March 2017 Healthcare Cost Savings of Phytosterol Food Supplements in the European Union Economic Implication of Managing Cardiovascular Disease with Phytosterol Food Supplements with Demonstrated LDL-cholesterol Reduction Capabilities An Independent Economic Analysis Commissioned by Food Supplements Europe 1 Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 2 Table of Contents Abstract................................................................................................................... 3 The Benefits of Phytosterols for LDL Cholesterol Reduction and Potential CVD Health Cost Savings ..................................................................................... 5 Background............................................................................................................................... 5 The Health Benefits of Phytosterols ...........................................................................12 Research Methods................................................................................................................15 Empirical Results..................................................................................................................21 References...............................................................................................................................32 Appendix II: The Cost of Cardiovascular Disease.................................................36 3 Abstract This case study explores the possible direct economic benefit that could be expected from the daily use of 1.7 grams of phytosterols – through fortified food sources or food supplements – as a means to reduce low-density lipoprotein (LDL) cholesterol concentration by those target individuals at the highest risk of developing cardiovascular disease (CVD). This report examines aggregated indications demonstrating that the use of phytosterols can potentially reduce CVD-attributed hospital utilisation costs in the European Union (EU) among those at a high risk of experiencing a costly, CVD-attributed event. Thus, a targeted phytosterol regimen is recommended as a means to help control rising societal healthcare costs and as a means for high-risk individuals to lower LDL-cholesterol and minimise the chance of having to deal with potentially detrimental diseaseattributed events. Target Population—31.1 million adults age 55 and older with severe hypercholesterolemia in the EU have an expected 24.3% risk of experiencing a costly CVD-attributed hospital event. The total cost of addressing CVD in the EU will be € 1,328 billion over the next 5 years, or € 34,637 per event over the same period. Science-based Impact of Phytosterols Use—the relative risk of experiencing a CVD event is reduced by 26.6% for every 1 mmol/L reduction in LDL cholesterol levels, irrespective of how LDLcholesterol is reduced. The expected reduction in LDL cholesterol levels given the use of 1.7 grams of a phytosterols food supplement daily is 0.372 mmol/L among severe hypercholesterolemic adults age 55 and older. This translates to an absolute risk reduction risk of 2.3% basis points given a 24.3% CVD-event risk level for the average European. Economic Implications (Total EU) o Total Avoidable CVD-attributed Costs per year (S): € 5.30 billion o Net Avoidable CVD-attributed Costs per year (B): € 4.09 billion o Net Avoidable CVD-attributed Costs per person per year (B/Pop): € 170.66 per target person o Benefit/cost ratio (€ Avoided CVD-attributed Costs per € 1 spent on phytosterols): € 4.37 Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 4 5 The Benefits of Phytosterols for LDL Cholesterol Reduction and Potential CVD Health Cost Savings Background Hypercholesterolemia is the presence of high total cholesterol levels in the blood and its presence is correlated to a higher risk of cardiovascular disease CVD1 [1]. Cholesterol is a lipid-based substance present in all body cells and is delivered from foods from an animal origin including eggs, dairy products, meat, poultry, and fish and via endogenous synthesis. [1]. Cholesterol is required to build cell membranes, and it acts as a precursor of important molecules including hormones. However, consuming too much cholesterol can lead to a higher risk of developing CVD [1]. Thus, the consumption amount and the metabolism of cholesterol is primarily dependent on individual diet choices, it is considered by medical professionals as a modifiable risk factor for CV[6]. D that can be managed through a nutrition-based solution [1]. The cut-off level of hypercholesterolemia is 5.0 mmol/L of total cholesterol according to the World Health Organization (WHO); however, severe hypercholesterolemia is 6.2 mmol/L of total cholesterol [5]. According to the 2016 ESC/EAS Guidelines for the Management of Dyslipidemias, treatment with an intense dose of statins is recommended for male patients age 55 and older with CVD and female patients age 60 and older with CVD, or any patient with a baseline low-density lipoprotein (LDL) cholesterol level of greater than 5 mmol/L, should be treated with an intense dose of statins [6]. A healthy diet and lifestyle are the cornerstones of CVD prevention and should be followed irrespective of concomitant drug treatment. Phytosterols are recommended for both: individuals with high cholesterol levels at intermediate or low global CVD risk who do not qualify for pharmacotherapy and as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL-cholesterol target levels on statins or are statinintolerant [19]. The presence of cholesterol, or more specifically, higher concentrations of LDL cholesterol and lower concentrations of functional high-density lipoprotein (HDL) cholesterol, promotes the development of plaque in the arteries that leads to blood flow restriction [1]. The average LDL cholesterol level of someone with severe hypercholesterolemia is approximately 4.8 mmol/L based on a fixed LDL cholesterol to HDL cholesterol ratio of 3.4 for someone at an average risk of experiencing a CVD event [2]. 1 CVD is strictly defined as events associated with the following ICD/ISHMT codes: 0901 (hypertensive diseases), 0902 (angina pectoris), 0903 (acute myocardial infarction), 0904 (other ischaemic heart disease), 0907 (heart failure), 0908 (cerebrovascular diseases), and 0909 (atherosclerosis) [4]. The choice of ISHMT codes reflects the author’s conservative judgment that these events are nearly always associated with CVD as the main underlying or direct cause. The presence of cholesterol promotes the development of plaque in the arteries that leads to blood flow restriction and can in turn increase the risk of experiencing a CVD-attributed medical event. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 6 According to the WHO’s Global Health Observatory (GHO) statistics, Europe has the highest prevalence of hypercholesterolemia in the world, at 54% of the total population age 25 and older, and 20% of the total population has severe hypercholesterolemia [3]. It is expected that the prevalence of hypercholesterolemia is greater among Europeans age 55 and older, however exact figures for the entire EU for this target population cohort, and the prevalence of hypercholesterolemia - for this target population cohort per EU country is not currently known. Thus, a conservative measure of the prevalence of hypercholesterolemia was adopted for the purposes of this case study. See Chart 1 for the percent of the population age 25 and older with severe hypercholesterolemia (6.2 mmol/L) per EU country. See Table 1 for estimated mean total cholesterol, LDL cholesterol levels by EU country, and the share of the population with severe hypercholesterolemia by EU country. Chart 1 Percent of the Population age 25 and older with Very High Total Cholesterol Baseline Levels (6.2 mmol/L) per EU Country, %, 2015 EU Average: 19.7% of Total Population Source: World Health Organization, Global Health Observatory and Frost & Sullivan analysis. 