Rapid-acting Insulin Analogues Research Articles

Advances in newer basal and bolus insulins: impact on type 1 diabetes.

Insulin administration is vitally important to maintain a good glycaemic control in people with type 1 diabetes mellitus (T1DM). The purpose of this review is to give a clinically relevant overview of the newer basal and bolus insulin analogues and to highlight their practicalities of use and advantages in specific categories of patients with T1DM. Second-generation rapid-acting insulin analogues (i.e. faster insulin aspart and ultrarapid-acting lispro) have shown to be safe, efficient and superior in controlling postprandial plasma glucose levels without an increase in hypoglycaemia. The newest basal insulin analogues, insulin glargine U300 and degludec, have proven to be efficient in reducing hypoglycaemic events due to a more stable action profile. The second-generation rapid-acting and basal insulin analogues approach better the desired physiological insulin pattern of the beta cell. Due to a faster absorption, it is possible to inject the prandial insulin analogues more closely or even after meals without compromising postprandial glucose control. Due to more stable release patterns, basal insulins now have more reliable and longer profiles, covering basal insulin demands in a superior way, leading to a better glycaemic control with less hypoglycaemia (especially nocturnal events) and an improved quality of life.

Subcutaneous Rapid-acting Insulin Analogs for Diabetic Ketoacidosis.

Diabetic ketoacidosis (DKA), characterized by hyperglycemia, metabolic acidosis, and ketosis, is a serious complication of diabetes mellitus. Treatment focuses on fluid restoration, correction of hyperglycemia, and inhibition of ketogenesis. Insulin is considered a fundamental component of DKA treatment as it promotes the peripheral tissues' utilization of glucose in peripheral tissues by reducing hepatic gluconeogenesis and suppressing ketogenesis.1.

Efficacy and Cardiovascular Safety of Insulins.

Insulin is a lifesaving drug for patients with type 1 diabetes mellitus. Many type 2 diabetes mellitus patients will eventually require insulin. The rapid-acting and long-acting insulin analogues (RAIAs and LAIAs) have a pharmacological profile that closely mimics normal human physiology when compared to Neutral Protamine Hagedorn (NPH) insulin and regular human insulin, respectively. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were found to have a proven cardiovascular safety. They are preferred over insulin in many recent guidelines. Fixed-ratio combinations of GLP-1RAs and insulin are also recommended when either of these molecules fail to achieve glycaemic control. Despite decades of experience in using insulin, there is a debate among the scientific community over the safety of exogenous insulin, especially regarding their cardiovascular safety and the risk of cancer. There is also an ongoing debate regarding the safety, even though two long-acting insulin analogues (glargine and degludec) have proven their cardiovascular non-inferiority. Drugs with proven safety are often preferred in patients with pre-existing cardiovascular disease or at high risk of cardiovascular disease. In this review we will critically analyse efficacy and safety issues related to insulin molecules to help in clinical decision making.

Efficacy and Safety of Intramuscular Insulin Lispro vs. Continuous Intravenous Regular Insulin for the Treatment of Dogs With Diabetic Ketoacidosis.

The use of rapid-acting insulin analogs as routes of administration other than IV has never been described for the treatment of dogs with diabetic ketoacidosis (DKA). This study aims to compare the efficacy and safety of a new protocol based on IM administration of insulin lispro with that of low-dose IV continuous rate infusion of regular insulin in the treatment of canine DKA. Client-owned dogs with naturally occurring DKA were included. Dogs treated with IM insulin lispro (Group L, n = 11) received 0.25 U/kg. The goal was to achieve a drop of at least 10% in blood glucose between 1 h and the next. If this goal was not achieved, the insulin dose was repeated hourly; otherwise, the insulin dose was not repeated up to a maximum of 3 h, after which the insulin dose was repeated anyway. When blood glucose was ≤250 mg/dL, the insulin dose was reduced to 0.125 U/kg IM every 3 h. Cases receiving IV continuous rate infusion of regular insulin (Group R, n = 13) were treated according to a previously published protocol. The median time to resolution of ketosis was significantly shorter in Group L (12 h; range, 4–27 h) compared to Group R (23 h; 10–46 h; P = 0.04). The median times to resolution of acidemia and ketoacidosis were 13 h (4–35 h) and 17.5 h (4–35 h) in Group L, and 22 h (9–80 h) and 23.5 h (10–80 h) in Group R, respectively. These differences were not significant (P = 0.06 and P = 0.09, respectively). The median length of hospitalization did not differ significantly between groups (P = 0.67). There were no differences in the frequency and severity of adverse events (hypoglycemia, hypokaliemia, and hypophosphatemia) between groups. The new protocol based on IM administration of insulin lispro preliminarily appears effective and safe for treatment of canine DKA.

