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 RESEARCH ARTICLE

An exploratory study examining lipid-lowering medications in reducing fasting serum lipids in schizophrenia patients treated with atypical antipsychotics

Brenda Vincenzi, MD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

Christina P. C. Borba, PhD, MPH

Schizophrenia Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Deborah A. Gray, MBA, MS

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

Paul M. Copeland, MD

Harvard Medical School, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

Xingyue Wang, ScB

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

Xiaoduo Fan, MD

Schizophrenia Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Gowri G. Aragam, AB

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

David C. Henderson, MD

Schizophrenia Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

BACKGROUND: We present a retrospective study examining response to treatment with fibrates or statins in schizophrenia patients.

METHODS: We identified the patient population using the Research Patient Data Registry. Demographic data, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non–HDL-C) levels were obtained before initiation of treatment with lipid-lowering medication (LLM) and after LLM treatment was initiated (N = 183).

RESULTS: Treatment with LLMs resulted in a statistically significant decrease in total cholesterol, triglycerides, LDL-C, and non–HDL-C. An independent-samples t test comparing the statin treatment–alone group with the fibrate treatment–alone group showed a significant reduction in triglyceride levels from baseline to 1-year follow-up in the fibrate treatment–alone group.

CONCLUSIONS: The results of this study indicate that schizophrenia patients respond to LLMs in a manner consistent with the general population. Future studies would benefit from a larger sample, as well as comparisons between more specific treatment groups, such as those defined by type of statin or fibrate, to observe differential effects on specific markers of dyslipidemia in this population.

KEYWORDS: schizophrenia, fibrate treatment, statin treatment, metabolic disorders, atypical antipsychotics

ANNALS OF CLINICAL PSYCHIATRY 2013;25(2):141-148

  INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death worldwide.1,2 Dyslipidemia—a disruption in the amount of lipids in the blood—is an important risk factor for CVD.3 Lipid abnormalities have become increasingly prevalent in the United States, with a significant increase in morbidity rates within the past decade.4,5 Factors contributing to dyslipidemia include low high-density lipoprotein cholesterol (HDL-C), high low-density lipoprotein cholesterol (LDL-C), high total cholesterol, and high triglyceride levels. Apart from contributing to the development of dyslipidemia, these factors have been independently associated with a higher incidence of CVD.6-9 The prevailing opinion is that after high LDL-C and low HDL-C levels, high plasma triglycerides should be regarded as a risk factor for developing CVD.10 High total cholesterol and LDL-C levels are strong independent risk factors for coronary heart disease (CHD).11 Total cholesterol levels of 160 mg/dL—well below the average level in the United States—put patients at increased risk for heart disease. Low levels of HDL-C, defined as <40 mg/dL in men and <50 mg/dL in women, also are firmly established as an independent risk factor for CHD.12

In 1989, Gordon et al12 analyzed data from 4 large prospective studies—the Framingham Heart Study, the Lipid Research Clinics Prevalence Mortality Follow-Up Study, the Coronary Primary Prevention Trial, and the Multiple Risk Factor Intervention Trial. The data showed that for every 1 mg/dL (0.026 mmol/L) increase in HDL-C plasma level, there was a decrease in CHD risk—approximately 2% in men and 3% in women—independent of other risk factors, including plasma LDL-C. Recent negative results obtained in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial suggested that improving HDL-C levels in plasma alone does not necessarily translate into cardiovascular risk reduction; the data also demonstrated that increasing HDL-C levels through pharmacotherapy is neither adequate nor necessary for predicting cardiovascular benefit.13,14

It also has been observed that the leading cause of premature death in schizophrenia patients is related to CVD.15 The literature review by Hennekens et al15 revealed that not only do schizophrenia patients have a 20% reduced life expectancy compared with the general population (age 57 vs age 72 in men and age 65 vs age 80 in women, respectively), but also that more than two-thirds of schizophrenia patients, compared with approximately one-half of the general population, die of CHD. Ray et al16 showed that patients with psychiatric diagnoses who used typical and atypical antipsychotics had a similar, dose-related increased risk of sudden cardiac death compared with patients not taking antipsychotics.

