The use of human ultralente is limited by great intraindividual variability in overnight plasma insulin profiles

Lindström, Torbjörn; Po, Olsson; Arnqvist, Hans

doi:10.1080/003655100750019242

Cited by 11 publications

(8 citation statements)

References 13 publications

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“…It is well established and widely accepted that basal human insulin preparations [Ultralente and neutral protamine Hagedorn (NPH) insulin] fall short of these desired properties [3,4]: they not only are suspensions that have to be thoroughly resuspended prior to injection, a requirement often ignored by many patients [5], but also show a pronounced peak effect, which can impose the risk of nocturnal hypoglycaemia. Furthermore, variability in the PD profile is high [6,7]– indeed, so high for Ultralente that it is hardly used any more [8]. The major disadvantage of NPH insulin, in addition to high variability, is its suboptimal duration of action: end of action is reported to occur after only 12–14 h [9–11].…”

Section: Introductionmentioning

confidence: 99%

Towards peakless, reproducible and long‐acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies

Heise

Pieber

2007

Diabetes Obesity Metabolism

224

219

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While the advantages of the two basal insulin analogues, glargine and detemir, over neutral protamine Hagedorn are well established, the relative merit of the two compared with each other has been a matter of some controversy. The two analogues are popularly perceived to differ from each other in their pharmacodynamic (PD) profiles, in particular with regard to 'flatness' and duration of action. The aim of this review, therefore, is to give a complete overview on the available PD data of both analogues as derived with the glucose clamp technique. In order to improve parity across studies, a common definition for duration of action (time from injection to plasma glucose >8.3 mmol/l) was applied and study data were recalculated when necessary. Despite differences in methodological details, the results of most clamp studies were very consistent. Glargine and detemir both typically show a gentle rise and fall in glucose-lowering action over time. Duration of action with both analogues is dose dependent, but in the clinically relevant range of 0.35-0.8 U/kg it is close to 24 h in people with type 1 diabetes and in excess of this in people with type 2 diabetes. While both analogues seem to be very similar with regard to the mean shape of their PD profile and duration of action, detemir shows less within-subject variability in its metabolic effect. These findings in experimental glucose clamp studies are consistent with observations in clinical trials and support routine once daily use with either analogue, in particular in people with type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Towards peakless, reproducible and long‐acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies

Heise

Pieber

2007

Diabetes Obesity Metabolism

224

219

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“…A high variability for Ultralente (Eli Lilly & Company, Indianapolis, IN, USA) was confirmed in a healthy volunteer study where the intra-subject CV was 67% for a 24-h insulin exposure [47]. This compared to significantly lower values of 19 and 15% for neutral protamine Hagedorn (NPH) insulin (Novo Nordisk, Bagsvaerd, Denmark) and insulin glargine, respectively [46]. For NPH insulin, intrasubject CV values of 24 and 28% were reported for maximum plasma concentration (C max ) and area under the concentration time-curve from time zero to infinity [AUC (0-∞) ], respectively, in a study of adults with T1D who were given four separate test injections [41].…”

Section: Measuring Variability In the Pharmacokinetic Profile Of Basamentioning

confidence: 89%

“…Those that have made this assessment suggest that the extent of variability is considerable. For example, a study of Ultralente reported an intra-subject CV of 50% in mean nocturnal plasma insulin concentration in patients with T1D [46]. A high variability for Ultralente (Eli Lilly & Company, Indianapolis, IN, USA) was confirmed in a healthy volunteer study where the intra-subject CV was 67% for a 24-h insulin exposure [47].…”

Section: Measuring Variability In the Pharmacokinetic Profile Of Basamentioning

confidence: 96%

Variability of glucose‐lowering effect as a limiting factor in optimizing basal insulin therapy: a review

