Short-acting Insulin Analogues Research Articles

Expected Basal Insulin Requirement during CSII therapy by Age Group, Sex and BMI, based on 25,718 Young People with Type 1 Diabetes in the DPV Registry.

Background Since the introduction of insulin pumps into the therapy of paediatric subjects, different approaches have been taken to find optimal basal rates. Previously, the DPV registry provided circadian basal rate patterns for different age groups. As the number of pump users has increased recently and short-acting insulin analogues are now predominant, we performed a new analysis with a larger data pool. Methods We included all recent basal profiles from T1D patients between 1 and 25 years from the DPV 2021 data pool. We excluded night-time-only pump users, human regular insulin users, and daily basal rates < 0.05 U/kgBW/d and >1.0 U/kgBW/d. Results In the analysis of profiles from 25,718 young persons with T1D, differences in the daily pattern of basal rates were found between age groups. In addition, we saw significant (p<0.001) differences in total daily basal dose between genders in all age groups except adults. In addition, the shape of the expected basal-rate pattern differed by BMI, HbA1c and use of continuous glucose monitoring. Discussion This analysis demonstrates multiple factors influencing basal patterns and insulin requirement, including age group, gender, overweight, HbA1c, bolus frequency and sensor use. As circadian basal rates are still mandatory for initiating insulin pump therapy with or without automation, a multimodal approach is necessary to estimate optimal basal rates.

Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus.

Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and manypatients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-β29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that ismore effective than placebo throughout the meal period; however, compared withan active comparator insulin aspart, the post-prandial control ismore effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.

A case of type 1 Diabetes mellitus unresponsive to insulin glulisine

A 29-year-old man applied to the internal medicine outpatient clinic with fatigue and high plasma glucose levels. He had type 1 Diabetes Mellitus for 10 years and was using insulin glargine U300 and insulin glulisine for treatment. His glycosylated hemoglobin level was 16.7%, and he was hospitalized. Insulin doses were calculated as 1 unite/kg /day; glulisine 3x8 unit/day and glargine U300 1x18 unit/day were ordered. Although we increased the total insulin dosage to 1,5 units/kg/day, the plasma glucose measurements did not improve. The short-acting insulin analog was switched to insulin aspart based on the fact that insulin autoantibodies might cause this situation. On aspart treatment, the patient suffered from hypoglycemia with the same doses of glulisine. The occurrence of insulin autoantibodies against glulisine was confirmed clinically. Basal insulin dose was reduced to 20 units, and aspart 3x6 units/day was enough for plasma glucose control. &#x0D; Hyperglycemia due to autoantibodies against analog insulins is very rare. Here we report a type 1 Diabetes Mellitus patient who was on glulisine treatment for 10 years, and whose blood glucose measurements deteriorated recently. Hyperglycemia was regulated after the insulin switch from glulisine to aspart. This rare case report must be kept in mind in hyperglycemic patients with a history of long-time analog insulin treatment.

PSUN242 Severe Hypernatremia in a patient with combined Hyperosmolar Hyperglycemic State and Diabetic Ketoacidosis

