Hyperlipidemias: Maitland-van der Zee AH

Peters B, Maitland-van der Zee AH. · Utrecht University, Faculty of Science, Division of Pharmacoepidemiology and Pharmacotherapy, The Netherlands. · Pharmacogenomics. · Pubmed #18781848 No free full text.

Abstract: In developed countries, cardiovascular disease is one of the leading causes of death. Among other statins, pravastatin is abundantly prescribed to reduce risk of coronary artery disease by lowering cholesterol. Genetic factors are thought to be partly responsible for the interindividual variation in the response to pravastatin. This article reviews the most important studies conducted on the pharmacogenetics of pravastatin. Currently there is no evidence to advocate pharmacogenetic testing before initiating therapy.

Maitland-van der Zee AH, Boerwinkle E. · Human Genetics Center, Health Science Center at Houston, University of Texas, 1200 Hermann Pressler, Houston, TX 77030, USA. · Curr Atheroscler Rep. · Pubmed #15811254 No free full text.

Abstract: Cardiovascular disease is one of the leading causes of death, especially in developed countries. Blood cholesterol lowering by way of statin therapy is a common risk-lowering therapy. The risk reduction for coronary artery disease for patients using statins is 27%. These reductions, however, are average effects for all patients included in the trials. There is notable interindividual variation in response to statins, and the origins of this variation are poorly understood. Pharmacogenetics seeks to determine the role of genetic factors in variation of drug response. In patients with primary hypercholesterolemia, 23 studies have examined the effects of genetic polymorphisms at 20 different loci on the lipid response to statin treatment, and 18 studies examined genetic polymorphisms involved in the benefits of statin therapy in the prevention of cardiovascular disease. Even though many studies have been performed, few results have been replicated. It is our contention that larger sample sizes and consideration of multiple genes are needed in the field of pharmacogenetics of statin response.

Mantel-Teeuwisse AK, Kloosterman JM, Maitland-van der Zee AH, Klungel OH, Porsius AJ, de Boer A. · Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands. · Drug Saf. · Pubmed #11368251 No free full text.

Abstract: Many drugs besides lipid-lowering drugs affect serum lipid levels in either a potentially harmful or beneficial way, and may therefore increase or decrease the risk of cardiovascular disease. Diuretics, beta-blocking agents, progestogens, combined oral contraceptives containing 'second generation' progestogens, danazol, immunosuppressive agents, protease inhibitors and enzyme-inducing anticonvulsants adversely affect the lipid profile. They increase total cholesterol, low density lipoprotein cholesterol and triglycerides by up to 40, 50 and 300%, respectively, and decrease high density lipoprotein cholesterol by a maximum of 50%. Conversely, alpha-blocking agents, estrogens, hormone replacement therapy, combined oral contraceptives containing 'third generation' progestogens, selective estrogen receptor modulators, growth hormone and valproic acid show mostly beneficial effects on the lipd profile. Some drugs, for example, isotretinoin, acitretin and antipsychotics, mainly elevate triglyceride levels. Adverse or beneficial effects on serum cholesterol levels do not always translate into a higher or lower, respectively, incidence of cardiovascular disease. because these drugs may influence cardiovascular risk through multiple pathways. In some cases, excessive cholesterol levels occur, for example, with protease inhibitor therapy, and several cases of pancreatitis attributable to drug-induced hypertriglyceridaemia have been reported. Some general guidelines on the management of drug-induced dyslipidaemia can be given. Replacement of the dyslipidaemia-inducing drug by an equivalent alternative therapy is preferred. However, such alternatives are often difficult to find. If there is no equivalent alternative and treatment with the dyslipidaemia-inducing drug must be initiated, monitoring of serum lipid levels is important. If drug use is expected to be long term, the existing guidelines for the management of dyslipidaemia in the general population can be applied to drug-induced dyslipidaemia. In cases of extreme hyperlipidaemia, medication use should be reassessed.