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% Romania Greece Bulgaria Croatia Sweden Czech Republic Slovakia Spain Poland Lithuania Portugal Cyprus Hungary Latvia Slovenia Estonia Malta Austria Finland Italy Netherlands France Belgium Ireland United Kingdom Germany Denmark Luxembourg 12.1% 12.8% 14.2% 14.3% 14.8% 15.3% 15.7% 16.4% 16.7% 17.0% 17.6% 17.7% 17.9% 18.0% 18.1% 18.5% 19.2% 19.4% 19.7% 20.1% 20.1% 20.6% 21.6% 21.7% 21.7% 24.6% 25.5% 25.6% 7 Table 1 Total Burden of Cardiovascular Disease: Mean Total Cholesterol and LDL Cholesterol Levels by EU country, 2009 Country Mean Total Cholesterol Level2 Expected LDL cholesterol Baseline Level3 % of Population age 25 and older with Severe Hyper- cholesterolemia)4 Austria 6.0 4.6 19.4 Belgium 6.1 4.7 21.6 Bulgaria 5.8 4.4 14.2 Croatia 5.8 4.4 14.3 Cyprus 5.9 4.6 17.7 Czech Republic 5.5 4.2 15.3 Denmark 6.1 4.7 25.5 Estonia 6.0 4.6 18.5 Finland 5.7 4.4 19.7 France 5.8 4.4 20.6 Germany 5.4 4.2 24.6 Greece 5.6 4.3 12.8 Hungary 6.0 4.6 17.9 Ireland 6.1 4.7 21.7 Italy 5.8 4.4 20.1 Latvia 6.0 4.6 18 Lithuania 6.0 4.6 17 Luxembourg 6.2 4.8 25.6 Malta 6.0 4.6 19.2 Netherlands 6.0 4.6 20.1 Portugal 5.7 4.4 17.6 Poland 5.9 4.5 16.7 Romania 5.9 4.5 12.1 Slovakia 5.9 4.5 15.7 Slovenia 6.0 4.6 18.1 Spain 5.9 4.5 16.4 Sweden 5.5 4.3 14.8 United Kingdom 6.0 4.6 21.7 Total EU 5.7 4.4 20.3 2 World Health Organization. Global Health Observatory (GHO) data. Retrieved at: http://gamapserver.who.int/gho/interactive_charts/ncd/risk_factors/cholesterol_mean/atlas.html. Includes the average of both female and male findings age 25 and older 3 In order to determine the expected LDL cholesterol concentration per country from the observed mean total cholesterol levels, the authors used the fixed LDL cholesterol to HDL cholesterol ratio of 3.4 for someone at an average risk of experiencing a CHD event (http://www.exrx.net/Testing/LDL%26HDL.html.). This implies that the expected LDL-concentration is approximately equal to (3.4*Mean Total Cholesterol)/(1 + 3.4). 4 Severe Hypercholesterolemia is ≥ 6.2 mmol/L. Europe has the highest prevalence of hyper- cholesterolemia (5.0 mmol/dL) in the world, at 54% of the total population, and 20% of the total EU population has severe hyper- cholesterolemia (6.2 mmol/dL). Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 8 For the purposes of this case study on the use of phytosterols, event risk is defined as the ratio of the total number of observed CVD-attributed outcomes requiring a set of hospital services observed in a given population relative to the total target population. In other words, an event is defined as a person experiencing an CVD-attributed event that requires professional medical attention and, consequently, hospital service utilisation such as outpatient or office-based provider visits, hospital inpatient stays, emergency room visits, prescribed medications, and home care such as home nursing and medical devices used at home [4]. It should be noted that the dataset used for this analysis is seemingly implying that the correlation between CVD event rate per EU country (the ratio of cumulative number of hospital events relative to total population age 55 and over) and the mean total cholesterol levels per EU country is not statistically significant. But because each EU country was treated as its own case study, this comparison ignores many factors that determine the differences in the risk of CHD in a given country which was not controlled for in this study. According to hospital utilisation statistics provided by the World Health Organization, Regional Office of Europe as first reported in the Food Supplements Europe economic case study of the benefits of omega-3 utilisation, over 38.0 million CVD-attributed hospital events occurred from 2011 to 2015 in the EU among adults age 55 and older as defined by the aforementioned ICD/ISHMT codes [5, 7]. Thus, each individual adult age 55 and older in the EU has a one in four chance of experiencing a CVD-attributed event requiring formal and informal heath care services over the next five years. These CVD-attributed events include both primary and secondary CVD cases. In other words, it is expected that a total of 38.4 million CVD-attributed hospital events are expected over the next 5 years (2016 to 2020) among adults age 55 and older in the EU, or 24% of the target population will experience a CVD-attributed hospital event [5, 7]. Growth trends in CVD-attributed events by EU country does vary by a number of reasons such as target market population growth, quality-of-care by EU country, and general health of the target population which was controlled for when projecting CVD-attributed events over the next five years. Table 2 shows the social burden of CVD on the EU population by nation. Among adults age 55 and older in the EU, 24% of this target population will experience a CVD-attributed hospital event over the next 5 years. 9 Table 2 Burden of Cardiovascular Disease: CVD-attributed Event Risk, 2011-202056 Country Total Population, age 55 and older [7] Total Population, age 55 and older with Severe Hypercholesterolemia Expected Event rate (Risk) Expected Number of CVD events among Target Population7 Austria 2,574,872 499,525 38.2% 196,959 Belgium 3,378,041 729,657 21.9% 148,174 Bulgaria* 2,395,715 340,192 31.3% 149,911 Croatia* 1,366,757 195,446 23.5% 64,364 Cyprus 217,517 38,501 3.6% 1,570 Czech Republic 3,224,578 493,360 27.4% 176,680 Denmark 1,705,383 434,873 17.9% 61,056 Estonia* 408,180 75,513 27.1% 22,162 Finland 1,801,776 354,950 24.2% 87,374 France 20,023,397 4,124,820 18.6% 744,430 Germany 27,840,013 6,848,643 38.2% 2,126,100 Greece 3,544,810 453,736 20.6% 146,132 Hungary 3,107,068 556,165 31.7% 197,073 Ireland 1,051,651 228,208 26.4% 55,568 Italy 20,248,958 4,070,041 19.4% 785,117 Latvia 630,755 113,536 26.3% 33,116 Lithuania 900,267 153,045 64.7% 116,574 Luxembourg 139,939 35,824 27.2% 7,603 Malta 134,864 25,894 17.0% 4,580 Netherlands 5,078,117 1,020,702 16.6% 168,431 Portugal 3,233,995 2,003,132 22.9% 148,337 Poland 11,381,429 540,077 32.1% 731,401 Romania 5,966,193 721,909 30.8% 367,357 Slovakia 1,455,578 228,526 35.2% 102,584 Slovenia 647,904 117,271 22.4% 29,080 Spain 13,719,534 2,250,004 13.9% 382,424 Sweden 2,992,914 442,951 20.6% 123,034 United Kingdom 18,426,690 3,998,592 13.4% 493,429 Total EU 157,596,895 31,095,091 24.3% 7,670,620 Source: [4] European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis and Frost & Sullivan 5 [8] Eurostat. European Commission (http://ec.europa.eu/eurostat/data/database) 6 [5] The World Health Organisation, Regional Office of Europe and Frost & Sullivan analysis 7 Calculated by taking the product of the expected event rate (Risk) and the total population, age 55 and older with severe hypercholesterolemia. All figures are rounded. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 10 Total expenditures of addressing medical events requiring a mix of hospital services for all EU adults age 55 and older is expected to be € 1,328 billion over the next 5 years, or approximately € 265.7 billion per year after controlling for purchasing power parity across each country within the EU [4,5, 10]. A significant portion of this cost is related to events that require expensive hospital care services, especially inpatient procedures and emergency room visits. This cost also includes treatment-specific pharmaceuticals, outpatient visits, and informal costs such as post-treatment home/nursing care services. Furthermore, there are significant indirect costs of CVD on society as a whole including less productivity income for the state due to CVD-attributed deaths. Table 3 shows the costs of CVD for the EU population by country. The average cost of a CVD-attributed hospital event in the EU will be € 34,637 per event [4, 9]8 . The average cost of each CVD-attributed event is calculated by taking total expenditure over the next 5 years and dividing it by the cumulative number of events. This cost calculation approach was adopted because some CVD-attributed events and its residual post treatment disease management costs may stretch beyond one year for a given event. For example, the cost of inpatient care, which is the expenditure for care of patients who requires hospital admission at the beginning of the CVD-attributed event, and post-treatment informal costs such as home nurses, medical equipment for home use and lost productivity which is typically spent over several months or years after the initial event are nearly equal in share of cost burden at 32.9% each. The cost of medications for managing CVD makes up an additional 19.1% of the financial burden of CVD. The remaining services contributing to CVD-attributed healthcare costs make up a combined 15.1% of the cost burden and include primary care (5.7%), outpatient care (8.3%) and ambulance and emergency (A&E) (1.1%). For details on the average annual cost of a CVDattributed hospital event by cost component for the total EU and the annual cost of a CVD-attributed hospital event by cost component by selected EU countries, see Appendix 2. 