgs at 12 months. The proportion of T1DM patients who could achieve optimal glycemic control increased slightly from 14.3 to 18.2% but the proportion of T2DM patients who could achieve optimal glycemic control increased from 30.8 to 53.8%. Patient satisfaction showed a sustained improvement throughout the duration of study. In four T1DM patients who had paired CGM data, insulin degludec provided greater reductions in glycemic variability endpoints with increased time-in-range when compared with previous insulin glargine. DISCUSSION: Our data suggested that the effectiveness of insulin degludec was consistent with the results seen in clinical trials with lower risk of patients-reported hypoglycemia, and a significant improvement in glycemic control. Patients also reported higher treatment satisfaction. More long-term and cost-effectiveness data are needed to establish the role of this ultra-long-acting insulin in real-world settings.

Comparison of pharmacodynamics between insulin glargine 100 U/mL and insulin glargine 300 U/mL in healthy cats.

Insulin glargine (IGla) is a synthetic human-recombinant insulin analog that is used routinely in people as a q24h basal insulin. The 300 U/mL (U300) formulation of IGla is associated with longer duration of action and less within-day variability, making it a better basal insulin compared with the 100 U/mL (U100) formulation. We hypothesized that in healthy cats, IGlaU300 has a flatter time-action profile and longer duration of action compared with IGlaU100. Seven healthy neutered male, purpose-bred cats were studied in a randomized, crossover design. Pharmacodynamics of IGlaU100 and IGlaU300 (0.8 U/kg, subcutaneous) were determined by the isoglycemic clamp method. The time-action profile of IGlaU300 was flatter compared with IGlaU100 as demonstrated by lower peak (5.6 ± 1.1 mg/kg/min vs 8.3 ± 1.9 mg/kg/min, respectively; P = 0.04) with no difference in total metabolic effect (ME; P = 0.7) or duration of action (16.8 h ± 4.7 h vs 13.4 h ± 2.6 h; P = 0.2). The greater fraction of ME in the 12- to 24-h period postinjection (35 ± 23% vs 7 ± 8% respectively; P = 0.048) and lower intraday GIR% variability (7.8 ± 3.7% vs 17.4 ± 8.2% respectively; P = 0.03) supports a flatter time-action profile of IGlaU300. There were no differences in onset and end of the action. In summary, although both formulations have a similar duration of action that is well below 24 h, the ME of IGlaU300 is more evenly distributed over a 24 h period in healthy cats, making it a better candidate for once-daily injection in diabetics compared with IGlaU100.

Evaluation of Cell Proliferation in Rat Mammary Glands Is Not Predictive of the Carcinogenic Potential of Insulin In Vivo.

For nonclinical safety-assessment of insulin analogues in vivo, mitogenic effects are compared to that of human insulin. Besides histopathologic evaluation, this usually includes assessment of cell proliferation (CP) in mammary glands. Insulin analogue X10 is recommended as positive control, due to its known carcinogenic effect in rat mammary glands. Here, we discuss the mitogenic effect of insulin in vivo and use of X10 as positive control. We present results from 4 nonclinical rat studies evaluating effects of repeated dosing with insulin detemir (≤26 weeks) or degludec (52 weeks) in mammary glands. Studies included human insulin-dosed groups as comparators, CP, and histopathologic evaluation. One study included an X10-dosed group (26 weeks), another ≤3 weeks of dosing with X10 or human insulin evaluating effects of these comparators. Neither human insulin, insulin detemir, degludec, nor X10 induced mammary tumors or increased CP in the studies. The CP marker proliferating cell nuclear antigen varied within/between studies and was not correlated with the remaining markers or CP fluctuations during estrous cycle, whereas the other CP markers, Ki-67 and 5-bromo-2'-deoxyuridine (BrdU), correlated with estrous cycle changes and each other. In conclusion, we propose that the mitogenic effect of insulin in rat mammary glands is weak in vivo. Cell proliferation evaluation in nonclinical safety assessment studies is not predictive of the carcinogenic potential of insulin, thus, the value of including this end point is debatable. Moreover, X10 is not recommended as positive control, due to lack of proliferative effects. Typical CP markers vary greatly in quality, BrdU seemingly most reliable.

An Overview of Prospective Drugs for Type 1 and Type 2 Diabetes.

