Interviews by Distributor Type
\r\n\tSimilar to many purposeful engineering and social endeavors, knowledge has a cradle to grave systematic life cycle with many distinct phases and requirements for generation to disposal.
\r\n\tApart from focus on knowledge, the essential and desirable skills and qualities of the human agent in the quest for generation, deployment and value creation from knowledge requires a systems framework for optimal impact. We refer to the total human ability for successful management and deployment of knowledge as competence. This goes well beyond ownership or access to knowledge and encompasses many other dimensions such as experience, appropriate skills, quality, efficiency and ability to innovate n complex settings and go beyond known body of knowledge.
\r\n\tIt is argued that successful management of knowledge requires competent entities individuals, teams to whole enterprises. This edited book focuses on knowledge, its life cycle and essential processes and systematic assessment and management of competence at individual, team or enterprise level when applied within the context of engineering mission critical systems.
Looking at the present food chain, concerns are related to anxiety among consumers about the quality of the food they eat, GMOs, use of pesticides and antibiotics, and industrialization of the agricultural system. Growing consumer demand for organic food (OF) is based on most of these facts [1, 2]. Although OF is generally considered to present less risk than conventional foods, this debate has been re-launched as a direct consequence of rising concerns related to risks associated with intensive agricultural production, food industrialization, and the effects of food technologies and food scares [1, 3]. An increasing number of organic brands, certification labels, and wider range of organic product categories has been observed in terms of efforts to provide higher food safety and food quality. But these factors do not seem to have increased consumers’ perceived value of organic food products nor trust in OF. Moreover, consumers seem to be ambivalent about channels of distribution as trust/mistrust appears to be an important factor in deciding, not only where to buy products, but also whether to buy OF products or not [17].
From the production and supply side, there are some unique challenges to the cost and logistics of moving locally or regionally produced organic food to the market. Of particular interest are the operations size and the situation of small and medium size farms. The production of the latter is of little interest to mainstream grocery chains as it is limited to a few hundred tons. Among other factors, production methods and operations size are key here. Large-scale farming is sustained by important economies of scale while small scale farming leads to higher prices. This covers the extra costs of not using fertilizers and antibiotics. As a result, there is a wide variety of product classifications depending on the production methods and thus, the operations’ size. This in turn gives raise to 2 distinct distribution systems: long channels, eg. retail chains, that add value through price and high distribution intensity, and short channels, eg. direct from producers, that add value through their production methods and sustainable practices. Hence, discrepancies between market realities, the value chain and the value delivery system are still a challenge for the organic food sector. The main issue here is to determine the factors on which the different production methods and distribution systems rely on in order to add value to the organic food products offered. This study first presents the current literature related to the structure of the production and distribution of the organic food system and market, supported by an integrative production-distribution model. The model integrates the different levels of the production/supply side key factors. Challenges and strategies that add value to the organic food products are analyzed. These strategies are used by (i) the pre-supply, (ii) the supply/production, and (iii) the distribution channels.
From a production standpoint, there are various categories of production methods. In Canada, there are three main classes of production labels: (i) organic, (ii) transitional organic, and (iii) all other labels regrouping local, natural, pesticide-free and ecologically friendly. The first product class is well defined and regulated since 2009, while the second and third categories are neither - clearly - defined nor regulated.
The use of the term “organic” is restricted to farms, products, processors and other intermediaries in the value chain between production and consumption which has been certified by Certifying Bodies (CB). These CBs are independent and private fee-for-service agencies that are generally overseen by National Food Inspection Agencies. Organic certification is an arduous process which, if enacted on a farm previously farmed using conventional methods, requires at least three years to ensure all chemicals have leached from the soil and that organic amendments have had the opportunity to rebuild soil fertility.
“Transitional organic” is also a restricted label and describes farms which have made the commitment to move toward organic certification. For instance, the "transitional" label is applied to farms label is applied, for example, to farms which have switched to certifiable organic methods and are in the 36-month period between the last use of chemicals and the time the land can be assumed free of chemicals, and the farm can be certified organic.
Labels like “local”, “natural”, “pesticide-free” and “ecologically friendly” are not regulated and tend to be used by small farms catering to local/regional clientele. With the exception of marketing board-regulated products like dairy or chicken, production and handling of foods sold under these labels is for the most part not monitored or regulated except by governmental agencies and district health units. As a result information on farms operating outside of the organic certification system is scattered and incomplete.
Lastly, “organic” foods have to be differentiated from “functional” foods [4]. Organic foods tend to be regulated and are based on supply side value while functional foods are not very regulated and are based on demand side value. While both types of product are marketed to achieve the same objective, i. e. healthy products, the market positioning is very different.
According to the Canadian General Standards Board, "Organic production is a holistic system designed to optimize the productivity and fitness of diverse communities within the agro-ecosystem, including soil organisms, plants, livestock and people. The principal goal of organic production is to develop enterprises that are sustainable and harmonious with the environment. " [5]. It is worth noting that the organic movement, which began as an alternative style of production among small farms looking both to reduce their environmental footprint and to differentiate their products from commercially produced foods, has been admitted to the mainstream market. Certification, which came about to prevent fraudulent claims, has enabled large players to get into the game, facilitating the long-distance shipping and distribution of organic products required to bring them to grocery stores and wholesale clubs. It applies within the value chain the same downward pressure on price exhibited in the conventional food value chain. This has resulted, for some small farmers concerned with the philosophical aspects of organic production, in diminished credibility of the organic standard and a refusal to participate. It has also hardened the value chain against entry by these small farmers [6].
Further, to be qualified as organic, processed foods must be processed in certified facilities. Added-value processing in Canada is limited by the small number of certified processors. Handlers of organic products must also be certified. This is the other major factor, and one that could mitigate the seasonality of foods: further processing could provide a wider market and a longer selling window for perishables. By characterizing producers\' use of the value chain to get products to the consumer, we can break the organic producers down into three categories: large, small and medium-sized operations.
Large producers are characterized by organic cash crops, which are either exported or processed after they leave the farm, by livestock or field crops which are most likely to go to distributors and processors for further treatment [7]. Most dairy farms would be considered large producers in this context.
Medium-sized producers tend to produce for a smaller geographical market [7]. Limited by infrastructure, some of these producers are now working together to develop their own products, partnering up with complementary businesses to be able to expand the offerings of their on-farm market to attract more customers. Others have partnered with small regional processor/distributors to reach restaurants and specialty food retailers. Most medium producers offer on-farm markets as stationary storefronts, incorporating products sold on consignment or retailed for other area producers.
Small organic producers tend to not use distribution intermediaries. Instead they focus on direct relationships with consumers through farmers\' markets and on-farm markets. They may supply some restaurants, specialty retailers, or small grocers, but these relationships are painstakingly developed and rely on niche marketing and personal relationships. These are the small farms most likely to give up on organic certification due to the paperwork and expenses involved.
In conventional food systems, there exists between producers and consumers of food products a series of handlers involved in the processing and distribution. Since organic products have entered into the mainstream market, a similar mainstream value chain has developed for organic products being sold through conventional outlets. Traditional retail, with its focus on profit, seeks consistent supplies of products. Imports from warmer climates offer this consistency; we see California and Mexico lettuce occupying shelves year-round because, for reasons of efficiency, retailers prefer to deal with a single supplier rather than displace the year-round supplier with a seasonally-available product.
Organic food has emerged as an important segment of food retailing in recent years. The organic food industry has steadily moved from niche markets, e. g. , small specialty stores, to mainstream markets, e. g. , large supermarket chains [8, 9]. Ten years ago the bulk of OF sales were made in specialty stores (95%) while the remaining 5% were realized in mainstream stores. Nowadays, the trend has been reversed [10]. Farmers’ markets among other alternative distribution channels are being used and are characterized by a direct link between the producer and the consumer [11]. In some countries, distributors are promoting their own line of OF products under specific brand names [12, 13, 14].
