Comparative Analysis of the Use of Lipid Modifying Agents in the Republic of Serbia and Nordic Countries in the Period 2015-2017 A

1 Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia 2 International Center for Cardiovascular Diseases MC Medicor, Izola, Slovenia 3 Institute of Public Health of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia 4 Emergency Center, Clinical Center of Vojvodina, Novi Sad, Serbia 5 Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia 6 Clinic for Nephrology and Clinical Immunology, Clinical Center of Vojvodina, Novi Sad, Serbia


INTRODUCTION
According to the World Health Organization (WHO), cardiovascular diseases (CVD) are the leading cause of death in the world. In 2016, 17.9 million deaths from CVD were recorded, which represents 31% of the total mortality in the world [1]. WHO data on the European region show that CVD are the cause of more than a half of deaths [2]. Similar data were also recorded in Serbia, where CVD were the cause of 51.8% of deaths of all causes in 2018. However, a decrease of 4.5% in women and 1.7% in men in the mortality rate due to CVD was noted in Serbia in the period from 2009 to 2018, although in the same period an increase in the general mortality rate was also observed [3].
Even though CVD are the dominant cause of death in modern times it can be prevented in as many as 80% of cases. Prevention of CVD means eliminating or reducing risk factors, and it is believed that decreasing of cholesterol level, smoking prevalence and blood pressure level can have the greatest benefits [2]. It is estimated that these three risk factors are responsible for the development of 75% of all CVD in the world [4].
Hyperlipoproteinemias (HLPs) are metabolic disorders of increased blood lipid levels. The positive effects of lowering blood lipid levels on the occurrence of CVD are well documented. Small changes in lipid levels have a major impact on health. An increase in total cholesterol by 1% increases the risk of developing ischemic heart disease by 2-3%. It has also been shown that only by reducing low-density lipoproteins (LDL), mortality and morbidity from ischemic heart disease can be reduced by 40% [4]. This is the precise reason why the treatment of HLPs is the most important tasks of CVD prevention.
There are several classes of drugs used as monotherapy or, if necessary, in combination for the treatment of HLP. The most important groups of hypolipidemic drugs are: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibrates, anionic-exchange resins, nicotinic acid and cholesterol absorption inhibitors [4]. Numerous randomized studies have shown that the use of statins reduces cardiovascular risk. Statins cause a reduction in serum total cholesterol level and a reduction in the risk of major adverse cardiovascular events in vari-ous patients, for example those with high and low risk, both women and men, younger and older [5][6][7][8][9][10]. Despite all this knowledge, serum cholesterol-lowering therapy is insufficiently used in the population of patients with high risk of heart attack and CVD. In the PURE study that included 22 countries in 2016, 66% of people aged 35 years -70 years with CVD use statins in high-income countries (Sweden and Canada), 27% in middle-income countries (Poland, Turkey and Brazil) and about 5% in low-income countries (China and India) [11,12]. In the SHARE study in 2013, only 42% of people over the age of 50 years with previous CVD taking serum cholesterol-lowering therapy with large variations between different countries (55% -56% in Belgium, Denmark and Norway; 27% -29% in Estonia and Slovenia) [11,13]. The study examining the use of hypolipidemic drugs in Serbia in the period 2004-2008 showed that their use is 6 -8 times lower than in the Scandinavian countries. An inversely proportional relationship between the use of this group of drugs and CVD mortality was also observed [14]. Insufficient use of hypolipidemic drugs can cause a high incidence of CVD and complications associated with CVD, which includes and a high mortality rate [15 -17].

AIM
The aims of this study were: 1. An analysis of the use of drugs in the treatment of HLPs in the Republic of Serbia during 2015, 2016 and 2017. 2. When comparing the use of the same drugs between Republic of Serbia and the Kingdom of Norway and the Republic of Finland, two countries that have well-developed pharmacotherapeutic practices, in the mentioned period.

METHODS
The analysis was designed as a comparative, pharmaco-economic, retrospective, time series study. Data on drugs use during 2015, 2016 and 2017 were observed. Drugs use data in the Republic of Serbia were taken from the official website of the Medicines and Medical Devices Agency of Serbia (ALIMS) [18][19][20]. Drugs use data in the Kingdom of Norway Use of drugs is calculated by the methodology of Defined Daily Doses (DDD) according to the Anatomical Therapeutic Chemical (ATC) classification. DDD is a statistical unit of measure of drug use, the value of which represents the average daily dose of drug use in an adult and does not depend on the price, dosage form and packaging size of the drug. The number of DDD per 1000 inhabitants per day (DDD/1000 inh/day) provides an insight into how many inhabitants (from 1000) used a certain drug and were exposed to its action during the day. Evaluation of drug use over time at the national and international levels has been simplified and improved through the use of DDD [23].