AIMS: The aim of this study is to provide an overview of several emerging anti-diabetic molecules. BACKGROUND: Diabetes is a complex metabolic disorder involving the dysregulation of glucose homeostasis at various levels. Insulin, which is produced by ß-pancreatic cells, is a chief regulator of glucose metabolism, regulating its consumption within cells, which leads to energy generation or storage as glycogen. Abnormally low insulin secretion from ß-cells, insulin insensitivity, and insulin tolerance lead to higher plasma glucose levels, resulting in metabolic complications. The last century has witnessed extraordinary efforts by the scientific community to develop anti-diabetic drugs, and these efforts have resulted in the discovery of exogenous insulin and various classes of oral anti-diabetic drugs. OBJECTIVE: Despite these exhaustive anti-diabetic pharmaceutical and therapeutic efforts, long-term glycemic control, hypoglycemic crisis, safety issues, large-scale economic burden and side effects remain the core problems. METHODS: The last decade has witnessed the development of various new classes of anti-diabetic drugs with different pharmacokinetic and pharmacodynamic profiles. Details of their FDA approvals and advantages/disadvantages are summarized in this review. RESULTS: The salient features of insulin degludec, sodium-glucose co-transporter 2 inhibitors, glucokinase activators, fibroblast growth factor 21 receptor agonists, and GLP-1 agonists are discussed. CONCLUSION: In the future, these new anti-diabetic drugs may have broad clinical applicability. Additional multicenter clinical studies on these new drugs should be conducted.

Comparison of pharmacodynamics and pharmacokinetics of insulin degludec and insulin glargine 300 U/mL in healthy cats.

Insulin glargine 300 U/mL (IGla-U300) and insulin degludec (IDeg) are synthetic insulin analogs designed as basal insulin formulations. In people, IGla-U300 is more predictable and longer acting compared with glargine 100 U/mL. The duration of action of IDeg in people is > 42 h, allowing flexibility in daily administration. We hypothesized that IDeg would have longer duration of action compared with IGla-U300 in healthy purpose-bred cats. Seven cats received 0.4 U/kg (subcutaneous) of IDeg and IGla-U300 on two different days, >1 wk apart. Exogenous insulin was measured and pharmacodynamic parameters were derived from glucose infusion rates during isoglycemic clamps and suppression of endogenous insulin. The Shapiro-Wilk test was used to assess normality, and normally distributed parameters were compared using paired t-tests. There was no difference between IDeg and IGla-U300 in onset, peak action, or total metabolic effect. On average, time to peak action (TPEAK) of IGla-U300 was 145 ± 114 min (95% confidence interval [CI] = 25-264) longer than TPEAK of IDeg (P = 0.03) and duration of action (TDUR) of IGla-U300 was 250 ± 173 min (95% CI = 68-432) longer than TDUR of IDeg (P = 0.02). The "flatness" of the time-action profile (as represented by the quotient of peak action/TDUR) was significantly greater for IGla-U300 compared with IDeg (P = 0.04). Overall, insulin concentration measurements concurred with findings from isoglycemic clamps. Based on these data, IDeg is not suitable for once-daily administration in cats. The efficacy of once-daily IGla-U300 in diabetic cats should be further investigated.

[Basal insulin degludec (Tresiba®)]. / Le médicament du mois. Insuline basale dégludec (Tresiba®).

Insulin degludec (Tresiba®) is characterized by an original mode of prolonged and continuous insulin release after its subcutaneous injection. Thereby, it has a very long glucose-lowering effect, around 42 hours, and a better reproducibility from both a pharmacokinetic and pharmacodynamic point of view. Its efficacy and safety have been assessed in the phase 3 clinical programme BEGIN as compared with insulin glargine U100, in patients with type 1 diabetes (T1D) and type 2 (T2D). For a similar glucose control (reduction in glycated haemoglobin), less hypoglycaemic episodes were recorded, including severe hypoglycaemia, during the nocturnal period, with insulin degludec than with insulin glargine U100. This clinical benefit has been confirmed in the complementary SWITCH programme in T1D and T2D patients at higher risk of hypoglycaemia, in the double-blind cardiovascular outcome trial DEVOTE in T2D patients at high cardiovascular risk and in real-life conditions in the observational European EU-TREAT study in patients with T1D and T2D. Insulin degludec (Tresiba®) is indicated and reimbursed for the treatment of patients with T1D, combined with a prandial insulin, and T2D, alone or combined with oral antidiabetic agents, a glucagon-like peptide-1 receptor agonist or a short-acting insulin.

