A10: Drugs used in diabetes
The disease these drugs treat is covered in the diabetes primer.
How do drugs used in diabetes work?
The group is split into insulins and their analogues (A10A), blood glucose lowering drugs other than insulins (A10B), and other drugs used in diabetes (A10X) [1].
Insulins promote the uptake of glucose into muscle and fat, and reduce the output of glucose from the liver [2].
The blood glucose lowering drugs act at different sites:
- The biguanide metformin (A10BA02) reduces glucose output from the liver and increases glucose uptake in muscle.
- Sulfonylureas, such as gliclazide (A10BB09), increase insulin secretion from the beta cells of the pancreas.
- Thiazolidinediones, such as pioglitazone (A10BG03), are insulin sensitizers: they increase glucose uptake in muscle, fat and liver, and reduce glucose output from the liver.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin (A10BH01), stimulate the extra insulin release triggered by gut hormones (incretin effect) by inhibiting the breakdown of glucagon-like peptide-1 (GLP-1).
- GLP-1 receptor agonists, such as liraglutide (A10BJ02), stimulate the incretin effect by activating GLP-1 receptors.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin (A10BK03), block the reabsorption of glucose in the first part of the kidney tubule (proximal tubule) [2].
Disease progression
Type 2 diabetes is progressive, with a continuing decline in beta cell function and worsening insulin sensitivity, as described in the diabetes primer. A mechanism-based disease progression model, built on two phase 3 trials comparing pioglitazone with metformin or gliclazide, described this progression as a loss of beta cell function and insulin sensitivity over time. It separated each drug’s immediate symptomatic effect, modeled as a step change, from any long-term disease-modifying effect. Only pioglitazone improved beta cell function over time [2].
Efficacy
The efficacy endpoints, glycated hemoglobin (HbA1c) and fasting plasma glucose, are the same whichever drug class is used, and are described with the design of diabetes trials in the diabetes primer. Semi-mechanistic models link the drug to glucose, and glucose to HbA1c, with indirect response models or with transit compartments that follow the aging red blood cells [2]. In a model built on a phase 2 study of tesaglitazar, the red blood cell lifespan was estimated at 135 days [3].
Glucose tolerance tests, given intravenously or orally, are used to estimate insulin sensitivity, insulin secretion and beta cell function. An integrated glucose-insulin model, with feedback in both directions between glucose and insulin, was built for intravenous tests in healthy volunteers and patients [4], and then extended with glucose absorption and the incretin effect to describe oral tests [5].
For insulins, the pharmacodynamic gold standard is the glucose infusion rate (GIR) during a test that holds blood glucose at a normal level (euglycemic clamp), which indicates the glucose-lowering effect, as for insulin degludec (A10AE06) [6].
Safety
Low blood glucose (hypoglycemia) is the most common toxicity of insulin and the sulfonylureas, and both have narrow therapeutic indices [7]. Liraglutide acts on insulin and glucagon secretion in a glucose-dependent way, so its risk of hypoglycemia is low. Nausea is its most common adverse event, and it is dose-dependent and transient [8].
A buildup of lactic acid in the blood (lactic acidosis) is the feared adverse effect of the biguanides, but its incidence with metformin is very low. Graham and colleagues suggested keeping the mean plasma concentration of metformin over a dosing interval below 2.5 mg/L to minimize this risk. Metformin is excreted unchanged in urine, and its clearance falls approximately in proportion to creatinine clearance. They therefore recommend reducing the dose in renal impairment in proportion to the reduced creatinine clearance [9].