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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 9  |  Issue : 3  |  Page : 165-168

Adverse effects of statins – Myths and facts


Ashwin Clinic, Apollo Group of Hospitals, Chennai, Tamil Nadu, India

Date of Web Publication3-Dec-2019

Correspondence Address:
Dr. D Prabhakar
Ashwin Clinic, Apollo Group of Hospitals, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JICC.JICC_35_19

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  Abstract 


Treatment with statins for dyslipidemia is confronted by both patient and doctor and social media-related myths. The common myths and the relevant facts in light of the recent ACC/AHA guidelines on the management of blood cholesterol 2018 are interesting. Most common side effects listed with statins are statin-associated muscular symptoms, new-onset type 2 diabetes mellitus, intracranial hemorrhage, and elevation of liver enzymes. The current article reviews the myths and the facts about the side effects associated with statins and how to tackle the side effects practically.

Keywords: Dyslipidemia, myalgia, new-onset diabetes mellitus, side effects, statins


How to cite this article:
Prabhakar D. Adverse effects of statins – Myths and facts. J Indian coll cardiol 2019;9:165-8

How to cite this URL:
Prabhakar D. Adverse effects of statins – Myths and facts. J Indian coll cardiol [serial online] 2019 [cited 2019 Dec 7];9:165-8. Available from: http://www.joicc.org/text.asp?2019/9/3/165/272172




  Introduction Top


The cholesterol treatment trialists (CTT) meta-analysis showed that 1 mmol (38.7 mg%) reduction of low-density lipoprotein (LDL) cholesterol reduced the risk of major cardiac events by 10%–12% in the 1st year and then by 25% every year thereafter.[1] In right earnest, the doctor prescribes a statin. What does the patient do? Go to Google, and it says, “Are statins more dangerous than cholesterol itself?” Then, the patient confronts the doctor or simply stops the medication. The common myths and facts of both the doctors and patients are demystified. The recent dyslipidemia guidelines provide a lot of armamentaria to fight the myths.[2]


  Statin Safety and Statin-Associated Side Effects Top


The most important step in the initiation of statin therapy is a good clinician–patient discussion. First, assess the predisposing factors for statin side effects – for new-onset diabetes mellitus and statin-associated muscle symptoms (SAMSs). Second, discuss the net clinical benefit of statins. Third, weigh benefits against the potential side effects of the individual patient. Finally, start statins.[2]

Myth: Statins produce muscle symptoms in all patients. It cannot be identified

The entire spectrum of muscular symptoms is now termed as SAMSs.[2] The predisposing factors for SAMS are given in [Figure 1]. This spectrum has four types of SAMS as shown in [Table 1].
Figure 1: Predisposing factors for statin-associated muscle symptoms

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Table 1: Types of statin-associated muscle symptom and their characteristics

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Myth: Mechanisms of muscle damage are not known?

The mechanism of muscle damage is reduction in the synthesis of mevalonic acid, which reduces the energy production and muscle injury thereafter.[3]

Myth: Creatine phosphokinase levels are always elevated

No. The elevation of creatine phosphokinase is based on the type of SAMS highlighted in [Table 1].

Myth: I have pain over the left calf only – due to statins – 6 months after starting medication

The characteristic statin-associated myalgia is early-onset, bilateral, symmetrical muscle pain over the proximal muscles [Figure 2].
Figure 2: Clinical diagnosis of statin-associated muscle symptom is with the following

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Myth: My patient had persistent rhabdomyolysis even after I stopped statins. Hence, it has to be some other cause

Statins can be an environmental trigger for anti-HMG-CoA reductase. This is a rare complication that leads to severe rhabdomyolysis by an autoimmune response.[4] This disorder possibly develops in persons who have a genetic susceptibility. This entity is called anti-HMG-CoA reductase necrotizing autoimmune myositis. Due to its severity, one has to be aware of such an entity and promptly institute treatment with immunosuppressants.