L'insuline dégludec (Tresiba®) présente un mode original de libération prolongée et continue d'insuline, ce qui lui confère une durée d'action ultra-longue, avoisinant 42 heures, et une plus grande reproductibilité, à la fois sur le plan pharmacocinétique et pharmacodynamique. Son efficacité et sa sécurité d'emploi ont été validées dans le programme d'essais cliniques de phase 3 BEGIN en comparaison à l'insuline glargine U100, aussi bien dans le diabète de type 1 (DT1) que de type 2 (DT2). Pour un même niveau de contrôle glycémique (attesté par la réduction du taux d'hémoglobine glyquée), il y a eu moins d'hypoglycémies, y compris sévères, durant la période nocturne, avec l'insuline dégludec qu'avec l'insuline glargine U100. Ce bénéfice a été confirmé dans le programme complémentaire SWITCH chez des patients DT1 et DT2 à plus haut risque hypoglycémique, dans la grande étude DEVOTE, contrôlée en double aveugle, chez des patients DT2 à risque cardiovasculaire et, en vie réelle, dans l'étude observationnelle européenne EU-TREAT chez des patients DT1 et DT2. L'insuline dégludec (Tresiba®) est indiquée et remboursée dans le traitement des patients DT1, en association avec une insuline prandiale, et DT2, seule ou en combinaison avec des antidiabétiques oraux, un agoniste des récepteurs du glucagon-like-peptide 1 ou une insuline à action rapide.

Pharmacokinetic and pharmacodynamic differences of new generation, longer-acting basal insulins: potential implications for clinical practice in type 2 diabetes.

The treatment of type 2 diabetes (T2D) is often complicated by factors such as patient co-morbidities, complex drug-drug interactions, and management of adverse events. In addition, some of these factors are highly dependent on the nature of the treatment regimen and the molecular and physical properties of the drugs being used to treat patients with this disease. This calls for a better understanding of how the properties of individual drugs affect the overall outcome for patients with diabetes. Clinical pharmacology studies to assess the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of new diabetes drugs play an important role in advancing our understanding of the interactions between a drug and the human body. Specific PK and PD techniques such as the glucose clamp test can be applied to assess the properties of drugs used for the treatment of diabetes. Basal insulin analogs are a common treatment option for the maintenance of glycemic control in patients with T2D. These drugs work by mimicking endogenous insulin secretion within the body and provide stable and prolonged insulin action to achieve optimal glucose levels. Insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg) 100 U/mL and 200 U/mL represent a new generation of longer-acting basal insulins. These drugs demonstrate improved PK and PD properties compared with previous basal insulins, allowing them to more closely mimic physiological basal insulin secretion. Here we review the methods used to evaluate the PK and PD profiles of Gla-300 and IDeg and describe studies that have investigated the PK/PD properties of these drugs in type 1 diabetes. The aim of this review is to inform primary care physicians of the value and limitations of data from clinical pharmacology studies when prescribing these agents for the management of T2D.

The Relevance of Clinical Pharmacology Studies of Basal Insulins to Primary Care.

Pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs form the basis for the development of drugs used in everyday clinical practice, such as commonly used insulin products. PK measures the concentration of a drug in the body, and reflects the rates and amounts absorbed and processed. PD is the biologic effect of a drug in the body, including the time-course of when the biologic effect starts, peaks, and ends. While the determination of PK/PD parameters is important and foundational for the development of different insulin products, studies are often complex and can be difficult to translate into real-world clinical practice. In this roundtable, the speakers discuss PK/PD concepts, focusing on the differentiation of basal insulin analogs and their use in individualized diabetes therapy. First, the speakers discuss the euglycemic glucose clamp methodology-the standard technique for evaluating PK/PD of insulin-including how it is performed, what parameters it measures (and how they can be interpreted), and its limitations. Next, the speakers discuss how PK/PD impacts drug development, with particular focus on PK/PD studies used in the development of the second-generation basal insulin analogs insulin glargine 300 U/mL (Gla-300) and insulin degludec. Finally, the speakers discuss how PK/PD data translate into clinical practice, including the relationship between PK/PD and drug efficacy and safety, and how it influences dosing strategies, hypoglycemia risk, and patient education. Further, the speakers discuss how the PK/PD profile of basal insulins can inform primary care providers when selecting appropriate individualized therapy for patients.