Impact of Accelerating Insulin on an Artificial Pancreas System Without Meal Announcement: An In Silico Examination.

Controlling postprandial blood glucose without the benefit of an appropriately sized premeal insulin bolus has been challenging given the delays in absorption and action of subcutaneously injected insulin during conventional and artificial pancreas (AP) system diabetes treatment. We aim to understand the impact of accelerating insulin and increasing aggressiveness of the AP controller as potential solutions to address the postprandial hyperglycemia challenge posed by unannounced meals through a simulation study. Accelerated rapid-acting insulin analogue is modeled within the UVA/Padova simulation platform by uniformly reducing its pharmacokinetic time constants (α multiplier) and used with a model predictive control, where the controller's aggressiveness depends on α. Two sets of single-meal simulations were performed: (1) where we only tune the controller's aggressiveness and (2) where we also accelerate insulin absorption and action to assess postprandial glycemic control during each intervention. Mean percent of time spent within the 70 to 180 mg/dL postprandial glycemic range is significantly higher in set (2) than in set (1): 79.9, 95% confidence interval [77.0, 82.7] vs 88.8 [86.8, 90.9] ([Note to typesetter: Set all unnecessary math in text format and insert appropriate spaces between operators.] P < .05) for α = 2, and 81.4 [78.6, 84.3] vs 94.1 [92.6, 95.6] (P < .05) for α = 3. A decrease in percent of time below 70 mg/dL is also detected: 0.9 [0.4, 2.2] vs 0.6 [0.2, 1.4] (P = .23) for α = 2 and 1.4 [0.7, 2.8] vs 0.4 [0.1, 1.4] (P < .05) for α = 3. These proof-of-concept simulations suggest that an AP without prandial insulin boluses combined with significantly faster insulin analogues could match the glycemic performance obtained with an optimal hybrid AP.

New Guidance on Managing Inpatient Hyperglycaemia during the COVID‐19 Pandemic

The COVID-19 pandemic has had a dramatic impact on the provision of acute inpatient care with specialists from all disciplines having to manage patients outside of their usual speciality areas. In many UK hospitals diabetes consultants and diabetes inpatient specialist nurses have been redeployed to the wards to care for COVID-19 positive or suspected cases. Consequently, clinicians relatively unfamiliar with managing hyperglycaemia have been required to do so as the usual input from diabetes specialist teams has not been possible in many areas. The National Diabetes Inpatient COVID-19 Response Group was formed to provide guidance to those involved in the care of inpatients with diabetes during this crisis. We have published in a previous issue of this journal guidance on care at the ‘front door’ aimed at emergency departments and admitting teams [1]. We now present guidance on the management of inpatient hyperglycaemia (Figure 1). We recognise that most hospitals will already have established local guidance in place. The current guidance is intended to help supplement and update existing guidance with a particular reference to supporting those less experienced in insulin use. In this respect, it is tailored to manage hyperglycaemia but as much as possible reducing the risk of overcorrection resulting in hypoglycaemia. It thus sets more liberal glycaemic targets than have been suggested in previous UK guidelines [2]. The COVID specific diabetes algorithms aim to achieve a ‘lower’ target of 6.0 mmol/L (higher than the previous of 4.0mmol/L) yet to keep blood glucose levels less than 10.0 mmol/L with up to 12.0 mmol/L being acceptable. Uniquely, it provides 3 different correction regimes for rapid acting analogue insulin based on the information available to the clinician. Firstly, if the person with diabetes knows their own ‘correction dose’ this should be used (e.g. for people with type 1 diabetes who are DAFNE trained, 1 unit reduces the blood glucose by 3.0 mmol/L). Secondly, if the total daily dose is known the correction is based on intervals of less than 50 units/day, 50-100 units/day and over 100 units/day. Finally, where none of the previous are known, the correction is based on weight with intervals of less than 50 kg, 50-100 kg and > 100 kg (for insulin naïve people or those newly presenting). The guidance recommends commencement of a basal insulin if hyperglycaemia persists after several correction doses of rapid acting insulin within a 24 hr period. The algorithm recommends a starting dose related to the person’s weight and specific issues such as age, fragility and renal function. There are then dosing regimens related to the particular basal insulin available in individual hospitals. There is also a dose adjustment regimen for the basal regimen based on the blood glucose levels immediately prior to the timing of the basal insulin. Finally, the guidance recognises that the insulin dose may need adjustment, particularly the basal insulin dose when there is a change in insulin sensitivity such as can occur with improving infection, reduction in corticosteroid treatment and in those recovering from COVID-19 related insulin resistance. Although, this guidance has been introduced for use during the present pandemic it is possible that this more judicious glucose target that has been previously advocated by some [3] and the early intervention with basal insulin may become the established guidance for the future.

