What are the main classes of Oral Hypoglycemic Agents (OHAs)?

Main Classes of Oral Hypoglycemic Agents

The primary classes of oral hypoglycemic agents include biguanides, sulfonylureas, meglitinides, thiazolidinediones (TZDs), DPP-4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors, each with distinct mechanisms of action and clinical profiles that guide their selection based on patient-specific factors. 1

Biguanides (Metformin)

• Metformin remains the most widely used first-line oral agent for type 2 diabetes, primarily reducing hepatic glucose production while enhancing insulin sensitivity in liver and muscle tissue 1
• This class is weight-neutral with chronic use and carries no intrinsic risk of hypoglycemia 1
• Common gastrointestinal side effects (nausea, diarrhea) typically occur early in treatment 1
• Critical contraindications include advanced renal insufficiency and alcoholism due to rare but serious risk of lactic acidosis 1
• Metformin may provide modest cardiovascular benefits, though clinical trial data are not robust 1

Sulfonylureas (Insulin Secretagogues)

• Sulfonylureas represent the oldest oral agent class, stimulating insulin release by closing ATP-sensitive potassium channels on pancreatic β-cells 1
• These agents demonstrate high glucose-lowering efficacy (expected HbA1c reduction 1.0-1.5%) 1
• Major limitations include modest weight gain and significant hypoglycemia risk, particularly in elderly patients 1
• Studies demonstrate a secondary failure rate that may exceed other drugs, attributed to progressive β-cell dysfunction 1
• Examples include glyburide, glipizide, glimepiride, and older agents like chlorpropamide and tolbutamide 1

Meglitinides (Glinides)

• Meglitinides are shorter-acting secretagogues (such as repaglinide and nateglinide) that stimulate insulin release through mechanisms similar to sulfonylureas 1
• These agents may be associated with less hypoglycemia compared to sulfonylureas 1
• They require more frequent dosing (typically before meals) due to their rapid onset and short duration of action 1
• Glucose-lowering effectiveness is generally lower than sulfonylureas (expected HbA1c reduction 0.5-1.0%) 1

Thiazolidinediones (TZDs)

• TZDs (pioglitazone and rosiglitazone) are peroxisome proliferator-activated receptor γ activators that improve insulin sensitivity in skeletal muscle and reduce hepatic glucose production 1
• These agents demonstrate high glucose-lowering efficacy and may be more durable in effectiveness than sulfonylureas and metformin 1
• Pioglitazone showed modest cardiovascular benefit in patients with overt macrovascular disease, while rosiglitazone is no longer widely available due to myocardial infarction concerns 1
• Significant side effects include weight gain, fluid retention leading to edema/heart failure in predisposed individuals, increased bone fracture risk, and possible bladder cancer risk with pioglitazone 1
• TZDs carry no intrinsic hypoglycemia risk 1

DPP-4 Inhibitors (Gliptins)

• DPP-4 inhibitors enhance circulating concentrations of active GLP-1 and GIP, primarily regulating insulin and glucagon secretion in a glucose-dependent manner 1
• These agents demonstrate moderate glucose-lowering efficacy (expected HbA1c reduction 0.5-1.0%) 1
• DPP-4 inhibitors are weight-neutral and carry minimal hypoglycemia risk when used as monotherapy 1
• When combined with sulfonylureas, hypoglycemia risk increases by 50% compared to sulfonylurea alone 1
• Dosing requires adjustment based on renal function for most agents except linagliptin 1
• Cardiovascular outcome trials demonstrated safety but no cardiovascular benefit, with concerns about heart failure for saxagliptin and alogliptin 1

SGLT2 Inhibitors

• SGLT2 inhibitors block renal glucose reabsorption, causing glucosuria and lowering blood glucose independent of insulin action 1
• These agents provide moderate glucose-lowering efficacy with beneficial weight loss and blood pressure reduction 1
• Critical safety concerns include increased risk of genital mycotic infections, urinary tract infections, acute kidney injury, dehydration, and orthostatic hypotension 1
• Canagliflozin specifically carries increased risk for lower-limb amputation (HR 1.97) and fractures (HR 1.26) 1
• Caution is warranted when combining with diuretics, ACE inhibitors, or angiotensin receptor blockers 1

Alpha-Glucosidase Inhibitors (AGIs)

• AGIs (acarbose and miglitol) retard gut carbohydrate absorption, slowing the rise in postprandial glucose 1
• These agents demonstrate lower glucose-lowering efficacy (expected HbA1c reduction 0.5-1.0%) 1
• Primary indication is reducing postprandial glucose fluctuations and improving glycemic stability 1
• Main side effect is flatulence due to unabsorbed carbohydrates reaching the colon 1
• AGIs are used infrequently in the U.S. and Europe 1

Less Commonly Used Oral Agents

• Colesevelam (bile acid sequestrant) has unclear glucose-lowering mechanism with additional LDL-cholesterol reduction benefit; constipation is the main side effect 1
• Bromocriptine (dopamine agonist) is available only in the U.S. with unclear mechanism and role 1

Clinical Selection Algorithm

When selecting an oral agent, prioritize metformin as first-line therapy unless contraindicated 1. For patients requiring additional therapy:

• Add sulfonylureas for high glucose-lowering efficacy when hypoglycemia risk is acceptable and cost is a concern 1
• Choose DPP-4 inhibitors when weight neutrality and low hypoglycemia risk are priorities 1
• Select SGLT2 inhibitors when cardiovascular or renal protection is needed (based on newer evidence not fully represented in these guidelines) 1
• Consider TZDs for durability of effect, but weigh carefully against fluid retention and fracture risks 1
• Reserve AGIs primarily for postprandial glucose control 1

Critical Pitfalls to Avoid

• Never use metformin in patients with advanced renal insufficiency or alcoholism due to lactic acidosis risk 1
• Avoid sulfonylureas in elderly patients or those at high hypoglycemia risk; choose agents with shorter duration of action if necessary 1
• Do not overlook fluid retention risks with TZDs in patients with heart failure predisposition 1
• Remember to adjust DPP-4 inhibitor doses based on renal function (except linagliptin) 1
• When combining agents, recognize that sulfonylureas increase hypoglycemia risk even with drugs that don't typically cause hypoglycemia alone 1