[Basal insulin degludec - liraglutide fixed ratio combination (Xultophy®)]. / Le médicament du mois. Combinaison en proportion fixe insuline basale dégludec-liraglutide (Xultophy®).

Xultophy® (IDegLira) is a fixed ratio combination of basal insulin degludec and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Insulin degludec is characterized by an original mode of prolonged and continuous insulin diffusion after its subcutaneous injection. Thereby, it has a very long half-life, around 25 hours, and a better reproducibility from both a pharmacokinetic and pharmacodynamic point of view, with less hypoglycaemia, especially at night. Liraglutide is a well-known once-daily GLP-1 receptor agonist that showed a cardiovascular and renal protection in patients with type 2 diabetes at high cardiovascular risk. Both molecules exert complementary antihyperglycaemic effects, which allows a better glucose control, both in the fasting and postprandial states. IDegLira is more effective than another basal insulin regimen in reaching individualized glycated haemoglobin target, with a lower daily dose of insulin. It has a better tolerance profile, with a more favourable effect on body weight and less hypoglycaemia compared with a basal insulin and less gastrointestinal adverse effects when compared with liraglutide alone. Xultophy® is presented as a prefilled pen and is indicated in the management of type 2 diabetes not well controlled with basal insulin. The dose of IDegLira is progressively uptitrated, starting from 16 dose steps up to a maximum of 50 dose steps per day (corresponding to 50 IU insulin degludec and 1.8 mg liraglutide).

Le Xultophy® (IDegLira) est une combinaison, en proportion fixe, d'une nouvelle insuline basale, l'insuline dégludec, et d'un agoniste des récepteurs du glucagonlike peptide-1 (GLP-1), le liraglutide. L'insuline dégludec présente un mode original de libération prolongée et continue d'insuline, ce qui lui confère une demi-vie ultra-longue, avoisinant 25 heures, et une plus grande reproductibilité, à la fois sur le plan pharmacocinétique et pharmacodynamique, avec moins d'hypoglycémies, notamment nocturnes. Le liraglutide est un agoniste des récepteurs du GLP-1 à injection quotidienne qui a démontré une protection cardiaque et rénale chez des patients avec un diabète de type 2 (DT2) et un haut risque cardiovasculaire. Les deux molécules exercent des effets antihyperglycémiants complémentaires, permettant un meilleur contrôle de la glycémie, à jeun et en période post-prandiale. La combinaison IDegLira permet d'atteindre plus souvent la cible individualisée d'hémoglobine glyquée, avec une dose d'insuline plus faible. Elle offre également un meilleur profil de tolérance, avec un effet plus favorable sur le poids corporel et moins d'hypoglycémies par comparaison à une insuline basale seule et moins de manifestations indésirables digestives par rapport au liraglutide seul. Le Xultophy® est présenté sous forme de stylo pré-rempli et indiqué dans le traitement du DT2 insuffisamment contrôlé sous insuline basale. La dose de la combinaison IDegLira est titrée progressivement en commençant par 16 doses unitaires par jour jusqu'à un maximum de 50 doses unitaires par jour (correspondant à 50 UI d'insuline dégludec et 1,8 mg de liraglutide).

Evaluation of the innate immunostimulatory potential of originator and non-originator copies of insulin glargine in an in vitro human immune model.