Myth: Myalgia – Is it a myth? It is just a nocebo effect

Suggesting that a particular drug can produce a side effect will precipitate the same side effect whether the patient is taking the particular drug or placebo. This nocebo effect or side effect by suggestion has been demonstrated in SAMSs in several studies. In the, Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial, 511 patients were randomized to atorvastatin 20 mg or placebo for 10 weeks, and then, the groups were crossed over.[5] In the overall analysis, SAMS was noticed in 42.6% of persons with atorvastatin alone, 26.5% of persons with placebo alone, and 9.8% with both medications, and 17.3% had no SAMS. When the intolerant group of persons was randomized to ezetimibe or evolocumab, the incidence of SAMS was 28.8% and 20.7%, respectively (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.39–1.19, P = 0.17). These data clearly show that there is a prominent nocebo effect in SAMS.

Myth: I have lots of shortcuts to prevent myalgia – coenzyme Q10, Vitamin D, red yeast rice, berberol (plant extract), and glucosamine

None of these has been definitely proven to reduce SAMS. Although there is some genetic basis in the use of coenzyme Q 10, there is a variant within COQ2 gene which produces mild asymptomatic deficiency and expression of muscle drug transporter – The 2018 american college of cardiology (ACC) guideline has clearly given a Class III – no benefit status – for the routine use of coenzyme Q10 for the treatment of SAMS.[2]

Myth: Once statin-associated muscle symptom is proven – Statins cannot be used

Following resolution of myalgia, three strategies can be adopted: (1) use a lower dose of the same statin, (2) use a different statin, and (3) use a lower dose of statin with other agents, such as ezetimibe. Finally, in case of recurrent SAMS, it is reasonable to use nonstatin therapy.[2]

Myth: Following administration of statins, routine creatine kinase and liver functions must be monitored

Routine measurement of creatine kinase (CK) and transaminase levels is not useful and is a Class III indication (not useful). Check the CK levels in case of severe myalgia or muscle weakness. Check liver function only if there are signs and symptoms, suggestive of liver toxicity. Severe statin-associated hepatotoxicity is very rare. A thorough evaluation of nonstatin etiologies is suggested in case of persistently elevated transaminase levels.[2]

Myth: Statins cannot be used in liver disease

In patients with increased atherosclerotic cardiovascular disease risk and associated chronic stable liver disease (such as nonalcoholic fatty liver disease), it is reasonable to use statins after baseline measurement and periodic monitoring and safety checks.[2]


  Statins Cause Diabetes I Do Not Want Them Top


The incidence of type 2 diabetes mellitus (T2DM) increases with statins, and there is a linear relationship with the dose. However, the benefits are more than the harmful effects of the development of diabetes. In the Jupiter trial on primary prevention comparing rosuvastatin 20 mg and placebo, there were 25% more cases of diabetes mellitus in the rosuvastatin arm. For 54 new cases of T2DM, 134 vascular events or deaths were prevented. The major CVD event reduction in the whole group (HR: 0.56; 95% CI: 0.46–0.69) was not significant for interaction with those who developed diabetes (HR: 0.63; 95% CI: 0.25–1.60).[6] Another interesting point is that in the heart outcomes prevention evaluation (HOPE)-3 trial (n = 12,705 persons) that used 10 mg of rosuvastatin, the HR for new-onset T2DM was 1.02.[7]

The CTT trial has a clear analysis about the risk and benefits of new-onset T2DM with statin therapy in primary prevention. It has shown that the risk is >50 times smaller than the absolute benefit of statin therapy.[1]


  New-Onset Diabetes Is Inevitable Top


Identify risk factors for new-onset T2DM mentioned in [Figure 3].
Figure 3: Risk factors for the development of new-onset type 2 diabetes mellitus

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Lifestyle modification to reduce the risk factors will reduce the incidence of T2DM. Recommended lifestyle changes are regular moderate-intensity physical activity, maintain a healthy dietary pattern, and achieve a modest weight loss.[2]

Myth: Statins are not beneficial in stroke because they bleed

The answer is yes and no. The net clinical benefit of reduction in ischemic stroke in stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial (atorvastatin vs. placebo) is 8.9% versus 11.9% which is offset by the higher incidence of intracranial hemorrhage – 2.3% versus 1.4%.[8] However, major meta-analyses involving nearly 248,000 patients and second women's health initiative show minimal to no association.[9] There is also no absolute correlation with LDL levels and hemorrhagic stroke.