Abstract Introduction Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the complications of diabetes with highest morbidity. In both, there are fluid shifts and osmotic diuresis with electrolyte disturbances that result in hyponatremia. With high glucose levels, sodium become falsely decreased due to dilutional effects of water shifting from intracellular to extracellular space. Hypernatremia is an uncommon electrolyte abnormality in this setting, with unclear exact etiology. We present a 35-year-old gentleman who was found to have severe hypernatremia in the setting of combined DKA and HHS. Clinical Case A 35-year-old male with class III obesity presented to the emergency department with altered sensorium and lethargy. Patient was having nausea and vomiting, along with polyuria, polydipsia and nocturia, prior to worsening encephalopathy. Physical exam showed rapid shallow breathing and lethargy. No focal neurologic deficits noted.Initial labs revealed severe hyperglycemia and hypernatremia with sodium at 164 mmol/L, severe metabolic acidosis, and acute kidney injury. Hemoglobin A1C was 9.8%. Ketonuria and ketonemia were present. Given the high osmolality, he was diagnosed with DKA and HHS.Free water deficit was 15.4 L. Insulin drip was started, along with 5 liters of intravenous Lactated Ringer's boluses. As blood glucose improved, patient was placed on dextrose-5% water infusion at 200 mL/hour.Encephalopathy improved approximately 48 hours after admission. His glucose stabilized, renal function improved, acidosis resolved, and sodium returned to normal. Sodium was corrected at a rate of 8 mmol/L daily. He was transitioned to general wards and started on an oral carbohydrate-restricted diet and subcutaneous insulin regimen containing long- and short-acting insulin analogs. Conclusion During severe hyperglycemia, glucose increases extracellular osmolality, creating a gradient for water to move from intracellular to extracellular compartments, leading to hyponatremia. As the renal threshold is reached, glucosuria ensues, causing osmotic diuresis and water loss. If this process continues, excess water loss can cause dehydration, further increase serum osmolality, and lead to hypernatremia.A previous study evaluated patients who present with hypernatremia during DKA. It was found that patients with new-onset diabetes are more likely to present with hypernatremia (1).Several etiologies contribute to altered sensorium in such patients, including cerebral hypoperfusion in the setting of dehydration and excess water loss, acidosis, and direct effect of ketone bodies on brain cells (2). As electrolyte abnormalities are corrected with adequate fluid selection, patients return to baseline mentation. It is best to correct hypernatremia at a rate of 6-8 mmol/L daily to prevent the complications of rapid correction. References KW Monroe, WD King, MH Nichols, JA Atchinson. Hypernatremia in diabetic ketoacidosis. Practical Diabetes Int 1997;14(6): 159-61. Elias Estifan, Sushant M. Nanavati, Vinod Kumar, et al. Salty diabetes: a case series of hypernatremia presenting with diabetic ketoacidosis. AME Case Rep 2019;3: 27. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method.

The year 2021 marks the 100th anniversary of the momentous discovery of insulin. Through years of research and discovery, insulin has evolved from poorly defined crude extracts of animal pancreas to recombinant human insulin and analogues that can be prescribed and administered with high accuracy and efficacy. However, there are still many challenges ahead in clinical settings, particularly with respect to maintaining optimal glycemic control whilst minimizing the treatment-related side effects of hypoglycemia and weight gain. In this review, the chronology of the development of rapid-acting, short-acting, intermediate-acting, and long-acting insulin analogues, as well as mixtures and concentrated formulations that offer the potential to meet this challenge, are summarized. In addition, we also summarize the latest advancements in insulin delivery methods, along with advancement to clinical trials. This review provides insights on the development of insulin treatment for diabetes mellitus that may be useful for clinicians in meeting the needs of their individual patients. However, it is important to note that as of now, none of the new technologies mentioned have superseded the existing method of subcutaneous administration of insulin.

Blood glucose management in gestational diabetes: A clinician's review

The prevalence of gestational diabetes mellitus (GDM) has been increasing globally and in India too, because of urbanization and the increasing occurrence of obesity. The management of GDM poses a clinical challenge, and this article focuses on its diagnosis and treatment. In India, screening of all pregnant women is recommended at the first antenatal visit and then repeat screening at 24–28 weeks of gestation if the initial screen is normal. Early intervention with counseling, glucose monitoring, diet, and exercise to achieve good glucose control could reduce both the maternal and fetal complications associated with hyperglycemia in pregnancy. The majority of cases of GDM may be managed by lifestyle modifications alone. Metformin may be prescribed as an alternative to insulin as per certain guidelines, though insulin remains the cornerstone of pharmacotherapy. Long-acting insulin detemir and short-acting insulin analogs such as insulin lispro or aspart are safe in pregnancy and help with control of blood glucose. Good glycemic control, achieved by lifestyle measures, monitoring, and medications when needed, may help achieve the goal of a successful pregnancy outcome.