In Canada, the total annual retail sales of certified organic products in 2009 were approximately $2 billion, with about 45% moving through mainstream supermarkets [15], and OF retail sales represented 1% of total retail food sales. More specifically, total mass market sales of certified OF products approximated CA $586 million allocated as follow: CA $175 million through small grocery stores, drug stores, and specialty stores, and CA $411 million in large grocery chains. These figures do not account for alternative distribution channels such as farmers’ markets, natural food stores, box delivery, and other channels such as restaurants. These channels totalize CA $415 million [16]. Conventional distribution channels, characterized by a longer channel where consumers do not see and interact with the producer and where the information about food is limited, is targeted toward consumers that look for a one-stop grocery shopping experience [6, 17]. These are the regular OF consumers. On the other hand, channels such as box delivery, specialty stores, and small grocery stores or even direct channels such as the farmer’s market are targeted toward consumers that look to interact – socially - with the producers [11], ask them questions about their production methods, food origin and variety, and cooking tips. These are the hardcore consumers. Most of the demand is coming from Europe and North America and these two regions are not self-sufficient. The main problem for producers and growers is to supply this demand. Large volumes of organic imports, coming in from other regions, are used to balance the undersupply. US sales of organic products grew in 2009 by 5. 3%, to reach 26. 6 billion US dollars, representing 3. 7% of the food market. In Europe, sales of organic products approximated EU 18’400 million in 2009 [18]. The largest market for organic products in 2009 was Germany (5. 8 billion euros) followed by France (3 billion euros) and the UK (2 billion euros).
The organic food market is characterized by consumers buying organic food products for different motivations and values. OF consumers also have different buying processes that are not the result of one decision but a series of decisions nested in each other. Among these, decisions about where to buy is here considered as it directly relates to consumers’ most used and trusted distribution channels.
Through the literature, several motivations to buy organic food have been identified and ranked. Personal health remains a strong motivating factor, organic food products being perceived as less associated with health risk than conventional food products [19]. Concerns for the environment and for animals’ wellbeing appear as other reasons for buying organic food [20, 21, 22]. Issues about food quality but also “eating to enjoy” is mentioned to be important motivations for OF consumption in several countries like France, Italy and Greece [23, 24]. Furthermore, tasty and nourishing products are considered as important motivations and [25] found that most organic consumers think that organic food tastes better than conventional. Last, organic products are associated by fewer consumers with local production because they like to support the local economy [6, 26]. The cultural differences cause consumers in different countries to have various motivations with regard to OF, such as health and tradition in France vs. health and environment in Sweden [2, 27].
In their study, [29] provided an overview of the personal motivations of organic food consumption within a framework linking these motivations to Schwartz’ values theory. When considering health as a motivation for purchasing organic food, it appears that consumers link it with the value of security, or safety and harmony. Good taste and eating to enjoy relates to hedonism or pleasure and sensuous gratification for oneself. The propensity to behave in an environment-friendly way (environment and animal welfare) relates to the value of universalism whereas supporting the local economy is related to the value of benevolence. But this latter is only highlighted in fewer studies. This is even more interesting as an important share of organic food is still imported because OF markets are not self-sufficient.
Given the prevailing climate of food-related fear and consumer uncertainty, trust indicators may have a significant role to play. Perceived risks pertaining to food consumption and lack of knowledge regarding organic products are leading consumers to rely on different indicators such as brand name, store image, label or partners like producers. Consumers’ trust toward the distribution channels also appear to be an important factor in deciding not only where to buy but also what to buy. This highlights the importance of examining the trust issue from the supply side. Indeed, the main OF market actors are contributing, at different levels and with different strategies to consumers’ level of knowledge of, preferences for, as well as trust/mistrust in OF products. As a matter of fact, building trust in the OF supply requires tools such as quality certification or labeling that have to be established and used as a promotion strategy. Trust orientations should be studied in the context of market actors such as producers/farmers and distributors or certifying bodies. Since markets differ in how the food system is organized, each player (producers/farmers, distributors, certifiers) adds a different value to the product and requires distinct distribution flows to do so. This is very likely to be in direct relation with the type of consumers and their preferred and most used channels of distribution.
Whereas the majority of previous research is focusing on the demand side, this study aims to uncover variations among supply side players (producers/farmers, distributors, certifiers) with regards to the OF supply chain and factors they rely on to add value to organic products. This value needs to be determined and estimated at all levels of the channel of distribution. Further, the logistics of the value delivery network need to be investigated. This will lead to an in-depth understanding of the value added in the organic food distribution system, the current market structure, as well as the determination of the challenges faced by the major players of the organic food industry. A second objective is to identify the different distribution strategies and arrangements to market organic foods and increase trust in OF products. Building trust in the OF supply requires more than just ensuring product quality and product knowledge, labeling or setting proper pricing and communication strategies, as trust is missing at various levels of the marketing value delivery system and the food supply chain. The dimensions of trust necessary to achieve market growth have to be integrated to the OF product positioning and the distribution strategies. In their effort to rebuild consumer confidence and satisfy consumer demand, such information is important for all market participants involved in the supply food system. Lastly, to support these two objectives it is important to provide a precise and useful profile of organic food consumers in relation with their preferred channel of distribution and main trust orientations.
To address the abovementioned objectives, our approach is based on an integrative production-distribution model (cf. Figure 1). There are 3 layers of decisions in this model (i) pre-supply: this is related to certification decisions, laws and regulations related to government agencies, and finally expert opinions on the industry structure and evolution, (ii) supply: this is related to the production, production methods, imports, and sold quantities, and (iii) channels of distribution: broken down into 3 main categories, long or standard channel, short channels, and direct channels.
Integrative Production-Distribution Model
The abovementioned objectives require a 2-level design. This design determines how distributors/producers manage similarities and differences between what consumers want and what they offer them. A supply-side study has been developed to assess the production-distribution model. This in turn will lead to the development of a second model that takes also into account the demand-side (production/market model). First, in the supply-side study, secondary data on the organic food industry was collected to understand its market structure; then in-depth interviews were conducted with producers, distributors and certifiers. Distributors and producers were profiled as follow: (i) by channel size and type, (ii) by organic food products variety, and (iii) by channel position (retailer, wholesaler, etc. ). Further, there is a three-prong challenge related to the interviews quality and consistency: (i) interviews had to cover a wide range of producers and distributors in the organic food industry, (ii) interviewees had to be decision makers or gate keepers in their channels of distribution/organization, and (iii) the sample size should be sufficient enough to ensure consistency of the results without reaching any saturation.
Secondary data was collected in Canada using major sources of information as well as informal interviews with 14 industry key players (experts, certifiers, and government representaitves). As gatekeepers to the organic label, these key players can provide the most recent and accurate information about the numbers and types of organic farms, products and businesses, as private enterprises, are under no obligation to do so. Information obtained from these gatekeepers, while fairly comprehensive within its scope, is not necessarily accurate. This is illustrated by the example that, in order to reach various target export markets, some farms, products and businesses are certified by multiple bodies simultaneously. Lastly, 2 sets of in-depth interviews, based on 2 thematic interview guides that lasted about 30 minutes to 45 minutes, were conducted with 90 respondents (cf. Table 1). The first set of interviews focuses on the production/supply aspects while the second set focuses on the distribution/market, and hence the distribution logistics and its impact on the consumer’s market. The interviews were recorded (digital voice recorder), transcribed, coded, and analyzed using content analysis [30]. This technique allows the researcher to include large amounts of textual information and methodically identifies its properties by detecting important structures of its content. Two separate judges coded the data to ensure a minimum of 80% correspondence.
