What is the pharmacology of anti-diabetic (Anti-Diabetic) medications, specifically oral hypoglycemic agents and injectable anti-diabetic medications?

From the Guidelines

The most effective pharmacologic approach for type 2 diabetes involves the use of metformin as the first-line medication, with SGLT-2 inhibitors and GLP-1 receptor agonists being preferred over other agents due to their benefits in reducing mortality, cardiovascular events, and severe hypoglycemia, as evidenced by the most recent and highest quality study 1. The pharmacology of anti-diabetic medications is complex and involves various mechanisms to control blood glucose levels.

• Insulin, the cornerstone treatment for type 1 diabetes and advanced type 2 diabetes, directly lowers blood glucose by facilitating cellular glucose uptake.
• Metformin, typically the first-line medication for type 2 diabetes, reduces hepatic glucose production and improves insulin sensitivity at doses of 500-2000 mg daily.
• Sulfonylureas like glipizide (5-20 mg daily) and glimepiride (1-8 mg daily) stimulate pancreatic insulin secretion.
• SGLT-2 inhibitors such as empagliflozin (10-25 mg daily) and dapagliflozin (5-10 mg daily) prevent glucose reabsorption in the kidneys, causing glucose excretion in urine.
• GLP-1 receptor agonists like semaglutide (0.25-1 mg weekly injection or 3-7 mg oral daily) and dulaglutide (0.75-4.5 mg weekly) increase insulin secretion, reduce glucagon, slow gastric emptying, and promote satiety.
• DPP-4 inhibitors such as sitagliptin (100 mg daily) prevent breakdown of endogenous GLP-1.
• Thiazolidinediones like pioglitazone (15-45 mg daily) enhance insulin sensitivity in peripheral tissues. Treatment selection depends on the patient's specific type of diabetes, disease progression, comorbidities, and potential side effects, with combination therapy often needed as the disease progresses to address multiple pathophysiological defects, as supported by the evidence from 1. Key considerations in the choice of pharmacologic agents include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, renal effects, delivery method, cost, and patient preferences, as outlined in 2 and 1. The use of SGLT-2 inhibitors and GLP-1 receptor agonists is preferred due to their benefits in reducing mortality, cardiovascular events, and severe hypoglycemia, as well as their favorable effects on weight and renal outcomes, making them a crucial part of the pharmacologic management of type 2 diabetes, as recommended by the most recent guidelines 1.

From the FDA Drug Label

ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism

The pharmacology of anti-diabetic medications, such as pioglitazone, involves decreasing insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ), which modulates the transcription of insulin responsive genes involved in the control of glucose and lipid metabolism 3.

Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 (e. g. cyclosporine) may likewise have the potential to increase plasma concentrations of repaglinide.

In contrast, repaglinide is metabolized by cytochrome P450 enzymes 2C8 and 3A4, and its metabolism may be altered by drugs that influence these enzyme systems via induction and inhibition 4. Key points about the pharmacology of these anti-diabetic medications include:

• Mechanism of action: Pioglitazone depends on the presence of insulin, while repaglinide is metabolized by cytochrome P450 enzymes.
• Key enzymes: PPARγ for pioglitazone, and cytochrome P450 enzymes 2C8 and 3A4 for repaglinide.
• Drug interactions: Pioglitazone and repaglinide may have different interactions with other drugs, such as inhibitors and inducers of cytochrome P450 enzymes.

From the Research

Pharmacology of Anti-Diabetic Medications

The pharmacology of anti-diabetic medications is a complex and multifaceted field, with various classes of drugs available to treat type 2 diabetes mellitus (T2DM) [ 5 ].

• Metformin: Metformin is the initial oral antihyperglycemic agent (OHA) of choice for most patients with T2DM [ 5 ].
• Sulfonylureas: Sulfonylureas are often used as add-on therapy to metformin, but they have been associated with increased risk of all-cause mortality and major hypoglycemic episodes compared to other OHAs [ 5 ].
• Incretin-based therapies: Incretin-based therapies, such as dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to be effective in improving glycemic control and reducing cardiovascular risk [ 6 ].
• Sodium-glucose cotransporter 2 inhibitors (SGLT2is): SGLT2is have been shown to have cardiovascular and renal protective effects, and are now considered preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease [ 6 ].

Mechanisms of Action

The mechanisms of action of anti-diabetic medications vary, and can affect cellular metabolism in several ways [ 7 ].

• Metformin: Metformin works by decreasing hepatic glucose production and increasing insulin sensitivity [ 7 ].
• Sulfonylureas: Sulfonylureas work by stimulating insulin release from pancreatic beta cells [ 7 ].
• Incretin-based therapies: Incretin-based therapies work by enhancing glucose-dependent insulin secretion and decreasing glucagon secretion [ 7 ].
• SGLT2is: SGLT2is work by inhibiting glucose reabsorption in the kidney, leading to increased glucose excretion in the urine [ 6 ].

Clinical Efficacy and Safety

The clinical efficacy and safety of anti-diabetic medications have been evaluated in several studies [ 8 ].

• Sitagliptin vs. glimepiride: A randomized, double-blind, non-inferiority trial found that sitagliptin was non-inferior to glimepiride in reducing HbA1c levels, and was associated with a lower risk of hypoglycemia and weight gain [ 8 ].
• Metformin and sulfonylurea combination therapy: A systematic review and meta-analysis found that metformin and sulfonylurea combination therapy was associated with an increased risk of hypoglycemia compared to other metformin-antidiabetic agent combinations [ 9 ].