Which Oral Hypoglycemic Agent (OHA) is good for controlling fasting blood sugar, which one for postprandial control, which should be taken before meals and which after, and what is their frequency of intake?

Oral Hypoglycemic Agents: Timing, Targets, and Frequency

Fasting Blood Sugar Control

Metformin is the optimal agent for controlling fasting blood sugar, as it reduces hepatic glucose production and improves basal glucose clearance without causing hypoglycemia. 1, 2

• Metformin increases basal metabolic clearance of glucose by 30-53% and reduces fasting blood glucose by 34-41% at therapeutic doses 2
• It works primarily by suppressing hepatic glucose output overnight and between meals 2
• Metformin remains first-line therapy for type 2 diabetes due to its high efficacy in lowering HbA1c, excellent safety profile, and low cost 1

Thiazolidinediones (pioglitazone) also effectively control fasting glucose by increasing insulin sensitivity, though they carry more safety concerns regarding fluid retention and weight gain 1

Postprandial Blood Sugar Control

Short-acting insulin secretagogues (repaglinide, nateglinide) are specifically designed for postprandial glucose control. 1, 3

• These agents have rapid onset and short duration of action, making them ideal for controlling post-meal glucose spikes 1, 4
• Repaglinide induces a more physiological insulin secretion profile during meals compared to sulfonylureas 4
• Exenatide twice daily and lixisenatide (GLP-1 receptor agonists) have greater postprandial effects, especially after the meals with which they are administered 1

Alpha-glucosidase inhibitors (acarbose) reduce postprandial glucose excursions by slowing carbohydrate absorption from the gut, improving the time relationship between plasma insulin and glucose increases after meals 4, 5

Timing of Administration: Before vs After Food

BEFORE MEALS (Pre-prandial):

Repaglinide: Take within 30 minutes before each meal 3

• Dose: 0.5-4 mg before each meal, maximum 16 mg/day 3
• Critical: Skip the dose if skipping the meal to prevent hypoglycemia 3
• Can be dosed 2,3, or 4 times daily based on meal pattern 3

Sulfonylureas (glimepiride, gliclazide MR): Take before meals 1

• Newer generation sulfonylureas have lower hypoglycemia risk than older agents like chlorpropamide, which is contraindicated during fasting 1

Alpha-glucosidase inhibitors (acarbose): Take with first bite of meal 5

• Must be taken at the start of the meal to effectively slow carbohydrate absorption 5

AFTER MEALS (Post-prandial):

Metformin: Typically taken with or after meals to minimize gastrointestinal side effects 1

• Standard dosing: Can be given twice or three times daily with meals 1
• Modified Ramadan dosing: Two-thirds of total daily dose immediately before sunset meal, one-third before predawn meal 1

Thiazolidinediones (pioglitazone, rosiglitazone): Can be taken without regard to meals 1

• Usually no change in timing required, as they have low hypoglycemia risk 1

Frequency of Administration

Once Daily:

• Metformin extended-release: 1000-2000 mg once daily with evening meal 1
• Sulfonylureas (glimepiride, gliclazide MR): Once daily dosing 1
• Thiazolidinediones: Once daily 1

Twice Daily:

• Metformin immediate-release: 500-1000 mg twice daily with meals (maximum 2500 mg/day) 1
• Repaglinide: Can be dosed before 2 main meals if eating only twice daily 3

Three Times Daily:

• Repaglinide: 0.5-4 mg before each of 3 main meals 3
• Metformin: Can be divided into three doses with meals 1

Four Times Daily:

• Repaglinide: Can be dosed before 4 meals if eating 4 times daily 3

Critical Clinical Algorithm

For predominantly elevated fasting glucose:

1. Start metformin 500 mg twice daily with meals, titrate to 1000 mg twice daily (or 2000 mg once daily if using extended-release) 1
2. Add thiazolidinedione if metformin contraindicated or insufficient 1

For predominantly elevated postprandial glucose:

1. Start repaglinide 0.5-1 mg within 30 minutes before each meal 3
2. Alternative: Add alpha-glucosidase inhibitor with first bite of meals 5
3. Consider short-acting GLP-1 agonists (exenatide twice daily, lixisenatide) 1

For both fasting and postprandial elevation:

1. Combine metformin (with/after meals) + repaglinide (before meals) 1
2. Metformin addresses fasting glucose; repaglinide addresses postprandial spikes 1, 2, 4

Common Pitfalls to Avoid

• Never use chlorpropamide due to high risk of prolonged, unpredictable hypoglycemia 1
• Do not take repaglinide if skipping a meal - this dramatically increases hypoglycemia risk 3
• Avoid sulfonylureas in patients with irregular meal patterns due to hypoglycemia risk when meals are skipped 1
• Do not use metformin in patients with severe renal impairment (CrCl <30 mL/min) due to lactic acidosis risk 5
• Reduce repaglinide starting dose to 0.5 mg in severe renal impairment (CrCl 20-40 mL/min) 3