Saudi Consensus for Low-Premixed Insulin Analogues in Type 2 Diabetes: Consensus Report

Dear Dr. Martin Hovland, We learned from the literature that premixed insulins are short-acting insulin or rapid-acting insulin analogue mixed with intermediate-acting insulin in a fixed ratio, addressing FBG and PPBG in one injection. There are two categories; high-mix and low-mix premixed insulins. We, a Saudi task force, gathered to develop an explicit, evidence-based consensus for the use of the low-mix premixed insulin for better glycemic control. The treatment with premixed aspart 30 was non-inferior to treatment with premixed insulin lispro 25. In addition, Self-monitored blood glucose levels were comparable. Safety profiles were similar between both treatments, as was the incidence of hypoglycemic episodes. The switch between both products of the low-mix family can be carried out without any problem. Both products of the low-mix premixed insulin analogues aspart 30/70 and premixed insulin lispro 25/75 have comparable efficacy and safety as shown from the medical literature. Therefore, we can change from one to another safely as demonstrated by the US FDA statement. In addition, the ergonomic features of KwikPen’s design and function may offer important advantages for the user during insulin administration.

PDB19 Costs and Opportunities Related to the Short-Acting Insulin Analogues Adoption: A Budget IMPACT Analysis

Short-acting insulin analogues (aspart, lispro and glulisine) are widely used in diabetes management. The efficacy and safety are well established for these drugs, however they have different pharmacokinetic characteristics and costs. The aim of this study is to analyze the differences among the short-acting insulin analogues available today, focusing on the opportunity to optimize therapy management costs. A budget impact model was developed to estimate the impact of a redistribution of the short-acting insulin analogues use (39% IAsp: 15% IGlu: 43% ILsp: 3% ILspBIos), according to clinical and economic considerations. The analysis involved two scenarios: in the first, the entire population (731.000) was considered and more equal market shares were assumed: (36% IAsp: 18% IGlu: 31% ILsp: 15% ILspBIos); in the second scenario two subgroups were evaluated, working age subgroup (181.202) and high-dose insulin user subgroup (35.482). In the working age subgroup market shares redistribution was the same adopted in the entire population scenario (36% IAsp: 18% IGlu: 31% ILsp: 15% ILspBIos), while in the high-dose insulin user subgroup, the impact of the switch to the biosimilar of insulin lispro analogue (100% ILspBIos) was evaluated. The analysis was conducted from the perspective of the Italian National Health Service over a 1-year time horizon. Market shares were derived from market analyses and retail price was adopted for drugs cost. The first scenario results showed savings for the INHS equal to € 6,264,451, which rose to € 12,873,580 in the second scenario considering the effects into specific subgroups. The robustness of the results was demonstrated by the sensitivity analysis. The results of the analysis highlight that a more appropriate use of short-acting insulin analogues can allow significant savings for the NHS, involving an optimization of the clinical and economic management of the therapy.

Understanding inhaled Technosphere Insulin: Results of an early randomized trial in type 1 diabetes mellitus.

Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action. Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation. The primary efficacy endpoint was a noninferiority of glycosylated hemoglobin (HbA1c) of 0.4% for TI compared with insulin lispro (LIS) in a 16-week phase 3 randomized clinical trial in type 1 diabetes mellitus. HbA1c values were similar in the TI and LIS groups at the beginning of the trial (7.8% and 7.6%, respectively) and at trial endpoint (7.7% and 7.6%, respectively). Least squares mean changes from baseline were similar between study groups. Glucose values after a standard meal were significantly lower with TI in the first 90 minutes post meal compared with LIS. Mild or moderate hypoglycemia event rates were also significantly lower with TI compared with LIS (5.97 vs 8.01, respectively; P = .0269). Cough was the most commonly reported adverse event with TI. Pulmonary function as measured by forced expiratory volume in 1 second was not different between groups at baseline, 16 weeks, or 4 weeks off study drug. HbA1c was unchanged and overall glucose control was comparable between groups. Treatment with TI resulted in improved post-meal glucose and a lower risk of hypoglycemia compared with LIS.