Dyslipidemia-induced cardiovascular complications may be an even greater threat to patients with schizophrenia or schizoaffective disorder who are treated with atypical antipsychotics. Second-generation antipsychotics have been known not only to directly induce insulin resistance but also to affect lipogenesis and lipolysis, leading to progressive lipid accumulation and adipocyte enlargement.17

The risk of dyslipidemia and other metabolic disorders such as obesity and diabetes mellitus has been shown to be 1.5 to 2 times greater in patients treated with atypical antipsychotics than in patients in the general population.18 Dyslipidemia associated with insulin resistance includes hypertriglyceridemia, an increase in very low-density lipoprotein (VLDL) secretion from the liver, an increase in atherogenic small, dense LDL, and a decrease in HDL-C.19,20

Antipsychotic-induced lipid abnormalities have been associated with atypical antipsychotic treatment. Although there are reports of abnormal LDL-C related to antipsychotics, the most common abnormalities are reduced HDL-C and hypertriglyceridemia, which have been linked to clozapine and olanzapine use.21-25 In a 5-year naturalistic study of 82 clozapine-treated patients with schizophrenia or schizoaffective disorder, weight significantly increased over time among all patients. Weight gain significantly correlated with increases in both total serum cholesterol and serum triglycerides.22

Clinically, a variety of lipid-lowering medications (LLMs) have been used concomitantly with atypical antipsychotics to alleviate their negative metabolic effects. In a retroactive study examining the efficacy of pravastatin, atorvastatin, fenofibrate, gemfibrozil, and lovastatin as LLMs in a clozapine-treated patient population, Landry et al26 found total cholesterol and triglyceride levels were significantly reduced in all patients. Fluvoxamine also has been found to be effective in lowering body mass index and triglycerides when coadministered with clozapine.27 However, fluvoxamine also inhibits cytochrome P450, 1A2, and 2C19 and may result in significantly elevated clozapine blood levels and potential toxicity.28 We also found that aripiprazole was effective in reducing total triglycerides (P = .001), and total VLDL cholesterol (P = .01), VLDL-1 cholesterol (P = .012), and VLDL-2 cholesterol (P = .012) in patients who were taking a stable dose of olanzapine.29

Of these LLMs, fibrates and statins often are compared, as they have both shown efficacy in improving lipid profiles in general population patients. Fibrates are a class of compounds that are used to reduce the risk of cardiovascular events by intervening in the development of dyslipidemias.30 Statins have been similarly prescribed. As shown by a recent meta-analysis,31 the use of statins reduces major vascular events by lowering LDL-C levels compared with control, regardless of baseline risk level. In small studies, statins have been shown to be effective in reducing lipid elevation associated with antipsychotic treatment.32 In the past decade, investigators have become more interested in the pharmacologic differences between fibrates and statins, which have revealed important factors that will affect how they are prescribed in a clinical setting.33,34

Statins are a group of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors.35 HMG-CoA reductase is the enzyme that catalyzes the rate-limited step in the biosynthesis of cholesterol. Statins cause a reduction in cholesterol, leading to increased expression of LDL receptors, resulting in clearance of LDL-C from the blood.36 Statins have been found to be highly effective in reducing LDL-C, but only moderately effective in reducing triglyceride levels and in increasing HDL-C, as these are indirect effects of statins’ main mechanism of action.37 Common side effects of statins include nausea or vomiting, diarrhea, abdominal pain, constipation, flatulence, heartburn, and headache. There is a rare risk of myopathy as a result of an increase in creatine phosphokinase.38

Fibrates act more directly on triglycerides and HDL-C, while having a less pronounced effect on LDL-C. Fibrates activate peroxisome proliferator-activated receptor α (PPAR α), a nuclear receptor that reduces triglyceride levels by stimulating the hepatic oxidation of free fatty acids and inducing the expression of lipoprotein lipase, which hydrolyzes triglycerides in plasma.39 Fibrates also increase the expression of apolipoprotein A-I and apolipoprotein A-II, which leads to increased HDL-C plasma levels.40 It is not surprising that statin-fibrate combination therapy has become an effective option for clinicians when treating patients with mixed dyslipidemias.41-46 Common reported adverse effects of fibrates have been mild and include transient gastrointestinal problems such as nausea, flatulence, and constipation. Other reported adverse effects include headache, anxiety, vertigo, dizziness, sleep disorders, arthralgia, rash, pruritus, urticaria, and blurred vision. Another potential adverse effect of fibrates is that they increase homocysteine and creatinine plasma levels. The coadministration of fibrates with statins is associated with a small increase in rhabdomyolysis. A recent pharmacoepidemiology safety study47 evaluated 584,784 patients who initiated statins or fibrate therapy. The incidence rates (IR) of rhabdomyolysis in patients using statins alone was 3.30/100,000 patient-years; the adjusted IR ratio for statin-fenofibrate combinations compared with statins alone was 3.75 (95% CI, 1.23 to 11.40).

