Shubhangam Sharma¹, Hemlata Verma² and Manish Jain³

¹Department of Pharmacology, M LB Medical College, Jhansi, UP, India.

²Department of Pharmacology, Gandhi Medical College, Bhopal, MP, India.

³Community medicine people dental academy Bhopal MP India.

Corresponding Author E-mail: vkverma0505@gmail.com

DOI : https://dx.doi.org/10.13005/bpj/1094

Abstract

Statins are the most widely prescribed drugs for the correction of dyslipidaemia and prevention of cardiovascular events in patients of Metabolic syndrome, so early detection of Adverse drug reactions(ADR) becomes necessary. This prospective, comparative study done in OPD setting in a tertiary care centre of central India aimed at finding out the ADRs of low dose atorvastatin in patients with metabolic syndrome versus the usual care group. Patients satisfying NCEP-ATPIII criteria for metabolic syndrome were divided into two groups in which one received statin therapy (Group A) and other did not(Group B). A total of 33 ADRs were recorded out of which 26 (38.23%) were in Group A and 7 (31.81%) were in Group B, with no significant difference in the ADRs recorded in both the groups. In patients with statin therapy, most common adverse effects were dyspepsia (10.29%) and elevation of hepatic transaminases(10.29%), followed by constipation (5.8%), sleep disturbances, myalgia and headache (2.9%). The adverse effect profile of group B was nearly similar with dyspepsia in 3 cases (13%) followed by constipation in 2 cases (9%) ,elevation in hepatic transaminases and headache in 1 case (4.5%). Definite (certain) relationship was established in 12% patients while probable in 23% and 65% ADRs were categorized as possible. Severity assessment recorded 73% of the total ADR as mild, 23% as moderate and only 3.8% as severe. Although statins are one of the safest medications for dyslipidaemia and metabolic syndrome as also proved in the present study; further studies of ADRs is needed for early detection, prevention and management of ADRs and reduced morbidity.

Keywords

ADRs; Atorvastatin; Metabolic syndrome; Dyslipidemia

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Copy the following to cite this article: Sharma S, Verma H, Jain M. Study of Adverse Drug Reaction of Low dose Atorvastatin in Patients With Metabolic Syndrome and Comparison With the usual Care Group. Biomed Pharmacol J 2017;10(1).

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Introduction

Metabolic syndrome (MetS) is a constellation of cardiometabolic risk determinants comprising of obesity (Central adiposity), glucose intolerance and insulin resistance, dyslipidaemia  (including  hypertriglyceridemia, increased  free  fatty  acids  and  decreased HDL–Cholesterol) & hypertension.^(1,2) Statins  are one of the major pharmacotherapeutic modalities for  lipid management which also reduce coronary events in  population  at  risk and  in  patients with  stable  coronary disease. ^[3,4]  These  are  the   most  effective  and  best  tolerated  agents  for  the treatment of dyslipidemia. These drugs are competitive and reversible inhibitors  of  HMG-CoA  reductase which  plays a central role in the production  of cholesterol in the liver. Because statins  are  similar to HMG-CoA  on a molecular level they take the  place of  HMG-CoA in the enzyme and reduce the rate by which it is able to produce  mevalonate, the next molecule in the cascade that eventually produces cholesterol,as well as a number of other compounds.Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, they also increase high-density lipoprotein (HDL) cholesterol  and reduce triglyceride and VLDL concentrations.⁽⁴⁾

Mevalonate not only acts as precursor of cholesterol but also serves as a precursor for non-steroid isoprenoids such as CoQ10,  heme-A, and farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These intermediates of mevalonate pathway impact the benefits as well as risk of statins.⁽⁵⁾ An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. ⁽⁶⁾ Characteristics predisposing individuals to statin adverse effects include but are not limited to multiple or serious comorbidities, including impaired renal or hepatic function, history of previous statin intolerance or muscle disorders, unexplained ALT elevations ≥3 times ULN, patient characteristics or concomitant use of drugs affecting statin metabolism and also age >75 years.⁽⁷⁾

Adverse drug reaction and quality of life are most important in terms of patient health.  For statins, as for all medications, vigilance for potential AEs is imperative. Recognition of potential statin AEs is needed and may be fostered by an improved awareness both of relevant literature and of its limitations. Most statin adverse effects, including the musculoskeletal (rhabdomyolysis) and gastrointestinal systems are dose-related⁽⁸⁾. That is, higher doses bring increased risks. Also dose-related are elevations in plasma fibrinogen levels⁽⁹⁾ and liver enzyme indices ⁽¹⁰⁾ .Each doubling of the statin dosage also doubles the incidence of liver enzyme elevations that exceed three times the upper limit of normal. Hence, rational dosing is key with statins for not only achieving target low-density cholesterol (LDL-C) levels, but also for avoiding adverse effects.

Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity. Hence this study was undertaken to study the adverse effect profile of low dose atorvastatin in patients of metabolic syndrome, a more vulnerable group for statin AEs.

Methods and Materials

This prospective and randomized observational study was conducted in the OPD patients at a tertiary care hospital in Bhopal. This study has been conducted observing ethical guidelines of Biomedical research on human participants following ethical review procedures, general ethical issues enshrined therein for prospective studies and after approval from the institutional ethical committee, as required.

Table 1: Age Group Wise Distribution Of Cases

S. No.	Age group (yrs)	Group A (n=68)		Group B (n=22)		Total
		No.	%	No.	%	No.	%
1	21-30	6	8.8	1	4.5	7	7.7
2	31-40	8	11.76	4	18.18	12	13.33
3	41.50	27	39.7	9	40.9	36	40
4	51-60	20	29.41	6	27.27	26	28.8
5	61-70	7	10.29	2	9	9	10
	Total	68	100	22	100	90	100

 

Inclusion Criteria

Patients ready to give consent for the study.

Age group 20-70 years.

Patients satisfying at least 3 parameters of metabolic syndrome as per NCEP ATP-III (National Cholesterol

Education Program Adult Treatment Panel III ) criteria.

Exclusion Criteria

Patients not ready to give consent for study.

Age less than 20 years and greater than 70 years.

Patients with recent Myocardial infarction.

Pregnancy.

Patients already taking statins or other hypolipidaemic drugs.

Grouping of Patients

Patient Were Divided into 2 Groups –

Group A-Patients satisfying at least 3 parameters of metabolic syndrome as per the  NCEP ATP-III criteria, who received statin therapy (Atorvastatin 20 mg/day).
Group B-Patients satisfying at least 3 parameters of metabolic syndrome as per the  NCEP-ATP-III criteria, but did not take statin therapy due to any of  the  following  reasons.

Non-compliance.

Contra-indications.

A total of 90 cases were studied in which group A (patients receiving statin therapy) included 68  cases (n=68) and group B (patients not taking statin therapy) included 22 cases (n=22). Both the groups also received target driven treatment for hypertension and elevated glucose, as required The cases were followed up for 3 months.

Evaluation and Statistical Analysis

The ADRs were recorded and summarized in a tabulated form and represented in percentages; Chi square value was calculated and also, a p-value of less than 0.001 was considered statistically significant. Causality assessment was done by using WHO (UMC) causality assessment scale. Severity assessment was done on a scale of mild, moderate and severe.

Figure 1:  Causality Assessment (WHO-UMC) of ADRs Click here to View figure

 

Results and Discussion

During the study a total of 90 patients having metabolic syndrome as per the NCEP-ATP-III criteria were enrolled, of which 68 were in Group A –who received statin therapy and 22 in Group B- who did not receive statin therapy. The characteristics of the patients in both the groups in terms of age group, sex wise distribution, lipid profile, liver function were comparable at baseline. Majority of patients were in the age group 41-60 years in both the groups. There were more females as compared to males in both the groups. There were 55.88% females in group A and 54.5% females in group B. Overall, there were 55.5% females in both the groups collectively. A high prevalence of metabolic syndrome (41.1%) in urban Asian Indian adults (Age 20-75 years) in Chennai was reported by Ramchandran A et al (2003); which was more common in women than in men (45.5% Vs 36.1%)⁽¹¹⁾  Similar observations have been recorded in this study.

