Table II.

Evidence For, and Suggestive Of, Dose/Potency Dependence of Statin Adverse Effects (AEs)

AE	Comment
All AEs	- OR 1.4; 95% CI 1.09-1.80, p=0.008 statin therapy vs placebo¹⁷⁵ (meta-analysis of placebo-controlled RCTs). - OR 1.44; 95% CI 1.33-1.55, p<0.001 intensive- vs moderate-dose statin therapy¹⁷⁶ (meta-analysis of RCTs).
AEs Leading to Discontinuation of Therapy	- OR 1.28; 95% CI 1.18-1.39, p<0.001 intensive- vs moderate-dose statin therapy¹⁷⁶ (meta-analysis of RCTs). Note: Though intensive-dose statins lead to more discontinuation due to AEs than moderate-dose statins, moderate-dose statins do not necessarily lead to more discontinuation due to AEs than placebo¹⁷⁷ (meta-analysis of RCTs).
CK Elevation	Although some meta-analyses fail to show significant CK elevations with statins (usually moderate dose) vs placebo,¹⁷⁷ meta-analysis of head-to-head RCTs of high- vs low- potency statins showed a significant increase in CK elevation with high-dose statins: CK elevation OR 6.12 with higher- vs lower- dose statin therapy (95% CI 1.36-27.5).¹⁷⁸ The odds appeared to be greater for lipophilic statins, which can more readily enter muscle tissue. CK elevation OR 9.97 with intensive vs less intensive statins (95% CI 1.3-77.9, p=0.028).¹⁷⁶
LFT Elevation	- Meta-analyses of RCTs show significant increases in LFTs with statin vs placebo (risk difference per 1000 patients 4.2, 95% CI 1.5-6.9).¹⁷⁷ - Meta-analysis of head-to-head RCTs of higher- vs lower- potency statins showed significant increase in LFT elevation with higher-dose statins: LFT (transaminase) elevation OR 2.7 (1.5-5.0) with higher vs lower dose statins.¹⁷⁸ The effect appeared to be greater for hydrophilic statins (pravastatin, the most hydrophilic, is actively taken up into the liver). LFT elevation (alanine or aspartate aminotransferase ≥3 times the ULN) OR 4.5 (95% CI 3.3-6.2) with intensive- vs nonintensive- statin therapy.¹⁷⁶ - In a different study design, looking not at dose, but LDL-C reduction, the magnitude of LDL-C drop was not related to AE risk. In contrast, the higher the statin dose needed to achieve a given LDL-C reduction, the higher the rates of elevated LFTs.¹⁸¹ For many reasons, this type of study is less interpretable from a dose-response standpoint.^a
Rhabdomyolysis	- Excess rhabdomyolysis cases on cerivastatin primarily involved high-potency use and/or combination with gemfibrozil, which increases the effective dose.¹⁷⁰, ¹⁷¹, ¹⁷⁹ - Drugs that inhibit the CYP3A4 system and thereby increase statin concentrations (e.g. for atorvastatin, simvastatin, lovastatin, and cerivastatin) increase risk for statin AEs (including rhabdomyolysis) 6-fold,¹⁶⁷ supporting a dose relationship of statins to AEs. - In a VA database, when statins were combined with agents that inhibit their clearance (CYP3A4 inhibitors) the rate of rhabdomyolysis was increased 3- to 5-fold.¹⁸⁵ - US FDA Advisory advised caution with high-dose (40mg) rosuvastatin due to elevated risk of rhabdomyolysis.¹⁸⁰ - In a meta-analysis of RCTs, the percent LDL-C reduction was not associated with rhabdomyolysis risk. (However, LDL-C reduction is a problematic metric – see footnote a; and footnote b in Table IV – and more so across trials since sample differences can swamp dose effects.¹⁸¹ ^a) - In the SEARCH trial in which 12,064 subjects were randomized to 20 or 80mg simvastatin, there were 49 cases of “definite myopathy” in the simvastatin 80mg group and 2 in the simvastatin 20mg group.¹⁸⁶ ^b There were 49 of “incipient myopathy” in the simvastatin 80mg group and 6 in the simvastatin 20mg group.^b - See also Table IV, ‘Risk Factors for Statin Adverse Effects (AEs).’
Non-CK Elevating Muscle Symptoms	Recurrence of statin AEs was significantly higher when subjects were rechallenged with an equivalent expected potency statin, relative to a lower potency statin (~95% vs 55%, p<0.01).³⁷
Cancer	According to a meta-analysis of statin RCTs, achieved LDL-C levels were significantly inversely related to cancer risk (p=0.009), though LDL-C reduction was not.¹⁸¹ On average statins do not increase cancer in those under age 70 years in clinical trials (see Table VII). One could postulate a relation to LDL-C transport of antioxidants or cholesterol status as a precursor to vitamin D.
Proteinuria	FDA Advisory: “Mild, transient proteinuria (or protein in the urine, usually from the tubules), with and without microscopic hematuria (minute amounts of blood in the urine), occurred with Crestor [rosuvastatin], as it has with other statins, in Crestor's pre-approval trials. The frequency of occurrence of proteinuria appeared dose- related.” ¹⁸⁰
Glycemia	- Atorvastatin 80mg increased glycemia significantly on average in the PROVE-IT –TIMI trial.¹⁸⁴ - Rosuvastatin 20mg vs placebo significantly increased HbA1c (p=0.001), and increased newly diagnosed diabetes mellitus (relative risk 1.25; p=0.01) in the JUPITER trial.¹⁸⁷ - Lower statin potencies have led to reproducible elevations in glucose in individual subjects,¹⁸² but elevations in glucose or HbA1c have usually not been reported on average in RCTs of low- or moderate-dose statins (although in one RCT the statin group exhibited a modest but statistically significant increase in HbA1c¹⁸³).