\n\t\t\t\tInterviewees \n\t\t\t | \n\t\t\t\n\t\t\t\tProduction/ distribution\n\t\t\t | \n\t\t\t\n\t\t\t\tDistribution/ market\n\t\t\t | \n\t\t
Retail chains | \n\t\t\t0 | \n\t\t\t7 | \n\t\t
Small grocery stores | \n\t\t\t0 | \n\t\t\t2 | \n\t\t
Specialty stores | \n\t\t\t0 | \n\t\t\t12 | \n\t\t
Organic producers/farmers’ markets | \n\t\t\t15 | \n\t\t\t17 | \n\t\t
Certifiers | \n\t\t\t0 | \n\t\t\t8 | \n\t\t
Organic food experts | \n\t\t\t0 | \n\t\t\t7 | \n\t\t
Other distributors | \n\t\t\t15 | \n\t\t\t7 | \n\t\t
Total | \n\t\t\t30 | \n\t\t\t60 | \n\t\t
Interviews by Distributor Type
The secondary data analysis led to the compilation of information coming from various sources, then information gaps were determined. These gaps relate to discrepancies between dollar sales and dollar production, the characterization of the value delivery system, and exports/imports of organic foods. Results from this phase have been used to design and structure both interview guides:
The production/supply interview guide is composed of 5 sections; 3 sections related to marketing mix elements of organic foods (product, price, and place), a 4th section about the organic food market, and the last section deals with certification and labeling.
The distribution/market interview guide is composed of three main sections. The first section probes distributors to discuss their perceptions of the current OF market and the structure of their distribution channel. The second and third sections deal with distributors’ perception of consumers’ concerns, trust issues related to their distribution strategies, and how consumers’ concerns are addressed.
These 2 sets of interviews are complementary. Hence, the analyses have been combined for the sake of obtaining more exhaustive and integrative results. 59 keywords, clustered in 13 themes, have been generated from the interviews transcriptions. These themes are classified as follow: (i) production and supply: the section presents the challenges and issues that producers/farmers deals with when marketing their organic foods; (ii) value delivery system: value creation throughout the distribution channels; (iii) market/industry structure: this theme category covers various market trends and the demand as perceived by the supply side, (iv) distribution strategies: this section groups all distribution strategies as well as distribution logistics; (v) trust issues: these are consumers concerns regarding OF and the corresponding distribution strategies used to increase trust; and (vi) sustainability: this last category deals with the impact of sustainability on the organic food industry.
Information on the production of organic foods tends to be collected and provided in terms of acreage in production and not in final retail sales value, making it difficult to bridge between production and economic value. Retail numbers, when provided, are generally estimated based on current market values and expected yields by acre for the crops in production. They do not account for any added-value processing which may occur between the producer and the consumer. Further, because certifying bodies deal only with certified or transitional organic products and businesses, their numbers do not reflect the uncounted number of small mixed-production farms operating outside of the certification process. These farms are selling under one of the "natural" and "local" alternative labels commonly used in direct-to-customer sales at Farmers\' Markets and on-farm stores.
By characterizing producers\' use of the value chain to get products to the consumer, organic producers can be broken down into three categories: large, small and medium-sized operations. Like the medium-sized farming/processing operations, larger processing and distribution centers tend to co-pack with conventional products, ensuring sufficient throughout to be profitable. These enterprises tend to be closed systems; like the large retail outlets they serve, those are interested mainly in consistency of product and supply and so they contract with large growers for their raw products. Smaller packing, processing and distribution operations are often spawned by the producers themselves as a way of making their products more marketable. This adds value and extends the selling window for their own products; basically building in forward integration of the value chain. To maintain year-round clientele these operations supplement with organic imports on a seasonal basis and retail the products of other producers.
There seems to be little overlap between large, medium and small producers at the processing, distribution and sales stages. There is very little shared infrastructure between these levels. The processing and distribution system for large producers is, for the most part, closed; it\'s available to those large producers only. The system for the medium-sized producers, developed by those same medium-sized producers, tends to remain closed because they are still struggling to maintain their position; they\'ve done enormous amounts of work in establishing themselves and often consider the information and infrastructure they\'ve developed to be proprietary.
It is clear from the interviews that the organic food system tends to echo the conventional system in terms of the size and distribution of margin within the value chain - more details will be given in the upcoming sections. There are effectively three distribution chains of increasing efficiency at work in the organic food system, culminating in three types of retail. As in any distribution structure, every intermediary involved in the organic value chain must be able to add sufficient margin to cover its operating costs and generate enough profit to justify continued operation. The final price paid by the consumer reflects a share paid to each participant. This price must also be low enough to be attractive to consumers. Entry into the market of large supermarket chains has had a significant impact on price, producing downward pressure on the value chain in much the same way it has occurred in the conventional chain. While this has made organics more accessible and increased the volume of sales, the return to a focus on price has decreased the value of the organic label to small farmers.
Further to this, according to the supply side, distributors perform different distribution flows, thus creating distinct “organic values” sold through their channel of distribution. The “organic value” is directly related to the efficiency of the value delivery system. It is also clear that there are two distribution perspectives: long/medium size channels such as retail chains and small grocery stores versus short channel such as specialty stores, farmers’ market, and producers. Long/medium channels have a price/variety driven value, while short channels offer a value based on traceability and quality. This supports the importance of pricing. Prices tend to be higher in shorter channels than in longer channels as there are more flows performed by fewer channel members. Hence, shorter channels need larger margins to stay in business.
Organic Value Creation
In terms of product lifecycle, the OF market is not at maturity yet. Overall, distributors agree that the OF market is growing and shows substantial opportunities. More specifically they mentioned an increasing diversification of product lines and channels of distribution. Most of these distributors argued that the organic food market is demand driven; it is basically based on a derived demand, “I am wishing, that at the retail level, we would have a better supply of it to meet the demands of our customers”. This demand is exponentially growing, leading distributors to rely more and more on imports to compensate the under-supplied of local and national production. Further, many conventional channels are increasing their organic sales adopting conventional marketing strategies to organic food products; including organic versions of conventional brands. This is done to satisfy the needs of wider OF segments. The increasing number of distribution channels is also based on an increasing number of supermarkets and food store chains offering and widening their offer of organic foods at very competitive prices. Further, with the growth in popularity of organic food products, many wholesalers have entered the organic food supply chain. They have been encouraged by chain stores that need larger quantities at regular delivery times, and have to work through them because of high demand, “I am wishing, that at the retail level, we would have a better supply of it to meet the demands of our customers”. Consequently, imports from regions with large organic farming activities (eg. California) still prevails. The second major trend is pricing. All interviewees including distributors, certifiers, and experts agree that price is a key factor to enhance organic foods demand. However, price has been more discussed as a cost-control tool rather then as a market price-sensitivity issue, “but one of the most difficult things is to make it price competitive”. It is clear that the industry is slowly moving toward a price skimming strategy. Third, all interviewees agree to say that consumers are becoming more educated and make smarter food choices. However, there are clear differences in their purchasing behavior. Producers and farmers’ markets managers stated that their customers have specific needs and motivations to buy organic foods, such as health and support of local farmers. Conversely, consumers buying from conventional channels, i. e. retail chains, are looking for a different shopping and consumption experience. This is directly related to the OF adoption process. Consumers trusting the labels and certifications are in the interest-evaluation-trial phase while consumers trusting stores are in the adoption phase.