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.

895-P: Improved Glycemic Control with Insulin Glargine 300 U/mL vs. Glargine 100 U/mL in Type 1 Diabetes

PK/PD of clinical doses of Glargine 300 U/mL (Gla-300) and Gla-100 differ (Diabetes Care 2019;42:85), but any clinical relevance has been difficult to demonstrate. Aim: to demonstrate that PK/PD differences of individual doses of Gla-300 vs. Gla-100 translate into clinical benefits in T1DM, as shown by interstitial glucose (IG) (CGM). Methods: 18 persons with T1DM (age 40±12 yrs, diabetes duration 26±12 yrs, A1C 7.2±0.5 %, 55±6 mmol/mol) were randomized to Gla-300 or Gla-100 titrated for 3 months, followed by 2 month washout, and alternate treatment for 3 more months. Titrated mealtime rapid-acting insulin analogs were continued with both Gla-300 and Gla-100. Blinded CGM (iPro, Medtronic) was used during last 2 weeks of each 3-month treatment period. Results: After 3 months, A1C was no different with Gla-300 vs. Gla-100 (both 6.9±0.5 %, 52±6 mmol/mol). CGM revealed lower 24 h IG (Figure); % time in range (70-180 mg/dl) was higher (82±8 vs. 72±10), whereas % time above range (&amp;gt;180 mg/dl, 16±7 vs. 24±8), % time below range (particularly from midnight to pre-breakfast) (&amp;lt;70 mg/dl, 2±3 vs. 4±4) and IG nocturnal variability (% CV 25±7 vs. 37±12) were lower with Gla-300 vs. Gla-100 (p&amp;lt;0.05). Dose was higher with Gla-300 (0.35±0.08 U/kg) vs. Gla-100 (0.28±0.07 U/kg). Conclusions: Titrated Gla-300 improves glucose control, reduces variability and hypoglycemia risk vs. Gla-100, as predicted from PK/PD differences of individual doses. Disclosure L. Paola: None. P. Cioli: None. P. Candeloro: None. A. Marinelli Andreoli: None. G.B. Bolli: Consultant; Self; Sanofi. C.G. Fanelli: Advisory Panel; Self; Eli Lilly and Company, Sanofi. F. Porcellati: None. Funding Sanofi

148-LB: Timely Administration of Rapid-Acting Insulin in Hospitalized Children with Diabetes: A Quality Improvement Project