Oh et al48 recently reported that antipsychotic-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of adenosine monophosphate–activated protein kinase (AMPK) activity. AMPK plays a critical role in the regulation of hepatic lipid homeostasis by inhibition of lipogenesis and stimulation of fatty acid oxidation. Oh et al48 proposed a model whereby atypical antipsychotics affect AMPK regulation by increasing messenger ribonucleic acid levels of sterol regulatory element–binding proteins to enhance lipid synthesis, and decreasing PPAR-α–mediated fatty acid oxidation by reducing AMPK signaling.48

In light of these data, one could speculate that antipsychotic-mediated dysregulation of lipid metabolism may affect the metabolic pathways of LLMs, resulting in different therapeutic outcomes compared with the general population.

Further investigation is needed to determine what, if any, differences exist between the effectiveness of statins vs fibrates in improving specific markers of dyslipidemia in schizophrenia patients. To our knowledge, there have been no publications examining the efficacy of fibrate treatment in comparison with statin treatment in antipsychotic agent–treated patients.

In the study by Landry et al,26 a differential analysis between treatment groups was not performed, and the study also was limited by small sample size. We now present an exploratory retrospective study examining treatment response with fibrates or statins in a population of schizophrenia patients. We hypothesized that all LLMs would be effective in reducing LDL-C and triglycerides and in increasing HDL-C. We also proposed that fibrate treatment would be more effective than statins alone in reducing elevated triglyceride levels in patients taking antipsychotic medications.

  METHODS

The patients examined in this study included inpatients and outpatients with recorded visits to Massachusetts General Hospital (Boston, MA, USA) between May 15, 1999, and January 23, 2009. Following institutional review board (IRB) approval, identification of the patients was achieved using the Research Patient Data Registry (RPDR). The RPDR is an electronic database identifying diagnosis by International Classification of Diseases-9 (ICD-9) criteria while linking administrative, clinical, and laboratory data. Exact diagnosis codes are not required because the RPDR enables use of its hierarchical tree structure to query and segregate the patient population in question. The RPDR contains patient records that include demographic data, diagnoses, inpatient and outpatient encounter information, provider information, procedural data, as well as a medication record. Patient identifiers are encrypted, and access to medical records is possible through proper IRB approval.

Patients with schizophrenia disorder diagnoses (ICD-9 295-295.9) were queried for a treatment history with statins and/or fibrates (N = 876) using the electronic database of medical records. Laboratory test results were cross-referenced with known dates of statin or fibrate administration, and patients were eliminated if the start of lipid-lowering treatment could not be determined or if sufficient pretreatment and posttreatment laboratory test results were not available (N = 677). Additional patients were eliminated if a psychiatric diagnosis could not be confirmed using clinicians’ notes (N = 16). Demographic data, total cholesterol, triglycerides, LDL-C, HDL-C, and non–HDL-C (total cholesterol minus HDL cholesterol) were collected before initiation of treatment with LLMs and at 6 months and 1 year after LLM treatment began (6 months±2 months and 1 year±2 months; N = 183). Of the 183 patients, 18 had switched from statins alone, fibrates alone, or a combination of the 2.

Statistical analysis

Statistical analysis was performed using SPSS version 17.0 (SPSS Inc). For all analyses, a value of P < .05 (2-tailed) was considered statistically significant. Descriptive analysis for demographic data was performed. The primary analyses were conducted using the 183 patients and a paired-samples t test to examine the mean difference for total cholesterol, triglycerides, LDL-C, HDL-C, and non–HDL-C of all LLM treatment, comparing baseline with 6-month follow-up and baseline with 1-year follow-up. Additionally, an independent-samples t test was conducted to assess the mean difference for change between those who received statin treatment alone (n = 155) and fibrate treatment alone (n = 13), comparing baseline with 1-year follow-up. Additionally, chi-square comparisons were performed to examine the frequency of baseline triglyceride elevations (using 150 mg/dL and 200 mg/dL as cutoffs) between the 2 treatment groups (statin treatment [n = 155] and fibrate treatment [n = 28]).