The increasing number of distribution channels seems to be mainly based on an increasing number of supermarkets and food store chains offering OF products and widening their offer of organic foods at more competitive prices. As a matter of fact, the diversification of the offer is the main driver of the market growth for supermarkets and retail chain managers. Most conventional channels are increasing their organic sales using conventional marketing strategies for organic food (like offering organic versions of conventional brands). This helps satisfying the needs of a wider number of OF segments.
From the producers and farmers’ perspective, being able to expand supply is a big issue that translates into poor supply reliability and poor availability at the demand level. More wholesalers have entered the organic food supply chain with the growth in popularity of organic food products. They have been encouraged by chain stores because demand is up and they need larger quantities at regular delivery times, and wholesalers are key here. Consequently, imports from other regions with large organic farming activities still prevails. On the other hand, “local food” consumption is starting to drive the organic food demand. These products are a superior quality alternative to what is called “industrial organic” offered in supermarkets and retail chains. Producers are also making efforts in diversifying their offering and widening their product lines. It is interesting to note that direct channels offer competitive prices with regards to retail chain and supermarket. This represents a serious alternative for consumers looking to buy organic.
From the organic food specialty stores’ perspective (independent stores as well as small chain stores), the organic market shows differences with supermarkets in terms of variety, price and quality. In other words, supermarkets are able to provide consumers with a larger variety, lower prices and convenience whereas specialty stores differentiate themselves with the quality and the origin of their products. The main difference between suppliers is determined in terms of short-direct/long channel of distribution, with producers offering traceability and quality. This is also related to the value offered in these channels: price versus quality.
Consumers have different trust orientations/levels depending on the type of distribution channel they use: trust related to labeling and certification, trust in the store selling OF, and trust in the production origin. Table 2 presents the distributors perspective on consumers’ trust and ways to increase trust in organic food products.
\n\t\t\t\tDistributors \n\t\t\t | \n\t\t\t\n\t\t\t\tTrust more\n\t\t\t | \n\t\t\t\n\t\t\t\tTrust less\n\t\t\t | \n\t\t\t\n\t\t\t\tTo Increase trust\n\t\t\t | \n\t\t
Retail chains | \n\t\t\tProduct labels ++ Certification labels + | \n\t\t\tBrands | \n\t\t\tPrice Accuracy Consumers’ education Quality | \n\t\t
Small Grocery Stores | \n\t\t\tProduct labels ++ Store reputation ++ Store manager ++ | \n\t\t\tBrands | \n\t\t\tConsumer education Knowing the producer Price accuracy | \n\t\t
Specialty stores | \n\t\t\tProduct labels ++ Certification labels ++ | \n\t\t\tBrands | \n\t\t\tConsumers’ education Quality | \n\t\t
Consumers’ education Knowing the producer | \n\t\t|||
Organic producers | \n\t\t\tCertification labels + Production methods ++ | \n\t\t\tNA | \n\t\t\tConsumers’ education | \n\t\t
Certifiers/ Experts | \n\t\t\tCertification labels ++ | \n\t\t\tNA | \n\t\t\tInformation on the labels Consumers’ education Knowing the producer Production methods Certification process | \n\t\t
Other distributors | \n\t\t\tProduct labels ++ Certification labels + | \n\t\t\tNA | \n\t\t\t\n\t\t |
Trust Levels by Distributors
Retail chain managers mention – unanimously – that the product label is important. They also acknowledge that there are different types of consumers based on their level of trust. Consumers buying in these outlets feel very confortable knowing what to buy and finding all information they look for. Retail chains selling organics use intensive distribution strategies, as their customers are also looking for a one-stop shopping experience. Hence, convenience and price are the main drives of the organic value here. This relegates other product attributes such as certification, brand name and country of origin to a passive role. From a strategic standpoint, retail chain managers are using conventional marketing strategies to increase their OF market share. For instance, price-skimming strategies, shelf-space and shelf life, as well as product differentiation are used to penetrate this fast growing market segment. Conversely, the organic value marketed in small grocery stores is mainly based on the relationship with the manager, the store reputation and also on the product/certification label. Managers’ strategies are mainly targeted towards store loyalty; consumers trust the store hence they trust the manager, “I would guess trust because the consumer is trusting me as a store owner”. Since the clientele base is smaller than in chain stores, managers are more approachable and they know some of their customers by name. This enhances the trust relationship between the store and the consumers, which is very important to stay afloat and in business. Further, this is a guarantee for quality and counterbalances the lack of brand effect. Lastly, managers argue that consumers buying in their store are knowledgeable and ask about specific product attributes when buying organic. As for retail chains, branding is not important.
Specialty stores managers observe that consumers trust labels, i. e. , product label and certification label. The value offered in this channel is based on the width and depth of the product lines, and also on the traceability of organic foods via certification labels. Hence, labeling is important as a source of information. Managers acknowledge also that OF consumers are more knowledgeable; thus they are able to recognize and also to evaluate the different certification labels. What is interesting though is that managers do not see any difference between consumers with regards to their trust level. It is important to note that even if brands are crucial to position the store offering, brands are not used to increase trust in this market.
Most organic producers and farmers’ markets managers acknowledged that consumers trust certification. This is important, especially knowing that not all producers are certified. They say that when consumers approach them to buy organic foods, they look for certification labels. However, when producers discuss the production methods with them, when they show them around, consumers start building a trust relationship that acts as a certification seal, “I think that’s part of the trust, to open your farm and have it open for your customers so they can come and see”. Therefore, the organic value is based on the production methods. This value offsets price sensitivity and the need for branding.
Lastly, other distributors, such as wholesalers, reiterate the importance of labeling and pricing, but they also add a new emerging and fast growing trend: local foods. The discussion revolved around several aspects of “local foods”. Some relate it to organics saying that there is a clear difference between what they called “industrial organic” – sold through long channels – and “local organic” – sold through short channels. Furthermore, some said that more consumers want to buy local even if it is not organic, “the fact that the product is organic is less important than the fact that it is direct selling”. This, obviously, deepens the divide between the market segments.
To recapitulate, there are several market clusters based on distinct trust orientations and distinct organic values. Consumers rely on various cues to build their trust in the OF products offered in all distribution channels. Labeling – product labeling and certification labeling - plays a key role to inform consumers and strengthen trust whereas brands do not add to the level of trust in OF whatever the type of distribution channel. Last, local foods and local organic foods represent serious new trends in the industry. Trust orientations depend also on the channel length. Long channels rely on standardized organic values such as certification and pricing while short channels rely on product traceability, production methods, as well as the store/manager loyalty/reputation.
The interviews aimed also at uncovering the distributors strategies used to increase trust towards organic food products and to address consumers’ concerns. Results are presented by type of distribution channel in Table 2. It is clear that the common denominator to all distributors as well as certifiers and experts is consumers’ education, “If the government puts out some information, made it more available to the public, what organic actually meant, then that would increase the trust, and show people what it is supposed to achieve, and what it’s not”. While almost all interviewees emphasize that education is a prerequisite to stabilize the demand and increase trust, this has to be nuanced. Consumer education can be seen from different angles: mass communication as part of a push strategy or providing information/building awareness as part of a pull strategy. These strategies are related to what has been said above regarding channel length. Hence, we can confidently associate pull strategies to short channels while push strategies are associated to long channels.
From a long channel perspective, retail chain managers suggest that price plays an important role in increasing consumers’ trust. There is a lot of competition in the market and one way to differentiate the offering is to charge the lowest price to consumers; a price that reflects the organic value of what organic means to these consumers. One need to keep in mind that consumers shopping from these points of sale are not very knowledgeable about organics nor they buy organic for principle oriented reasons. According to the retail chain managers, their customers mainly buy organic for health reasons, but they also are price conscious.