Background: The preferred management of insulin-dependent diabetes (IDDM) for pediatric patients includes rapid-acting insulin analogs administered at mealtimes in conjunction with carbohydrate counting. Hospitalized children with IDDM are dependent on hospital personnel to administer rapid-acting insulin, which should occur within 15-30 minutes of the onset of eating. Delays in insulin administration can result in hyperglycemia, poor patient satisfaction, and inappropriate insulin regimen adjustments. At the Children’s Hospital at Montefiore (CHAM), we found that rapid-acting insulin is administered within 15 minutes of glucose check at breakfast time in only 18% of patients, and within 30 minutes of glucose check in only 40% of patients. Methods: We formed a multi-disciplinary team and used process mapping to identify barriers to timely insulin administration and implement interventions. We studied the time to rapid-acting insulin administration at breakfast for children with IDDM admitted to the 6th floor of CHAM from November 2018 to present before and after PDSA cycles, which have included nurse and resident education in carbohydrate counting, standardization of diabetes menus to include carbohydrate content, and standardization of communication method between nurses and residents. Results: As of December 2019, median time from blood sugar check to rapid-acting insulin administration at breakfast improved from 32.5 minutes at baseline to 26 minutes. The percentage of children with IDDM who receive rapid-acting insulin within 15 minutes of blood sugar check has not changed, but the percentage of children who receive rapid-acting insulin within 30 minutes of blood sugar check improved from 40% at baseline to 60%. Conclusions: Timely administration of rapid-acting insulin to hospitalized children with IDDM is a complex process involving coordination of care by multiple providers, and can be improved upon with a multidisciplinary team approach. Disclosure L. Eng: None. D. Duhame: None. L. Underland: None.

Hypoglycaemia and its management in primary care setting.

Hypoglycaemia is common in patients with type 1 diabetes and type 2 diabetes and constitutes a major limiting factor in achieving glycaemic control among people with diabetes. While hypoglycaemia is defined as a blood glucose level under 70 mg/dL (3.9 mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycaemic control. Severe hypoglycaemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycaemia is the most important safety outcome in clinical studies of glucose lowering agents. The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycaemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycaemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycaemic events with the use of newer anti-diabetic drugs. Increased hypoglycaemia risk is observed with the use of insulin and/or sulphonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycaemia and cardiovascular outcomes show features of "frailty." Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycaemia, impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia and with history of severe hypoglycaemia. Patients with impaired awareness of hypoglycaemia benefit from real-time CGM. The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycaemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycaemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycaemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycaemia. Several therapeutic considerations are important to reduce hypoglycaemia risk during pregnancy including administration of rapid-acting insulin analogues rather than human insulin, pre-conception initiation of insulin analogues, and immediate postpartum insulin dose reduction.

MON-640 Endogenous Insulin and C-Peptide Suppression Test Using a Rapid-Acting Insulin Analog in the Diagnosis of Insulinoma

C-peptide suppression test (CPS) was shown to diagnose the cause of hyperinsulinemic hypoglycemia, i.e. insulinoma, as effectively as supervised 72-hour fast test with less time consuming and cost. In the conventional CPS, regular insulin (RI) is used to induce hypoglycemia that subsequently suppresses endogenous insulin secretion. As RI is measurable in plasma insulin (PI) assay, plasma C-peptide (PCP) but not PI response is therefore used for assessment of endogenous insulin secretion in CPS using RI. As rapid acting insulin analogs (RA) are not measurable in a selected PI assay, both PCP and PI levels can be used to assess endogenous insulin secretion if an RA is used instead of RI in CPS. There is no study on PI and PCP responses to RA in insulinoma. This study aimed to examine efficacy of modified CPS, so-called insulin and C-peptide suppression test (ICPS) by using an RA (insulin aspart) in the diagnosis of insulinoma. Ten patients, 7 with histopathological proven insulinoma (IN) and 3 with non-insulinoma (non-IN), underwent ICPS. Blood samples were collected for measurement of plasma glucose (PG), PCP, and PI using a Roche Cobas 8000 module e602 which does not measure insulin aspart at before and every 10-20 minutes during intravenous infusion of insulin aspart at the rate of 0.05-0.075 unit/kg/hr. The test was terminated if the patients had a PG level of <40 mg/dL. There was no difference in baseline biochemical data between two groups. At the end of the test, IN had significantly higher PCP level (range: 0.60-10.20 vs. 0.31-0.48 ng/mL and median: 4.67 vs. 0.47 ng/mL; p = 0.017), lower percentage of PCP suppression (range: 2.10-53.10% vs. 63.08-91.24% and mean: 24.78 ± 19.4% vs. 73.17 ± 15.7%; p = 0.005), higher PI level (range: 1.13-113.70 vs. 0.22-0.73 µIU/mL and median: 21.29 vs. 0.49 µIU/mL; p = 0.017) and lower percentage of PI suppression (range: -14.63-81.32% vs. 88.14-96.10% and mean: 28.45 ± 36.2% vs. 93.31 ± 4.5%; p = 0.003) than did the non-IN. No overlapping of these parameters was observed between IN and non-IN. Using the same cut-off levels as the supervised 72-hour fast test, the insulin criterion (≥3 µIU/mL) in ICPS had a sensitivity of 86% and a specificity of 100% and the C-peptide criterion (≥0.6 ng/mL) in ICPS had a sensitivity of 100% and a specificity of 100%. There was a high correlation of 89% between using PCP and PI responses. In conclusion, ICPS using an RA is effective in the diagnosis of insulinoma.

