Regarding the mechanisms of action of statins and other lipid-lowering agents, all of the following statements are TRUE EXCEPT:

Explanation

## Mechanism of Action Review This question tests understanding of how different hyperlipidemic agents work at the molecular level. ### Correct Mechanisms (Options 0, 1, 2) **Option 0 — Statins (HMG-CoA Reductase Inhibitors)** - Inhibit the rate-limiting enzyme in cholesterol synthesis - Reduce hepatic cholesterol by 50–60%, triggering upregulation of LDL receptors - Net effect: ↓ LDL-C by 20–55% depending on potency and dose [cite:KD Tripathi 8e Ch 32] **Option 1 — Ezetimibe (Cholesterol Absorption Inhibitor)** - Blocks NPC1L1 transporter in the small intestine brush border - Reduces intestinal cholesterol absorption by approximately 54% - LDL-C reduction: 15–20% as monotherapy; additive with statins [cite:Harrison 21e Ch 397] **Option 2 — PCSK9 Inhibitors (Monoclonal Antibodies)** - PCSK9 normally binds and degrades hepatic LDL receptors - Inhibitors prevent this degradation → ↑ LDL receptor recycling - Result: ↓ LDL-C by 40–60% [cite:KD Tripathi 8e Ch 32] ### Incorrect Mechanism (Option 3 — Fibrates) **Key Point:** Fibrates **DECREASE** LDL-C (or have minimal effect), NOT increase it. **Fibrate Action via PPAR-α Activation:** 1. Increase lipoprotein lipase activity → ↓ triglycerides (primary effect) 2. Decrease hepatic VLDL synthesis → ↓ LDL-C (modest, 5–20% reduction) 3. Increase HDL-C by upregulating apoA-I and apoA-II **Warning:** The stem says fibrates "increase LDL-C by upregulating apoB synthesis" — this is **backwards**. Fibrates do NOT upregulate apoB; they reduce VLDL/LDL production. This is the FALSE statement. ### Summary Table | Drug Class | Primary Target | Main Effect | LDL-C Change | | --- | --- | --- | --- | | Statins | HMG-CoA reductase | ↓ Hepatic synthesis | ↓ 20–55% | | Ezetimibe | NPC1L1 transporter | ↓ Intestinal absorption | ↓ 15–20% | | PCSK9 inhibitors | PCSK9 protein | ↑ LDL receptor recycling | ↓ 40–60% | | Fibrates | PPAR-α | ↓ VLDL synthesis, ↑ TG clearance | ↓ 5–20% or ↔ | **High-Yield:** Fibrates are **triglyceride-lowering agents first**, not LDL-lowering agents. They may even slightly raise LDL-C in some patients with metabolic syndrome.