Effect of Different Insulin Therapies on Obstetric-Fetal Outcomes

To evaluate the effectiveness of the different insulin therapies on obstetrics-fetal outcomes in women with pregestational diabetes mellitus. We enrolled 147 pregnant women with pre-existing type 1 or 2 diabetes mellitus. Clinical and biochemical parameters were analysed in relation to obstetric and fetal outcomes. 14.2% received treatment with Neutral Protamine Hagedorn insulin and short-acting insulin analogues; 19% with premixed human insulin; 40.1% with insulin glargine and lispro, 6.2% with detemir and aspart and 20% with continuous subcutaneous insulin infusion. All 5 types of treatment achieved a reduction of the mean HbA1c during pregnancy (p = 0.01). Pre-pregnancy care was carried out for 48% of patients. We found no statistically significant differences between the different insulin therapies and the obstetric-fetal outcomes. In conclusión, the different insulin therapies used in patients with pregestational diabetes mellitus does not seem to affect obstetric-fetal outcomes.

Insulin therapy-new insulin analogues

A multitude of short-acting and long-acting insulin analogues are currently available for the treatment of diabetes mellitus, which mimic physiological insulin secretion better than normal insulins. By the use of ultrarapid insulin analogues postprandial glucose increases can be significantly reduced. Newer long-acting insulin analogues have avery stable action profile and reduce the rate of hypoglycemia, especially nocturnal hypoglycemia, even more than first generation long-acting insulin analogues. Future developments focus on a further acceleration of prandial insulin effects with a simultaneous shorter effect time and an even more prolonged action of long-acting insulin analogues.

How do short-acting insulin analogues compare with regular human insulin for adults with type 2 diabetes mellitus?

How do short-acting insulin analogues compare with regular human insulin for adults with type 2 diabetes mellitus?

Melatonin Concentrations and Sleep Quality in Patients with Type 2 Diabetes and Obesity

Abstract There is a close relationship between melatonin as a circadian regulator and insulin, glucagon and somatostatin production. This study aimed to describe subgroups of type 2 diabetes mellitus (T2DM) patients that may benefit from melatonin clock-targeting properties. The study involved 38 participants: 26 T2DM patients, and 12 participants without diabetes in the control group. Subjects were asked to complete the questionnaire of Pittsburgh Sleep Quality Index (PSQI). Standard biochemical venous sample testing was performed, and a sample of saliva was collected for melatonin testing. Melatonin concentration in participants without obesity (body mass index (BMI) &lt; 30 kg/m2) was significantly higher than in obese participants: 13.2 (6.4; 23.50) pg/ml vs 5.9 (0.78; 13.1) pg/ml, p = 0.035. Subjects with BMI 30 kg/m2 had a significantly higher PSQI score than non-obese subjects: 7 (4.5; 10) vs 5.5 (3; 7), p = 0.043. T2DM patients showed significantly lower levels of melatonin than the control group: 6.1 (0.78; 12.2) pg/ml vs 17.8 (8.2; 25.5) pg/ml, p = 0.003. T2DM patients using short-acting insulin analogues showed a significantly higher PSQI score than patients not using insulin: 9 (6; 10) vs 6 (3; 8), respectively (p = 0.025). Poor sleep quality was more prevalent in patients with diabetic retinopathy than in those without this complication (p = 0.031). Lower melatonin levels were detected in T2DM and obese patients. Furthermore, poor sleep quality was observed in T2DM patients using short-acting insulin analogues and those with diabetic retinopathy, and obese individuals.

Continuous subcutaneous insulin infusion vs modern multiple injection regimens in type 1 diabetes: an updated meta-analysis of randomized clinical trials.