Instability of Insulin Aspart Diluted in Dextrose

Insulin aspart (Novorapid) is a rapid-acting insulin analog that is maintained in hexameric form by phenolic preservatives (phenol and metacresol) and stabilized by insulin-zinc complex. According to the manufacturers, insulin can be independently diluted either in 5% dextrose solution (D5%) or 0.9% sodium chloride solution. In reality, in most clinical units, such as the neonatal intensive care unit (NICU), insulin aspart is more frequently diluted in D5% than in saline solution due to sodium restriction. However, injectable dextrose solutions contain glucose degradation products (1) that are capable of binding proteins—like insulin—through a glycation phenomenon. Therefore, dilution of Novorapid in D5% would be more likely to cause glycated insulin and may raise a worrisome problem in terms of insulin stability. The objective of this study was to investigate the stability of insulin aspart diluted in D5% at both adult and neonate therapeutic concentrations in order to ensure its appropriateness in the preparation of insulin aspart. To address this issue, insulin aspart diluted in D5% was assayed by a stability-indicating method using high-performance liquid chromatography (HPLC) coupled with an ultraviolet (UV) detector. The nature of the formed product was determined by HPLC coupled with a mass spectrometer. The effect of …

Effect of Subcutaneous Insulin on Spirometric Maneuvers in Patients with Type 1 Diabetes: A Case-Control Study.

In order to compare spirometric maneuvers in adults according to the presence of type 1 diabetes, a case-control study including 75 patients with type 1 diabetes and 75 controls matched by sex, age, and body mass index were designed. In addition, 75 patients with type 1 diabetes were added to examine the potential the impact of subcutaneous insulin therapy on pulmonary function. Lung function measurements were assessed according to the global initiative for chronic obstructive lung disease guidelines. Basal insulin included long-acting insulin analogues and the delivered background insulin in patients with pump therapy. Bolus insulin included rapid-acting insulin analogues and the delivered insulin to cover postprandial hyperglycemias. Patients with type 1 diabetes showed lower spirometric values in comparison to the control group, together with a higher prevalence of forced expiratory volume in the first second (FEV1) <80% (10.7% vs. 2.7%, p = 0.044) and restrictive ventilatory pattern (10.7% vs. 0%, p = 0.006) The dose of basal insulin (U/kg/day) showed a negative correlation with forced vital capacity (FVC) (r = −0.205, p = 0.012) and FEV1 (r = −0.182, p = 0.026). The optimal cut-off value for identifying patients with a restrictive spirometric pattern was 0.5 U/kg/day of basal insulin. Additionally, basal insulin (U/kg/day) independently predicted the presence of both a restrictive spirometric pattern (OR = 77.1 (3.2 to 1816.6), p = 0.007) and an abnormal FEV1 (OR = 29.9 (1.5 to 562.8), p = 0.023). In patients with type 1 diabetes, higher basal insulin dosage seems to be related with an impairment of pulmonary function.