Peters BJ, Maitland-van der Zee AH, Stricker BH, van Wieren-de Wijer DB, de Boer A, Kroon AA, de Leeuw PW, Schiffers P, Janssen RG, van Duijn CM, Klungel OH. · Division of Pharmacoepidemiology and Pharmacotherapy, Faculty of Science, Utrecht University, Utrecht, The Netherlands. · Pharmacogenet Genomics. · Pubmed #18551043 No free full text.

Abstract: INTRODUCTION: The GNB3 C825T polymorphism has been shown to affect lipid parameters, atherosclerosis progression, and incidence of myocardial infarction (MI). Therefore, we assessed whether the effectiveness of statins in reducing the risk of MI was modified by the GNB3 C825T polymorphism. METHODS: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they used antihypertensive drugs and had a diagnosis of hypercholesterolemia before their first MI. Controls met the same eligibility criteria, but were not hospitalized for MI. Logistic regression analysis was used to calculate odds ratios (OR) and synergy index with corresponding 95% confidence intervals (CI), and to adjust for potential confounding factors. RESULTS: We included 459 cases and 1805 controls. The risk of MI was significantly lower among participants exposed to statins compared with participants not exposed to statins (adjusted OR: 0.37, 95% CI: 0.29-0.47). The GNB3T allele was associated with a reduced risk of MI (adjusted OR: 0.74, 95% CI: 0.60-0.92). Among homozygous wild-type (CC) individuals (n=1119), exposure to statins was associated with a lower risk of MI (OR: 0.48, 95% CI: 0.34-0.67). However, T allele carriers (CT and TT) who used statins had an even stronger reduced risk of MI (OR: 0.27, 95% CI: 0.19-0.39). Overall, the interaction between exposure to statins and the GNB3 C825T polymorphism was significantly increased on the multiplicative scale (synergy index: 1.67, 95% CI: 1.06-2.65). CONCLUSION: Our findings show that T allele carriers of the GNB3 C825T polymorphism have less risk of MI and are more likely to benefit from statin therapy in a hypercholesterolemic population of antihypertensive drug users.

Maitland-van der Zee AH, Klungel OH, Stricker BH, Veenstra DL, Kastelein JJ, Hofman A, Witteman JC, Leufkens HG, van Duijn CM, de Boer A. · Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University. Utrecht, The Netherlands. · Pharmacogenetics. · Pubmed #15128051 No free full text.

Abstract: This study aimed to assess the potential cost-effectiveness of screening men for their angiotensin-converting enzyme (ACE)-genotype before starting statin therapy. We used a combination of decision-analytic and Markov modelling techniques to evaluate the long-term incremental clinical and economic effects associated with genetic testing of men with hypercholesterolemia before starting treatment with statins. The study was performed from a health care payer perspective. We used data from the Rotterdam study, a prospective population-based cohort study in the Netherlands, which was started in 1990 and included 7983 subjects aged 55 years and older. Men treated with cholesterol-lowering drugs at baseline or with a baseline total cholesterol > or = 6.5 mmol/l were included. The ratio of difference in lifelong costs between the screening strategy and the no screening strategy to difference in life expectancy between these strategies was calculated. We also performed a cost-utility analysis. The base case was a 55-year-old man with hypercholesterolemia who was initially untreated. Several univariate sensitivity analyses were performed. All costs were discounted with an annual rate of 5%. Screening men for their ACE-genotype was the dominant strategy for the base case analysis, because the screening strategy saved money (851 Euro), but life expectancy was not changed. Screening was the dominant strategy for all age-groups in our cohort. Even in 80-year-old subjects, with the shortest life-expectancy, it was cheaper to screen than to give lifelong treatment to men with a DD genotype without success. Even if all DD subjects were treated with other (non-statin) cholesterol-lowering drugs, screening remained the cost-effective strategy. The results of the cost-utility analysis were similar. Discounting the effects with 5% per year also had no major impact on the conclusions. If other studies confirm that men with the DD genotype do not benefit from treatment with statins, screening for ACE genotype in men most likely will be a cost-effective strategy before initiating statin therapy.