BACKGROUND: The manufacture of insulin analogs requires sophisticated production procedures which can lead to differences in the structure, purity, and/or other physiochemical properties of resultant products that can affect their biologic activity. Here, we sought to compare originator and non-originator copies of insulin glargine for innate immune activity and mechanisms leading to differences in these response profiles in an in vitro model of human immunity. METHODS: An endothelial/dendritic cell-based innate immune model was used to study antigen-presenting cell activation, cytokine secretion, and insulin receptor signalling pathways induced by originator and non-originator insulin glargine products. Mechanistic studies included signalling pathway blockade with specific inhibitors, analysis of the products in a Toll-like receptor reporter cell line assay, and natural insulin removal from the products by immunopurification. FINDINGS: All insulin glargine products elicited at least a minor innate immune response comparable to natural human insulin, but some lots of a non-originator copy product induced the elevated secretion of the cytokines, IL-8 and IL-6. In studies aimed at addressing the mechanisms leading to differential cytokine production by these products, we found (1) the inflammatory response was not mediated by bacterial contaminants, (2) the innate response was driven by the native insulin receptor through the MAPK pathway, and (3) the removal of insulin glargine significantly reduced their capacity to induce innate activity. No evidence of product aggregates was detected, though the presence of some high molecular weight proteins argues for the presence of insulin glargine dimers or others contaminants in these products. CONCLUSION: The data presented here suggests some non-originator insulin glargine product lots drive heightened in vitro human innate activity and provides preliminary evidence that changes in the biochemical composition of non-originator insulin glargine products (dimers, impurities) might be responsible for their greater immunostimulatory potential.

Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp).

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

Comparison of liraglutide plus basal insulin and basal-bolus insulin therapy (BBIT) for glycemic control, body weight stability, and treatment satisfaction in patients treated using BBIT for type 2 diabetes without severe insulin deficiency: A randomized prospective pilot study.

AIMS: We examined whether 0.9 mg/day liraglutide plus basal insulin (Lira-basal) is superior to basal-bolus insulin therapy (BBIT) for type 2 diabetes (T2DM) without severe insulin deficiency as determined by glucagon stimulation. METHODS: Fifty patients receiving BBIT were enrolled in this 24-week, prospective, randomized, open-labeled study. After excluding subjects with fasting C-peptide immunoreactivity (CPR) < 1.0 ng/mL and CPR increase < 1.0 ng/mL at 6 min post glucagon injection, 25 were randomly allocated to receive Lira-basal (n = 12) or continued BBIT (n = 13). Primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight (BW), 7-point self-monitored blood glucose (SMBG), and Diabetes Treatment Satisfaction Questionnaire status (DTSQs) scores. RESULT: The Lira-basal group demonstrated reduced HbA1c, whereas the BBIT group showed no change. BW was reduced in the Lira-basal group but increased in the BBIT group. The Lira-basal group also exhibited significantly reduced pre-breakfast and pre-lunch SMBG. DTSQs scores improved in the Lira-basal group but not the BBIT group. Plasma lipids, liver function, and kidney function were not significantly changed in either group. CONCLUSIONS: Lira-basal therapy is superior to BBIT for T2DM without severe insulin deficiency. This study was registered with UMIN Clinical Trials Registry (UMIN000028313).

Initiation of Basal Insulin Analog Treatment for Type 2 Diabetes and Reasons Behind Patients' Treatment Persistence Behavior: Real-World Data from Germany.

BACKGROUND: Poor treatment persistence can affect the real-world effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. METHODS: Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from market-research panels, participated in the survey. Patients were asked if they had ≥7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" (≥1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. RESULTS: The 131 participants from Germany included 55 (42.0%) continuers, 50 (38.2%) interrupters and 26 (19.9%) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2%) and expectation to improve glycemic control (42.0%). More than 95% of participants received training before and during insulin initiation (considered as helpful by 81.7%); most (67.2%) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7%), improved physical well-being (49.1%), and instruction by physician or other HCP (45.5%). The most common reasons contributing to interruption/discontinuation were perceived weight gain (52.0%/50.0%), hypoglycemia (22.0%/38.5%), and potential adverse effects (30.0%/26.9%). CONCLUSIONS: Quality interactions between physicians or other HCPs and their patients before and during the initiation of basal insulin may help to manage patient expectations and to improve persistence to insulin therapy.

Switching from Premixed Insulin To Basal Insulin Analogue For Type 2 Diabetes and Role of Dipeptidyl Peptidase-4 Inhibitors.