RESULTS
Use of ATC group C drugs is most dominant in all three countries, during three years of observation. The share of use of lipid-modifying  Table 2. Distribution of drug use in group C expressed as DDD /1000 inh/day and as a percentages for 2017 between the three observed countries C -drugs for CVD C01 -cardiac therapy C02 -antihypertensives C03 -diuretics C04 -peripheral vasodilators C07 -beta blocking agents C08 -calcium channel blockers C09 -agents acting on the renin-angiotensin system C10 -lipid modifying agents DDD -DDD/1000 inh/day agents (C10) in ATC group C has a growth trend during the observed period in all countries. However, the use of ATC group C10 drugs was 3-4 times lower in Serbia than in Norway or Finland. By far the most common C10 representatives were monocomponent statins (C10AA) in all countries during the entire observation period. These data are shown in Table 1.
The share of hypolipidemic drugs in the use of all drugs from group C can be seen in the example from 2017. During 2017, the total use of hypolipidemic drugs in the territory of the Republic of Serbia amounted to 38.59 DDD/1000 inh/day (6.18%) and was in fifth place in terms of use of drugs in group C. In the Kingdom of Norway and the Republic of Finland, hypolipidemic drugs are much more represented in the total use of drugs for the treatment of CVD. In the Kingdom of Norway, in 2017, the use of hypolipidemic drugs amounted to 135.56 DDD/1000 inh/day (31.93%) and was in the second place in terms of use among C group drugs. In the Republic of Finland, the situation is similar to that in the Kingdom of Norway. Use of hypolipidemic drugs in the Republic of Finland in 2017 was 112.63 DDD/1000 inh/day (19.81%) and took second place in the use of drugs of group C ( Table 2).
In the Republic of Serbia, in the ob-

DISCUSSION
In all three investigated countries, the use of drugs for the treatment of CVD (group C) polipidemic drugs) and this drug is in third place in terms of statin use. In the Republic of Finland, among the statins, the three most commonly used drugs are simvastatin, atorvastatin and rosuvastatin. The most widely used statin drug in the Republic of Finland during the first two years was simvastatin. Due to the negative trend, simvastatin in the third observed year moved to the second place in terms of statin use, and was replaced by atorvastatin in the first place, which recorded a positive trend in the same period. Another statin that recorded a positive trend during the observed three years is rosuvastatin. It was in third place in terms of statin use.
The share of fibrates in the Republic of Serbia was 8.63% in 2015, 10.53% in 2016 and 9.67% in 2017 of all drugs from the C10A group. The most used fibrate in the Republic of Serbia was fenofibrate. In the Kingdom of Norway, the use of fibrates during the observed period was not registered, while in the Republic of Finland it amounted to about 0.50% of the total use of hypolipidemic drugs.
Ezetimibe is a drug that belongs   dominates during the observed period. This use is the highest in absolute and relative terms in the Republic of Serbia. There is a much higher use of hypolipidemic drugs in the Kingdom of Norway and the Republic of Finland in relation to the use of these drugs in the Republic of Serbia. In all three countries, a discrete increase in the use of C10 drugs was noted during the observed period. It can be seen it Table 2, that in the Republic of Serbia drugs for the treatment of CVD are used much more than drugs for primary and secondary prevention of these diseases, such as hypolipidemic drugs, similar to the previous study. In addition, a previous study showed that in Serbia, drugs for the prevention of CVD (statins) are used more in secondary than in primary prevention [14]. However, compared to the results from previous study, the use of hypolipidemic drugs in Serbia is higher [15].
Of all hypolipidemic drugs, statins are most commonly prescribed in all three countries. The use of statins has increased in Western societies since the publication of the Scandinavian Simvastatin Survival Study (4S) in 1994 [25]. After the intensive growth of statin use at the beginning of the 21st century, their use has stabilized in recent years and recorded a slight growth of this group of drugs from year to year. Compared to the previous research, use of statins in Serbia has increased about 24 times from 2004 [15]. In addition to evidence of efficacy and safety, changes in national prescribing requirements are needed to further increase statin use [26]. One of the reasons for significantly lower prescribing of statins in Serbia compared to other countries may be the differences in the legislation on prescribing these drugs [15]. The Republic Health Insurance Fund (RFZO) of the Republic of Serbia has very strict criteria for reimbursement of statin costs. Indications for which statins can be prescribed at the expense of the RFZO in the Republic of Serbia are the prevention of secondary myocardial infarction and stroke and the familial form of HLP. For the first indication, the share of the RFZO is 15-25% of the price of the medicine, while for the second indication it is 50 RSD [25,26]. In   [4]. This data is especially important, taking into account that in Serbia there has been a decline in mortality rate due to CVD in the previous period [3]. It has also been found that the emergence of generic drugs contributes to an increase in drug use [27]. All these factors probably had an impact on increasing statin use in Serbia, but it is necessary for this trend to continue. In all three countries, prescribing simvastatin decreases in favour of atorvastatin.
Possible reasons for this are new studies, such as the CURVES study (Comparative Dose Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with Hypercholesterolemia) which proved that atorvastatin treatment led to a significantly greater reduction in LDL concentration than equivalent doses of simvastatin [30]. Also, a multicenter study STELAR (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin) showed that rosuvastatin at a dose of 10 mg was significantly more effective in lowering atherogenic LDL cholesterol levels than atorvastatin administered at the same dose. This could be the reason for the increase in rosuvastatin prescribing [31]. Although the efficacy of statins is well documented and their positive impact on CVD prevention is known, caution should be exercised when prescribing them. Their pharmacovigilance should be taken into account and prescribed only when they are really necessary [14]. Useful tools have been developed that can be applied when making a statin prescribing decision [32].
Other lipid-modifying drugs, such as fibrates and ezetimibe, have had negligible use both in Serbia and in other two observed countries. These results were expected given that they are second-line drugs for serum lipid reduction, and in line with other published studies [33,34].