What are the initial and subsequent pharmacological treatments for type 2 diabetes, including dosing and timing of medications such as metformin, DPP-4 (Dipeptidyl Peptidase-4) inhibitors, GLP-1 (Glucagon-Like Peptide-1) receptor agonists, sulfonylureas, meglitinides, thiazolidinediones, and SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors?

Comparison of Diabetic Medications and When to Use Each

Initial Therapy

Metformin is the mandatory first-line agent for all patients with type 2 diabetes unless contraindicated or not tolerated. 1

Drug Class	When to Give	Key Indications	Contraindications/Cautions	Dosing
Metformin (Biguanide)	First-line at diagnosis	• All type 2 diabetes patients • Continue as foundation even when adding other agents	• eGFR <30 mL/min/1.73 m² • Acute illness with dehydration	• Start 500 mg once or twice daily with food • Titrate to max 2000 mg/day • Halve dose if eGFR 30-44 • Consider dose reduction eGFR 45-59 [1]

Second-Line Therapy (Add to Metformin)

For patients with established ASCVD, heart failure, or CKD: SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit are mandatory additions regardless of A1C level. 1

Drug Class	When to Give	Key Indications	Major Benefits	Major Risks	Dosing Considerations
SGLT2 Inhibitors	Preferred for: • ASCVD • Heart failure (especially preferred) • CKD with eGFR ≥30	• Cardiovascular disease benefit • Heart failure reduction • CKD progression slowing • Weight loss desired	• CV mortality reduction • HF hospitalization reduction • CKD protection • Weight loss 2-3 kg • No hypoglycemia	• Genital mycotic infections • DKA risk (rare) • Volume depletion • Requires eGFR ≥30	• Continue even if A1C at goal • Use with metformin as dual first-line in high-risk patients [1]
GLP-1 Receptor Agonists	Preferred for: • ASCVD • Weight loss needed • Avoiding hypoglycemia	• Cardiovascular benefit (liraglutide, semaglutide, dulaglutide, albiglutide) • Significant weight loss • Injectable therapy acceptable	• CV mortality reduction • Weight loss 3-5 kg • No hypoglycemia • A1C reduction 1.0-1.5%	• GI side effects (nausea, vomiting, diarrhea) • Pancreatitis risk • Injectable	• Long-acting preferred (once weekly) • Semaglutide 0.5-1 mg weekly most effective [2] • Start low, titrate slowly for GI tolerance [1]
DPP-4 Inhibitors	When: • SGLT2i/GLP-1 RA not suitable • Avoiding hypoglycemia • Weight neutrality needed	• Oral therapy preferred • Low hypoglycemia risk • Elderly patients	• Weight neutral • No hypoglycemia • Well tolerated • A1C reduction 0.6-0.8%	• Less effective than GLP-1 RA or SGLT2i • More expensive than sulfonylureas • Heart failure risk with saxagliptin	• Sitagliptin 100 mg daily • Dose adjust for renal function [1]
Sulfonylureas	When: • Cost is primary concern • Rapid A1C reduction needed • Other agents unavailable	• Low-resource settings • Need for inexpensive therapy • Rapid glycemic control	• A1C reduction 1.0-1.5% • Inexpensive • Oral therapy	• High hypoglycemia risk (24% vs 2% with SGLT2i) • Weight gain 2-3 kg • Cardiovascular neutrality	• Glimepiride 1-8 mg daily • Glipizide 5-40 mg daily • Start low dose, titrate slowly [1,3]
Thiazolidinediones (TZDs)	When: • Other options exhausted • Insulin resistance prominent	• Alternative when other agents unsuitable • Avoid in elderly	• A1C reduction 0.9-1.2% • No hypoglycemia • Durable effect	• Weight gain 2-4 kg • Fluid retention/heart failure • Bone fractures • Bladder cancer concern	• Pioglitazone 15-45 mg daily • Contraindicated in heart failure [1,4]