Small-vessel ischemia is more prone for hemorrhage. However, this group has 79% coronary plaques and 37% stenotic lesions.[10] They will benefit from statins the most.


  Statins Produce Cancers and Cognitive Dysfunction Top


The american heart association (AHA) guideline has made a clear statement that memory and cognition disorders are rare and unclear. There are case reports. There was no increase in memory/cognition problems in large three randomized controlled trials.

There is unclear/unfounded association between cancers, renal function, tendon rupture, interstitial lung disease, and low testosterone.[2]

Myth: The risks of statins are more than the side effects in the overall picture

For 10,000 patients treated for 5 years, the risk and benefit are given in [Figure 4].
Figure 4: Risks and benefits of statins in 10,000 patients treated for 5 years

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For every 10,000 patients treated for 5 years, the incidence of side effects is given – 5 will develop myopathy, 5–10 hemorrhagic stroke, 50–100 diabetes mellitus, while 500–1000 events will be averted.[11]


  Social Media Hype: Statins Increase Calcium in the Plaque, the Increased Plaque is a Marker For Acute Coronary Syndrome, So Statins Should Not Be Given Top


Social media combined two separate papers – one mentioning that coronary artery calcium (CAC) increases during statin therapy and another mentioning that increase in CAC is a marker for acute coronary syndrome (ACS).

Statins regress the plaque and increase the coronary calcium score in the plaque. This stabilizes the plaque and reduces ACS. This is called the plaque paradox.[12]


  Conclusions Top


The infrequent and rare side effects of statins can be challenging and have to be managed carefully. A large majority of patients will tolerate statin rechallenge either with same statin, lower dose statin, alternative statin, or an in combination with nonstatins.

Statin therapy is usually well tolerated and safe and modifiable by treatment change. “Adverse effects of statins” has become a myth, and the fact is that it is now called “statin-associated side effects.”

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.  Back to cited text no. 1
    
2.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 2019;139:e1082-143.  Back to cited text no. 2
    
3.
Hla D, Jones R, Blumenthal RS, Martin SS. Assessing Severity of Statin Side Effects: Fact Versus Fiction. Available from: https://www.acc.org/latest-in-cardiology/articles/2018/04/09/13/25/assessing-severity-of-statin-side-effects. [Last accessed on 2019 Sep 27].  Back to cited text no. 3
    
4.
Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med 2016;374:664-9.  Back to cited text no. 4
    
5.
Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90.  Back to cited text no. 5
    
6.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr., Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.  Back to cited text no. 6
    
7.
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021-31.  Back to cited text no. 7
    
8.
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.  Back to cited text no. 8
    
9.
Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE, et al. Statins and intracerebral hemorrhage: Collaborative systematic review and meta-analysis. Circulation 2011;124:2233-42.  Back to cited text no. 9
    
10.
Gongora-Rivera F, Labreuche J, Jaramillo A, Steg PG, Hauw JJ, Amarenco P, et al. Autopsy prevalence of coronary atherosclerosis in patients with fatal stroke. Stroke 2007;38:1203-10.  Back to cited text no. 10
    
11.
Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.  Back to cited text no. 11
    
12.
Ferencik M, Chatzizisis YS. Statins and the coronary plaque calcium “paradox”: Insights from non-invasive and invasive imaging. Atherosclerosis 2015;241:783-5.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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Abstract
Introduction
Statin Safety an...
Statins Cause Di...
New-Onset Diabet...
Statins Produce ...
Social Media Hyp...
Conclusions
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