Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2018 Executive Summary

Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2017 executive summary

Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary.

Insulin is essential for type 1 and advanced type 2 diabetics to maintain blood glucose levels and prolong lives. The traditional administration requires frequent subcutaneous insulin injections that are associated with poor patient compliance, including pain, local tissue necrosis, infection, and nerve damage. Taking advantage of emerging micro- and nanotechnologies, numerous alternative strategies integrated with chemical approaches for insulin delivery have been investigated. This review outlines recent developments in the controlled delivery of insulin, including oral, nasal, pulmonary, transdermal, subcutaneous and closed-loop insulin delivery. Perspectives from new materials, formulations and devices at the micro- or nano-scales are specifically surveyed. Advantages and limitations of current delivery methods, as well as future opportunities and challenges are also discussed.

Emerging micro- and nanotechnology based synthetic approaches for insulin delivery

OBJECTIVE To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units·mL−1 (Gla-300), compared with insulin glargine 100 units·mL−1 (Gla-100) at steady state in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS A randomized, double-blind, crossover study ( N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steady-state study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units·kg−1 (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units·kg−1 Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units·kg−1 of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h.

RESULTS At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤105 mg·dL−1) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100.

CONCLUSIONS Gla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.

https://care.diabetesjournals.org/content/diacare/38/4/637.full.pdf

New Insulin Glargine 300 Units·mL−1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared With Insulin Glargine 100 Units·mL−1

OBJECTIVE —This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS —In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. RESULTS —INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P P P –1 · min –1 , respectively; P P CONCLUSIONS —INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.

http://care.diabetesjournals.org/content/diacare/28/5/1077.full.pdf

Time-Action Profile of Inhaled Insulin in Comparison With Subcutaneously Injected Insulin Lispro and Regular Human Insulin

Insulin glulisine injection [3B-Lys, 29B-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin. The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption. Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg. The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075–0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general. The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly — but consistently —greater than those of insulin lispro in healthy volunteers across a wide range of BMIs. Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and adds to the flexibility in postprandial blood glucose control.

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glulisine

Aims
To characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM).

Methods
A total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability.

Results
The cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15–21] and 33.4% (95% CI 28–41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.

Conclusions
Gla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.

Low within- and between-day variability in exposure to new insulin glargine 300 U/ml.

Insulin glargine is processed in vivo into soluble 21A-Gly-human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub-study compared metabolism and metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla-300) with insulin glargine 100 U/ml (Gla-100, Lantus®, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla-300 (n = 12), and 0.4 U/kg Gla-100 (n = 30) once daily in randomized order for 8 days prior to a 36-h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC-MS/MS). Glargine metabolism was the same regardless of Gla-100 or Gla-300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla-100, and 4 days for Gla-300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla-300 administration compared with M1 profiles after Gla-100.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dom.12283

Reinhard H.A. Becker

Papers

New Insulin Glargine 300 Units·mL−1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared With Insulin Glargine 100 Units·mL−1

Time-Action Profile of Inhaled Insulin in Comparison With Subcutaneously Injected Insulin Lispro and Regular Human Insulin

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glulisine

Low within- and between-day variability in exposure to new insulin glargine 300 U/ml.

Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml