Subcutaneous insulin: pharmacokinetic variability and glycemic variability

Guerci, Bruno; Sauvanet, J.-P.

doi:10.1016/s1262-3636(05)88263-1

Cited by 85 publications

(61 citation statements)

References 97 publications

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“…Consequently, supper and/or bedtime dosing with NPH insulin may be associated with increased risk for hypoglycemia in the evening/early nighttime, as well as a waning effect in early morning hours when hepatic requirements and fasting plasma glucose (FPG) levels are increased ("dawn phenomenon"). 9 Pharmacokinetic/pharmacodynamic studies have confirmed that, compared to NPH insulin, both long-acting analogs have a more prolonged and consistent duration of action, without the marked post-injection peak characteristic of NPH insulin. [34][35][36][37][38] Duration of action is most reliably measured through euglycemic clamp studies in patients with type 1 diabetes, rather than in healthy subjects or those with type 2 diabetes, because of the confounding influence of endogenous insulin secretion.…”

Section: Rapid-acting Analogsmentioning

confidence: 98%

“…All insulin molecules have a tendency to self-aggregate into hexameric complexes and these clusters must dissociate into dimers and monomers to diffuse through interstitial fluid, penetrate the capillary wall, and enter the bloodstream. 9 The unique pharmacologic features of individual insulin analog preparations largely alter the rate of hexamer dissociation and the subsequent movement of free insulin into the circulation, i.e., the time-concentration profile of activity.…”

Section: Biochemical Characteristics Of Insulin Analogsmentioning

confidence: 99%

“…Upon injection, insulin glargine precipitates into stable hexamers within the physiologically pH-neutral environment, thereby prolonging its dissociation and subsequent absorption. 9 The marketed formulation of insulin glargine also includes small amounts of added zinc, which further delay absorption. 13 Insulin detemir has been modified from the human insulin structure through the addition of a C14 fatty acid side chain at position B29.…”

Section: Rapid-acting Insulin Analogsmentioning

confidence: 99%

“…Equally important is the need for reproducible and non-variable activity, which has been a significant limitation with traditional insulin products. 9 …”

Section: Pharmacokinetic and Pharmacodynamic Characteristics Of Insulmentioning

confidence: 99%

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Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Hartman

2008

Clinical Medicine & Research

116

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Despi te 85 years of research since Banting and Best's isolation of insulin-containing extracts, 1 diabetes still remains one of the most significant causes of morbidity and mortality in the world, and its global impact is likely to accelerate over the coming decades. 2,3 Much of the medical and economic consequences of diabetes are attributable to its associated microvascular and macrovascular complications. [4][5][6] Two classic large-scale clinical studies, the Diabetes Control and Complications Trial (DCCT) 6 and the UK Prospective Diabetes Study (UKPDS), 7 demonstrated that intensive blood-glucose control policies can decrease the frequency of complications, arguing that physicians and patients should strive to mimic, as closely as possible, the serum levels of insulin produced by a healthy person. Secretion of insulin by the pancreas, however, is under complex regulation that depends on the intake of nutrients, other gastrointestinal peptides (e.g., incretins), and overall metabolic levels (i.e., exercise versus rest). 8 These physiological variables, which pose real challenges to the accurate metabolic replacement of insulin, are further complicated by the fact that diabetes requires self-management and therefore depends on the psychology, motivation, and understanding of the patient. A growing body of medical research has demonstrated that intensive control of serum glucose levels can minimize the development of diabetes-related complications. Success with insulin management ultimately depends on how closely a given regimen can mimic normal physiologic insulin release patterns.The new insulin analogs, including the rapid-acting analogs (aspart, lispro, glulisine), the long-acting basal analogs (glargine, detemir), and the premixed insulin analog formulations (75% neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been formulated to allow for a closer replication of a normal insulin profile.The rapid-acting analogs can be administered at mealtimes and produce a rapid and short-lived insulin spike to address postprandial glucose elevations, while the long-acting analogs come close to the ideal of a smooth, relatively flat, 24-hour basal insulin supply, with less variability in action compared to NPH insulin. Despite these clear pharmacologic advantages, measurable clinical benefits in a complex disease such as diabetes can be hard to measure.To date, reviews of insulin analog studies have not found a dramatic overall improvement in glycosylated hemoglobin (HbA1c) outcomes compared to traditional human insulins, although all-analog basal-bolus regimens were associated with significantly lower HbA1c than all-human-insulin basal bolus regimens in some studies. Beyond HbA1c comparisons, however, insulin analogs have been shown in many instances to be associated with lower risks of hypoglycemia, lower levels of postprandial glucose excursions, better patient adherence, greater quality of life, and higher satisfaction with treatment.The long-act...

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Section: Rapid-acting Analogsmentioning

confidence: 98%

Section: Biochemical Characteristics Of Insulin Analogsmentioning

confidence: 99%

Section: Rapid-acting Insulin Analogsmentioning

confidence: 99%

“…Equally important is the need for reproducible and non-variable activity, which has been a significant limitation with traditional insulin products. 9 …”

Section: Pharmacokinetic and Pharmacodynamic Characteristics Of Insulmentioning

confidence: 99%

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Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Hartman

2008

Clinical Medicine & Research

116

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“…The various subcutaneous insulin preparations available are primarily differentiated by the shape of their plasma time-concentration profiles, which depicts their duration of action (slow, rapid or prolonged) and their ultimate effect on glucose levels [6] [7].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Safety and Efficacy of Glaritus<sup>&reg;</sup> versus Lantus<sup>&reg;</sup> in Combination with Insulin Lispro among Adults with Type 1 Diabetes Mellitus-Phase IV Study

Puppalwar¹,

Sawant²,

Silgiri³

et al. 2017

OJEMD

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Objective: The present study assessed safety and efficacy of Glaritus® among adults with Type 1 Diabetes Mellitus (T1DM). Methodology: This prospective, randomized, multicenter, comparative, non-inferiority, open-label, parallel group, phase IV study was conducted in 14 study centers in India. Subjects were randomly allocated to receive either Glaritus® or Lantus® for 12 weeks. Each week, the dose of insulin was titrated to maintain target fasting blood glucose (FBG) level range of 80 -120 mg/dL. Results: A total of 171 subjects were randomized (Glaritus® arm-86; Lantus® arm-85) and 161 subjects completed the study. The mean change in the glycosylated haemoglobin (HbA1c) levels from visit 3 (baseline) to visit 6 (end of trial) in Glaritus® arm was −0.69 ± 1.81 and in Lantus® arm was −0.53 ± 1.94. The mean change in glucose levels between week 1 and end of week 11 in Glaritus® arm was −8.81 ± 34.57 and in Lantus® arm was −5.28 ± 30. At least one hypoglycemic episode was experienced by 27.2% subjects of Glaritus® arm and 28.6% subjects of Lantus® arm. A total of 24 adverse events (AEs) such as pain, pyrexia, few infection related including urinary tract infections, metabolic related such as decreased appetite, musculoskeletal, neurological and skin related were re-

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An adaptive clinical Type 1 diabetes control protocol to optimize conventional self‐monitoring blood glucose and multiple daily‐injection therapy

Wong

Chase

Compte

et al. 2008

Adaptive Control & Signal

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The objective of this study was to develop a safe, robust and effective protocol for the clinical control of Type 1 diabetes using conventional self-monitoring blood glucose (SMBG) measurements, and multiple daily injection (MDI) with insulin analogues.A virtual patient method is used to develop an in silico simulation tool for Type 1 diabetes using data from a Type 1 diabetes patient cohort (n = 40). The tool is used to test two prandial insulin protocols, an adaptive protocol (AC) and a conventional intensive insulin therapy (IIT) protocol (CC) against results from a representative control cohort as a function of SMBG frequency. With the prandial protocols, optimal and suboptimal basal insulin replacement using a clinically validated, forced-titration regimen is also evaluated. A Monte Carlo (MC) analysis using variability and error distributions derived from the clinical and physiological literature is used to test efficacy and robustness. MC analysis is performed for over 1 400 000 simulated patient hours. All results are compared with control data from which the virtual patients were derived.In conditions of suboptimal basal insulin replacement, the AC protocol significantly decreases HbA 1c for SMBG frequencies 6/day compared with controls and the CC protocol. With optimal basal insulin, mild and severe hypoglycaemia is reduced by 86-100% over controls for all SMBG frequencies. Control with the CC protocol and suboptimal basal insulin replacement saturates at an SMBG frequency of 6/day. The forced-titration regimen requires a minimum SMBG frequency of 6/day to prevent increased hypoglycaemia. Overaggressive basal dose titration with the CC protocol at lower SMBG frequencies is likely caused by uncorrected postprandial hyperglycaemia from the previous night. AN ADAPTIVE CLINICAL TYPE 1 DIABETES CONTROL PROTOCOL 409From the MC analysis, a defined peak in control is achieved at an SMBG frequency of 8/day. However, 90% of the cohort meets American Diabetes Association recommended HbA 1c with just 2 measurements a day. A further 7.5% requires 4 measurements a day and only 2.5% (1 patient) required 6 measurements a day. In safety, the AC protocol is the most robust to applied MC error. Over all SMBG frequencies, the median for severe hypoglycaemia increases from 0 to 0.12% and for mild hypoglycaemia by 0-5.19% compared with the unrealistic no error simulation. While statistically significant, these figures are still very low and the distributions are well below those of the controls group.An adaptive control protocol for Type 1 diabetes is tested in silico under conditions of realistic variability and error. The adaptive (AC) protocol is effective and safe compared with conventional IIT (CC) and controls. As the fear of hypoglycaemia is a large psychological barrier to appropriate glycaemic control, adaptive model-based protocols may represent the next evolution of IIT to deliver increased glycaemic control with increased safety over conventional methods, while still utilizing the most commonly used forms of inte...

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Subcutaneous insulin: pharmacokinetic variability and glycemic variability

Cited by 85 publications

References 97 publications

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Evaluation of Safety and Efficacy of Glaritus<sup>&reg;</sup> versus Lantus<sup>&reg;</sup> in Combination with Insulin Lispro among Adults with Type 1 Diabetes Mellitus-Phase IV Study

An adaptive clinical Type 1 diabetes control protocol to optimize conventional self‐monitoring blood glucose and multiple daily‐injection therapy

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Subcutaneous insulin: pharmacokinetic variability and glycemic variability

Cited by 85 publications

References 97 publications

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence

Evaluation of Safety and Efficacy of Glaritus&lt;sup&gt;&amp;reg;&lt;/sup&gt; versus Lantus&lt;sup&gt;&amp;reg;&lt;/sup&gt; in Combination with Insulin Lispro among Adults with Type 1 Diabetes Mellitus-Phase IV Study

An adaptive clinical Type 1 diabetes control protocol to optimize conventional self‐monitoring blood glucose and multiple daily‐injection therapy

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Product

Resources

About

Evaluation of Safety and Efficacy of Glaritus<sup>®</sup> versus Lantus<sup>®</sup> in Combination with Insulin Lispro among Adults with Type 1 Diabetes Mellitus-Phase IV Study