Meta-analyses of clinical trials comparing CSII with traditional insulin injections usually show a small, but significant advantage of CSII with respect to HbA1c and risk of severe hypoglycemia. On the other hand, CSII is associated with a small, but relevant risk of ketoacidosis, mainly due to malfunction of insulin pump and/or catheter occlusion. During last time, the technology of insulin pumps and infusion sets has improved as the profound evolution in type and schemes with traditional insulin injections. Aim of the present study is to update previous meta-analyses comparing CSII with traditional insulin injections in subjects with type 1 diabetes. Specific subgroup analyses were designed for assessing the effects of CSII in comparison with basal-bolus MDI, with short-acting analogues as bolus and long-acting analogues as basal insulin. In addition, an exploratory analysis was performed to verify the effect of CSII in insulin-naïve patients with type 1 diabetes. The present analysis includes all randomized clinical trials comparing CSII with traditional injections in type 1 diabetes, with a duration of at least 12 weeks. Animal studies were excluded, whereas no language or date restriction was imposed. If duplicate publications of a single trial were present, the paper containing more adequate information was considered as principal publication. In trials comparing CSII with basal-bolus MDI, performed before the introduction of rapid-acting analogues, regular human insulin was used for CSII, and as prandial insulin in control groups. CSII was associated with a significant reduction of A1c, in comparison with MDI, irrespective of the use of either human insulin or rapid-acting analogues. However, in trials with rapid-acting analogue the advantage of CSII was significantly smaller than in trials with regular human insulin (HbA1c difference: - 0.29[- 0.46; - 0.13] vs - 1.93[- 1.84; - 0.42]%; p = 0.02). Different rapid-acting analogues provided similar results (HbA1c reduction vs MDI: - 0.25 [- 0.48; - 0.02]%, p = 0.03, and - 0.29 [- 0.49; - 0.09]%, p = 0.005, for lispro and aspart, respectively). In addition, in trials comparing CSII with basal-bolus MDI, CSII reduced HbA1c to a similar extent irrespective of the use of either NPH or long-acting analogues as basal insulin in the control groups (HbA1c reduction vs MDI: - 0.31 [- 0.55; - 0.06]%, p = 0.01, and - 0.20 [- 0.38; - 0.03]%, p = 0.02, for NPH and long-acting analogues, respectively. With respect to severe hypoglycemia, CSII did not produce a significant reduction of risk in comparison with traditional insulin injections. Conversely, CSII was associated with a significant increase in the incidence of reported diabetic ketoacidosis (DKA). Notably, the increased risk of DKA was significant in trials comparing CSII with conventional insulin therapy, whereas only a nonsignificant trend toward an increased risk was observed in comparisons with basal-bolus MDI. Only two trials comparing CSII with basal-bolus MDI, both using rapid-acting analogues, were performed on insulin-naïve type 1 diabetic patients. When those two trials were analyzed separately, CSII did not produce any relevant effect on HbA1c (difference from control: - 0.10[- 0.38; + 0.17]%; p = 0.46). No meta-analysis could be performed on either severe hypoglycemia or DKA, which were not reported by one of the two trials. CSII seems to produce a small improvement in HbA1c in patients with type 1 diabetes inadequately controlled with MDI. This apparent effect, which could be partly due to publication bias, is smaller when MDI is properly performed using basal-bolus schemes with short-acting insulin analogues. Other outcomes different from HbA1c (such as quality of life) could be relevant for the choice of CSII instead of MDI. In addition, further studies are needed to better define the profile of patients who could benefit most from CSII.