The Clinical Role of Insulin Degludec/Insulin Aspart in Type 2 Diabetes: An Empirical Perspective from Experience in Australia.

Treatment intensification in people with type 2 diabetes following failure of basal insulin commonly involves the addition of a rapid-acting insulin analogue (basal plus one or more prandial doses; multiple daily injections) or by a switch to premixed insulin. Insulin degludec/insulin aspart (IDegAsp), comprising rapid-acting insulin aspart and ultra-long-acting insulin degludec in solution, enables both fasting and post-prandial glucose control, with some advantages over other treatment intensification options. These include straightforward dose titration, flexibility in dose timing, low injection burden, simplicity of switching and a lower risk of hypoglycaemia. In Australia, where insulin degludec on its own is not available, IDegAsp enables patients to still benefit from its ultra-long-acting properties. This review aims to provide guidance on where and how to use IDegAsp. Specifically, guidance is included on the initiation of IDegAsp in insulin-naïve patients, treatment intensification from basal insulin, switching from premixed or basal-bolus insulin to IDegAsp, up-titration from once- to twice-daily IDegAsp and the use of IDegAsp in special populations or situations.

Reassessment of an Innovative Insulin Analogue Excludes Protracted Action yet Highlights the Distinction between External and Internal Diselenide Bridges.

Long-acting insulin analogues represent the most prescribed class of therapeutic proteins. An innovative design strategy was recently proposed: diselenide substitution of an external disulfide bridge. This approach exploited the distinctive physicochemical properties of selenocysteine (U). Relative to wild type (WT), Se-insulin[C7UA , C7UB ] was reported to be protected from proteolysis by insulin-degrading enzyme (IDE), predicting prolonged activity. Because of this strategy's novelty and potential clinical importance, we sought to validate these findings and test their therapeutic utility in an animal model of diabetes mellitus. Surprisingly, the analogue did not exhibit enhanced stability, and its susceptibility to cleavage by either IDE or a canonical serine protease (glutamyl endopeptidase Glu-C) was similar to WT. Moreover, the analogue's pharmacodynamic profile in rats was not prolonged relative to a rapid-acting clinical analogue (insulin lispro). Although [C7UA , C7UB ] does not confer protracted action, nonetheless its comparison to internal diselenide bridges promises to provide broad biophysical insight.

Insulin analogs versus human insulins for the management of diabetes: An evidence-based review

Insulin analogs are preferred by many physicians over human insulins in the management of Type 1 diabetes and in patients with Type 2 diabetes who require insulin. Insulin analogs have a pharmacological profile that is close to the normal physiological action of insulin. There is a notion among some clinicians that insulin analogs offer advantages over human insulins, including better glucose control, less hypoglycemia, and flexibility. A large number of clinical studies, along with systematic reviews, have compared insulin analogs to human insulins in regard to glucose control, rates of hypoglycemia, quality of life, and cost-effectiveness. For Type 1 diabetes, rapid-acting insulin analogs offer better glucose control and less rates of hypoglycemia compared to regular human insulin. Long-acting basal insulins result in less nocturnal hypoglycemia compared to neutral protamine Hagedorn (NPH) insulin but no difference in glucose control in patients with Type 1 diabetes. For patients with Type 2 diabetes, rapid-acting insulins offer no advantage for glucose control or rates of hypoglycemia when compared to regular insulin. There was only a reduction in rates of nocturnal hypoglycemia with no difference in glucose control with the use of basal insulin analogs compared to NPH insulin in Type 2 diabetes. The cost of insulin analogs is considerably higher than human insulins and favorable cost-effectiveness was only demonstrated with rapid-acting insulin analogs in Type 1 diabetes. The available evidence does not support the routine use of insulin analogs over human insulins. There are only few situations where insulin analogs have shown clear benefit over human insulin. In a large percentage of patients cost consideration and lack of better glucose control would favor the use of human insulins.

Biosynthetic Human Insulin and Insulin Analogs.