8 European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis, Frost & Sullivan. The average cost of each CVD-attributed event is calculated by taking total expenditure over the next 5 years and dividing it by the cumulative number of events. This event cost was taken because some events and its residual post treatment disease management costs may stretch beyond one year for a given patient. Total expenditures of addressing medical events requiring a mix of hospital services for all EU adults age 55 and older is expected to be € 1,328 billion over the next 5 years, or approximately € 265.7 billion per year. 11 Table 3 Total Burden of Cardiovascular Disease: CVD-attributed Event Costs, 2016-2020 Country Average Annual Cost of CVDattributed Hospital Event, € /event [4,8]9 h: Adjusted Average Annual Cost of CVDattributed Hospital Event, € /event10 Adjusted Average Annual Cost of CVD-attributed Hospital Events6 Austria € 27,683 € 28,248 € 5,563,689,141 Belgium € 25,422 € 25,422 € 3,766,879,931 Bulgaria € 13,493 € 29,684 € 4,449,944,019 Croatia € 16,666 € 30,555 € 1,966,649,272 Cyprus € 42,229 € 51,613 € 81,040,635 Czech Republic € 14,384 € 26,371 € 4,659,228,314 Denmark € 39,916 € 31,362 € 1,914,830,363 Estonia € 10,861 € 17,068 € 378,269,071 Finland € 32,954 € 30,208 € 2,639,397,093 France € 37,304 € 41,034 € 30,546,939,340 Germany € 33,921 € 37,313 € 79,331,165,848 Greece € 27,666 € 38,041 € 5,558,991,998 Hungary € 7,224 € 13,244 € 2,610,030,846 Ireland € 57,865 € 57,865 € 3,215,470,206 Italy € 32,361 € 35,597 € 27,947,817,630 Latvia € 15,298 € 24,040 € 796,105,211 Lithuania € 6,424 € 11,777 € 1,372,897,126 Luxembourg € 31,284 € 28,677 € 218,037,429 Malta € 27,954 € 38,436 € 176,030,706 Netherlands € 49,663 € 49,663 € 8,364,780,897 Portugal € 27,666 € 33,814 € 5,015,879,512 Poland € 22,808 € 41,814 € 30,582,781,633 Romania € 13,493 € 29,684 € 10,904,621,372 Slovakia € 8,660 € 13,609 € 1,396,067,143 Slovenia € 16,666 € 22,916 € 666,396,987 Spain € 33,823 € 41,339 € 15,809,040,425 Sweden € 27,666 € 23,410 € 2,880,224,373 United Kingdom € 31,318 € 26,099 € 12,878,000,037 Total EU € 29,118 € 34,637 € 265,691,206,557 9 European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis, Frost & Sullivan 10 Average annual cost of CVD-attributed hospital event, € /event adjusted for purchasing power parity (PPP) ratios provided by the World Bank. See Table 7 in this report or [10] http://data.worldbank.org/indicator/PA.NUS.PPPC.RF for the PPP ratios The average cost of a CVD- attributed hospital event in the EU will be € 34,637 per event. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 12 The Health Benefits of Phytosterols Current treatment guidelines state that LDL cholesterol should be the primary target of therapy, since the main substrate for atherosclerotic plaque formation is oxidised LDL particles. It has been shown that different methodologies of cholesterol reduction (inhibiting cholesterol absorption or cholesterol synthesis) can lead to a reduction in the risk of coronary artery disease event rate [11, 12, 13, 14]. It had been predicted that a 1% reduction in LDL cholesterol reduces the risk of coronary artery disease by 1.2–2.0% [15]. Also, in a meta-analysis of the effects of LDL cholesterol concentration reduction on the risk of coronary artery disease by Gould et al. (2007), it was estimated that a 1 mmol/L (38.7 mg/dl) reduction in LDL cholesterol provides a 26.6% decrease in the relative risk of experiencing any CHD-related event and a 28.0% decrease in the relative risk of a CHDattributed death [16]. Thus, any intervention, including a nutrition-based regimen that is shown to reduce a person’s LDL cholesterol level, ought to also help reduce the odds of experiencing a costly CVD event. One such nutrition-based regimen that has shown significant promise in lowering LDL cholesterol levels is the daily use of phytosterols. Phytosterols11 are structurally related to cholesterol found in animals and are present in high concentrations in vegetable oils and nuts [17, 18, 19]. There are many types of phytosterols, of which beta-sitosterol and campesterol are among the most abundant. Phytosterol consumption has been shown to lower LDL cholesterol levels through a mechanism of action in which phytosterols hinder cholesterol absorption in the digestive tract. Because of the strong connection to reducing cholesterol levels, the European Food Safety Authority (EFSA) has assessed positively health claims for the consumption of phytosterols as part of a diet that reduces blood cholesterol levels [20, 21]. EFSA scientists stated in an Opinion, and supported by Regulations (EC) No 983/2009 and (EU) No 384/2010, that LDL cholesterol can be reduced by 7 to 10 % within two to three weeks on average if a person consumes 1.5 to 2.4 grams of phytosterols per day [20, 21]. In addition, the European Atherosclerosis Society (EAS) Consensus Panel states that when plant sterols and stanols are taken at 2 g/day there is casual significant inhibition of cholesterol absorption and lowers LDL cholesterol levels by between 8 and 10%, leading the Panel to conclude that phytosterols are a potent dietary option available for reducing LDL cholesterol levels. 11 Phytosterols comprise of both plant sterols and plant stanols. Any intervention, including a nutrition-based regimen that is shown to reduce a person’s LDL cholesterol level, ought to also help reduce the odds of experiencing a costly CVD event. 13 Multiple meta-analyses that explore both the expected health benefits, and consequential financial impact, from the use of phytosterols and resulting reduction of LDL cholesterol levels have been conducted over the last decade. In their clinical and financial impact analysis, Phillips, Belsey, and Shindler found that the daily use of products with added 1.6 grams of phytosterols by individuals with high cholesterol levels in the UK reduced total cholesterol levels by 5.9% and LDL cholesterol levels by 8.5% [22]. Based on the connection between lower LDL-levels and the decrease of CVD events, these reductions might in turn reduce overall CVD event risk and CVD-attributed costs at an expected rate of £86 million per year. Gerber et al. (2006) substantiated these findings with their review of the potential healthcare cost reduction that could be realised in Germany if those with high cholesterol blood levels daily used phytosterols. Their analysis amounted to a total of 117,000 CVD cases over 10 years and a cost reduction of 1.3 billion over the same period [23]. In 2013, Shanahan and de Lorimier reviewed the phytosterol health literature and calculated the potential health care cost savings that could be realised by people with high cholesterol in the United States [24]. It was found that the expected relative risk reduction of a CHD-related medical event, given the regular use of phytosterols among the target population of US adults age 55 and over was 11.2%, which implied an annual average of 283,389 avoided events from 2013 to 2020 and that 2,267,111 cumulative avoided events over that period could be expected [24]. A recent meta-analysis that looks at the potential health benefits that can be derived from the daily use of phytosterols was the work of Ras, Geleijnse, and Trautwein in 2014, which specifically evaluated the expected effects of phytosterol use across a spectrum of regimen levels on LDL cholesterol levels [25]. In this work, a total of 124 clinical studies were systematically analyzed. The average phytosterol daily usage amount across all of the studies was 2.1 grams per day. The weighted results show that the observed average reduction in LDL cholesterol levels at the average daily usage amount of 2.1 grams was 8.4% of baseline when compared to a placebo. Also, the effects do vary by daily usage amount as shown in Chart 1 and Table 4, where the observed reduction in LDL cholesterol levels was 5.7% for the subset of clinical studies that tested daily usage amounts of one gram per day or less and the observed reduction in LDL cholesterol levels was 12.4% for the subset of clinical studies that tested daily usage amounts more than three grams per day [25]. The strength of the correlation between the average reduction of LDL cholesterol (%) and average phytosterol use (g/d) is very strong (R2 > 0.99) and implies that the EFSA recommendation of 2.0 grams per day of phytosterols will yield an expected reduction of LDL cholesterol of 8.4%. For the purposes of this case study, the risk-reducing activity is the daily intake of 2.0 grams of phytosterols per day which is expected to result in a 8.4% reduction in the observed in LDL cholesterol levels based on the work of Ras, Geleijnse, and Trautwein (2014) [25]. However, the average person in the EU acquires 300 mg of their required phytosterol intake from their diet [25]. This means that the average person has an expected 1.7 grams phytosterol intake deficiency that could be addressed with a phytosterol supplement. The EFSA recommendation of the use of 2.0 grams per day of phytosterols/ phytostanols will yield an expected reduction of LDL- cholesterol of 8.4%. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 14 Chart 1 Average Reduction of LDL cholesterol (%) as a Function of Average Phytosterol Use (g/d) Table 4 Average Reduction of LDL cholesterol (%) as a Function of Average Phytosterol Use (g/d) Study Arms Category Average Phytosterol and Phytostanol Use (g/d) Average Reduction of LDL-choelesterol (%) 1 0.6 5.7 2 1.1 6.4 3 1.7 7.6 4 2.1 8.4 5 2.6 10.3 6 3.3 12.4 EFSA recommendation 2.0 8.4 adjusted-EFSA recommendation 1.7 7.7 Source: [25] Ras, Geleijnse, and Trautwein (2014) y = 4.672e0.2942x R² = 0.99428 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 (Y) Average Reduction of LDL- choelesterol (%) (X) Average Phytosterol Use (g/d) 15 Research Methods This case study explores the possible direct economic benefit that could be expected from the daily use of 1.7 grams of phytosterols – through fortified food sources or food supplements – as a means to reduce LDL cholesterol concentration by those target individuals at the highest risk of developing CVD. Specifically, a review of the scientific literature related to phytosterol intake and its possible effect on reducing LDL cholesterol levels is provided. Furthermore, this case study deduces the expected financial benefits for people with elevated blood cholesterol levels using phytosterols and provides the expected economic benefit equivalent for EU-based healthcare payer decision makers. The health economic analysis presented in this case study is based on the assessment of various cost scenarios and determines the difference between scenarios to derive the potential savings, or loss, that occurs if one scenario of events occurred versus another [24]. The benefits considered in this model are avoided medical expenditures related to avoided CVD-attributed medical care service utilisation through the adoption of a riskreducing activity (S). All calculated monetary benefits derived from this analysis will be adjusted downward to reflect the 300 mg of phytosterol intake addressed through diet. and the use of phytosterol-fortified foods [26]. The result of these potential healthcare savings provides an economic indication of the monetary benefits the user of phytosterols food supplements can yield for all of society through medical cost reduction and increased productivity. Table 5 provides a list of the key variables used to conduct this health economic analysis. Table 5 List of Key Variables used in this Economic AnalysisA Number of possible avoided events (A) if everybody in the target population of adults age 55 and older with severe hypercholesterolemia used phytosterol B Total potential net economic benefits yet to be realised from the daily use of phytosterols B/Pop Net Benefit per User C Total cost of a phytosterol regimen d The expected per person cost of phytosterol utilisation per year h The expected cost of a CVD-attributed medical event N* Absolute Risk Reduction Pop Target Population: Adults age 55 and older with severe hypercholesterolemia Riskx Risk of a CVD event RRx-1/RRx Relative risk of a CVD event given a 1 mmol/L (38.7 mg/dL) reduction in LDL cholesterol d Mean reduction in serum LDL cholesterol (mmol/L) concentration achieved through the consumption of phytosterols S Total potential savings from reduced hospital service utilisation following CVD-attributed hospital events that are realisable if the entire target population of adults age 55 and older with severe hypercholesterolemia were to sufficiently utilise 2.0 grams of phytosterols per day S/C Total Benefit Cost Ratio S/Pop Total Benefit per User Source: Frost & Sullivan analysis Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 16 In this case study, the following two scenarios are compared: A) the non-use of phytosterols and B) 100% utilisation of phytosterols among a specified population. The difference in total expected health care costs between the two scenarios is the total potential net savings (or loss) that is possible through 100% utilisation of phytosterols. The difference between the two scenarios is also the total number of avoidable events that is possible if everyone used phytosterols at cholesterol lowering levels. In order to determine the number of CVD events between the two states, a measure of the relative risk (RR) of these two event states can be used to determine the number of people who would need to use phytosterols in order to realise its benefit. If the relative risk reduction measure is known, then an absolute risk reduction given the risk profile of a predetermined target population can be determined. For the purposes of this case study, N* is absolute risk reduction and N* can be expressed as: 1. 𝑁∗ = 𝑅𝑖𝑠𝑘* 1 − 𝑅𝑅*-. 𝑅𝑅* / where the term 00123 001 / is the ratio of the relative risk of a CVD event between a user of phytosterols versus a non-user. Specifically, the term 𝑅𝑅*-. 𝑅𝑅* is the relative risk of a CVD event given a 1 mmol/L (38.7 mg/dL) reduction in LDL cholesterol. According to Gould et al (2007), the relative risk of experiencing a CVD event was found to be reduced by 26.6% for every 1 mmol/L reduction in LDL cholesterol [12]. The expression d is the mean reduction in serum LDL cholesterol (mmol/L) concentration achieved through the consumption of phytosterols. As stated above, the work of Ras, Geleijnse, and Trautwein (2014) implies that the mean reduction in serum LDL cholesterol (mmol/L) concentration achieved through the consumption of 2.0 grams of phytosterols per day was 8.4% [25]. However, as stated above, the average person in the EU acquires 300 mg of their required phytosterol intake from their diet [25]. This means that the average person has an expected 1.7 grams phytosterol intake deficiency that could be addressed with a phytosterol supplement. Using the relationship equation in Table 4, then the adjusted mean reduction in serum LDL cholesterol (mmol/L) concentration achieved through the consumption of 1.7 grams of phytosterols per day is 7.7% Assuming that the baseline total cholesterol levels of 6.2 mmol/L and the expected baseline LDL cholesterol levels of 4.8 mmol/L is considered severe hypercholesterolemic, then the mmol/L equivalent of the decrease in LDL cholesterol levels given the use of phytosterols is 0.372 mmol/L.12 See the Appendix for a detailed explanation of the calculations used to derive the relative risk estimates used in this case study. 12 The general calculation of this figure is based on the product of the baseline LDL cholesterol level (4.8 mmol/L) and the expected decrease in LDL cholesterol of 8.4%. Reducing serum LDL cholesterol concentration reduces the risk of coronary artery disease—it had been predicted that a 38.7 mg/dL reduction in LDL cholesterol reduces the risk of coronary artery disease by 26.6%. 17 Overall, adults age 55 and older in the European Union with high LDL cholesterol base levels face a 24.3% chance of experiencing a CVD event. Based on an application of equation 1, it is expected that given the daily intake of 2.0 grams of phytosterols, this risk can be reduced by 2.3% basis points. However, the potential absolute risk reduction of a given country varies due to the level of CVD risk the citizens of these countries face. For example, adults age 55 and older in Lithuania with high LDL cholesterol levels face a very high risk of experiencing a CVD event—consequently the potential health benefits of using a phytosterol supplement is much greater. Overall, the 2.3% absolute risk reduction corresponds to 170,542 possible CVD-attributed hospital events that could be avoided throughout the European Union per year. However, likely risk reduction benefits from using phytosterols per day varies by EU country based on the observed CVD-attributed event rates of each country. For example, the absolute risk reduction in Lithuania is 7.3% and in Austria it is 4.3%, because each country’s population has a relatively high risk of experiencing a CVD-attributed event. Table 6 and Chart 2 provide the CVD risk descriptive statistics used in this case study. Phytosterol consumption has been shown to lower LDL cholesterol baseline levels through a mechanism of action in which phytosterols hinder cholesterol absorption in the digestive tract. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 18 Chart 2 Risk of a CVD-attributed Event and the Absolute Risk Reduction Potential per Target User, EU, 2015 Note: The EU weighted average absolue rsk reduction (2.3%) is calculated by taking a weighted average of the absolute risk reductions by the total target population (Total Population, age 55 and older with Severe Hypercholesterolemia). Source: Author calculations based on the findings of [25] Ras, Geleijnse, and Trautwein (2014), [16] Gould et al (2007), [8] Eurostat, and the [5] World Health Organisation 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% Cyprus United Kingdom Spain Netherlands Malta France Denmark Italy Sweden Greece Total EU Belgium Slovenia Portugal Croatia Finland Czech Republic Latvia Ireland Estonia Luxembourg Bulgaria Romania Poland Hungary Slovakia Germany Austria Lithuania 3.6% 13.4% 13.9% 16.6% 17.0% 18.6% 17.9% 19.4% 20.6% 20.6% 24.3% 21.9% 22.4% 22.9% 23.5% 24.2% 27.4% 26.3% 26.4% 27.1% 27.2% 31.3% 30.8% 32.1% 31.7% 35.2% 38.2% 38.2% 64.7% 0.4% 1.5% 1.5% 1.9% 1.9% 2.0% 2.1% 2.1% 2.1% 2.2% 2.3% 2.5% 2.5% 2.5% 2.6% 2.6% 2.8% 3.0% 3.0% 3.1% 3.2% 3.4% 3.4% 3.5% 3.6% 3.9% 3.9% 4.3% 7.3% Risk of CHD event among Target Population Given Use of Phytosterols Absolute Risk Reduction Given the daily intake of 2.0 grams of phytosterols, CVD- event risk can be reduced by 2.7% basis points, or can lead to 170,542 possible CVD-attributed hospital events throughout the European Union per year. 19 Table 6 CVD Benefits from Phytosterol Use: Average Expected Relative Risk Measurements by EU Country, 2015 Country N*: Absolute Risk Reduction Indicator Pop x N* = A: Annualised Average # of Avoided CVD-attributed Events from use of Phytosterol Supplements, 2016 - 202013 Austria 4.3% 4,206 Belgium 2.5% 3,953 Bulgaria 3.4% 1,648 Croatia 2.6% 717 Cyprus 0.4% 27 Czech Republic 2.8% 2,143 Denmark 2.1% 2,288 Estonia 3.1% 430 Finland 2.6% 1,833 France 2.0% 17,218 Germany 3.9% 66,085 Greece 2.2% 1,262 Hungary 3.6% 3,554 Ireland 3.0% 1,496 Italy 2.1% 17,288 Latvia 3.0% 609 Lithuania 7.3% 1,896 Luxembourg 3.2% 292 Malta 1.9% 95 Netherlands 1.9% 3,861 Portugal 2.5% 2,292 Poland 3.5% 12,247 Romania 3.4% 2,979 Slovakia 3.9% 1,401 Slovenia 2.5% 536 Spain 1.5% 5,698 Sweden 2.1% 1,408 United Kingdom 1.5% 13,079 Total EU 2.3%14 170,542 Source: Author calculations based on the findings of [25] Ras, Geleijnse, and Trautwein (2014), [16] Gould et al (2007), [8] Eurostat, and the [5] World Health Organisation 13 Target Population is all adults age 55 and older with sever hypercholesterolemia levels, which is assumed to be approximately 20% of the EU population. 14 2.3% is calculated by taking a weighted average of the absolute risk reductions by the total target population (Total Population, age 55 and older with Severe Hypercholesterolemia). Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 20 21 Empirical Results The potential savings from reduced medical care service utilisation following CVD events, S that is realisable if the entire target population were to utilise a phytosterol regimen at cholesterol lowering levels can be expressed as: 2. 𝑆 = ℎ ∗ 𝐴 = ℎ ∗ 𝑃𝑜𝑝 ∗ 𝑁∗ = ℎ ∗ 𝐴 ∗ 𝑅𝑖𝑠𝑘* 1 − 00123 001 / The term h is the expected per-person cost of a CVD event and A is the number of possible avoided events if everybody in the target population of adults age 55 and older with severe hypercholesterolemia used a phytosterols regimen per year. A is calculated by taking the product of the absolute risk reduction indicator N* and the target population Pop (Adults age 55 and older with severe hypercholesterolemia). For the purposes of this case study, we are interested in the total potential cost savings between the extreme scenarios of non-use and 100% use, thus the removal of current users would be necessary to determine the proportion of health benefits already realised by current phytosterol users and the proportion of non-users yet to realise the benefits of phytosterols. An easy way to do this is to observe the population’s purchasing behavior through consumer research and identify only those who have purchased phytosterols. The cumulative net savings achieved over consecutive years can also be calculated by summing the annual output over the indicated years while discounting future years to their present value. There is a cost of using phytosterols that must also be considered. The net benefits that can be realised from avoided CVD-attributed medical events are: 3. 𝐵 = 𝑆 − 𝐶 = (ℎ ∗ 𝐴) − (𝑃𝑜𝑝 ∗ 𝑑) where S is the total potential savings from reduced hospital service utilisation following avoided CVD-attributed medical events that are realizable if the entire target population were to sufficiently utilise phytosterols daily and the cost of phytosterol utilisation is represented by the parameter C. The total cost of a phytosterol regimen, assuming 100% utilisation by the entire observed population can be represented by C = Pop*d where d is the expected per person cost of phytosterol utilisation per year. Note that the entire target population of adults age 55 and older with severe hypercholesterolemia must take the given regimen in order for the total number avoided events to be realised. The result of this calculation provides an economic indication of the net monetary benefits B that the use of phytosterols can yield for society through hospital cost reduction and increased productivity due to avoided bed rest and loss of life. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 22 Also, it should be noted that equation 3 is a generalised model that determines the net economic effect of using a given health-enabling nutrient on the odds of a predefined set of event outcomes. Because of the additive nature of the model, one can easily add in additional expected health benefits and costs that are related to the health condition of interest. However, for the purposes of this study, only the cost savings potential due to the hypothesised relationship between phytosterol use and LDL cholesterol reduction was assessed. As stated previously, the purchase and utilisation of phytosterols is required to capture these potential cost savings from avoided CVD-attributed medical events. However, the cost of phytosterols, like other healthcare costs, will vary by country, the sales channel, the supplier, and other variables. Consequently, the cost of phytosterols will vary to reflect these economic realities. One way to control for this variance is to adjust observed market prices by the purchasing power of each country’s citizens. 15 However, it is difficult to find reliable information on the cost of phytosterol food supplements in Europe since the majority of food supplement products in the market contain a mix of various components and food ingredients and thus it is not feasible to find the cost of phytosterols as single ingredient. For the few single component products that were found, the cost per 1,000 mg ranged from € 0.24 to € 0.47 (average € 0.33; median € 0.28) based on a review conducted by the authors of this case study. Consequently, a 1.7 gram daily regimen of a phytosterol food supplement would cost on average € 0.56 daily or a median price of € 0.48 per day. Furthermore, phytosterols from margarine, one of the main carriers for phytosterols in food, is typically priced at € 1.59 to € 2.99 per 250 gram pack. Each 250 gram pack delivers approximately 15 grams of phytosterols. Thus, the expected consumer price of phytosterols from margarine is € 0.10 to € 0.18 per gram or € 0.16 to € 0.30 per 1.7 grams. Assuming that the consumer would replace a standard margarine with a margarine enriched with phytosterols, the additional cost per day would be between € 0.08 and € 0.13 per gram per day. 15 [10] The World Bank. http://data.worldbank.org/indicator/PA.NUS.PPPC.RF. According to the World Bank, purchasing power parity (PPP) is a factor that adjusts a given country's domestic value of a Euro required to buy a given product to a baseline country’s value of a Euro. For the purposes of this analysis, the purchasing power of a Euro in Belgium was assumed to be 100 versus the other European Union countries. It should be noted that PPP merely reflects the relative value of a Euro across two and more countries and does not establish the baseline value of a Euro. The purchase and utilisation of phytosterols is required to capture these potential cost savings from avoided CVD- attributed medical events. 