Lispro insulin for the treatment of severe subcutaneous insulin resistance

Objective – To evaluate the clinical usefulness of the short-acting insulin analogue lispro in continuoussubcutaneous insulin infusion (CSII) in type 1 patients with brittle diabetes due to severe subcutaneousinsulin resistance who would otherwise require treatment with alternative insulin delivery systems (eg.by intraperitoneal insulin pump) necessary to prevent recurrent diabetic ketoacidosis.Research design and methods – We proceeded in three patients with severe subcutaneous insulinresistance with a subcutaneous bolus test comparing the effects on plasma insulin levels and glycaemiaof 15-30 U of regular insulin versus the same amount of lispro insulin. The successful bolus testprompted us to use lispro insulin in CSII in these patients. Adaptation of the insulin dose was made onthe basis of daily capillary blood glucose measurements.Results – In all patients lispro insulin was started in CSII (H-tron pump at 44 U/day) initially resultingin an improved metabolic control as reflected by acceptable blood glucose levels and by the HBA1clevels that dropped from 11 +/- 1% before to 7.9 +/- 1% during lispro treatment. During the following 8weeks a progressive rise in blood glucose levels and rise in HbA1c levels to 10.3 +/- 0.1% was seenwith consequently insulin dose adjustment to more than 500 U/day. Finally in all patients further insulindelivery by an intraperitoneal pump was required.Conclusions – In three patients with subcutaneous insulin resistance the administration ofsubcutaneous lispro insulin resulted in acceptable metabolic control, but progressively all three patientsdeveloped a resistance syndrome against subcutaneous lispro insulin completely comparable to theresistance syndrome against subcutaneous regular insulin. Subcutaneous treatment with the insulinanalogue therefore seems to overcome the problem of insulin resistance only temporarily.

New faster-acting insulin Fiasp® — do we need a new meal-time insulin?

Studies aiming at improving the treatment of patients on insulin therapy are conducted bidirectionally. On the one hand, there are attempts to find modified insulin that acts even faster and has shorter effect than currently used short-acting insulin analogs, and on the other hand researchers work to develop more stable basal insulins. Fiasp® is one of the new developments in this field. Addition of two excipients — niacinamide and L-arginine — resulted in faster hypoglycemic effect of insulin aspart while maintaining the stability of drug formulation. Clinical trials assessing pharmacokinetic parameters of Fiasp® showed a 2 times faster onset of action (4 vs. 9 min), 2 times higher exposure to insulin 30 minutes after its administration and 74% more hypoglycemic activity during the first 30 minutes following subcu­taneous injection. Clinical trials of Fiasp® were conducted under the acronym Onset. Overall, these studies included over 3,000 patients with diabetes, both type 1 and type 2. In patients with type 1 diabetes (DM1) comparable or better diabetes control was observed in the Fiasp® groups compared with groups treated with Novorapid, with significantly lower blood glucose levels in the early postprandial period. It has also been demon­strated that administration of insulin Fiasp® within 20 min of the beginning of the meal was associated with comparable results to Novorapid administered before the meal. Fiasp® is commercially available in Poland, but it is not yet widely used due to the high price and no reimburse­ment from NFZ.

Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus.

The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus. For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication. We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant. Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach. We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects. Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.

Pooled Analysis of Clinical Trials Investigating the Pharmacokinetics (PK) of Ultra-rapid Insulin BioChaperone Lispro (BCLIS) vs. Lispro (LIS) in Subjects with Type 1 (T1D) and Type 2 (T2D) Diabetes

BCLIS is an ultra-rapid insulin lispro formulation designed to accelerate the time-action profile vs. conventional short-acting insulin analogs. PK characteristics of single doses of BCLIS and LIS were characterized in four randomized, double-blind, crossover studies in altogether 112 T1D and 51 T2D subjects who received BCLIS and LIS (0.2 U/kg in studies 1 and 2, individualized doses in studies 3 and 4) subcutaneously by syringe. Insulin absorption was consistently faster with BCLIS than with LIS as indicated by reaching early half-maximum insulin levels (early t50%max) 8.4 (95% confidence interval [-9.6;-7.2]) and time to maximum levels (tmax) 10.0 [-14.3;-5.8] min earlier (p&amp;lt;0.0001 for both comparisons). Early insulin exposure was significantly greater for BCLIS for up to 2 hours after administration (Figure). BCLIS also showed faster offset of exposure, with a 22.3 [-28.8;-15.7] min earlier time to late half-maximum insulin levels (late t50%max) (p&amp;lt;0.0001) and a 24% lower late exposure (AUC2-6h; Figure). Total exposure (AUC0-6h) was similar for both formulations in all studies (treatment ratio in pooled analysis 0.99 [0.95;1.03], p=NS). In conclusion, BCLIS consistently shows faster onset and offset of exposure than conventional LIS in both T1D and T2D. Disclosure T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research &amp; Development, MedImmune, Merck Sharp &amp; Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. A. Ranson: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. B. Alluis: None. E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. S. Glezer: Stock/Shareholder; Self; Sanofi. Stock/Shareholder; Spouse/Partner; Sanofi. Employee; Self; ADOCIA, Novo Nordisk Inc.. Employee; Spouse/Partner; Pfizer Inc., Teva Pharmaceutical Industries Ltd.. Stock/Shareholder; Spouse/Partner; Teva Pharmaceutical Industries Ltd. G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA.

