Diabetes
What is Diabetes?
Disease definition & pathophysiology
Diabetes mellitus is a chronic metabolic disorder characterized by high blood sugar (hyperglycemia) resulting from impaired insulin secretion, insulin action, or both.
Two main types exist: Type 1 diabetes (T1DM) involves autoimmune destruction of the insulin-producing cells of the pancreas (pancreatic beta-cells), leading to absolute insulin deficiency.
Type 2 diabetes (T2DM) is characterized by insulin resistance combined with progressive beta-cell dysfunction, influenced by genetic, lifestyle, and environmental factors.
Commonly used Pharmacodynamic (PD) Models
- Glucose-insulin homeostasis models (minimal model, insulin-glucose feedback models).
- Disease progression models describing beta-cell function decline over time (glycated hemoglobin (HbA1c) progression).
- Indirect-response or target-engagement models evaluating insulin secretion or sensitivity.
Patient characteristics
Typical patient population
T1DM commonly presents in childhood or adolescence, but it can start at any age.
T2DM usually appears in adulthood, but increasingly also in younger people as obesity becomes more common.
T2DM is far more common, accounting for about 90–95% of all diabetes [1].
Risk factors & disease progression indicators
Risk factors for T1DM include genetics and autoimmunity.
T2DM risk factors include obesity, sedentary lifestyle, poor diet, family history, age, high blood pressure, and abnormal blood lipids.
Disease progression indicated by rising HbA1c, decreasing beta-cell function (lower insulin secretion), increasing insulin requirements, and presence of diabetes complications (damage to the eyes, kidneys and nerves).
How the progression of type 2 diabetes is separated from drug effects in a model is covered under drugs used in diabetes.
Diagnosis & biomarkers
Key Clinical Biomarkers
Diagnosis relies primarily on blood glucose criteria [1]: - Fasting plasma glucose (FPG) ≥126 mg/dL (≥7.0 mmol/L) - 2-hour plasma glucose ≥200 mg/dL (≥11.1 mmol/L) after oral glucose tolerance test (OGTT) - HbA1c ≥6.5% - Random plasma glucose ≥200 mg/dL (≥11.1 mmol/L) with classical symptoms
HbA1c is key for monitoring blood sugar control (glycemic control) over time.
Disease Severity Classification
Severity is often described by the level of glycemic control, judged by HbA1c, and by the presence of complications.
How can Diabetes be treated?
Treatment aim (PD-targets)
The main treatment aims are normalization of blood glucose, preservation of beta-cell function, and reduction of long-term diabetic complications.
PD-targets include insulin secretion, insulin sensitivity, glucose absorption, and renal glucose excretion.
Common Drug Classes & Regimens
All of the classes below sit in ATC A10 Drugs used in diabetes, which carries the pharmacometric modelling notes for them.
Insulin (mandatory in T1DM, second-line or advanced-stage T2DM)
- Rapid-acting (lispro A10AB04, aspart A10AB05, glulisine A10AB06), long-acting (glargine A10AE04, detemir A10AE05, degludec A10AE06):
- MoA: Lowers blood glucose by increasing glucose uptake into tissues and reducing glucose output from the liver.
Non-insulin glucose-lowering drugs (T2DM)
- Biguanides (Metformin, A10BA02):
- MoA: Reduces hepatic glucose production, improves insulin sensitivity.
- Sulfonylureas (Gliclazide A10BB09, Glimepiride A10BB12):
- MoA: Stimulates pancreatic insulin secretion.
- SGLT2 inhibitors (Empagliflozin A10BK03, Dapagliflozin A10BK01):
- MoA: Increases renal glucose excretion by blocking glucose reabsorption.
- GLP-1 receptor agonists (Semaglutide A10BJ06, Liraglutide A10BJ02, Dulaglutide A10BJ05):
- MoA: Enhances insulin secretion, suppresses glucagon secretion, promotes weight loss.
- DPP-4 inhibitors (Sitagliptin A10BH01, Linagliptin A10BH05):
- MoA: Enhances endogenous GLP-1 activity, improving insulin secretion.
Dose Adjustments
Dose adjustments needed based on renal function (especially metformin, SGLT2 inhibitors and insulin).
Pediatric insulin dosing tailored by weight, glucose response, and age.
Elderly patients often require lower or more cautious dosing due to risk of low blood sugar (hypoglycemia).
Commonly used PK-models
- Population PK models describing insulin kinetics and dynamics, considering factors like body weight, renal function, and insulin resistance.
- Physiologically-based PK (PBPK) models used to characterize absorption and disposition of oral anti-diabetic drugs.
- PK-PD models linking drug exposure to glycemic endpoints (HbA1c, fasting glucose), insulin sensitivity, and beta-cell function.
Clinical studies
The standard endpoint is HbA1c, a continuous measure and the gold standard for long-term glycemic efficacy, while fasting plasma glucose follows glycemic control in real time. HbA1c forms as glucose glycates hemoglobin in red blood cells, which live about 120 days, so it reflects mean glucose over 2 to 3 months, and early-phase studies are often too short for it to reach steady state [2].
For drugs other than insulin in type 2 diabetes, confirmatory trials should be randomized, double-blind and parallel-group, and the primary endpoint is the difference between treatments in the change in HbA1c from baseline to the end of the trial. They typically last 6 months, and at least one trial should show that the effect is maintained over at least 12 months. The new drug should be superior to placebo when given alone (monotherapy) in at least one study of 3 months or more, superior to placebo when added to background therapy, and no worse than an established drug by more than a set margin (non-inferior), for which 0.3% HbA1c (3 mmol/mol) is generally accepted. Add-on trials should enroll patients who are not at target on an established drug, at a stable dose for the 8 to 12 weeks before the study, and keep that background dose unchanged unless safety requires a change. Dose-ranging studies of 8 to 12 weeks should use glucose-based measures as the primary endpoint, and those of 12 weeks or more should use HbA1c. The development program is expected to characterize cardiovascular safety, especially for a new mechanism of action, but a benefit on long-term complications, which only large and long trials can show, is not required for approval [3].
Clinical pharmacology studies
Pharmacokinetic studies should take into consideration that, in a significant number of patients with type 2 diabetes, slow emptying of the stomach (delayed gastric emptying) or a change in how long the gut takes to move its contents along (gastrointestinal transit time) can be expected to complicate drug absorption [3].