ALT = alanine aminotransferase; CK = creatine kinase; CYP = cytochrome P450; HbA1c = glycosylated hemoglobin; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL-C = low-density lipoprotein cholesterol; LFTs = liver function tests; OR = odds ratio; PROVE-IT–TIMI = Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction trial; RCT = randomized controlled trial; SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; ULN = upper limit of normal; VA = US Department of Veterans Affairs.

Statin use is associated with transcriptional upregulation of HMG-CoA reductase.¹⁸⁸ We suggest that persons on statins with more unfavorable antioxidant/oxidant state may (on average) upregulate HMG-CoA reductase especially strongly in response to statins. Lesser LDL-C reduction for the same dose may signal a less favorable oxidant/antioxidant milieu on average,¹⁸⁹ which in turn may be associated with higher risk of statin AEs.⁵¹-⁵³ Consistent with this, LDL-C tachyphylaxis occurred with high-dose atorvastatin, but not if coenzyme Q10 was concurrently administered (2005 International Coenzyme Q10 Association Meeting presentation¹⁹⁰). LDL-C reduction for a given dose may not be a good way to examine dose effects. For some persons, the same statin dose may confer a lesser LDL-C reduction due to factors that promote oxidation and thus may also increase AE risk. In contrast, for some persons, the same statin dose may confer greater LDL-C reduction due to factors that increase statin assimilation or reduce clearance, which may also, by causing functionally greater statin ‘dose,’ increase AE risk. (See also Table IV, footnote b.)

“Definite myopathy” was defined as muscle symptoms with CK elevations exceeding 10× ULN (meeting definitions of rhabdomyolysis that do not require renal involvement); “incipient myopathy” was defined as CK exceeding 3× ULN and more than 5× baseline CK, coupled with an ALT elevation exceeding 1.7× baseline ALT without an isolated ALT elevation at any other visit, irrespective of muscle symptoms.¹⁸⁶ (Note that ALT elevation reflects liver compromise and is not a characteristic of myopathy. However, concurrent muscle and liver dysfunction may signal widespread cellular consequences of statins.)