The disease these drugs treat is covered in the diabetes primer.
Endpoint. HbA1c, glycated hemoglobin, is the most commonly used biomarker of glycemic management and a surrogate endpoint for anti-diabetic drug approval [1].
HbA1c is not an Emax on concentration. It accumulates by glycation over the red cell lifespan, so it lags mean glucose and is written as a transformation of the glucose profile, not as a drug effect [1,2].
Typical structure. Provocations (OGTT, IVGTT) need the glucose-insulin feedback loop stated explicitly, and integrated models carrying both species have been built for intravenous and for oral provocation data [3,4].
Long trials drift. Type 2 diabetes progresses under treatment, so comparing drugs over a year needs disease progression on beta cell function and insulin sensitivity, not a fixed baseline [5].
Clamp readouts. Insulin degludec was profiled by the glucose infusion rate of a euglycemic clamp, a pharmacodynamic readout: in 65 healthy men, body mass index was inversely correlated with the 24 hour GIR AUC [6].
References
[1]
Lledó-García R, Mazer NA, Karlsson MO. A semi-mechanistic model of the relationship between average glucose and
HbA1c in healthy and diabetic subjects. J Pharmacokinet Pharmacodyn 2013;40:129–42.
https://doi.org/10.1007/s10928-012-9289-6.
[2]
Hamrén B, Björk E, Sunzel M, Karlsson M. Models for
Plasma Glucose,
HbA1c, and
Hemoglobin Interrelationships in
Patients with
Type 2
Diabetes Following Tesaglitazar Treatment. Clin Pharmacol Ther 2008;84:228–35.
https://doi.org/10.1038/clpt.2008.2.
[3]
Silber HE, Jauslin PM, Frey N, Gieschke R, Simonsson USH, Karlsson MO. An
Integrated Model for
Glucose and
Insulin Regulation in
Healthy Volunteers and
Type 2
Diabetic Patients Following Intravenous Glucose Provocations. J Clin Pharmacol 2007;47:1159–71.
https://doi.org/10.1177/0091270007304457.
[4]
Jauslin PM, Silber HE, Frey N, Gieschke R, Simonsson USH, Jorga K, et al. An
Integrated Glucose-Insulin Model to
Describe Oral Glucose Tolerance Test Data in
Type 2
Diabetics. J Clin Pharmacol 2007;47:1244–55.
https://doi.org/10.1177/0091270007302168.
[5]
de Winter W, DeJongh J, Post T, Ploeger B, Urquhart R, Moules I, et al. A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying
Type 2
Diabetes Mellitus. J Pharmacokinet Pharmacodyn 2006;33:313–43.
https://doi.org/10.1007/s10928-006-9008-2.
[6]
Li T, Liu H, Li S, Yu H, Li J, Tan H, et al. The
Effect of
BMI on
Pharmacokinetic and
Pharmacodynamic Parameters of
Insulin Degludec:
Results from an
Euglycemic Glucose Clamp Study. Clin Pharmacokinet 2023;62:449–56.
https://doi.org/10.1007/s40262-022-01207-1.