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Diabetes Research and Clinical Practice Feb 2019New concentrated insulins (exceeding 100 units/mL) and dedicated devices have recently become available, offering new treatment options for people with diabetes, for... (Review)
Review
New concentrated insulins (exceeding 100 units/mL) and dedicated devices have recently become available, offering new treatment options for people with diabetes, for basal and prandial insulin supplementation. The concentrated insulin formulations range from 2-fold concentration (insulin lispro 200 units/mL) with rapid-acting prandial action to 5-fold concentration (human regular insulin, 500 units/mL) with basal and short-acting prandial actions. Long-acting basal insulins include degludec 200 units/mL and glargine 300 units/mL. Concentrated insulins have been developed with the goal of easing insulin therapy by reducing the volume and number of injections and in some cases making use of altered pharmacokinetic and pharmacodynamic properties. This review summarizes the unique characteristics of each concentrated insulin to help healthcare providers and people with diabetes understand how to best use them.
Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Compounding; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Insulin, Regular, Human; Insulins
PubMed: 30583034
DOI: 10.1016/j.diabres.2018.12.007 -
Cell Metabolism Apr 2021The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve... (Review)
Review
The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery and therapeutic efficacy. Normal endogenous insulin secretion consists of a highly orchestrated physiologic loop wherein multiple metabolic signals trigger the pancreatic β cells to secrete the precise amount of insulin into the portal system required to maintain euglycemia. Accordingly, in the treatment of diabetes, attempting to replicate this complex physiology with exogenous insulin therapy given subcutaneously presents a clinical challenge. In this context, recombinant DNA-based technology has enabled the development of insulin analogs that have been specifically designed to confer advantageous pharmacodynamic features that can better mimic endogenous insulin secretion. In this review, we discuss the development of the most widely available insulin preparations and provide evidence-based insight into their use in clinical practice.
Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Delivery Systems; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Lispro
PubMed: 33826916
DOI: 10.1016/j.cmet.2021.03.014 -
BioDrugs : Clinical Immunotherapeutics,... Aug 2020The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin... (Review)
Review
The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin glargine) and Admelog (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.
Topics: Biosimilar Pharmaceuticals; Drug Approval; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulins; United States
PubMed: 32681425
DOI: 10.1007/s40259-020-00431-0 -
Indian Journal of Endocrinology and... 2018This communication reviews available high concentration insulins and their basic as well as clinical pharmacology. It classifies all high concentration insulins, and...
This communication reviews available high concentration insulins and their basic as well as clinical pharmacology. It classifies all high concentration insulins, and describes their pharmacokinetic and pharmacodynamic properties. The article discusses the utility of high concentrations insulins, lists indications for these preparations, highlights caveats for their safe use, and proposes pragmatic contraindications to their prescription.
PubMed: 29535954
DOI: 10.4103/ijem.IJEM_300_17 -
Therapeutic Advances in Chronic Disease Nov 2015Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially,... (Review)
Review
Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections.
PubMed: 26568812
DOI: 10.1177/2040622315608646 -
Pharmaceutical Research Nov 2022While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and...
While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1 g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.
Topics: Humans; Insulin; Excipients; Insulin Lispro; Insulin, Regular, Human; Zinc; Drug Stability
PubMed: 35978148
DOI: 10.1007/s11095-022-03367-y -
Journal of Obstetrics and Gynaecology... Apr 2014Diabetic pregnancies have attendant risks. Adverse fetal, neonatal, and maternal outcomes in a diabetic pregnancy can be avoided by optimum glycemic control. Most... (Review)
Review
Diabetic pregnancies have attendant risks. Adverse fetal, neonatal, and maternal outcomes in a diabetic pregnancy can be avoided by optimum glycemic control. Most pregnancies with GDM can be managed with non-insulinic management, which includes medical nutrition therapy. However, many necessitate concomitant insulinic management. The new insulin analogs present undoubted advantages in reducing the risk of hypoglycemia, mainly during the night, and in promoting a more physiologic glycemic profile in pregnant women with diabetes. Rapid-acting insulin analogs seem to be safe and efficient in reducing postprandial glucose levels more proficiently than regular human insulin, with less hypoglycemia. The long-acting insulin analogs do not have a pronounced peak effect as NPH insulin, and cause less hypoglycemia, mainly during the night. The review focuses on glycemic goals in pregnancy, insulinic management of GDM, and posology of insulin and its analogs. Clear understanding of the insulinic management of GDM is essential for women's health care providers to provide comprehensive care to women whose pregnancies are complicated with diabetes and rechristen the ''diabetic capital of the world'' to the ''diabetic care capital of the world.''
