Abstract
Glucose clamp studies form an integral part of the early development of insulin therapies. Data generated in these studies are used to establish pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the agents, but methodological differences confound comparison of results from different glucose clamp studies. The first part of this series on glucose clamp studies discussed practical tips for the interpretation of glucose clamp studies. The second part of the series compares the PK/PD profiles of longer-acting basal analogue insulins, insulin degludec (IDeg) and insulin glargine U300 (Gla-300). The patient populations for glucose clamp studies with these analogue insulins differ, and therefore direct comparison of the data is not always possible. The maximum duration of action of IDeg is reported as 42 h and that of Gla-300 as 36 h, translating to 24 h coverage. The plasma insulin concentration of IDeg is 56 times that of Gla-300. Results from phase III clinical trials for these analogue insulins confirm the predictability and low within-subject variability observed in glucose clamp studies. Insight into the PK/PD profiles of longer-acting basal analogue insulins allows the treating physician to utilise these characteristics to optimise the treatment of their patients with diabetes.
Highlights
Exogenous insulin is used to treat hyperglycaemia in selected patients diagnosed with diabetes mellitus (DM)
To accurately replicate physiological basal insulin coverage, duration of action exceeding 24 h is required with a peakless PD profile to further minimise the risk of hypoglycaemia.[5]
As the conditions of the study population in glucose clamp studies should reflect the conditions in the general treatment population, the use of steady-state conditions is recommended as this most accurately replicates the use of long-acting analogue insulins in the treatment population.[13]
Summary
Exogenous insulin is used to treat hyperglycaemia in selected patients diagnosed with diabetes mellitus (DM). The PK/PD properties of an analogue insulin, as determined during early clinical development, can be used to predict the potential, be it high or low, of the insulin to induce hypoglycaemia. An analogue insulin should present with a peakless PK profile, which translates into constant and predictable plasma insulin concentration and reduced risk for hypoglycaemia.[2] In contrast, high variability in the PK profile indicates a higher probability of hypoglycaemia episodes and difficulty in titrating a patient’s exogenous insulin treatment to a required glucose target. To accurately replicate physiological basal insulin coverage, duration of action exceeding 24 h is required with a peakless PD (time–activity) profile to further minimise the risk of hypoglycaemia.[5] To address the current unmet need in basal analogue insulins, two longer-acting insulin analogues have been developed: insulin degludec (IDeg) and insulin glargine U300 (Gla-300). Following is a practical application of these points to compare results published from glucose clamp studies of IDeg and Gla-300
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