The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back

Abstract

Glucose clamp studies assessing the time-action profile of long-acting insulin analogues have reported conflicting results. In an attempt to reconcile the data, we organised an expert meeting of four leading European clamp groups, during which consensus was reached on some but not all points discussed. In this paper, which reflects our personal views only, we aim to provide guidance for readers and reviewers on the interpretation of this type of clamp study and to clarify its inherent limitations.Glucose clamp studies are either performed manually or using an automated procedure, but differences in clamp methodology hardly seem a satisfactory explanation for the conflicting results. (Un)conscious investigator-related bias, especially during manual studies, cannot be ruled out, despite attempts at blinding the study insulin during the clamp.The duration of action of study insulins is influenced by many factors, such as glucose and insulin levels prior to injection, endogenous insulin secretion, insulin dose, definitions used for onset and end of action, and insulin sensitivity (which is influenced by the necessity of fasting during the clamp). These factors limit the translation of clamp study results into daily practice.Because of the inherent limitations of the glucose clamp technique and the lack of reproducibility of the outcomes, its results should be regarded as no more than an indication of the clinical action profile of long-acting insulin preparations.

A practical guide to the interpretation of PK/PD profiles of longer-acting analogue insulins. Part one: The principles of glucose clamp studies

“…25 The use of a study population of patients diagnosed with Type 1 diabetes mellitus is recommended, as endogenous insulin secretion will not affect results obtained. 3,25 However, during the initial stages of Type 1 diabetes mellitus β-cell function may not be entirely lost, resulting in production of endogenous insulin. 26 During infusion of glucose and exogenous insulin to establish the hyperinsulinaemic euglycemic state prior to initiation of the clamp study, the duration of action of the exogenous insulin injected prior to the clamp and time of discontinuation prior to administration of study insulin must be considered to avoid masking the glucose-lowering effect of the study insulin.…”

“…The time-action profiles of long-acting analogue insulins are thus best studied once steady-state conditions have been reached. 3 Steady-state is achieved when the absorption of a drug is equal to its elimination, after approximately four to five half-lives. It is recommended that glucose clamp studies for long-acting insulin analogues are performed at steady-state conditions in a study population of patients diagnosed with diabetes mellitus.…”

“…It is recommended that glucose clamp studies for long-acting insulin analogues are performed at steady-state conditions in a study population of patients diagnosed with diabetes mellitus. 3 It has been suggested that the results of clamp studies where the study insulin was administered during the morning cannot be directly compared with those of clamp studies where insulin was administered at night. 28 As the majority of patients using basal analogue insulins administer these at night, the same dosing schedule should be followed in glucose clamp studies.…”

“…Several basal analogue insulins are currently under development aiming at prolonged duration of action and more predictable absorption than the analogue insulins currently available. [2][3][4] Regulatory approval of new biological products, including analogue insulins, requires complete description of pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new chemical entities in humans. 5 The glucose clamp study is regarded as the gold standard to establish PK and PD profiles of basal analogue insulins.…”

Omitting breakfast and lunch after injection of different long-acting insulin preparations at bedtime: a prospective study in patients with type 2 diabetes

“…Findings from glucose clamp studies of long-acting insulin analogues are difficult to interpret and are of questionable relevance for clinical practice in patients with type 2 diabetes [4]. Despite scant comparative data showing clinical superiority over NPH insulin, long-acting insulin analogues are increasingly used in type 2 diabetes [5].…”