Statin adverse effects: Sorting out the evidence

Checking transaminase levels before initiating therapy is recommended by both the ACC/AHA and FDA.^1,13 Routine monitoring is not necessary, the ACC/AHA guideline states, because RCTs have found little evidence of ALT/AST elevation.¹ But here, too, evidence varies. An older meta-analysis (13 trials and nearly 50,000 participants) concluded that as a class, statins have no greater risk of transaminase elevations than placebo.²² But the 135-RCT meta-analysis⁴ found otherwise: Statins did increase the risk of transaminase elevation (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.24-1.84) compared with placebo, with differences associated with particular drugs and higher doses associated with more clinically significant elevations.⁴ It is important to note, however, that there was significant heterogeneity among the studies and no consistent definition of clinical significance.

THE BOTTOM LINE: Statins have been shown in multiple prospective studies to be safe for patients with chronic liver disease.^22,23

Statin use and diabetes:
 Is there a link?


Recent studies have found an increased risk of new-onset type 2 diabetes in statin users, with a greater risk associated with higher potency statins, including rosuvastatin and atorvastatin.^4,24 Although the exact mechanism is not known, statins may modify insulin signaling in peripheral tissues or directly impair insulin secretion.

The ACC/AHA guideline reports an excess rate of diabetes of one per 1000 patient-years for moderate-intensity therapy and 3 per 1000 patient years for high-intensity therapy.¹ The 2013 meta-analysis found that the elevated risk of diabetes was relatively small (OR=1.09; 95% CI, 1.02-1.16).⁴ No difference among various statins was found.

In another meta-analysis—this one encompassing 17 RCTs and >110,000 patients—no statistically significant difference in the incidence of new-onset diabetes was seen based on either the specific statin being taken or the intensity of therapy (high vs moderate).²⁴

THE BOTTOM LINE: Physicians should monitor patients taking statins for signs and symptoms of hyperglycemia.

Statins may be renoprotective

Statin use has been found to be associated with an increased risk of tubular proteinuria—an effect that is both dose- and potency-dependent.²⁵ Nonetheless, it has been suggested that statins may be a rare example of a drug class that is renoprotective in the long term, despite having an increased rate of proteinuria in the short term.²⁵

The evidence? In prospective studies, statin therapy has been shown to slow the progression of kidney disease in diverse patient populations, including renal transplant recipients and those with chronic kidney disease (CKD).^26,27

The Kidney Expert Panel of the National Lipid Association (NLA) has concluded that statins do not appear to cause significant proteinuria or acute kidney injury. The panel does not recommend routine monitoring for proteinuria or kidney function in statin users unless otherwise indicated, but does recommend a lower dose for patients with CKD.²⁸

THE BOTTOM LINE: Kidney Disease Improving Global Outcomes guidelines recommend that patients who have CKD, but are not on dialysis, be treated with statin therapy. Statins are contraindicated for patients on dialysis, as clinical trials have failed to show significant cardiovascular benefit.²⁹

Intracerebral hemorrhage: 
Statins increase recurrence risk


Routine monitoring 
of transaminase levels is not necessary, according to the ACC/AHA guideline.In recent years there has been considerable concern about a statin-induced increased risk for intracerebral hemorrhage (ICH). In a major prospective study in which patients were put on high-dose statin therapy or placebo after an acute ischemic or hemorrhagic stroke, the overall incidence of a recurrent stroke was significantly lower in the statin group.30 Among those who’d had an ICH, however, the recurrence rate was 73% higher for patients taking statins.

A subanalysis that looked only at patients who’d had a hemorrhagic stroke as their initial event (n=93) found that the absolute risk of recurrent ICH was 15.6% for patients randomized to atorvastatin vs 4.2% for those on placebo.³¹ Despite being based on a small subset of the original study group, the increased risk was statistically significant in multivariate analysis (hazard ratio [HR]=1.69; 95% CI, 1.1-2.6).

A subsequent decision analysis study based on these results proposed that patients with a history of spontaneous deep ICH would need an exceedingly high 10-year cardiovascular event risk (>40%) for the benefits of statin therapy to outweigh the risk.³² The risk is particularly high for those with a history of lobar ICH, which has an extremely high recurrence rate. However, subsequent retrospective and observational studies have found that patients who were already on statins when the ICH occurred had less severe strokes and more favorable outcomes, with a lower mortality rate at 90 days post-ICH.^33-35

A 2010 ICH guideline from the AHA/American Stroke Association states that there is “insufficient data to recommend restrictions on use of statin agents” for patients who have had an ICH.³⁶