Abstract
Glucose clamp studies are used to determine pharmacokinetics (PK) and pharmacodynamics (PD) of analogue insulins. With the development of longer-acting basal analogue insulins, including glargine 300 (Gla-300) and insulin degludec (IDeg), results from numerous glucose clamp studies are readily available. However, interpreting PK/PD profiles in a scientifically sound manner can be a challenging feat. This is the first in a series of publications that will suggest practical tips for interpreting and comparing results from glucose clamp studies. Variations in the glucose clamp methodology, duration of clamp studies and glucose clamp targets influence the study design and results significantly. Selection of study populations, including healthy patients or patients with Type 1 or 2 diabetes mellitus, has important implications. The dose of study insulin should reflect that of the general treatment population, and ideally steady-state conditions should be used. During the study the plasma insulin concentration and glucose infusion rate describe the pharmacokinetics and pharmacodynamics of the study insulin. With these practical tips in mind, results of glucose clamp studies can be interpreted in a scientifically correct manner. The next article in this series will discuss the interpretation of PK/PD profiles using two newly developed longer-acting basal analogue insulins: Gla-300 and IDeg.
Highlights
According to the guidelines for the treatment of diabetes published by the Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA), treatment with exogenous insulins is recommended for patients diagnosed with Type 2 diabetes mellitus who are unable to reach glycaemic control on oral antidiabetic agents.[1]
Several basal analogue insulins are currently under development aiming at prolonged duration of action and more predictable absorption than that associated with the analogue insulins currently available.[2,3,4]
The glucose clamp study is regarded as the gold standard to establish PK and PD profiles of basal analogue insulins.[6]
Summary
According to the guidelines for the treatment of diabetes published by the Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA), treatment with exogenous insulins is recommended for patients diagnosed with Type 2 diabetes mellitus who are unable to reach glycaemic control on oral antidiabetic agents.[1]. Where glucose clamp studies are performed in healthy volunteers or patients diagnosed with Type 2 diabetes mellitus, the effect of endogenous insulin secretion on the glucose infusion rate (GIR) must be accounted for. 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.[3,26] during the initial stages of type 1 diabetes mellitus β-cell function may not be entirely lost, resulting in production of endogenous insulin.[27] During infusion of glucose and exogenous insulin to establish the hyperinsulinemic 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.[25]. In order to establish the application of new analogue insulins in the clinical setting, phase three clinical trials with specific outcomes for diabetes are required
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