  RESULTS

The demographics for age, race, and primary antipsychotic treatment at baseline are reported in TABLE 1. Although 64.5% of the total sample had baseline triglycerides >150 mg/dL and 43.7% had triglycerides >200 mg/dL, only 19.5% received a fibrate.


TABLE 1

Demographic and clinical characteristics of schizophrenia patients treated for hyperlipidemia (N=183)

Characteristic Mean SD
Age (years) 57 11
Sex No. %
Male 99 54%
Female 84 46%
Marital status Mean SD
Single 113 62
Married 25 14
Widowed 13 7
Divorced 31 17
Missing data 1 .5
Ethnicity    
White 136 74
African American 22 12
Asian 3 2
Hispanic 17 9
Other 5 3
Antipsychotic    
Olanzapine 40 22
Aripiprazole 19 10
Clozapine 24 13
Risperidone 47 26
Perphenazine 4 2
Quetiapine 34 19
Haloperidol 8 4
Ziprasidone 7 4
SD: standard deviation.

The paired-samples t test was used to analyze lipid parameters for all patients receiving LLM (either fibrate or statin) treatment for dyslipidemia (TABLE 2). There was a statistically significant difference comparing baseline treatment with first follow-up treatment (6 months±2 months) and baseline treatment to final treatment (12 months±2 months) for total cholesterol, triglycerides, LDL-C, and non–HDL-C. Treatment with LLMs resulted in a decrease in total cholesterol, triglycerides, LDL-C, and non–HDL-C.


TABLE 2

Paired-samples t test assessment of lipid parameters over the course of treatment (N=183)

  Mean±SD t P
Total cholesterol (mg/dL)
Baseline 195±46    
6-month follow-up 174±41 6.102 <.001
12-month follow-up 167±41 7.064 <.001
Triglycerides (mg/dL)
Baseline 217±123    
6-month follow-up 183±103 4.037 <.001
12-month follow-up 175±129 3.776 <.001
LDL-C (mg/dL)
Baseline 108±41    
6-month follow-up 92±36 5.519 <.001
12-month follow-up 89±33 5.916 <.001
HDL-C (mg/dL)
Baseline 45±14    
6-month follow-up 46±14 –1.700 .091
12-month follow-up 45±15 0.382 .703
Non–HDL-C (mg/dL)
Baseline 149±45    
6-month follow-up 127±40 9.923 <.001
12-month follow-up 123±39 7.409 <.001
HDL: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; non–HDL-C: non–high-density lipoprotein cholesterol; SD: standard deviation.

At baseline there were significant differences between the statin-alone and fibrate-treated groups for triglycerides (P = .001) and HDL-C (P = .021) but not for non–HDL-C (P = .063), total cholesterol (P = .263), or LDL-C (P = .728). An independent-samples t test comparing the statin treatment–alone group (n = 155) with the fibrate treatment–alone group (n = 13) showed a significant mean difference for change between groups for triglyceride levels from baseline to the 1-year follow-up in the fibrate alone group (P = .03) (TABLE 3). The mean change was –133.92±146.55 mg/dL for the fibrate alone–group and –32.43±108.62 mg/dL for the statin alone–group. There was no statistically significant mean difference in change between the 2 groups for total cholesterol, LDL-C, HDL-C, and non–HDL-C.

There was a significant difference in frequency of treatment with fibrates based on a triglyceride cutoff of 150 mg/dL, with a greater number of those receiving fibrates having higher rates of baseline triglyceride >150 mg/dL (82% who received fibrates and 61% of those who received statins; P = .052). Using a cutoff of 200 mg/dL showed similar results (71% who received a fibrate and 39% of those who received statins; P = .002).


TABLE 3

Independent-samples t test assessment of lipid parameters comparing fibrate treatment vs statin treatment at baseline to 1-year follow-up

  Statin treatment alone
(n=155)
Fibrate treatment alone
(n=13)
   
  Baseline
mean±SD
Mean
change±SD
Baseline
mean±SD
Mean
change±SD
t Mean change
P value
Total cholesterol (mg/dL) 193±46.80 –26.24±53 209±47.33 –20.85±24.59 –0.671 .509
Triglycerides (mg/dL) 201±110.80 –32.43±108.62 307±146.71 –133.92±146.55 2.441 .030
LDL-C (mg/dL) 107±40.13 –18.92±42.38 117±43.35 –2.46±28.15 –1.373 .172
HDL-C (mg/dL) 46±14.66 –0.72±12.53 37±6.56 3.31±5.59 –1.147 .253
Non–HDL-C (mg/dL) 147±45.22 25.52±50.09 172±43.80 24.15±26.49 0.163 .872
HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; non–HDL-C: non–high-density lipoprotein cholesterol; SD: standard deviation.