23 Thus, for the purposes of this case study, a average daily cost of 1.7 grams of phytosterols was set at € 0.56 per day, or approximately € 204.54 per year. This median price was then weighted by each country’s PPP ratio from the World Bank in order to best represent the expected variance in phytosterol prices observed in other EU markets not included in the subset of countries listed above [10]. Accordingly, the cost of phytosterol utilisation required to realise the expected benefits by the total target population of all adults age 55 and older with severe hypercholesterolemia (>6.2 mmol/L) at risk of experiencing a CVDattributed medical events per year, C, is expected to be € 1.213 billion per year. Table 7 shows the expected daily and annual costs of using phytosterol daily in the EU after ensuring purchasing power parity across all EU countries and the total potential cost of phytosterols per country. Table 7 Economic Benefits from Phytosterols Food Supplement Use: Expected Consumer Price per Phytosterols Supplements per Day per EU Country, adjusted for Purchasing Power Parity, 2015/2016 Country d/day: Average Daily Cost of 1.7 grams of a Phytosterol Food Supplement, € /day d: Average Annual Cost of Phytosterols Food Supplement, € /year PPP: Purchasing Power Parity Weights, 2014/2015 (Belgium € = 100) Austria € 0.55 € 202.49 98 Belgium € 0.57 € 206.59 100 Bulgaria € 0.26 € 95.02 45 Croatia € 0.31 € 113.61 55 Cyprus € 0.46 € 169.40 82 Czech Republic € 0.33 € 120.68 55 Denmark € 0.72 € 261.81 127 Estonia € 0.40 € 145.22 64 Finland € 0.63 € 231.13 109 France € 0.56 € 204.54 91 Germany € 0.53 € 192.27 91 Greece € 0.44 € 159.54 73 Hungary € 0.29 € 106.36 55 Ireland € 0.61 € 222.95 100 Italy € 0.53 € 192.27 91 Latvia € 0.36 € 132.21 64 Lithuania € 0.31 € 113.61 55 Luxembourg € 0.63 € 229.08 109 Malta € 0.41 € 150.80 73 Netherlands € 0.57 € 208.63 100 Portugal € 0.29 € 104.32 82 Poland € 0.41 € 149.31 55 Romania € 0.26 € 95.02 45 Slovakia € 0.35 € 128.86 64 Slovenia € 0.42 € 153.41 73 Spain € 0.47 € 171.81 82 Sweden € 0.61 € 222.95 118 United Kingdom € 0.68 € 247.49 120 Median EU € 0.56 € 204.54 -- The average cost of using phytosterols at recommended daily intake levels is approximately €0.56 per day, or approximately €204.54 per year. Source: Frost & Sullivan analysis Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 24 Given the annual average cost per person for a CVD-related event (€ 34,637) and the 170,542 possible of avoidable CVD-attributed events if the entire target population of users per year, the total potential avoidable hospital utilisation cost for all EU adults over the age of 55 with hypercholesterolemia given the use of phytosterols would average €5.30 billion per year to health care cost payers. Cyprus has the lowest potential savings (€1.2 million per year) and Germany had the highest potential savings of €2.2 billion in avoided hospital event costs per year. Overall, the five largest EU countries (France, Germany, Italy, Spain, and the UK) can expect potential cost savings in excess of €160 million per year. Table 7 and Chart 3 show the total healthcare costs savings that are possible from avoided CVD-attributed hospital events by EU country. Chart 3 Phytosterols Summary Economic Results, Total Potential Health Care Cost Savings, € million, Annualised Average, EU, 2015-2020 Total EU: €5.30 billion Source: Frost & Sullivan analysis. The daily use of 1,700 mg of supplement by all Europeans age 55 and older with high LDL- cholesterol and potentially yields €5.30 billion in avoidable health care costs per year. 25 Table 7 Economic Benefits from Phytosterols Food Supplement Use: Avoided Healthcare Costs by EU Country, 2015 Country A: Annualised Average # of Avoided CVD- attributed Events from use of Phytosterols h: Adjusted Average Annual Cost of CVD- attributed Hospital Event, € /event S = A*h: Expected 1 Year Total Avoided Cost of CVD-attributed Events C: Total Cost of Phytosterols per year B = S - C: Net Benefit Austria 4,206 € 28,248 € 116,421,563 € 19,623,323 € 96,798,240 Belgium 3,953 € 25,422 € 100,489,547 € 32,559,074 € 67,930,473 Bulgaria 1,648 € 29,684 € 22,229,744 € 4,590,059 € 17,639,685 Croatia 717 € 30,555 € 11,955,933 € 3,175,339 € 8,780,593 Cyprus 27 € 51,613 € 1,160,027 € 1,154,366 € 5,661 Czech Republic 2,143 € 26,371 € 30,824,293 € 9,109,321 € 21,714,972 Denmark 2,288 € 31,362 € 91,314,254 € 29,032,906 € 62,281,348 Estonia 430 € 17,068 € 4,674,021 € 2,028,765 € 2,645,256 Finland 1,833 € 30,208 € 60,404,936 € 16,161,808 € 44,243,128 France 17,218 € 41,034 € 642,296,218 € 173,800,271 € 468,495,946 Germany 66,085 € 37,313 € 2,241,662,933 € 323,925,959 € 1,917,736,974 Greece 1,262 € 38,041 € 34,915,609 € 9,265,860 € 25,649,748 Hungary 3,554 € 13,244 € 25,676,191 € 10,588,597 € 15,087,594 Ireland 1,496 € 57,865 € 86,575,611 € 11,040,681 € 75,534,930 Italy 17,288 € 35,597 € 559,465,405 € 157,289,923 € 402,175,482 Latvia 609 € 24,040 € 9,312,405 € 2,701,848 € 6,610,557 Lithuania 1,896 € 11,777 € 12,181,892 € 2,955,942 € 9,225,949 Luxembourg 292 € 28,677 € 9,120,676 € 2,100,946 € 7,019,730 Malta 95 € 38,436 € 2,656,492 € 749,730 € 1,906,762 Netherlands 3,861 € 49,663 € 191,728,960 € 42,802,905 € 148,926,055 Portugal 2,292 € 33,814 € 63,403,958 € 13,467,077 € 49,936,881 Poland 12,247 € 41,814 € 279,323,560 € 36,776,514 € 242,547,045 Romania 2,979 € 29,684 € 40,201,768 € 8,299,931 € 31,901,837 Slovakia 1,401 € 13,609 € 12,131,024 € 4,623,316 € 7,507,708 Slovenia 536 € 22,916 € 8,937,330 € 3,256,172 € 5,681,158 Spain 5,698 € 41,339 € 192,721,220 € 63,399,319 € 129,321,901 Sweden 1,408 € 23,410 € 38,966,407 € 14,615,794 € 24,350,613 United Kingdom 13,079 € 26,099 € 409,608,977 € 214,748,639 € 194,860,338 Total EU 170,542 € 34,637 €5,300,360,955 € 1,213,844,388 € 4,086,516,567 Source: Frost & Sullivan analysis Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 26 Table 8 Avoided Healthcare Costs from Phytosterol Supplement Use: Avoided Costs of Hospital Events and Benefits per Target User by EU Country, 2015 Country B: Expected Net Benefits from Avoided Cost of CVDattributed Events S/Pop: Total Benefit per User (Adjusted Avoided CVD-attributed Healthcare Costs per person per EU country), €/person, Europe, Annualised Average, 2016- 2020 S/C: Benefit Cost Ratio (€ Avoided Costs and Gains per € 1 spent on Phytosterols Food Supplements) Austria € 96,798,240 € 233.06 € 5.93 Belgium € 67,930,473 € 137.72 € 3.09 Bulgaria € 17,639,685 € 65.34 € 4.84 Croatia € 8,780,593 € 61.17 € 3.77 Cyprus € 5,661 € 30.13 € 1.00 Czech Republic € 21,714,972 € 62.48 € 3.38 Denmark € 62,281,348 € 209.98 € 3.15 Estonia € 2,645,256 € 61.90 € 2.30 Finland € 44,243,128 € 170.18 € 3.74 France € 468,495,946 € 155.71 € 3.70 Germany € 1,917,736,974 € 327.31 € 6.92 Greece € 25,649,748 € 76.95 € 3.77 Hungary € 15,087,594 € 46.17 € 2.42 Ireland € 75,534,930 € 379.37 € 7.84 Italy € 402,175,482 € 137.46 € 3.56 Latvia € 6,610,557 € 82.02 € 3.45 Lithuania € 9,225,949 € 79.60 € 4.12 Luxembourg € 7,019,730 € 254.59 € 4.34 Malta € 1,906,762 € 102.59 € 3.54 Netherlands € 148,926,055 € 187.84 € 4.48 Portugal € 49,936,881 € 139.44 € 4.71 Poland € 242,547,045 € 117.40 € 7.60 Romania € 31,901,837 € 55.69 € 4.84 Slovakia € 7,507,708 € 53.08 € 2.62 Slovenia € 5,681,158 € 76.21 € 2.74 Spain € 129,321,901 € 85.65 € 3.04 Sweden € 24,350,613 € 87.97 € 2.67 United Kingdom € 194,860,338 € 102.44 € 1.91 Total EU € 4,086,516,567 € 170.46 € 4.37 Net health care cost savings from avoided CHD- attributed events can is as much as €1.65 billion per year, or €3.74/€1 spent on a phytosterol supplement regimen per year. Source: Frost & Sullivan analysis 27 As shown in Tables 7 and 8, the total net benefit, B, for the entire EU target population all adults age 55 and older with severe hypercholesterolemia is € 4.09 billion per year. This means that for every € 1.00 spent on a phytosterol daily regimen, there would be a certainty equivalent return to the primary payers of healthcare costs, which include governments and insurance companies, of € 4.37 to society in the form of avoided healthcare expenditures attributed to CVD. In fact, all 28 EU countries have benefit cost ratios greater than € 1.00 which is an indication of phytosterol’s cost effectiveness. The greatest net benefits are found in Germany, where an expected annualised net benefit from avoided CVD-attributed healthcare costs is € 1.92 billion per year. Germany is followed by France and Italy with € 468.5 million and € 402.2 million in per year in total net benefits, respectively. Chart 4 shows the net benefits from avoided CVD-attributed events through the use of phytosterol supplements and Chart 5 displays the monetary gains in health care cost savings per € 1.00 spent on a phytosterol regimen. Tables 7 and 8 describe the detailed results of the economic analysis by EU country. Chart 4 Phytosterols Summary Economic Results, Total Net Benefits (Potential Health Care Cost Savings Excluding Expected Cost of Supplement), € million, Annualised Average, EU, 2015-2020 Total EU: €4.09 billion Source: Frost & Sullivan analysis. The total net benefit, B, for the entire EU target population of adults age 55 and older with severe hyper- cholesterolemia is € 4.09 billion per year. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 28 Chart 5 Phytosterols Summary Economic Results, Expected Cost Effectiveness or the expected € Gains in Health Care Cost Savings per € 1.00 Spent on a Phytosterol Regimen, EU, 2015-2020 Total EU: €4.37/ €1 Spent on Phytosterol Supplement Source: Frost & Sullivan analysis. Chart 6 shows per EU country statistics on the total CVD health economic benefits per potential user of a phytosterols regimen per day. As shown in the chart, the benefits per phytosterol user from the target population highly varies and is dependent on relative healthcare costs in each country and the risk of that given individual experiencing a CVDattributed event. Knowing per user benefits is a more useful measure of potential benefits because this statistic can be paired with consumer research insights in order to calculate the portion of the target population who are not current users of phytosterols and who are yet to realise the potential benefits of using phytosterol. Overall, the benefits per potential user (all adults age 55 and older with severe hypercholesterolemia) are expected to be € 170.46 per user. The greatest benefits per user was found to be in Ireland (€379 per target user per year) which is likely due to this country having a relatively high cost of care for CVD, after adjusting for purchasing power parity. On the other hand, the net benefits per person in Cyprus and Hungary, have small, yet still positive, benefits per person due to lower healthcare cost burden these countries have in general even after adjusting for purchasing power parity. It should be noted that this does not mean that these countries would not benefit from using phytosterols daily, because these countries are still avoiding a significant number of CVD-attributed events that are directly attributed to lower productivity, higher healthcare costs, and a lower quality of life. For every € 1.00 spent on a phytosterol daily regimen, there would be a certainty equivalent return to the primary payers of healthcare costs of € 4.37 in the form of avoided healthcare expenditures attributed to CVD. 29 Chart 6 Phytosterols Summary Economic Results, Total Potential Health Care Cost Savings per Capita, €/Target User, Annualised Average, EU, 2015-2020 Total EU: €170.46/Target User Source: Frost & Sullivan analysis. The benefits per potential user (all adults age 55 and older with severe hyper- cholesterolemia) are expected to be €170.46 per user for the EU as a whole. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 30 Concluding Remarks Phytosterols could confer significant potential healthcare cost savings for all EU adults over the age of 55 with hypercholesterolemia. As shown above, there has been a significant amount of research exploring the benefits of using phytosterols and there is an indication that phytosterols produce a likely positive impact on CVD risk reduction through the reduction of baseline LDL cholesterol levels of users. Furthermore, the potential benefits of using phytosterols increases with increases in the severity of hypercholesterolemia. The potential cost saving derived from the use of phytosterols is expected to be significant because of the direct link to lowering LDL cholesterol levels. It is because of this direct link that the postulation was made that there would be consequential impact on reducing the risk of experiencing a CVD event. Regarding the potential limitations of this case study, the potential healthcare cost saving calculations reported in this study only include the direct and indirect expenditures most likely to be associated with the use of phytosterols. These estimates do not include a number of additional benefits that can be gained from the use of phytosterols, including additional benefits related to avoiding other potentially costly CVD-attributed events such as reduced stress and worry experienced by patients and the families of patients. It also does not include productivity gains that can be derived from helping otherwise healthy people avoid CVD-attributed medical events, which directly impacts additional benefits to the state in the form of tax revenue. However, the economic model utilised for this analysis is a generalised model that determines the economic effect of using phytosterols on the chance a CVD-attributed event outcome, which is directly relevant to the social cost of healthcare. In addition, the current case study does not follow individual people over time due to data availability limitations. This economic model currently treats all of the people in the target population per EU country as a homogeneous set of people, including the expected risk of experiencing a CVD-attributed disease-attributed event. Thus, total social benefits are measured. Actual benefits realised per individual user will be a function of the specific CVD risk they face as indicated by their risk biomarker levels. The case study also makes the inference that in the phytosterol utilisation scenario all adults over the age of 55 with CVD use phytosterols from a base of zero usage among this population segment. In other words, the calculated net savings is actually the total potential net savings. However, because it is likely that a percentage of target population are already regular users of phytosterols, this portion of the target population is already realizing phytosterol’s risk-reducing benefits. According to the 2012 Council for Responsible Nutrition Consumer Survey on Dietary Supplements, less than 1% of U.S. adults over the age of 55 are regular users of phytosterols food supplements which imply that the target population highly underutilises phytosterols in general [24]. It is expected that the EU as a whole reflects similar phytosterol supplement consumption patterns to the U.S, though the use of phytosterols-fortified foods is likely greater in the EU compared to the U.S. Thus, this is the key reason why benefits per user were calculated so that once consumption trends per user per EU country are determined through future research, then calculation of total potential benefits yet to be realised per country can be easily determined. The potential cost saving derived from the use of phytosterol food supplements is expected to be significant because of the direct link to lowering LDL cholesterol levels. 31 In conclusion, this case study on the potential benefits of using phytosterols illustrates that there are significant health care cost savings likely to be realised. However, this can only be achieved through a concerted effort to identify high CVD-risk populations, such as those people with severe hypercholesterolemia, and encourage them to use phytosterols as a means to help minimise the risk they face. There are many ways to identify and motivate people at risk to use effective food supplements, including the use of innovative technologies that are able to identify high-risk populations before they experience costly acute treatment events or the use of incentives for consumers, health care professionals, and other key stakeholders to address the antecedents of disease. Once these innovative technologies and best practices are fully adopted and applied by the key stakeholders in the health care system in the European Union, then a smarter approach that utilises certain food supplements that have been shown scientifically to reduce the risk of experiencing a costly CVD event at controlling potential health care costs can be applied to truly maximize the total potential social benefit of avoided cases of CVD. Significant health care cost savings can to be realized through a concerted effort to identify high CVD risk populations and encourage them to use phytosterol food supplements as a means to help minimise the risk they face. Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 32 References [1] World Health Organization. Regional Office for Europe. European hospital morbidity database [1] Hypercholesterolemia. (2016) Genetics Home Reference. U.S. National Library of Medicine. 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M., Lin, X., Ma, L., & Ostlund, R. E. (2009). Phytosteroldeficient and high-phytosterol diets developed for controlled feeding studies. Journal of the American Dietetic Association, 109(12), 2043–2051. [18] Ostlund, R. (2002). Phytosterols in Human Nutrition. Annual Review of Nutrition , 22: 533-549. [19] Gylling, H. et al. (2014) Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis. 2014 Feb;232(2):346-60. Retrieved at http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(13)00694-1 33 [20] EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of health claims related to plant sterols and plant stanols and maintenance of normal blood cholesterol concentrations (ID 549, 550, 567, 713, 1234, 1235, 1466, 1634, 1984, 2909, 3140), and maintenance of normal prostate size and normal urination (ID 714, 1467, 1635) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA Journal 2010;8(10):1813. [22 pp.]