Biosynthetic human insulins and analogs have replaced animal insulins and permitted structural modifications to alter the rate of absorption, duration of action, improve reproducibility of effects, and modulate relative efficacy in various target tissues. Several forms of rapidly acting insulins nearly achieve rapid pharmacokinetics and pharmacodynamics similar to first-phase insulin release. There is need for even faster-acting analogs to mimic normal physiology and improve control of postprandial glycemic excursions. Two biosynthetic insulin analogs have sufficiently long duration of action for use as once-daily basal insulins; controversy persists regarding their respective risks of hypoglycemia and relative glycemic variability. Basal-bolus therapy and insulin pump therapy, including closed-loop automated insulin delivery, require rapid-acting insulin analogs. The longer acting insulins can provide stable, reproducible basal insulin with reduced rates of hypoglycemia, particularly nocturnal hypoglycemia, greater efficacy in reducing mean glucose and glucose variability while increasing time in glucose target range. Inhalable human insulin provides very rapid action. Premixture of rapid-acting analogs with protamine has been useful for some patients with type 2 diabetes. An insulin analog with preferential efficacy at the liver has been developed and tested clinically but not marketed. Current research is aimed at developing even faster-acting insulin analogs. Long-acting basal insulins coformulated with GLP-1 receptor agonists or with a rapidly acting insulin analog have valuable clinical applications. Excipients, chaperones, local heating of the infusion site, and hyaluronidase have also been used to accelerate the absorption of insulin analogs. Biosynthetic human insulins have radically revolutionized management of both type 1 and type 2 diabetes worldwide. The ability to manipulate the structure and formulation of insulin provides for more physiologic pharmacokinetics and pharmacodynamics, enabling improved glycemic control, reduced risk of hypoglycemia, and reduced rates of long-term complications.

Indian reality of managing type 2 diabetes: an expert review of global and national guidelines for optimum insulin use

Several guidelines provide recommendations on insulin therapy in people with type 2 diabetes mellitus (T2DM). Major global guidelines have been adapted in multiple countries, and local consensus recommendations have been published giving guidance on insulin therapy considering local realities. This expert review focuses on the recommendations from global and Indian guidelines on insulin therapy in people with T2DM. It emphasizes on a patient-centric approach, including the glycemic parameters, psychosocial aspects, phase of life, and the Indian realities of T2DM management in guiding optimum insulin therapy for initiation and intensification. Therapeutic inertia towards timely insulin initiation needs to be bridged. Owing to the high carbohydrate diet and high postprandial glucose (PPG) excursions, insulin co-formulation and premix insulins offering total glycemic control can be preferred for a timely insulin initiation in Indians with T2DM that is uncontrolled despite multiple oral antidiabetic drugs. They also provide simplicity and convenience for insulin initiation and intensification. Among basal insulins, insulin degludec and glargine U300 are found to be safer, and offer more dosing flexibility than the first-generation basal insulin analogs. Faster-acting insulin aspart has been shown to provide better PPG control and dosing flexibility compared to a rapid-acting insulin analog with a lower risk of hypoglycemia. Thus, based on available evidences, a preferred use of insulin analog over conventional human insulins is suggested, keeping cost considerations in mind. The review also discusses optimum use of concomitant medications with insulin therapy for T2DM management.

Biosimilars and Novel Insulins.

