藥物不良反應 副作用 Statins

2014年 CLINICAL REVIEW  有一篇文章
Statin Adverse Effects: Sorting out the Evidence; Clinician Reviews. 2014 November;24(11):41-43,46-50

哪一種statin 比較安全呢?

WHICH DRUG? POTENTIAL DIFFERENCES IN STATINS

肝毒性機率並不高
HEPATIC EFFECTS ARE RARE

Historically, statins have been linked to potential hepatotoxicity, with case reports of serum transaminase elevation, cholestasis, hepatitis, and acute liver failure. It is now recognized that hepatic AEs are rare and that statins are not associated with a risk for acute or chronic liver failure.1,11 In patients with coronary heart disease, the incidence of hepatotoxicity with statin use is reported to be less than 1.5% over the course of five years and appears to be dosedependent.1 In 2012, the FDA revised the labeling for most statins, relaxing its earlier recommendations formonitoring of liver function, clarifying the risk for myopathy, and providing additional information about drug interactions.13 Checking transaminase levels before initiating therapy is recommended by both the ACC/AHA and the 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 for transaminase elevations than placebo.22 But the 135-RCT meta-analysis4 found otherwise: Statins did increase the risk for transaminase elevation (odds ratio [OR], 1.51) 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 signifcant 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.2

Statins 會造成DM 嗎? 機率並不高, 各種STATINS之間差異也不大. 有一篇分析 11 萬名病患的統合分析發現, 沒有統計上意義.
STATIN USE AND DIABETES: IS THERE A LINK?
Recent studies have found an increased risk for newonset 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 1,000 patient-years for moderateintensity therapy and three per 1,000 patient-years for high-intensity therapy.1 The 2013 meta-analysis found that the elevated risk for diabetes was relatively small (OR, 1.09).4 No difference among various statins was found. In another meta-analysis—this one encompassing 17 RCTs and more than 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)

一篇收集 24 萬人的統合分析發現

1. 所有statins, 因為副作用停藥的比例 5.7%

2. Atovastatin 和 Rosuvsatatin 停藥機率最高

3. Atovastatin 和 Fluvastatin 發生肝指數上升機率最高 (OR 各為 2.6 及 5.2 )

4. 患者對於 Pravastatin 和 Simvastatin 耐受性最佳, 這兩個是最安全的, 因副作用停藥機率最低

5. Simvastatin 如果服用超過一天40mg, 會顯著增加 CK 及 GPT(ALT) 上升機率 (OR 4.1 及 2.8), 罹患橫紋肌溶解機率也會上升

A meta-analysis with more than 240,000 participants evaluated patients taking seven different statins (atorvastatin, fluvastatin, lovastatin, pravastatin, pitavastatin, rosuvastatin, and simvastatin), looking at AEs of the drugs both collectively and individually.4 As noted earlier, the overall discontinuation rate due to AEs for all statins was 5.7%. Discontinuation rates for each agent were not reported.4

The researchers did report, however, that atorvastatin and rosuvastatin had the highest discontinuation rates; atorvastatin and fluvastatin had the highest incidence of transaminase elevations (OR, 2.6 and 5.2, respectively); and pravastatin and simvastatin appeared to be the best-tolerated and safest statins, with the lowest discontinuation rates. However, higher doses of simvastatin (> 40 mg/d) significantly increased the risk for CK and transaminase elevations (OR, 4.1 and 2.8, respectively),4 as well as the risk for rhabdomyolysis when taken at the highest dose.15,16

藥物不良反應 Statins pitavastatin

rate of adverse reactions/side effects
不良反應/副作用的機率
注意, 應該扣去安慰劑的比例
安慰劑造成肢體疼痛的機率比pitavastatin 2mg, 4mg 還高
對於pitavastatin 4 mg 而言, 背痛和肢體疼痛機率比安慰劑低, 便秘機率大於安慰劑, 肌肉痠痛機率高於安慰劑.

警示

WARNINGS & PRECAUTIONS
Myopathy and Rhabdomyolysis: Risk factors include age 65 and greater, renal impairment, inadequately treated hypothyroidism, concomitant use of certain drugs, and higher doses of ZYPITAMAG. ZYPITAMAG is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil. The following drugs when used concomitantly with ZYPITAMAG may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1 g/day), fibrates, and colchicine. Discontinue ZYPITAMAG if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ZYPITAMAG in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis; e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ZYPITAMAG dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.
Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents.
Hepatic Dysfunction: Increases in serum transaminases can occur. Rare postmarketing reports of fatal and non-fatal hepatic failure have occurred. Consider liver enzyme testing before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZYPITAMAG.
Increases in HbA1c and Fasting Serum Glucose Levels: Increases of each have been reported with statins, including ZYPITAMAG. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

ADVERSE REACTIONS: The most frequent adverse reactions (rate ≥ 2%) are myalgia, back pain, diarrhea, constipation and pain in extremity. This is not a complete list of all reported adverse events.