Vora

Heise

2013

Diabetes Obesity Metabolism

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Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles. Keywords: basal insulin, diabetes mellitus, glucose fluctuation, glucose variability, insulin absorption, insulin degludec, insulin variability, PEGylated lispro Date submitted 26 October 2012; date of first decision 21 January 2013; date of final acceptance 25 February 2013 Introduction: The Elusive Goal of Euglycaemia and the Confounding Issue of Glucose VariabilitySuccessful management of blood glucose remains a major ongoing challenge for patients with type 1 (T1D) and type 2 (T2D) diabetes and their carers. While it is vital to limit chronic overexposure to hyperglycaemia, which increases the incidence and progression of diabetic complications [1][2][3], overzealous reduction of blood glucose can precipitate hypoglycaemia. At best, this is acutely unpleasant for the patient; at worst, it can have serious neurological sequelae, occasionally fatal. Fear of hypoglycaemia can be a major barrier to treatment adherence that undermines attempts to improve patient prognosis [4][5][6]. The challenge of lowering glucose towards euglycaemia while simultaneously avoiding hypoglycaemia is further compounded when blood glucose concentration is erratic and unpredictable because glucose variability underlies episodes of both hyper-and hypoglycaemia. Underpinning the success (or otherwise) of diabetes therapy in general, and insulin therapy in particular, are the pharmacokinetic/dynamic (PK/PD) properties of the regimens ...

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“…The major disadvantages of Ultralente are day-to-day variability in absorption, inconsistent peak patterns, and erratic therapeutic outcomes. 52 Insulin glargine is an insulin analogue with structural molecular modifications [Gly A21 , Arg B31 , Arg B32 ] that result in a shift of the isoelectric point and reduced solubility at physiologic pH. The consequent formation of microprecipitates after subcutaneous injection delays its absorption into the systemic circulation.…”

Section: Insulinmentioning

confidence: 99%

Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin

Chan¹,

Abrahamson²

2003

Mayo Clinic Proceedings

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Type 2 diabetes mellitus is a chronic metabolic disorder associated with high morbidity and mortality from long-term microvascular and macrovascular complications. Evidence from randomized controlled trials indicates that aggressive treatment directed at improving glycemic control reduces the incidence of diabetes-related microvascular complications. Traditionally, oral monotherapy for type 2 diabetes is initiated when diet and exercise do not control hyperglycemia, followed by the sequential, stepwise addition of oral agents as glycemic control deteriorates. Insulin is the last therapeutic option used, generally reserved for advanced stages of the disease when multiple oral combination treatment fails. Despite a better understanding of the pathophysiologic disease mechanisms in the past decade, the expanded armamentarium of targeted oral antidiabetic drugs, and the conclusive evidence of the benefits of stringent glycemic control, actual treatment outcomes in clinical practice remain suboptimal relative to established treatment goals (glycosylated hemoglobin A1c level <7%). Earlier detection and aggressive treatment are critical to address the natural progression of diabetes because multiple defects (insulin resistance, insulin insufficiency, glucotoxicity, and lipotoxicity) and vascular complications may be present at the time of diagnosis. Acknowledging the inadequacy of traditional strategies and underscoring the importance of insulin as an integral part of the therapeutic armamentarium, clinical trends are moving toward earlier use of insulin combined with 1 or more oral agents. Such strategies can address the multiple abnormalities present early in the disease course and may restore optimal control. A new treatment paradigm for patients with type 2 diabetes to achieve and maintain near-normal glycemic control is warranted.

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The use of human ultralente is limited by great intraindividual variability in overnight plasma insulin profiles

Abstract: Human ultralente insulin gives an insulin profile suitable for overnight substitution, but the great day-to-day variability limits its usefulness. It can be injected before dinner or at bedtime without any change in the insulin profile during the night.

Cited by 11 publications

References 13 publications

Towards peakless, reproducible and long‐acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies

Towards peakless, reproducible and long‐acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies

Variability of glucose‐lowering effect as a limiting factor in optimizing basal insulin therapy: a review

Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin

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