What is the comparison of oral hypoglycaemic agents (OHAs) for type 2 diabetes treatment?

Comparison of Oral Hypoglycemic Agents for Type 2 Diabetes Treatment

Metformin should be prescribed as first-line oral pharmacologic therapy for most patients with type 2 diabetes when lifestyle modifications fail to adequately control hyperglycemia. 1, 2

First-Line Therapy: Metformin

Metformin is superior to other oral hypoglycemic agents as first-line therapy due to:

• Efficacy: Produces similar HbA1c reductions (approximately 1 percentage point) compared to most other agents 1
• Safety profile: Lower risk of hypoglycemia compared to sulfonylureas 1, 2
• Weight effects: Associated with weight loss or weight neutrality, unlike sulfonylureas and thiazolidinediones which cause weight gain 1, 2
• Cardiovascular benefits: Favorable effects on plasma lipid profiles 1
• Cost-effectiveness: Less expensive than most newer agents 1

Dosing and Administration

• Initial dose: 500 mg once or twice daily with meals
• Gradual titration to 1000-2000 mg daily to minimize gastrointestinal side effects 2
• Maximum effective dose: 1500 mg/day (higher doses provide minimal additional benefit) 3

Contraindications

• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Hepatic disease
• Heart failure
• Excessive alcohol intake
• Risk of dehydration 2

Second-Line Therapy Options

When metformin monotherapy fails to achieve glycemic targets after 3 months at maximum tolerated dose, add one of the following:

1. Sulfonylureas

• Efficacy: Similar HbA1c reduction to other agents (0.7-1.0%)
• Advantages: Low cost, extensive clinical experience
• Disadvantages: Higher risk of hypoglycemia, weight gain
• Recommendation strength: Strong recommendation in resource-limited settings 1

2. SGLT-2 Inhibitors

• Efficacy: Moderate HbA1c reduction
• Advantages: Weight loss, low hypoglycemia risk, cardiovascular benefits
• Disadvantages: Higher cost, risk of genital infections, rare euglycemic ketoacidosis
• Example: Empagliflozin reduces HbA1c by approximately 0.7-0.8% as monotherapy 4

3. GLP-1 Receptor Agonists

• Efficacy: Good HbA1c reduction
• Advantages: Weight loss, low hypoglycemia risk, cardiovascular benefits
• Disadvantages: Injectable form (except oral semaglutide), gastrointestinal side effects, high cost

4. DPP-4 Inhibitors

• Efficacy: Slightly less effective than sulfonylureas (increases HbA1c by 0.12% compared to sulfonylureas) 1
• Advantages: Weight neutral, low hypoglycemia risk (OR 0.14 compared to sulfonylureas) 1
• Disadvantages: Higher cost, modest efficacy

5. Thiazolidinediones

• Efficacy: Similar to sulfonylureas
• Advantages: Low hypoglycemia risk, durability of effect
• Disadvantages: Weight gain, edema, increased risk of heart failure, bone fractures (especially in women) 1

Third-Line Therapy Options

When dual therapy fails to achieve glycemic targets:

1. Add human insulin (strong recommendation) 1

   • Most effective for glycemic control when oral agents are insufficient

2. Alternative triple oral therapy (if insulin is unsuitable):

   • Add DPP-4 inhibitor, SGLT-2 inhibitor, or thiazolidinedione to metformin + sulfonylurea 1

Comparative Safety Profiles

Hypoglycemia Risk

• Highest risk: Sulfonylureas
• Lowest risk: Metformin, DPP-4 inhibitors, SGLT-2 inhibitors, thiazolidinediones 1
• Combination of metformin plus sulfonylureas has 6 times higher risk of hypoglycemia than metformin plus thiazolidinediones 1

Weight Effects

• Weight loss: Metformin, SGLT-2 inhibitors, GLP-1 receptor agonists
• Weight neutral: DPP-4 inhibitors
• Weight gain: Sulfonylureas, thiazolidinediones, insulin 1

Specific Adverse Effects

• Metformin: Gastrointestinal side effects, vitamin B12 deficiency with long-term use 1, 2
• Thiazolidinediones: Edema, heart failure risk, bone fractures (contraindicated in serious heart failure) 1
• Sulfonylureas: Hypoglycemia, weight gain 1
• SGLT-2 inhibitors: Genital infections, volume depletion, rare euglycemic ketoacidosis 4
• DPP-4 inhibitors: Generally well-tolerated, potential joint pain 2

Common Pitfalls to Avoid

1. Therapeutic inertia: Failing to intensify therapy when HbA1c targets aren't met after 3 months 2
2. Discontinuing metformin: When adding other agents, continue metformin unless contraindicated 2
3. Ignoring renal function: Failing to adjust medication dosing based on eGFR 2
4. Overlooking vitamin B12 monitoring: In patients on long-term metformin therapy 2
5. Neglecting cardiovascular risk: Failing to consider agents with proven cardiovascular benefits in high-risk patients 2

Algorithm for Oral Hypoglycemic Agent Selection

1. Start with metformin unless contraindicated
2. If HbA1c target not achieved after 3 months:
   • For patients with established cardiovascular disease: Add SGLT-2 inhibitor or GLP-1 receptor agonist with proven CV benefit
   • For patients with chronic kidney disease: Consider SGLT-2 inhibitor
   • For patients with heart failure: Consider SGLT-2 inhibitor
   • For patients with cost constraints: Add sulfonylurea
   • For patients with obesity: Add GLP-1 receptor agonist or SGLT-2 inhibitor
   • For elderly patients with hypoglycemia concerns: Add DPP-4 inhibitor
3. If dual therapy insufficient after 3 months:
   • Consider triple oral therapy or insulin initiation

The evidence strongly supports metformin as first-line therapy, with selection of second-line agents based on patient-specific factors including comorbidities, risk of hypoglycemia, weight effects, and cost considerations.