. [21] The European Commission. (2014) Commission Regulation (EU) No 686/2014 of 20 June 2014 amending Regulations (EC) No 983/2009 and (EU) No 384/2010 as regards the conditions of use of certain health claims related to the lowering effect of plant sterols and plant stanols on blood LDL cholesterol Text with EEA relevance. Retrieved here http://eur-lex.europa.eu/legal- content/EN/TXT/?uri=uriserv%3AOJ.L_.2014.182.01.0027.01.ENG [22] Phillips, C.; Belsey, J.; Shindler, J. (2002) Flora pro.activ: a clinical and financial impact analysis. Journal of Drug Assessment. Vol. 3 No. 3 pp. 179-194 [23] A. Gerber1, T. Evers, H. Haverkamp, and K. W. Lauterbach. (2006) Cost-benefit analysis of a plant sterol containing low-fat margarine for cholesterol reduction. Eur J Health Econ 2006 • 7:247–254 [24] Shanahan, C. and de Lorimier, R. (2013). Smart Prevention—Health Care Cost Savings Resulting from the Targeted Use of Dietary Supplement. An Economic Case for Promoting Increased Intake of Key Dietary Complementary medicines as a Means to Combat Unsustainable Health Care Cost Growth in the United State. Frost & Sullivan. http://www.frost.com/sublib/display-market- insight.do?id=285115104 [25] Ras RT, Geleijnse JM, Trautwein EA. (2014) LDL cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. Br J Nutr. 2014 Jul 28;112(2):214-9. [26] Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39 [27] European Atherosclerosis Society (2015) Commentary on Phytosterol-added Foods. Focus on lifestyle: EAS Consensus Panel Position Statement on Phytosterol-added Foods. Retrieved in September 2016 at https://www.eas-society.org/?phytosterol_comment Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 34 Appendix I: Risk and Number Needed to Treat Calculations According to Grundy et al. (2004) the relationship between RRx and LDL concentration is non-linear such that as RRx increases by a certain percentage for every unit increase in LDL cholesterol [26]. This relationship can be represented with the following log-linear model: 1. 𝑙𝑜𝑔 𝑅𝑅* = 𝛼 + 𝛽𝑥 The slope b represents the rate at which CVD risk increases per unit increase in LDL cholesterol baseline level. Slope parameter b can be calculated from these results by taking the difference in relative risks for LDL cholesterol x-1 and x, or: 2. 𝑙𝑜𝑔 𝑅𝑅*-. − 𝑙𝑜𝑔 𝑅𝑅* = 𝛼 + 𝛽 𝑥 − 1 − (𝛼 + 𝛽𝑥) Solving for b yields the following identity: 3. 𝑙𝑜𝑔 00123 001 = −𝛽 This equation can be generalised to calculate the change in the relative risk of experiencing a CVD event at LDL cholesterol level x given a change of LDL cholesterol levels by any amount as shown below: 4. 𝑙𝑜𝑔 𝑅𝑅*-/ − 𝑙𝑜𝑔 𝑅𝑅* = 𝑙𝑜𝑔 0012E 001 = 𝛼 + 𝛽 𝑥 − 𝛿 − (𝛼 + 𝛽𝑥) where d is the expected change in LDL cholesterol given the use of a LDL cholesterol lowering regimen, like phytosterols, observed in the scientific literature. In other words, we can say that d is the pooled treatment effect of phytosterol supplement use on LDL cholesterol. This equation can be simplified to the following: 5. 𝑙𝑜𝑔 0012E 001 = −𝛿 ∗ 𝛽 Plugging in for -b yields: 6. 𝑙𝑜𝑔 0012E 001 = 𝛿 ∗ 𝑙𝑜𝑔 00123 001 Taking the anti-log of both sides of the equation yields: 7. 0012E 001 = 00123 001 / 35 The term in parentheses is the relative risk reduction in a CVD event given a 1 unit reduction in LDL cholesterol. The term on the right side of the equal sign can be included in a general absolute risk reduction equation as shown below which in turn can be used to determine the number of possible avoided events for a predetermined target population that could be realised from use of a phytosterol supplement: 8. 𝑁 = 𝑅𝑖𝑠𝑘* 1 − 00123 001 / Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 36 Appendix II: The Cost of Cardiovascular Disease The PPP-adjusted average cost of a CVD-attributed hospital event in the EU will be € 34,637 per event 16. The average cost of each CVD-attributed event is calculated by taking total expenditure over the next 5 years and dividing it by the cumulative number of events, and then adjusting each country’s expected cost by its PPP. The cost of inpatient care, which is the expenditure for care of patients who requires hospital admission at the beginning of the CVD-attributed event, and post-treatment informal costs such as home nurses, medical equipment for home use and lost productivity which is typically spent over several months or years after the initial event are nearly equal in share of cost burden at 32.9% each. The cost of medications for managing CVD makes up an additional 19.1% of the financial burden of CVD. The remaining services contributing to CVD-attributed healthcare costs make up a combined 15.1% of the cost burden include primary care (5.7%), outpatient care (8.3%) and ambulance and emergency (A&E) (1.1%). Appendix Chart 1 Total Burden of Cardiovascular Disease: CVD-attributed Event Costs by Service Type, European Union, 20151718 16 Source: European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis, Frost & Sullivan. The average cost of each CVD-attributed event is calculated by taking total expenditure over the next 5 years and dividing it by the cumulative number of events. This event cost was taken because some events and its residual post treatment disease management costs may stretch beyond one year for a given patient. 17 Adjusted for purchasing power parity (PPP). PPP ratios are provided by the World Bank and are reported in Table 8 of this report or http://data.worldbank.org/indicator/PA.NUS.PPPC.RF. 18 Note: A&E is ambulance and emergency services. Inpatient care is the expenditure for care of patients who requires hospital admission at the beginning of the CVD-attributed event. Informal Care includes post-treatment informal costs such as home nurses, medical equipment for home use and lost productivity which is typically spent over several months or years after the initial event. Outpatient care includes costs related to medical care provided on an outpatient basis, including diagnosis, observation, consultation, treatment, intervention, and rehabilitation services. Primary care is the day-to-day healthcare given by a health care provider. Source: European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis, Frost & Sullivan analysis 37 Appendix Chart 2 Total Burden of Cardiovascular Disease: CVD-attributed Event Costs by Service Type: Ranked by Total Hospital Event Costs, Selected EU Countries, 201519 Source: European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis, Frost & Sullivan analysis 19 Adjusted for purchasing power parity (PPP). PPP ratios are provided by the World Bank and are reported in Table 8 of this report or http://data.worldbank.org/indicator/PA.NUS.PPPC.RF. 11,777 13,244 13,609 22,916 24,040 25,422 26,099 26,371 28,248 28,677 29,684 30,208 31,362 34,637 35,597 37,313 38,436 41,034 41,339 41,814 49,663 51,613 57,865 - 20,000 40,000 60,000 80,000 100,000 120,000 140,000 Lithuania Hungary Slovakia Slovenia Latvia Belgium United Kingdom Czech Republic Austria Luxembourg Romania Finland Denmark Total EU Italy Germany Malta France Spain Poland Netherlands Cyprus Ireland Cost of CVD (€ /Event) by country Primary Care Outpatient Care A&E Inpatient Care Medications Informal Care Healthcare Cost Savings of Phytosterol Food Supplements in the European Union 38 Appendix III: List of Abbreviations A Number of possible avoided events (A) if everybody in a specified target population used phytosterol B total potential net economic benefits yet to be realised from use of a 1,000 mg phytosterol S/Pop Benefit per User BP Blood Pressure C Total cost of a phytosterol regimen CBA Cost-benefit analysis CI Confidence interval CHD Coronary heart disease CVD Cardiovascular disease d The expected per person cost of phytosterol utilisation per year EFSA European Food Safety Authority EU European Union g gram h The expected cost of a CVD-attributed event HDL High-density lipoprotein ICD International Classification of Diseases IHD Ischemic heart disease ISHMT International Shortlist for Hospital Morbidity Tabulation LDL Low-density lipoprotein mg milligram MI myocardial infarction mmol/L millimole per liter N* Absolute risk reduction Pop Target Population PPP Purchasing Power parity RCT Randomised controlled trials RRR Relative risk reduction S Total potential savings from reduced hospital service utilisation following CHD-attributed hospital events that are realisable if the entire target population were to sufficiently utilise a 1,000 mg phytosterol S/C Benefit Cost Ratio S/Pop Benefit per User U.S. United States of America WHO World Health Organization 39 This study was funded through a grant from Food Supplements Europe. 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