## First-Line Agent in Type 2 Diabetes **Key Point:** Metformin is the universally recommended first-line pharmacological agent for Type 2 diabetes mellitus in the absence of contraindications, as per ADA, EASD, and Indian guidelines. ## Mechanism of Action Metformin acts primarily by: 1. Decreasing hepatic glucose production (gluconeogenesis inhibition) 2. Improving peripheral insulin sensitivity 3. Reducing intestinal glucose absorption 4. Activating AMP-activated protein kinase (AMPK) ## Why Metformin is Preferred | Feature | Metformin | Insulin | Sulfonylureas | Thiazolidinediones | |---------|-----------|---------|---------------|--------------------| | **Weight effect** | Neutral/Loss | Gain | Gain | Gain | | **Hypoglycemia risk** | None | High | High | Low | | **CV benefit** | Yes (UKPDS) | Neutral | Neutral | Mixed | | **Renal function** | Contraindicated if eGFR <30 | Safe | Caution | Safe | | **Cost** | Low | High | Low | Moderate | | **First-line status** | Yes | No | No | No | **High-Yield:** Metformin is preferred because it: - Does NOT cause weight gain or hypoglycemia - Has proven cardiovascular and mortality benefits (UKPDS trial) - Is cost-effective - Improves insulin sensitivity rather than forcing insulin secretion ## Contraindications to Metformin **Warning:** Metformin is contraindicated in: - eGFR <30 mL/min/1.73 m² (risk of lactic acidosis) - Acute illness, sepsis, dehydration - Liver disease - Acute coronary syndrome - Contrast dye administration (hold 48 hours post-procedure) **Clinical Pearl:** In this patient with normal renal function and no contraindications, metformin monotherapy is the standard starting point. Insulin is reserved for severe hyperglycemia, pregnancy, or failure of oral agents. Sulfonylureas and thiazolidinediones are second-line agents due to weight gain and other adverse effects. [cite:Harrison 21e Ch 417]
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