Insulin therapy is the mainstay of treatment for type 1 diabetes and may be necessary in type 2 diabetes. Current insulin analogues present a more physiological profile, are effective, and with less risk of hypoglycemia, but they are expensive. Biosimilar insulins should offer the advantages of insulin analogues at reduced costs. In addition, current rapid-acting insulin analogues are not fast enough to control excessive postprandial glucose excursions in many patients. Biosimilar insulins demonstrated that are safe and effective, but interchangeability and automatic substitution remain an issue. Ultrafast-acting insulins should reduce postprandial hyperglycemia and improve flexibility in insulin dosing. This systematic review was conducted following widely recommended methods. We searched for each topic in Medline, Embase, the Cochrane Library, and SCISEARCH for relevant citations for the appropriate period. LY2963016 and MK-1293 are biosimilar insulins of insulin glargine, and SAR342434 is a biosimilar of insulin lispro. The abbreviated developed program demonstrated comparable efficacy and safety and supports their use for treatment of people with diabetes but no interchangeability. Faster-acting insulin aspart is a new formulation of insulin aspart with accelerated subcutaneous absorption. Faster aspart demonstrated noninferiority in reducing HbA1c as compared to insulin aspart with superiority in controlling postprandial hyperglycemia without increasing hypoglycemia, and flexible insulin dosing. Biosimilar insulins have comparable PK-PD profiles and equivalent efficacy and safety to original insulins at a lower price, making them available for more people with diabetes. Faster aspart is the first ultrafast-acting insulin. New upcoming clinical trials and more clinical experience with faster aspart will show the real potential of this new insulin.

Rapid-Acting Insulin Analogues Versus Regular Human Insulin: A Meta-Analysis of Effects on Glycemic Control in Patients with Diabetes

IntroductionThe aim of this meta-analysis was to investigate the impact of rapid-acting insulin analogues (RAIAs) and regular human insulin (RHI) on glycemic control, including long- and short-term glycemic variability as measured by glycated haemoglobin (HbA1c) and pre- and postprandial glucose (PPG).MethodsPubMed was searched for studies published between 1999 and 29 June 2016. Randomised controlled trials of patients with diabetes that assessed the effects of RAIAs or RHI on glycemic control, focusing on preprandial glucose, PPG and HbA1c, were included. Only studies that reported both means and standard deviations for those outcomes were analysed; from these data, weighted mean differences and 95% confidence intervals were generated to yield overall point estimates. The primary outcomes of the meta-analysis were the mean differences between RAIAs and RHI at the end of the study in PPG, preprandial glucose, and HbA1c.ResultsTwenty-seven studies (n = 7452) were included. The difference in PPG between RAIA- and RHI-treated patients was significant—in favour of RAIAs—in patients with type 1 diabetes (T1D) [− 22.2 mg/dL; 95% confidence interval (CI) − 27.4, − 17.0 mg/dL; P < 0.0001] but not in those with type 2 diabetes (T2D). For preprandial glucose, there was a non-significant trend favouring RHIs in T1D; no data were available for patients with T2D. In patients with T1D, the between-group difference in end-of-treatment (EOT) HbA1c favoured RAIAs (− 0.13%; 95% CI − 0.18, − 0.08%; P < 0.0001), but was not significant in patients with T2D. The main study limitations were the small number and heterogeneity of the included studies.ConclusionsThese results demonstrate that RAIAs are more effective at reducing PPG and improving HbA1c than RHIs in T1D. More data are required to assess the effect of these agents on glucose control in T2D.Plain Language SummaryIn patients with diabetes, the risk of complications is increased by poor control of blood glucose levels and high blood glucose variability. Complications may include cardiovascular disease, eye problems and amputation. Control and variability of blood glucose levels can be evaluated using a range of measures, including (i) glycated haemoglobin (HbA1c) level at the end of the treatment period; (ii) change in HbA1c level during the treatment period; (iii) fasting plasma glucose level; (iv) postprandial glucose (PPG) level; (v) change in blood glucose level after a meal. PPG levels following a meal are an important measure of overall metabolic control in diabetes, and reduction of glycemic variability (GV) can be achieved via reductions in PPG. Both rapid-acting insulin analogues (RAIAs; aspart, glulisine and lispro) and regular human insulin (RHI) are widely used in the management of diabetes. Using data from 27 randomised controlled trials involving more than 7000 patients, we investigated the impact of RAIAs and RHI on measures of glycemic control and variability in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Our results show that, in patients with T1D, RAIAs are more effective than RHI at reducing PPG excursions and HbA1c. This indicates that glycemic control is better with RAIAs than with RHI. More data are required to assess the effects of RAIAs and RHI on glycemic control and variability in patients with T2D.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-019-00732-w) contains supplementary material, which is available to authorized users.