Small grocery stores managers believe that trust should be increased if competition is to increase. The organic value marketed in this channel is mainly based on the relationship with the manager, the store reputation and also on the product/certification label. While pricing accuracy increases trust - if price reflects the value of OF products sold in these store - quality is not a key determinant to increase trust. Consumers associate quality with the store reputation and their relationship with the store manager, “the consumer is trusting me as a store owner, if it says organic on my bins, and I am in turn trusting the company that I am buying it from“. It is important to note that all interviews have been conducted with independent storeowners. Hence, the involvement of the store managers/owner is more important than in retail chains. They unanimously state that consumers’ education is key to increase loyalty and trust. They also argue that consumers are making smarter food choices but not all consumers are knowledgeable about organics. Hence, trust is increased by providing information about the product, the producer/farmer, and pricing.
As far as specialty stores go, the value offered in this channel is based on the width and depth of the product lines, and also on the traceability of organic foods via certification labels. Hence, education is crucial to keep current consumers and attract new ones. Education means information about the products and traceability. This is related – again – to the structure of the trust relationship. It is because of the type of store (specialty store) that expectations are different. Consumers expect that the quality is there and that the products are certified. This is also seen in the arguments put forward by the managers when asked about the reason why their customers buy organic; they mainly buy organic for heath, taste and environmental reasons. This is a clear indication that some of these consumers are very conscientious. Hence, the distribution strategies used to increase trust are mainly information driven; these are pull strategies.
Producers and farmers markets managers have the simplest distribution strategy. Most of these producers use direct channels and in most cases, they have small-scale operations. We have to keep in mind that most of these producers sell at farms gate and at the farmers market. They also supply some grocery stores or specialty stores. Hence, costs and margins are higher than in conventional channels. This is the only way to sustain the production operations as producers cannot offset the cost increase in their channel; i. e. , low sales volumes, keeping in mind that the organic value offered in these channels is based on the production methods. Hence, education is the key factor to increase trust, and of course the most important element is “knowing the producer”. As stated previously, they focus their activity on building long-term relationship with their clientele to increase their market base. This offsets the price sensitivity effects. It is also important to note that there are two main types of producers, those who produce organic because of health and environmental reasons, and those who do it because of market reasons (profit driven). Hence, the perception of trust may differ depending on the size of the farm operations.
Distributors as well as experts discussed what they call “industrial organic”, “conventional organic”, and “local organic”. It is interesting to note that some distributors do not trust certification. Rather, they think that organic should be local and sustainable, especially when it comes to supporting the local economy and the farmers, “I like supporting our local economy to that extent”. Sustainability as a differentiation strategy as well as a trust enhancing strategy is not important in Canada yet. However, most distributors said that in the future, the organic food distribution system should factor in sustainability, as it may be a condition to access the market. One could draw the parallel with green products, as now recyclable packaging is the industry norm. Conversely, other distributors and experts were skeptical about sustainability and said that for now it does not add any value to the current market and it is not a differentiation strategy.
This study attempts to provide readers with an overview of the structure and function of the market for organic food products in Canada based on the most current information available. In an attempt to produce a comprehensive picture, industry and government reports, academic papers, articles and personal communications have been reviewed for inclusion. Due to the difficulties inherent to the study of a relatively new market which includes players ranging from the private and not-for-profit to government and commercial/industrial, information on the Organic Food market remains partially incomplete. Further, to fill in the information gaps, a 2-prong design has been used along with a conceptual model of the existing organic processing and distribution structure. They are presented as a way to describe how the market has evolved. As can be seen in Figure 3 the production-market model takes into account the production/supply dynamics as well as the market dynamics.
OF Market Model
Findings show that the organic market is the fastest growing sector in the food industry with double-digit market growth rates. Although organic agriculture is now going mainstream, demand remains concentrated in Europe and North America. However, these two regions are not self-sufficient because production is not meeting demand. It is also obvious that the supply is not located where the demand is. Hence, large volumes of organic imports, coming in from other regions, are used to balance the undersupply. The main problem for producers and growers is not with respect to demand for organic products but being able to supply that demand. Another issue with organic foods as with any food in the value chain is the multiple dimensions attached to organic products. Not only it is production based, but it is also distribution based. In fact, there is a clear differentiation between two distinct distribution perspectives: long channels versus short size channels. This shows the current divide in the organic food supply and demand. Long channels strategies are convenience and price driven. They offer an organic value targeted toward a certain consumer profile; these are customers that buy organic mainly for health reasons. Conversely, short channels are production method driven. These channels serve consumers having a principle-oriented life style; thus the environment and the support of the local economy are the main drives of this market demand along with health reasons; but price is not a concern. The organic market is also segregated by the entry of large commercial/industrial supply chains and the lack of existing small-scale infrastructure.
All players from the supply side also mention an increasing diversification of OF products and distribution channels. Further, it is clear that the OF industry is slowly integrating new product lines. These trends are directly dependent on the product life cycle [6]. In addition, the marketing of organic foods is not at maturity yet, leading to a lack of market standardization. Ultimately this discussion converges towards store choice and store positioning. Organic foods are value-based products, thus the OF purchasing framework is different than for conventional products. It is based on consumers trust orientations. Overall, distributors link consumers’ trust in OF to different factors: organic labels, product labels, brands, traceability, advice, and/or store reputation. For consumers buying from supermarkets, organic labels are mainly what they trust, not brands. This is clearly different from results presented by [30] showing that OF consumers buying in supermarkets mainly rely on organic labels as well as brands. Consumers purchasing in specialty stores trust the store itself, the sales person advice, the products’ traceability (transparency of the supply chain) and organic labels they know. Hence, communication on the products quality and traceability, advices and information provided by store managers and sales persons (and store reputation) could increase consumers’ trust in OF. For consumers purchasing from producers and farmers markets, traceability is the main element of trust, which is addressed through a trustful relationship established between the producer and the consumer. Because of the differences in these trust dimensions and based on consumers’ specific interests and knowledge, providing standard information for all OF consumers may not be the best communication strategy.
Suppliers provided also their perception on several organic consumers’ characteristics that are in direct relation with the type of distribution channel used. For most suppliers, consumers are in general knowledgeable and are looking for authentic and healthy products, quality, and taste. Their level of knowledge as well as their motivation to consume organic products seems to differ depending on the point of sale they mostly use. In other words, consumers adopting short channels (producers/farmers market and specialty stores) are clearly looking for proximity with the producer, fresh products and quality, and a better understanding of the organic farming process. This segment shows a clear interest for the impacts of the production methods on health and on the environment. As mentioned by experts, there is a sub-segment in this target market that clearly differentiates between local food, industrial organic, and local organic. Conversely, consumers using standards channels of distribution – or long channels - are looking for convenience, healthy products and competitive prices. These consumers also seem to be confused between organic and natural products.
Lastly, certification and labeling systems serve as tools to enhance distribution and market development, create trust, and foster confidence. It is a commitment from producers/farmers to work with certain standards of production. According to [18], there are 80 countries using national standard of certification. Therefore, organic labels can be seen as an important source of trust. Several organic labels are now present on the Canadian market. This somehow induces some confusion, as some consumers do not know which one(s) to trust. Therefore, certification labels – assumed to play a central role - do not seem to have achieved that position in the OF consumers’ decision-making process yet: they need to gain awareness, understanding and credibility in order to do so.