EADSG Guidelines: Insulin Therapy in Diabetes.

Executive Summary and Recommendations A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A).Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A).Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin. Two or three premixed insulin injections per day may be used (A).The target glycated hemoglobin A1c (HbA1c) for all children with T1DM, including preschool children, is recommended to be < 7.5% (< 58 mmol/mol). The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications (B).For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose (SMBG) (B).Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus (T2DM) include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy (B).In T2DM patients, with regards to achieving glycemic goals, insulin is considered alone or in combination with oral agents when HbA1c is ≥ 7.5% (≥ 58 mmol/mol); and is essential for treatment in those with HbA1c ≥ 10% (≥ 86 mmol/mol), when diet, physical activity, and other antihyperglycemic agents have been optimally used (B).The preferred method of insulin initiation in T2DM is to begin by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon-like peptide-1 receptor agonist (GLP-1 RA) or in combination with other oral antidiabetic drugs (OADs) (B).If the desired glucose targets are not met, rapid-acting or short-acting (bolus or prandial) insulin can be added at mealtime to control the expected postprandial raise in glucose. An insulin regimen should be adopted and individualized but should, to the extent possible, closely resemble a natural physiologic state and avoid, to the extent possible, wide fluctuating glucose levels (C).Blood glucose monitoring is an integral part of effective insulin therapy and should not be omitted in the patient’s care plan. Fasting plasma glucose (FPG) values should be used to titrate basal insulin, whereas both FPG and postprandial glucose (PPG) values should be used to titrate mealtime insulin (B).Metformin combined with insulin is associated with decreased weight gain, lower insulin dose, and less hypoglycemia when compared with insulin alone (C).Oral medications should not be abruptly discontinued when starting insulin therapy because of the risk of rebound hyperglycemia (D).Analogue insulin is as effective as human insulin but is associated with less postprandial hyperglycemia and delayed hypoglycemia (B).The shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular (IM) injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them (A).Many patients in East Africa reuse syringes for various reasons, including financial. This is not recommended by the manufacturer and there is an association between needle reuse and lipohypertrophy. However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice (A).Health care authorities and planners should be alerted to the risks associated with syringe or pen needles 6 mm or longer in children (A).

Insulin therapy in neonatal diabetes mellitus: a review of the literature.

Neonatal diabetes mellitus (NDM) is a rare disorder, and guidance is limited regarding its optimal management. We reviewed insulin usage in NDM, with a focus on continuous subcutaneous insulin infusion (CSII). A PubMed search identified 40 reports of patients with NDM treated with insulin published between 1994 and 2016. Data concerning treatment of NDM are limited. CSII resolves some of the issues associated with insulin therapy in neonates. No clinical trials of CSII in NDM have been reported. Case reports suggest that CSII is a safe and effective means of treating NDM. CSII was initiated to improve glycaemic control, for practicality and convenience, and to overcome difficulties associated with the maintenance of long-term intravenous catheters. CSII can provide better glycaemic control than multiple daily injections, with few hypoglycaemic events. Continuous glucose monitoring integrated with the pump helps provide more precise control of blood glucose levels. CSII generally uses short-acting insulin or rapid-acting insulin analogues, and those that are approved for use in neonates appear to be appropriate for the treatment of NDM using an insulin pump. Information from case reports indicates that CSII is safe and effective for the management of NDM.