Simvastatin vs Pravastatin

## Overview

Simvastatin and pravastatin represent an important pharmacokinetic contrast within the statin class. Simvastatin is lipophilic and CYP3A4-dependent; pravastatin is hydrophilic and CYP-independent. Despite overlapping potency ranges, their clinical niches differ significantly.

## Mechanism of Action

Both inhibit HMG-CoA reductase. Simvastatin is a prodrug lactone; pravastatin is administered as the active hydroxy acid. Pravastatin's uptake into hepatocytes depends on OATP1B1/1B3 transporters rather than passive diffusion.

## Pharmacokinetics

Simvastatin: bioavailability ~5%, CYP3A4 metabolism, half-life 2–3 h, prodrug. Pravastatin: bioavailability ~17%, non-CYP metabolism (sulfation, enzymatic conjugation), half-life ~2 h. Pravastatin's non-CYP pathway makes it the safest statin in patients on multiple medications affecting CYP3A4.

## Pharmacodynamics

Both achieve moderate-intensity LDL-C lowering. Simvastatin 20–40 mg reduces LDL by 32–38%; pravastatin 40–80 mg reduces LDL by 30–34%. The potency difference is smaller than comparisons involving rosuvastatin or atorvastatin.

## Clinical Evidence

The PROVE IT-TIMI 22 trial directly compared pravastatin 40 mg with atorvastatin 80 mg (not simvastatin vs. pravastatin directly), but established that higher-intensity is superior in ACS. For patients not requiring high-intensity therapy, pravastatin is well-validated by CARE and LIPID trials.

## Safety

Simvastatin has the well-known 80 mg restriction. Pravastatin lacks these restrictions and is the statin of choice in many drug interaction-heavy settings. Rhabdomyolysis risk is low with both at standard doses.

## Key Takeaways

- Pravastatin: no CYP interactions, hydrophilic, preferred in complex polypharmacy
- Simvastatin: slightly higher potency, CYP3A4 dependent, 80 mg restricted
- Both moderate-intensity; neither suitable as sole therapy for very high-risk patients