Consumers’ interest in organic food has exhibited continued growth for the past two decades, which has attracted entrepreneurs and corporations seeing a big potential for this industry, and has also led to the creation of standards and regulations to guide the OF industry. Consumers are becoming more sophisticated in their purchasing decisions of OF, and companies are focusing on supply chain management in order to ensure high quality, traceability, and supply continuity. But the OF industry also faces some other challenges: (i) maintaining and increasing consumers’ trust in the OF products and the OF industry in general, and (ii) facing new and fierce competition from market intermediaries and other types of “sustainable” products (e. g. fair trade products and local products). The OF industry and all its stakeholders will have to elaborate strategic responses to these opportunities and challenges that are in direct link with the supply level and the distribution structure. The results also provide an insight into the structure of the organic food industry and the determinants of consumers’ trust. In fact, there are different levels of trust according to the channel members: trust related to the labeling and certification, trust related to the channel of distribution, and trust of the producer. These trust dimensions are direct consequences of the perceived added value to organic food provided by the producers, certifiers and distributors. This study has also some limitation, as results cannot be generalized. This research is exploratory and highlights the need to carry out quantitative and conclusive studies in order to generate not only conceptual clarifications but also answers regarding the Canadian organic food industry. This will in turn help to address implications of the consumer food consumption behavior for management and public policies.
Atherosclerotic cardiovascular disease (ASCVD), including its clinical manifestations, such as myocardial infarction (MI) and ischemic stroke (IS), is the leading morbidity and/or mortality cause worldwide. One of the most highly studied factors associated with ASCVD is low-density lipoprotein (LDL). Vast evidence has postulated that cholesterol-rich LDL and other apolipoprotein B (apoB)-containing lipoproteins (very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and lipoprotein(a) [Lp(a)]), are directly involved in the development of ASCVD [1].
\nStatins are the first-line anti-lipemic pharmacotherapy, having been shown to reduce both LDL-C levels and cardiovascular (CV) events. However, a considerable number of statin-treated patients do not achieve target LDL-C levels, even after maximal statin dose-treatment, or are intolerant to intensive statin therapy [2].
\nIn the aforementioned situations patients can largely benefit from an additional LDL-C lowering agent. Ezetimibe is a non-statin drug that can additionally reduce ASCVD risk, when added to a statin, leading to a total of 34–61% LDL-C reduction [3]. Proprotein Convertase Subtilisin-Like/Kexin Type 9 (PCSK9) inhibitors, one of the newest anti-lipemic agents, can lower LDL-C by 45–65%, and are also proven to have ASCVD risk reduction properties [4].
\nTherefore, the aim of this chapter is to address the question of therapeutic efficacy, as expressed through the lipid-lowering and anti-inflammatory effects, and atherosclerotic cardiovascular disease risk reduction when adding ezetimibe or PCSK9 inhibitors to statin therapy.
\n3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, have been one of the most frequently prescribed medications worldwide, since their introduction 30 years ago. Currently, there are six statin drugs available on the market—pitavastatin, atorvastatin, rosuvastatin, pravastatin, simvastatin and fluvastatin [5].
\nStatins are competitive, reversible inhibitors of HMG-CoA reductase, a rate-limiting step in the process of cholesterol biosynthesis. HMG-CoA is a microsomal enzyme—reductase which catalyzes the conversion of HMG-CoA to
Statins are composed of two parts, the pharmacophore, a dihydroxyheptanoic acid segment, and a moiety composed of a ring system with various substituents. According to the chemical modification of the ring system and the nature of its substituents, different statin structures are generated. Ring substituents define the solubility of the statins, along with many of their pharmacological properties. Among the statins, lovastatin, simvastatin, atorvastatin, and fluvastatin are lipophilic, whereas pravastatin and rosuvastatin are more hydrophilic. Different chemical structures lead to different pharmacokinetic properties, pharmacological effects and pleiotropic actions [7].
\nStatins can enter the systemic circulation passively, through the intestinal cells, and actively via the ATP-binding cassette (ABC) and solute carrier (SLC) transporters. Two enzyme groups are involved in statin metabolism, the cytochrome P450 (CYP450), and UDP-glucuronosyltransferase (UGT), mainly acting in the liver, and to a lesser extent, in the kidneys. Lipophilic statins are transported via passive diffusion, metabolized by the CYP450 enzymes, and mainly excreted through the biliary system. Hydrophilic statins enter the liver via active transport, and are actively excreted through the kidneys, mostly as unchanged drugs. Lipophilic statins have generally low bioavailability due to first pass metabolism. Absorption varies between 30 and 98%, and time to reach peak plasma concentration (Tmax) is within 4 h of administration. Statins are administrated orally as active hydroxy acids, except for lovastatin and simvastatin, which are administrated as lactone pro-drugs, and then hydrolyzed to the hydroxy acid form. Their bioavailability varies; pitavastatin has a bioavailability of 80%, whereas fluvastatin between 19 and 29%. The CYP3A4 isoenzyme is responsible for the metabolism of lovastatin, simvastatin and atorvastatin. Their active metabolites—2-hydroxy- and 4-hydroxy-atorvastatin acid from atorvastatin, and β-hydroxy simvastatin acid from simvastatin, carry a part of their inhibitory activity. Fluvastatin is mainly metabolized by the CYP2C9 isoenzyme. Pravastatin is eliminated by both the kidney and liver, mostly as an unchanged drug [6, 7, 8].
\nEzetimibe, a cholesterol absorption blocker, has been the focus of many trials supporting its use in ASCVD risk reduction. For patients that cannot achieve target treatment goals with statin therapy alone, ezetimibe has proven to be a safe, well-tolerated medication which, combined with statins, leads to additional LDL-C reduction, thus resulting in a significant morbidity and/or mortality benefit [9].
\nSerum cholesterol is derived from two major sources: cholesterol synthesized de novo in the liver and cholesterol that has been absorbed from the gastrointestinal tract. Statins reduce serum cholesterol by reducing its biosynthesis in the liver. Ezetimibe, on the other hand, targets gastrointestinal cholesterol absorption. Ezetimibe acts at the brush boarder of the small intestine, by selectively inhibiting the cholesterol transport protein Niemann Pick C1 like 1 protein (NPC1L1), thus preventing uptake of intestinal luminal cholesterol micelles into the enterocytes. The reduced cholesterol uptake leads to hepatic LDL-C stores depletion, resulting in upregulation of hepatic LDL receptors, causing LDL-C clearance from the blood. It is also suggested that ezetimibe inhibits the hepatic NPC1L1 as well, thus leading to reduced hepatic cholesterol absorption [3, 10, 11].
\nFollowing ingestion, the drug is extensively (>80%) metabolized to its active form—ezetimibe-glucuronide. Glucuronidation of the 4-hydroxyphenyl group, by uridine 5′-diphosphate-glucuronosyltransferase isoenzymes, forms the major ezetimibe metabolite in the intestine and liver. Total ezetimibe (sum of ‘parent’ ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1–2 h after administration. Both the parent compound and the glucuronidated compound are absorbed, and recirculated via the hepatobiliary excretion, thus providing long-term cholesterol absorption inhibition. This cycle accounts for the long half-life of ezetimibe—about 22 h, allowing for once-a-day dosing. About 10–15% of the drug is excreted in the urine, and the rest in the feces, mainly as the parent drug. Ezetimibe does not appear to be metabolized or interact with the cytochrome P450 pathway, thus it does not affect bioavailability and kinetics of commonly used drugs that are affected by the CYP450 family [10, 12].
\nThe discovery of PCSK9 in 2003 opened many new research directions in the cardiovascular field. Liver PCSK9 binds to the LDL receptor (LDL-R) and promotes its degradation in the endosomal/lysosomal pathway. Higher PCSK9 activity leads to lower liver LDL-R levels, resulting in reduced LDL-uptake from circulation, and thus in hypercholesterolemia [13].
