---

Diabetes Mellitus Drugs - Pharmacology

---

Overview of Diabetes Mellitus

• Fasting plasma glucose ≥ 126 mg/dL
• 2-hr postprandial glucose ≥ 200 mg/dL
• HbA1c ≥ 6.5%
• Target HbA1c for most patients: ≤ 7%

---

I. INSULIN

Mechanism of Action

• Blood glucose rises → glucose enters pancreatic β-cells via GLUT transporters → phosphorylated by glucokinase → ATP generated → ATP-sensitive K⁺ channels close → membrane depolarization → Ca²⁺ influx → pulsatile insulin exocytosis
• Exogenous insulin replaces (type 1) or supplements (type 2) endogenous secretion

Pharmacokinetics

• Produced by recombinant DNA technology (E. coli or yeast)
• Degraded in GI tract - must be given subcutaneously (or IV for emergencies)
• Inhaled formulation (Afrezza) also available
• Duration varies by formulation (see table below)

Insulin Preparations

Rapid-acting analogs (lispro, aspart, glulisine) and long-acting analogs (glargine, detemir, degludec) are preferred in type 1 diabetes due to more physiologic profiles.

Adverse Effects of Insulin

• Hypoglycemia - most important; higher risk with intensive regimens
• Weight gain
• Lipodystrophy at injection sites (rotate sites to avoid)
• Insulin resistance (rare, with large doses)

Intensive vs. Standard Therapy

• Intensive therapy (≥3 injections/day with frequent monitoring) significantly reduces microvascular complications (retinopathy, nephropathy, neuropathy)
• Trade-off: higher frequency of hypoglycemic episodes, coma, and seizures
• Intensive therapy NOT recommended in: advanced age, long-standing disease, significant microvascular complications already present, hypoglycemic unawareness

---

II. AMYLIN ANALOG

Pramlintide

• Synthetic analog of amylin (a hormone co-secreted with insulin from β-cells)
• Mechanism: Delays gastric emptying, decreases postprandial glucagon, improves satiety
• Use: Adjunct to mealtime insulin in both type 1 and type 2 diabetes
• Given by SC injection before meals
• Caution: Reduce mealtime insulin by 50% when starting to avoid severe hypoglycemia
• Contraindicated in: Diabetic gastroparesis, hypoglycemic unawareness, cresol hypersensitivity
• Cannot be mixed with insulin in the same syringe

---

III. GLP-1 RECEPTOR AGONISTS (Incretin Mimetics)

The Incretin Effect

• Oral glucose causes higher insulin secretion than IV glucose - this is the "incretin effect"
• Mediated by gut hormones GLP-1 and GIP (glucose-dependent insulinotropic polypeptide)
• Responsible for 60-70% of postprandial insulin secretion; markedly reduced in type 2 DM

Drugs

• Injectable: Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide
• Oral: Semaglutide (also available PO)

Mechanism

• Activate GLP-1 receptors → stimulate glucose-dependent insulin release → suppress glucagon → slow gastric emptying → reduce appetite

Key Benefits

• Dulaglutide, liraglutide, semaglutide - demonstrated reduction in cardiovascular events (CV death, MI, stroke, HF hospitalization); approved in patients with type 2 DM + established CVD
• Significant weight loss - major advantage
• GLP-1 RAs are now approved for heart failure with reduced ejection fraction (HFrEF)

Adverse Effects

• Nausea, vomiting, diarrhea (most common)
• Pancreatitis (rare but important)
• Contraindicated in personal/family history of medullary thyroid carcinoma or MEN type 2 (thyroid C-cell risk)
• Risk of hypoglycemia is low when used as monotherapy (glucose-dependent effect)

---

IV. ORAL AGENTS FOR TYPE 2 DIABETES

A. Biguanides - Metformin (FIRST-LINE)

The molecular mechanism involves inhibition of Complex I of the mitochondrial respiratory chain and activation of AMPK (AMP-activated protein kinase).

---

B. Sulfonylureas (Second-Generation)

---

C. Meglitinides

---

D. Thiazolidinediones (TZDs) - Insulin Sensitizers

---

E. DPP-4 Inhibitors ("Gliptins")

---

F. SGLT2 Inhibitors ("Gliflozins")

---

G. Alpha-Glucosidase Inhibitors

---

V. TREATMENT ALGORITHM FOR TYPE 2 DIABETES

Diagnosis of Type 2 DM
        ↓
Lifestyle modification (diet, exercise, weight loss)
        +
    Metformin (unless contraindicated)
        ↓
If HbA1c target not met, or patient has:
├── ASCVD/CVD → Add GLP-1 RA (liraglutide, semaglutide, dulaglutide)
├── HFrEF → Add SGLT2 inhibitor (empagliflozin, dapagliflozin)
├── CKD → Add SGLT2 inhibitor or GLP-1 RA
├── Need to minimize weight gain → GLP-1 RA or SGLT2i
├── Need to minimize cost → Sulfonylurea or TZD
└── Need to minimize hypoglycemia → DPP-4i, GLP-1 RA, SGLT2i, TZD
        ↓
If still not at target → Triple combination or add insulin

---

VI. Quick Reference Summary Table

---

Recent Evidence (2024-2026)

• SGLT2 inhibitors and GLP-1 RAs now extend beyond glycemic control to provide robust cardiovascular and renal protection in type 2 DM (PMID: 39937036 - pharmacologic options in T2DM with MASLD/liver disease)
• GLP-1 RAs show efficacy and safety in pediatric/adolescent type 2 DM and obesity (PMID: 40952752 - JAMA Pediatrics, 2025)
• Guidelines for older/frail adults with T2DM emphasize individualized targets and caution with high hypoglycemia-risk agents (PMID: 39572394)

---