Figure 2: Severity assessment of ADRs   Click here to View figure

 

Table 2: Sex Wise Distribution of Cases

S. No.	Sex	Group A (n=68)		Group B (n=22)		Total
		No.	%	No.	%	No.	%
1	Males	30	44.11	10	45.5	40	44.5
2	Females	38	55.88	12	54.5	50	55.5
	Total	68	100	22	100	90	100

 

The patients were assessed of having metabolic syndrome according to the NCEP-ATP-III criteria in accordance to which it was found that a total of 74.4% patients were having centripetal obesity, 82.3% of total patients were having high B.P. (B.P. >130/85 mmHg) and 75.5% of the patients were having high fasting plasma glucose levels (FPG >110 mg/dl) in both the groups collectively.

Table 3:  Changes in Level of Hepatic Transaminases in Patients of Group A and B

S.No.	Hepatic Transaminases	Group A (n=68)		Group B (n=22)
		No.	%	No.	%
1	No change	49	72	20	90.9
2	Mild Change	12	17.6	1	4.5
3	Moderate increase	6	8.8	1	4.5
4	Significant increase	1	1.4	0	0
	Total	68	100	22	100

Chi square value: 3.26; Significance P Value: 0.32(Not Significant)

The adverse effect analysis in our study revealed that the overall incidence of adverse effects was similar among both the groups and no statistically significant difference was observed (p value>0.001). Most common adverse effects were gastrointestinal system related. A total of 26 (38.23%) ADR were recorded in Group A and a total of 7 (31.81%) ADR were recorded in group B.

Table 4: Adverse Effects Observed in Patients of Group A and B.

S.No.	Adverse Effect	Group A (n=68)		Group B (n=22)
		No.	%	No.	%
1	Dyspepsia	7	10.29	3	13
2	Constipation	4	5.8	2	9
3	Pain in abdomen	1	1.4	0	0
4	Sleep Disturbance	2	2.9	0	0
5	Myalgia	2	2.9	0	0
6	Headache	2	2.9	1	4.5
7	Mood & Behaviour changes	1	1.4	0	0
8	Elevations in Hepatic transaminases	7	10.29	1	4.5
	Total	26	38.23	7	31.81

Chi square value: 3.23; Significance P Value: 0.863(Not Significant)

In patients with statin therapy, most common adverse effect was dyspepsia (10.29%), followed by constipation (5.8%), myalgia, headache and sleep disturbances (2.9%).Mood and behavioural changes were in the form of insomnia, depression, aggressiveness, behaviour change and were seen only in 1 patient (1.4%), while in patients without statin therapy,13% had dyspepsia and 9% complained of constipation and 4.5% of headache. All these adverse effects were clinically insignificant and did not need any change or termination of treatment.

The Statin Therapies for Elevated Lipid Levels compared Across doses of Rosuvastatin (STELLAR) trial randomized 2,431  participants with hypercholesterolemia to treatment with rosuvastatin; simvastalin or pravastatin,all in varying doses. The percentages of patients who reported adverse events during treatment were similar among randomized groups. Adverse events were generally mild and similar across groups. The most common adverse events overall were pain (6%), pharyngitis (5%), myalgia (4%), and headache (3%). Serious adverse events were reported in 29 patients, with the number of serious events ranging from 0 (with rosuvastatin 40 mg) to 5 (simvastatin 40 mg). Changes in clinical laboratory results (increases in liver or muscle enzymes) were generally small.⁽¹⁰⁾

Similarly, in the lipitor placebo-controlled clinical trial database of 16,066 patients with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality ⁽¹²⁾; again establishing that the adverse effects in both the groups were comparable. The five most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%),arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).⁽¹²⁾

Other Adverse Reactions Reported In Placebo-Controlled Studies Include malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase. Special senses: vision blurred, tinnitus.The reports are generally nonserious, and reversible upon statin discontinuation.⁽¹²⁾

In ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study involving 10,305 participants treated with 10 mg atorvastatin daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the both the groups was comparable during a median of 3.3 years of follow-up. ⁽¹²⁾

In Collaborative Atorvastatin Diabetes Study (CARDS) involving 2,838 subjects with type 2 diabetes treated with atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported. ⁽¹³⁾

Another study, the TNT (Treating to New Targets Study) ⁽¹⁴⁾ involving 10,001 with clinically evident CHD treated with atorvastatin 10 mg daily (n=5006) and 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years; which correlates to the present study in terms of safety of low dose atorvastatin.