\nThis led to a conclusion that the inhibition of PCSK9 would mean that more LDL receptors would be recycled to the surface of the cell, thus increasing the clearance of LDL cholesterol from the circulation. Since then various approaches to the pharmacological inhibition of PCSK9 have been investigated, and parenteral anti-PCSK9 monoclonal antibodies (MoAbs) have been the most successful strategy to date. MoAbs are now in late-stage (phase 3 clinical trials) testing [14].
\nAnti-PCSK9 MoAbs are known to bind at or near PCSK9’s binding site for the LDL-R. This sterically inhibits the interaction of PCSK9 with the LDL-R, thus reducing the degradation of the receptor. This markedly increases the clearance of LDL and substantially lowers plasma LDL cholesterol, as well as apolipoprotein-B100 [15]. In 2015, the Food and Drug Administration (FDA) approved the PCSK9 inhibitors alirocumab and evolocumab for patients with clinical atherosclerotic cardiovascular disease on maximally tolerated statin therapy who “require additional lowering of LDL-C” [16].
\nEvolocumab is a human monoclonal immunoglobulin G2 antibody directed against the circulating PCSK9 protein. Evolocumab is administered by subcutaneous injection to the abdomen, thigh, or upper arm. For patients with primary hyperlipidemia, who have clinical ASCVD, or heterozygous familial hypercholesterolemia, the recommended subcutaneous dose is 140 mg every 2 weeks or 420 mg once monthly. Maximum suppression of circulating unbound PCSK9 is seen after 4 h. Peak serum concentrations are obtained in 3–4 days, with an estimated bioavailability of 72%. The drug is estimated to have an effective half-life of 11–17 days [17].
\nAlirocumab is a human monoclonal immunoglobulin G1 [IgG1] isotype antibody that binds to circulating PCSK9, thus inhibiting its action on LDL-R. Alirocumab reduces free PCSK9 in a concentration-dependent manner. Following a single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurs within 4–8 h. Within 4–8 weeks after initiating or titrating alirocumab therapy, LDL-C levels should be tested to determine the response and the need for (additional) dose adjustments. The drugs’ median apparent half-life at steady state is 17–20 days. Peak serum concentrations are obtained in 3–7 days, with an estimated bioavailability of 85%. At low concentrations, the elimination of alirocumab occurs predominately via saturable binding to PCSK9. At higher concentrations, elimination is through a nonsaturable proteolytic pathway [18].
\nDuring the past 20 years, the extensive use of statin therapy among patients known to have an occlusive vascular disease, or are considered to be at increased risk of cardiovascular events, has been associated with descending actions on LDL and total cholesterol concentrations [19].
\nDifferent statins have different potencies, with the newer agents (e.g., atorvastatin and rosuvastatin) able to produce larger reductions in LDL cholesterol per mg of drug, compared to the older agents (e.g., simvastatin and pravastatin). Each dose doubling leads to an additional reduction of about 6 percentage points in LDL cholesterol (e.g., 43 vs. 49% reductions with atorvastatin 20 vs. 40 mg daily). The American College of Cardiology/American Heart Association (ACC/AHA) 2013 Blood Cholesterol Guideline classified statin regimens as being of low intensity (e.g., <30% LDL-C reduction with simvastatin 10 mg daily), moderate intensity (e.g., 30% to <50% reduction with simvastatin 20–40 mg, atorvastatin 10–20 mg, or rosuvastatin 5–10 mg daily), or high intensity (e.g., ≥50% reduction with atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily) [20].
\nHigh-intensity statin therapy would be expected to reduce LDL-C by at least 2 mmol/L in individuals with LDL-C concentrations of 4 mmol/L or more, but by only about 1 mmol/L in those presenting with concentrations of 2 mmol/L. Consequently, since vascular events rates reductions, in patients treated with statins, are related to the absolute reductions in LDL-C, intensive statin treatment should be used in individuals at higher risk of vascular events, rather than just on those with high cholesterol concentrations [21].
\nThe Cholesterol Treatment Trialists’ (CTT) Collaboration was settled to conduct meta-analyses of randomized controlled statin-oriented trials involving at least 2 years of treatment in at least 1000 patients. During the study treatment periods (on average 5 years), the average LDL-C reduction was about 1–1.5 mmol/L, comparing routine statin therapy vs. no routine statin therapy, with an additional LDL-C reduction of about 0.5 mmol/L in the trials comparing allocation to more vs. less intensive statin regimens. To summarize, an intensive statin regimen, compared to no statin therapy, reduced LDL-C concentrations by 1.5–2 mmol/L [22, 23].
\nStatins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. The Atherosclerosis Risk in Communities (ARIC) study, performed on 13,342 individuals, provided evidence that protection against ASCVD happens in a graded fashion with LDL-C level [24]. The CTT meta-analyses detected about 25,000 major vascular events (MVE) (composite of coronary deaths or non-fatal myocardial infarctions, strokes of any type, and coronary revascularisation procedures). Comparing routine vs. no routine statin treatment, there was a 20% proportional reduction in the MVE rate per mmol/L LDL-C reduction. Regarding the comparison of more vs. less intensive statin regimens, the average 0.5 mmol/L further LDL-C reduction lead to an additional 15% proportional reduction in the MVE rate [22, 23].
\nBy combining the findings from the two previously mentioned sets of trials, it can be concluded that a LDL-C concentration reduction by 2 mmol/L would reduce the MVE risk by about 45%. Given the aforementioned, larger LDL-C reductions should lead to larger risk reductions (e.g., 60–70% with 3–4 mmol/L LDL-C reductions); however, this is likely only to be clinically relevant in limited circumstances (such as for individuals with familial hypercholesterolemia who have very high LDL-C levels) [25].
\nHigh-intensity statin treatment (atorvastatin 80 mg) in the Treating to New Targets (TNT), the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial, demonstrated an additional 11–23% relative risk reduction of major CVD events, when compared to moderate-intensity statin therapy (atorvastatin 10 mg, simvastatin 20–40 mg, or pravastatin 40 mg). Nonetheless, the atorvastatin 80 mg treated patients still experienced a major CVD event during the trials (ranging from 4 to 11% per year). Mean LDL-C levels in the atorvastatin 80-mg groups ranged from 1.6 to 2.1 mmol/L [26, 27, 28, 29].
\nThe American College of Cardiology/American Heart Association 2013 Blood Cholesterol Guideline gives recommendations regarding statin therapy in terms of ASCVD prevention and risk reduction (Table 1) [20].
\nASCVD Statin Benefit Groups [20] Heart healthy lifestyle habits are the foundation of ASCVD prevention | \n|||
---|---|---|---|
Clinical ASCVD | \nLDL-C ≥ 4.9 mmol/L | \nDiabetes; age 40–75 years1 | \nEstimated 10-yr ASCVD risk ≥ 7.5%2; age 40–75 years1 | \n
High-Intensity statin (age ≤ 75 years) Moderate-intensity statin if >75 years or not a candidate for high-intensity statin | \nHigh-intensity statin Moderate-intensity statin if not a candidate for high-intensity statin | \nModerate-intensity statin High-intensity statin if estimated 10 year ASCVD risk ≥ 7.5% | \nModerate- to high-intensity statin | \n
Statin therapy in ASCVD prevention and risk reduction according to the 2013 ACC/AHA blood cholesterol guideline.
With LDL-C of 1.8–4.9 mmol/L.
Estimated using the Pooled Cohort Risk Assessment Equations.
ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein-cholesterol.
The CTT meta-analyses showed a 12% proportional reduction in vascular mortality per mmol/L LDL-C reduction, attributable to an approximately 20% proportional reduction in coronary deaths, 8% reduction in other cardiac deaths, and little effect on death due to all types of stroke combined. No matter the cause of coronary death, the risk reduction per mmol/L LDL-C reduction appear to be similar in patients with and without pre-existing vascular disease, and in those who present at different levels of baseline vascular risk [22, 23].
