What are the different classes of Oral Hypoglycemic Agents (OHAs) for an adult patient with Type 2 diabetes?

Classes of Oral Hypoglycemic Agents for Type 2 Diabetes

There are five main classes of oral hypoglycemic agents available for treating type 2 diabetes in adults: biguanides, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, and thiazolidinediones, with newer classes including DPP-4 inhibitors and SGLT2 inhibitors now playing critical roles in modern management. 1

Traditional Oral Agent Classes

Biguanides (Metformin)

• Metformin is the cornerstone first-line agent that decreases hepatic glucose output and enhances primarily hepatic and muscle insulin sensitivity without directly affecting β-cell function 1
• This class is weight-neutral with chronic use and does not independently cause hypoglycemia 1, 2
• Metformin addresses the primary pathophysiologic defect in type 2 diabetes—excessive hepatic glucose production in the presence of hyperinsulinemia 3
• The main contraindications are advanced renal insufficiency (eGFR <45 mL/min) and alcoholism due to rare but serious lactic acidosis risk 1, 2

Sulfonylureas (Second-Generation Preferred)

• These agents promote insulin secretion by closing ATP-sensitive potassium channels on pancreatic β-cells, stimulating insulin release 1
• Available agents include glimepiride, glipizide, and glyburide among second-generation options 1
• Major drawbacks include modest weight gain, significant hypoglycemia risk, and high secondary failure rates over time that may exceed other drug classes 1
• Should be avoided or used as last resort in older adults and those at high hypoglycemia risk 1, 2

Meglitinides (Nonsulfonylurea Secretagogues)

• Repaglinide provides short-term promotion of glucose-stimulated insulin secretion with faster onset and shorter duration than sulfonylureas 1
• This class targets postprandial glucose excursions specifically 4, 5

Alpha-Glucosidase Inhibitors

• Acarbose and miglitol slow the hydrolysis of complex carbohydrates and delay carbohydrate absorption in the small intestine 1, 3
• These agents work by competitively and reversibly inhibiting alpha-glucosidase enzymes (glucoamylase, sucrase, maltase, isomaltase) in the intestinal brush border 6
• Primary side effects are gastrointestinal (abdominal discomfort, diarrhea) and they do not cause hypoglycemia when used alone 6, 5

Thiazolidinediones (TZDs)

• Rosiglitazone and pioglitazone improve peripheral insulin sensitivity in muscle and adipose tissue by acting as insulin sensitizers 1, 3
• Troglitazone has been associated with fatal hepatic failure and is not recommended for use 1
• This class requires careful monitoring due to potential cardiovascular and hepatic concerns 1

Newer Agent Classes (Critical for Cardiovascular and Renal Protection)

DPP-4 Inhibitors (Dipeptidyl Peptidase-4 Inhibitors)

• Sitagliptin and other agents in this class have minimal side effects and minimal hypoglycemia risk 1
• These agents reduce HbA1c by 0.5-1.0% when added to metformin but do not reduce or increase major adverse cardiovascular outcomes 1, 2
• They are weight-neutral, making them suitable for patients where weight gain is a concern 2

SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors)

• Dapagliflozin, empagliflozin, and canagliflozin represent a paradigm shift by working through an insulin-independent mechanism—preventing renal glucose reabsorption and increasing glycosuria 2, 3
• This class reduces HbA1c by 0.5-1.0%, body weight by 1.5-3.5 kg, and systolic blood pressure by 3-5 mmHg 2
• SGLT2 inhibitors provide cardiovascular and renal protection, reducing MACE, all-cause mortality, heart failure hospitalizations, and CKD progression 1, 7
• They consistently reduce severe hypoglycemia compared to sulfonylureas and insulin because they do not independently cause hypoglycemia 1
• For patients with heart failure or chronic kidney disease, SGLT2 inhibitors are specifically recommended 7

GLP-1 Receptor Agonists (Injectable, with Oral Option)

• While primarily injectable (liraglutide, semaglutide, exenatide), oral semaglutide is now available 1
• This class demonstrates cardiovascular benefits among patients with established ASCVD or high cardiovascular risk, reducing MACE, all-cause mortality, and stroke 1
• GLP-1 agonists are highly heterogeneous, ranging from older agents like exenatide to more potent weekly injections like semaglutide 1
• They provide greater glycemic effectiveness than insulin with beneficial weight effects and lower hypoglycemia risk 7

Practical Treatment Algorithm

Initial Therapy Selection

• Start metformin immediately at diagnosis for HbA1c ≥7.5% or when lifestyle changes are anticipated to be insufficient 1, 7
• For highly motivated patients with HbA1c <7.5%, a 3-6 month trial of lifestyle modification alone is reasonable before adding metformin 1, 7

Dual Therapy (When Metformin Monotherapy Fails After 3 Months)

• Add SGLT2 inhibitor as preferred second agent, particularly if cardiovascular disease, heart failure, or CKD is present 2, 7
• Alternative second agents include DPP-4 inhibitors (weight-neutral, low hypoglycemia risk) or GLP-1 receptor agonists (if cardiovascular benefit needed and injectable acceptable) 1, 7
• Sulfonylureas remain an option but should be deprioritized due to hypoglycemia risk and weight gain 1, 2

Triple Therapy (When Dual Therapy Fails After 3 Months)

• Add a third oral agent from a complementary mechanistic class (e.g., metformin + SGLT2 inhibitor + DPP-4 inhibitor) 7
• GLP-1 receptor agonists are preferred over basal insulin for triple therapy due to greater efficacy, weight benefits, and lower hypoglycemia risk 7

Critical Pitfalls to Avoid

• Never delay dual therapy when HbA1c is ≥9%—monotherapy with metformin alone is insufficient and prolongs hyperglycemia 2
• Avoid sulfonylureas in older adults, those with irregular meal patterns, or high hypoglycemia risk 1, 2
• Do not use metformin when eGFR <30 mL/min or in patients with alcoholism or acute illness predisposing to lactic acidosis 1, 2
• Recognize that type 2 diabetes is progressive—fewer than 10% of patients maintain glycemic control with lifestyle alone over time, and secondary failure rates are high with sulfonylureas 1
• Monitor vitamin B12 levels periodically in patients on long-term metformin therapy 1, 7
• Assess renal function before starting metformin and SGLT2 inhibitors, and monitor periodically 2