Third-Line and Intensification

When dual therapy (metformin + second agent) fails to achieve A1C target after 3 months, add a third agent or initiate insulin. 1

Drug Class	When to Give	Key Indications	Major Benefits	Major Risks	Dosing Considerations
Basal Insulin	Mandatory when: • A1C ≥10% • Glucose ≥300 mg/dL • Symptomatic hyperglycemia • Weight loss/catabolism • Triple therapy failure	• Severe hyperglycemia • Symptomatic patients • Most effective glucose lowering	• Most effective A1C reduction (1.5-3.5%) • No maximum dose • Addresses insulin deficiency	• Highest hypoglycemia risk • Weight gain 2-4 kg • Requires monitoring • Injectable	• Start 10 units daily or 0.1-0.2 units/kg • Glargine, detemir, degludec preferred • Titrate every 3-7 days based on fasting glucose • Continue metformin [1,3,4]
Meglitinides (Glinides)	Rarely used: • Postprandial hyperglycemia • Irregular meal patterns	• Alternative to sulfonylureas • Flexible dosing with meals	• Lower hypoglycemia than sulfonylureas • Flexible dosing	• Hypoglycemia risk • Weight gain • Multiple daily doses • Expensive	• Repaglinide 0.5-4 mg before meals • Nateglinide 60-120 mg before meals [1]
Alpha-Glucosidase Inhibitors	Rarely used: • Postprandial hyperglycemia • Other agents unsuitable	• Modest A1C reduction • Weight neutral	• No hypoglycemia • Weight neutral • A1C reduction 0.5-0.8%	• Significant GI side effects • Multiple daily doses • Modest efficacy	• Acarbose 25-100 mg three times daily with meals [1]

Special Clinical Scenarios

Severe Hyperglycemia at Presentation

Initiate insulin immediately (with or without other agents) when A1C ≥10%, glucose ≥300 mg/dL, or symptomatic hyperglycemia with weight loss. 1, 3

Dual Therapy at Diagnosis

Consider initiating dual therapy (metformin + second agent) when A1C is ≥1.5% above target at diagnosis. 1

CKD Patients

Use metformin + SGLT2 inhibitor as dual first-line therapy for patients with eGFR ≥30 mL/min/1.73 m². 1

• Metformin: Continue until eGFR <30, dose reduce at eGFR <45 1
• SGLT2i: Preferred for CKD protection, requires eGFR ≥30 1
• GLP-1 RA: Add if additional glycemic control needed 1

ASCVD/Heart Failure Patients

SGLT2 inhibitors are the preferred second agent, especially when heart failure coexists. 1

• Alternative: GLP-1 RA with proven CV benefit 1
• Continue these agents even if A1C at goal 1

Critical Monitoring Requirements

Medication	Monitoring Parameter	Frequency	Action
Metformin	Vitamin B12 levels	After 4 years of use, then periodically	Supplement if deficient, especially with neuropathy/anemia [1]
Metformin	eGFR	Annually if ≥60; every 3-6 months if <60	Dose adjust at eGFR <45, stop at <30 [1]
All agents	A1C	Every 3 months until at goal, then every 6 months	Intensify therapy if not at target after 3 months [1]

Common Pitfalls to Avoid

• Never delay insulin when A1C ≥10% or glucose ≥300 mg/dL - these patients require immediate insulin therapy 1, 3
• Never discontinue metformin when adding other agents unless contraindicated - it remains the foundation 1
• Never use sulfonylureas as preferred second-line when SGLT2i or GLP-1 RA are available in patients with ASCVD/HF/CKD - the CV/renal benefits outweigh cost considerations 1
• Never delay treatment intensification - if A1C not at target after 3 months, add another agent immediately 1
• Never ignore cardiovascular comorbidities - SGLT2i and GLP-1 RA provide mortality benefit beyond glucose lowering 1