PubMed: 24757334
DOI: 10.1007/s13224-014-0525-4 -
Advances in Therapy Oct 2015Maternal metabolism changes substantially during pregnancy, which poses numerous challenges to physicians managing pregnancy in women with diabetes. Insulin is the agent... (Review)
Review
Maternal metabolism changes substantially during pregnancy, which poses numerous challenges to physicians managing pregnancy in women with diabetes. Insulin is the agent of choice for glycemic control in pregnant women with diabetes, and the insulin analogs are particularly interesting for use in pregnancy. These agents may reduce the risk of hypoglycemia and promote a more physiological glycemic profile than regular human insulin in pregnant women with type 1 (T1D), type 2 (T2D), or gestational (GDM) diabetes. However, there have been concerns regarding potential risk for crossing the placental barrier, mitogenic stimulation, teratogenicity, and embryotoxicity. Insulin lispro protamine suspension (ILPS), an intermediate- to long-acting insulin, has a stable and predictable pharmacological profile, and appears to have a favorable time-action profile and produce desirable basal and postprandial glycemic control. As the binding of insulin lispro is unaffected by the protamine molecule, ILPS is likely to have the same mitogenic and immunogenic potential as insulin lispro. Insulin lispro produces similar outcomes to regular insulin in pregnant women with T1D, T2D, or GDM, does not cross the placental barrier, and is considered a useful treatment option for pregnant women with diabetes. Clinical data support the usefulness of ILPS for basal insulin coverage in non-pregnant patients with T1D or T2D, and suggest that the optimal regimen, in terms of balance between efficacy and hypoglycemic risk, is a once-daily injection, especially in patients with T2D. Available data concerning use of ILPS in pregnant women are currently derived from retrospective analyses that involved, in total, >1200 pregnant women. These analyses suggest that ILPS is at least as safe and effective as neutral protamine Hagedorn insulin. Thus, available experimental and clinical data suggest that ILPS once daily is a safe and effective option for the management of diabetes in pregnant women.
Topics: Blood Glucose; Diabetes, Gestational; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Lispro; Insulin, Long-Acting; Pregnancy; Pregnancy in Diabetics; Retrospective Studies
PubMed: 26499176
DOI: 10.1007/s12325-015-0244-y -
Diabetes Therapy : Research, Treatment... Jun 2018Basal-bolus therapy (BBT) refers to the combination of a long-acting basal insulin with a rapid-acting insulin at mealtimes. Basal insulin glargine 100 U/mL and prandial... (Review)
Review
UNLABELLED
Basal-bolus therapy (BBT) refers to the combination of a long-acting basal insulin with a rapid-acting insulin at mealtimes. Basal insulin glargine 100 U/mL and prandial insulin lispro have been available for many years and there is a substantial evidence base to support the efficacy and safety of these agents when they are used in BBT or basal-plus therapy for patients with type 1 or type 2 diabetes mellitus (T1DM, T2DM). With the growing availability of alternative insulins for use in such regimens, it seems timely to review the data regarding BBT with insulin glargine 100 U/mL and insulin lispro. In patients with T1DM, BBT with insulin glargine plus insulin lispro provides similar or better glycemic control and leads to less nocturnal hypoglycemia compared to BBT using human insulin as the basal and/or prandial component, and generally provides similar glycemic control and rates of severe hypoglycemia to those achieved with insulin lispro administered by continuous subcutaneous insulin infusion (CSII). Studies evaluating BBT with insulin glargine plus insulin lispro in patients with T2DM also demonstrate the efficacy and safety of these insulins. Available data suggest that BBT with insulin glargine and insulin lispro provides similar levels of efficacy and safety in pediatric and adult populations with T1DM and in adult patients and those aged more than 65 years with T2DM. These insulin preparations also appear to be safe and effective for controlling T2DM in people of different ethnicities and in patients with T1DM or T2DM and comorbidities.
FUNDING
Eli Lilly and Company.
PubMed: 29654514
DOI: 10.1007/s13300-018-0422-4