INTRODUCTION: This study aimed to confirm the usefulness of basal insulin analogue plus oral antidiabetic drugs (OADs) for type 2 diabetes (T2D) patients inadequately controlled with premixed insulin with/without OADs and assess the role of dipeptidyl peptidase-4 (DPP-4) inhibitors within this regimen in clinical practice. METHODS: Spanish retrospective observational study that included 186 T2D patients with glycosylated hemoglobin (HbA1c) >7% (53 mmol/mol) despite premixed insulin with/without OADs who had been switched to basal insulin analogue plus OADs. Study data describing the situation before the treatment switch and 6 months later was retrospectively retrieved from patients' medical charts. RESULTS: Switching to a basal insulin plus OADs decreased HbA1c (-1.0%, p<0.001), fasting (-38.1 mg/dl, p<0.001) and postprandial glycemia (-36.1 mg/dl, p<0.001), with reduced body weight (-1.1 kg, p<0.001) and hypoglycemic episodes (-17.5%, p<0.001). 68 (36.6%) patients received a basal insulin plus DPP-4 inhibitor±metformin and 74 (39.8%) plus metformin only. The DPP-4 inhibitor±metformin group showed a greater HbA1c reduction than the metformin group (1.3±1.4% vs. 0.9±1.0%, p=0.022), with no significant differences between groups in hypoglycemic episodes. CONCLUSIONS: Basal insulin analogue plus OADs may be a useful treatment for type 2 diabetes patients inadequately controlled with premixed insulin. Administering DPP-4 inhibitors within this regimen may contribute to improve patients' glycemia, with a favorable weight-change profile and without increasing hypoglycemia risk.

Advances in Diabetes Pharmacotherapy: An Update for the Emergency Provider.

BACKGROUND: Diabetes mellitus is a disease that affects millions of Americans, and its prevalence is only anticipated to increase in coming years. It is estimated that diabetes-related visits account for 1% of all emergency department (ED) encounters. In recent years, there have been several new categories of medications approved for the treatment of diabetes, including new insulins, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 inhibitors. OBJECTIVE OF THE REVIEW: This review presents recently approved agents to treat diabetes, with a focus on basic mechanism, place in therapy, and toxicities the ED provider may encounter. DISCUSSION: Many of these new therapies have been incorporated as first- and second-line agents for the management of diabetes. Recently approved diabetes medications often have different mechanisms of action and adverse effect and overdose profiles compared to traditional agents, such as sulfonylureas and metformin. CONCLUSIONS: Emergency providers will encounter patients taking these newly approved medications, as well as treat those presenting with adverse effects and overdoses from them. As such, emergency providers must have a basic understanding of these new therapies so that they can optimally care for diabetic patients.

Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan.

AIMS: To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. METHODS: In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ±â€¯oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8-20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30-50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01-05:59) or severe (requiring assistance of another person). RESULTS: During the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: -0.54 mmol/L [-1.02; -0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. CONCLUSIONS: IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue.

Unmet needs in children with diabetes: the role of basal insulin.

The goal of insulin therapy in people affected by type 1 diabetes mellitus consists in achieving an optimal metabolic control and so HbA1c levels below 7.5%, according to the conclusions of relevant scientific studies. In any case it seems that this target is far from being achieved, mostly in the pediatric population. However, many important pharmacological, technological and cultural milestones have been placed both in therapy and management of insulin-dependent diabetes even if the gap between growing knowledge in these fields and its application in daily clinical practice appears still too wide. A fundamental component of these advancements concerns the design of new insulin basal analogues; molecules used to realize a basal-bolus model of therapy with MDI scheme. Degludec insulin has been recently approved for the pediatric utilization (aged 1 to 17 years). A registration trial for pediatric population (aged 6 to 17 years) is in progress for glargine U-300 insulin. These two insulin types have different biochemical and pharmacological properties and they represent two different ways to achieve the ideal basal analogue. Insulin degludec and insulin glargine U-300 are the newest basal analogues and each of them has proper pharmacokinetic and pharmacodynamic characteristics. Their characteristics represent an effort to create the ideal solution. The aim of this review is to summarize the pharmacokinetic and pharmacodynamic properties of these new insulins, to list the most significant scientific findings regarding their pharmacology as well as clinical uses, with particular reference to the pediatric population in order to declare them to clinical experience and to report data on an initial experience with these analogues, especially with degludec insulin. Once again, evolution goes through the specialized training of the staff involved in the care of the diabetic patient and the constant education of the latter.