  DISCUSSION

The results of this exploratory study support our initial hypotheses, indicating that schizophrenia patients respond to LLMs in a manner consistent with that of the general population. We found that patients taking statins or fibrates as LLMs experienced improved lipid profiles in the form of decreased total cholesterol, triglycerides, LDL-C, and non–HDL-C. A study of 318 patients in the general population on statin-fibrate combination therapy found significant reductions in total cholesterol, triglycerides, and non–HDL-C.49 Shah et al50 compared treatment effects of statin-fibrate combination therapy and monotherapy and found that atorvastatin and simvastatin significantly reduced LDL-C, whereas atorvastatin-fenofibrate combination therapy produced a significant reduction in triglycerides, but simvastatin-fenofibrate combination therapy did not do so in the general population.

Patients who received fibrates alone showed significantly greater baseline triglyceride levels and a greater reduction in triglycerides than those who took statins alone.50 This result is in agreement with a recently published guide to hyperlipidemia treatment in the general population, which states that although statins are preferred for reducing serum LDL-C, fibrates are more effective in reducing serum triglycerides.51 Despite this frequently observed benefit of fibrate therapy, using fibrates in treating dyslipidemia also has been challenged. A review by Wierzbicki52 cited inconsistent results in end point studies conducted with fibrates. Athyros et al53 also cautioned against the widespread use of fibrates in treating mixed dyslipidemia, stating that combination treatment with statins and fibrates should be further investigated through large-scale studies. Despite these uncertainties, both of these reviews described the benefits of fibrate treatment in resolving dyslipidemia in patients with high triglycerides and low HDL-C. Similarly, our results indicate the potential advantages of prescribing fibrates for schizophrenia patients with high triglycerides. It is important to note that a post hoc analysis showed that a subgroup of patients with elevated triglyceride levels in the highest third (>204 mg/dL) and HDL-C levels in the lowest third (<34 mg/dL) derived cardiovascular outcome benefit with statin and fibrate combination therapy.52 Additionally, in our study, although the fibrate-treated group had higher baseline triglyceride levels, the statin-treated group also showed elevated triglycerides—39% >200 mg/dL and 61% >150 mg/dL. This may suggest that fibrates are under-utilized in this population for elevated triglycerides.

There are several limitations to this study. It is possible that patients received treatment for lipid levels at other institutions that may not have been recorded in their medical record. Based on the selection criteria of schizophrenia patients treated with LLMs who had adequate baseline and follow-up lipid assessments, the results may be biased. It is not known what factors contributed to the large number of patients not receiving adequate baseline or follow-up lipid assessments (n = 677). We were not able to evaluate lifestyle changes, including diet and exercise, in this study or confirm compliance with a patient’s LLM, which could bias the results. Additionally, this was a retrospective study that was limited by small sample size. Because of its exploratory and hypothesis-generating nature, no confounding variables were controlled and a Bonferroni correction was not conducted in the data analysis, which also could bias the results. However, the results of this study further delineate the treatment effects between statins and fibrates in schizophrenia patients. Nasrallah et al54 used baseline data from patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study to determine that there is an 88% nontreatment rate for schizophrenia patients with dyslipidemia.

  CONCLUSIONS

Because of the high incidence of dyslipidemia in schizophrenia patients, the risk of resultant CVD, and the lack of research on LLMs to treat this population, we believe that this exploratory study will prove useful as a reference for further investigation. Future studies would benefit from a larger and more diverse sample, as well as comparisons between more specific treatment groups, such as those defined by type of statin or fibrate, to observe their differential effects on specific markers of dyslipidemia in this population.

DISCLOSURES: Dr. Vincenzi, Dr. Borba, Ms. Gray, Ms. Wang, and Ms. Aragam report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Copeland is a consultant to sanofiaventis. Dr. Fan is a consultant to Eli Lilly and Company. Dr. Henderson receives grant or research support from Novartis and Otsuka and is a consultant to Alkermes.

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CORRESPONDENCE: Brenda Vincenzi, MD Freedom Trail Clinic 25 Staniford Street Boston, MA 02114 USA E-MAIL: bvincenzi@partners.org