Another study which aimed at statin-associated muscle-related adverse effects,which  selected subjects from a subset of patients who participated in the University of California, San Diego (UCSD) Statin Effects Study reported the ADRs as muscle pain (93%), fatigue (88%), and weakness (85%). ⁽¹⁵⁾

Hepatic injury due to statins was reported by a group who analysed episodic reports of adverse drug reactions sent to the Swedish Adverse Drugs Reactions Advisory Committee between 1988 and 2010. They found 73 patients with hepatotoxicity of whom 30 [41%] were taking atorvastatin and 28 [38%] simvastatin with two deaths and one requirement for liver transplant.⁽¹⁶⁾  Previous studies have shown severe adverse hepatic events related to statins to be infrequent. In a post-hoc analysis of the GREACE  (Greek Atorvastatin and Coronary Heart Disease Evaluation) Study, seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal).⁽¹⁷⁾  Also,in TNT study persistent transaminase elevations (≥3 – ULN) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg.⁽¹⁴⁾

In our study, evaluation of hepatic transaminases was done under the heads of no change, mild change (<1.5 times the upper normal limit), moderate change (elevation from 1.5-3 times the UNL) and severe (>3 times the UNL). Results revealed that most of the cases had either no change (72% in group A and 90.9% in Group B) or mild changes (17.6% in group A and 4.5% in group B) to moderate elevations (8.8% in group A and 4.5% in Group B). Also, patients with mild change in hepatic transaminases were excluded because either the change was <1.5 times UNL or on repeated testing it was observed to be normal.

The Acute Liver Failure Study Group reported on 133 prospectively collected cases of acute liver failure due to drug-induced liver injury between 1998 and 2010;only 2 patients [1.5%] had taken atorvastatin. ⁽¹⁸⁾ In our study, severe change was observed in 1(1.4%) patient which required termination of therapy comparable to previous study.

Causality assessment done by WHO UMC causality assessment scale established definite (certain) relationship in 12% patients while probable in 23% and 65% ADRs were categorized as possible. Severity assessment recorded 73% of the total ADR as mild, 23% as moderate and only 3.8% as severe. In a similar study of severity assessment of adverse drug reaction and quality of life of dyslipidemia patients on atorvastatin or rosuvastatin versus controlled; done on 60 patients  of which 70% were male and 30% were female, it was found that total percentage of adverse drug reaction in group I (treated with atorvastatin)was mild -51.72, moderate 44.8, severe 3.45 and for group II(rosuvastatin) mild (6.89), moderate (86.2), severe (6.89). Also, most frequent adverse drug reaction associated with Atorvastatin was headache, weakness and constipation. ⁽¹⁹⁾

Conclusion

Since statins have become very popular and are being widely prescribed in recent years to lower blood cholesterol and thus find their utility in a spectrum of pathological conditions including hypercholesterolemia, dyslipidaemia, hypertension, diabetes mellitus, coronary artery diseases, etc; the  present study was undertaken to study the adverse effects of low dose Atorvastatin in patients with metabolic syndrome. From the present study, it can be concluded that low dose (20 mg/day) atorvastatin treatment is safe, well tolerated and adverse effects are few and mostly mild, transient and reversible emphasizing the fact that benefits of statins greatly outweigh its risks.

But as no drug is without potential for adverse effects, there is need for awareness of risks as well as benefits of all drugs, particularly like statins which have a wide spectrum of indications; and hence calls for further studies of ADRs for early detection, prevention and management of ADRs and reduced morbidity. The understanding of relatively common statin-associated adverse effects will enable clinicians in making decision in choosing appropriate statin in appropriate dose.

Acknowledgements

Authors would like to express their gratitude towards faculty members of department of Cardiology and also to all the patients enrolled in this study for their support and co-operation which enabled the conduction and completion of this study. Authors would like to extend their deep gratitude to Dr Sarabjeet Singh Sir, (DM Clinical Pharmacology) for his unstinting support and encouragement.

Declarations

Funding

none

Conflict of interest

none

Ethical approval

The   study  was  conducted  after  obtaining  approval  from  the  Institutional  Ethics  Committee.

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