What is the mechanism of action of Oral Hypoglycemic Agents (OHAs)?

Mechanism of Action of Oral Hypoglycemic Agents

Overview of OHA Classes and Mechanisms

Oral hypoglycemic agents work through five distinct mechanisms to lower blood glucose in type 2 diabetes, targeting different pathophysiologic defects including insulin resistance, impaired insulin secretion, and excessive hepatic glucose production 1, 2.

Primary Mechanisms by Drug Class

Biguanides (Metformin)

Metformin decreases hepatic glucose production as its primary mechanism, which directly addresses the elevated basal hepatic glucose output that causes fasting hyperglycemia in type 2 diabetes 1, 3.

• Metformin improves insulin sensitivity primarily in the liver and muscle tissue without directly affecting β-cell function 1, 3
• It decreases intestinal absorption of glucose as a secondary mechanism 3
• Metformin improves peripheral glucose uptake and utilization, enhancing insulin sensitivity 3
• Importantly, insulin secretion remains unchanged with metformin therapy, while fasting insulin levels may actually decrease, avoiding hyperinsulinemia 3
• Metformin is excreted unchanged in urine and undergoes no hepatic metabolism 3

Sulfonylureas (First, Second, and Third Generation)

Sulfonylureas bind to ATP-sensitive potassium channels on pancreatic β-cells, causing channel closure and subsequent insulin secretion 4, 5.

• These agents increase insulin secretion but can induce hyperinsulinemia and prolonged hypoglycemia 4, 6
• The mechanism involves depolarization of the β-cell membrane, calcium influx, and insulin granule exocytosis 4
• Third-generation sulfonylureas like glimepiride have advantages including lower hypoglycemia risk, no interaction with cardiovascular K-ATP channels, and possible increased insulin sensitivity 4
• During modest hypoglycemia (glucose ~50 mg/dL), the insulin secretory response to sulfonylureas is markedly blunted, which may explain the relatively low incidence of severe hypoglycemia despite their potent mechanism 5

Meglitinides (Repaglinide, Nateglinide)

Meglitinides provide short-term promotion of glucose-stimulated insulin secretion with rapid onset of action on β-cells 1, 4.

• These agents bind to both shared and unique sites on the ATP-sensitive potassium receptor/channel complex compared to sulfonylureas 5
• They induce a more physiological profile of insulin secretion during meals due to their rapid onset and offset 4
• Like sulfonylureas, their insulin secretory response is significantly reduced during hypoglycemia, providing protection from profound hypoglycemia 5

Thiazolidinediones (Pioglitazone, Rosiglitazone)

Thiazolidinediones improve peripheral insulin sensitivity by acting as insulin sensitizers in muscle and adipose tissue 1, 4.

• These agents increase tissue sensitivity to insulin, making them powerful therapeutic tools for insulin-resistant states 4
• They do not directly affect insulin secretion or cause hypoglycemia when used alone 7
• Pioglitazone provides glycemic durability and does not cause hypoglycemia 7

Alpha-Glucosidase Inhibitors (Acarbose, Miglitol)

Alpha-glucosidase inhibitors slow the hydrolysis of complex carbohydrates in the small intestine, thereby slowing carbohydrate absorption 1, 4.

• These agents improve the time relationship between plasma insulin and glucose increases after meals 4
• They work by competitive inhibition of intestinal brush border enzymes 8
• They are classified as antihyperglycemic rather than hypoglycemic agents because they do not cause hypoglycemia when used alone 8

Pathophysiologic Context

Addressing Multiple Defects

Type 2 diabetes results from defects in both insulin secretion and insulin action, requiring agents that target different mechanisms 2.

• Elevated basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia 2
• After meals, impaired suppression of hepatic glucose production and decreased insulin-mediated glucose uptake by muscle contribute equally to postprandial hyperglycemia 2
• Agents with different mechanisms of action have the greatest synergy when combined 1

Progressive Nature of Disease

Type 2 diabetes is a progressive disorder where β-cell function declines over time, eventually requiring multiple agents or insulin 1, 2.

• Monotherapy eventually becomes insufficient for most patients, necessitating combination therapy 1
• The UKPDS demonstrated that improved glycemic control, irrespective of the agent used, decreased microvascular complications by 25% 1, 2

Special Considerations in Renal Disease

Altered Pharmacodynamics in CKD

In advanced chronic kidney disease, decreased insulin clearance and reduced gluconeogenesis by the kidney alter the effectiveness and safety profile of oral hypoglycemic agents 1.

• Patients with ESKD experience decreased insulin degradation by kidney, liver, and muscle due to uremia 1
• This leads to reduced requirements for exogenous insulin and oral agents, with some patients experiencing "burn-out diabetes" requiring less or no medications 1
• Hypoglycemia risk increases substantially in advanced CKD due to impaired insulin clearance and decreased gluconeogenesis 1