\nRegarding the effect of different statins, and different statin treatment intensities, on coronary mortality, the TNT trial showed no significant differences in the risk of death from cardiovascular or noncardiovascular causes between the patients treated with 10 mg or 80 mg atorvastatin per day [27]. The IDEAL study compared the effects of high-intensity statin therapy (atorvastatin 80 mg/d) vs. low-intensity statin therapy (usual-dose simvastatin, 20 mg/d), on occurrence rates of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. The results failed to show a statistically significant difference in all-cause or cardiovascular mortality between the two treatment regimens [28]. The PROVE-IT trial aimed to compare the effects of 40 mg of pravastatin daily (standard therapy) vs. 80 mg of atorvastatin daily (intensive therapy) in patients hospitalized for acute coronary syndrome. The risk of death due to coronary heart disease, myocardial infarction, or revascularization was reduced by 14% in the atorvastatin group, as compared with 22.3% in the pravastatin group [29].
\nDespite what was previously elaborated, a significant on-statin treatment residual risk of major CV events still exists. A meta-analysis of statin trials shows that there is residual CVD event risk even with LDL-C levels <2 mmol/L. The aforementioned TNT trial, conducted on patients with stable coronary artery disease (CAD), described an 8.7% incidence of a major event, over 5 years, in patients receiving 80 mg atorvastatin daily, with on-treatment LDL-C concentrations of 1.8–2.6 mmol/L [24]. Findings like these point to the unmet needs of the patients treated with statins. Several cholesterol treatment guidelines recommend a LDL-C treatment goal of <2.6 mmol/L or < 1.8 mmol/L, depending on the level of risk. However, in the everyday clinical practise many high-risk patients fail to reach the goal [26].
\nThe most resent Guidelines, the 2016 European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) Guidelines for the management of Dyslipidemias and The 2017 Guidelines of the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) for Management of Dyslipidemia and Prevention of Cardiovascular Disease have recommended similar target LDL-C levels, and have suggested the use of combination therapy (ezetimibe and PCSK9 inhibitors) to achieve these targets in situations in which maximally tolerated statin monotherapy is insufficient (Table 2) [3, 26].
\nRisk profile of the patient | \nTreatment target goal of LDL-C [3] | \n
---|---|
Very high CV risk | \n<1.8 mmol/L, or at least 50% reduction if the baseline3 LDL-C is 1.8–3.5 mmol/L (COR1 I/LOE2 B) | \n
High CV risk | \n<2.6 mmol/L, or at least 50% reduction if the baseline LDL-C is 2.6–5.2 mmol/L (COR I/LOE B) | \n
Low/moderate CV risk | \nLDL-C goal of <3.0 mmol/L (COR IIa/LOE C) | \n
Treatment target goal of LDL-C according to the 2016 ESC/EAS guidelines for the management of dyslipidemias.
COR, class of recommendation.
LOE, level of evidence.
“Baseline LDL-C” refers to the LDL-C level in a subject not taking any lipid lowering medication.
CV, cardiovascular; LDL-C, low-density lipoprotein-cholesterol.
The AACE guidelines introduced an additional “extreme high-risk” category, which is not recognized by the ESC/EAS, and an additional treatment LDL-C target of <1.4 mmol/L. This “extreme high-risk” group represents patients with progressive disease, despite LDL-C levels of <1.8 mmol/L while on-statin therapy. The rationale of the aforementioned approach is in the individualization of the total CV risk reduction, which can be better done if goals are predefined. Treatment goals are defined and tailored to the total CV risk level of each individual patient. The “individualized approach “may possibly result with better patient adherence to the therapy. The growing number of evidence suggests that LDL-C lowering beyond the guidelines-set goals may lead to further reduction of CVD events, which can be especially beneficial in patients at very high CV risk [3, 30].
\nGiven what was previously discussed, in order to achieve this level of LDL-C reduction, combination therapy may be needed. The latest randomized clinical trials (RCTs), such as The LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy 2 (LAPLACE-2) trial, The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, and The Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control, demonstrated that extremely low LDL-C levels (<0.5 mmol/L) appear to be safe. Furthermore, The IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs. Simvastatin) and FOURIER trials demonstrated that not only such low levels are safe, but are also beneficial, in terms of additional CV risk reduction [30, 31, 32, 33, 34].
\nThe unmet needs in terms of LDL-C targets and ASCVD protection raised the question of statin combination therapy. It only needed to be right positioned. Such positioning was done in the 2016 ESC/EAS Guidelines for the management of Dyslipidemias (Table 3) [3], and also in The 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk [35].
\nClinical setting | \nCOR1 LOE2 | \nTreatment target goal of LDL-C | \nCOR1 LOE2 | \n
---|---|---|---|
Hypercholesterolemia If the goal is not reached with statins, ad-on ezetimibe | \nIIa/B | \nDepends of the risk profile of the individual patient | \nI/A | \n
FH Intense-dose statin, often in combination with ezetimibe | \nI/C | \n<2.6 mmol/L, or <1.8 mmol/L in presence of CVD | \nIIa/C | \n
ASC If the goal is not reached with the highest tolerable statin dose, ad-on ezetimibe in post-ACS patients | \nIIa/B | \n<1.8 mmol/L, or a reduction of at least 50% if the baseline3 LDL-C is 1.8–3.5 mmol/L | \n\n |
CKD stages 3–5 are high or very high CV risk patients The use of statins or ezetimibe ad-on statin is indicated in non-dialysis dependent patients | \nI/A | \nDepends of the risk profile of the individual patient | \nI/A | \n
Recommendations for ezetimibe add-on statin combination therapy according to the 2016 ESC/EAS guidelines for the management of dyslipidemias.
COR, class of recommendation.
LOE, level of evidence.
“baseline LDL-C” refers to the level in a subject not taking any lipid lowering medication.
ACS, acute coronary syndrome; FH, familial hypercholesterolemia; CKD, chronic kidney disease; LDL-C, low-density lipoprotein-cholesterol.
The FDA-approved ezetimibe indications are for treatment of primary hyperlipidemia, alone or in combination with a statin; mixed hyperlipidemia in combination with fenofibrates; in homozygote familiar hyperlipidemia (HoFH) in combination with atorvastatin or simvastatin; and in homozygous sitosterolemia (phytosterolemia) [3, 26, 35].
\nIn clinical studies, ezetimibe, as monotherapy, reduces LDL-C in hyper-cholesterolemic patients by 15–22%. Combined therapy with statins provides an incremental reduction in LDL-C levels of 15–20%, leading to a total LDL-C reduction by 34–61%, as previously mentioned [3].
\nThe most comprehensive data analysis for LDL-C lowering efficiency was performed by the group of Descamps, published in 2015. 27 differently designed trials (double-blind placebo and/or active controlled studies), in which statins (type of statin, statin brand, potency or dose difference) were compared with ezetimibe ad-on statin, were included, with over 21,671 patients, analyzing variables such as variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C. In this very comprehensive data analysis, ezetimibe ad-on statin was found to lead to significantly more pronounced LDL-C lowering, as compared to statin monotherapy [36].
\nData from a large retrospective observational study (more than 27,000 patients), published in 2014 by Toth, demonstrated a more pronounced LDL-C lowering effect of ezetimibe ad-on statin therapy, and a higher percentage of goal attainment (with respect to the risk profile of the patients), with one third of the patients not being able to attain the recommended LDL-C goal of <1.8 mmol/L. However, it was realized that there is a low prescription frequency of high-dose statins. Half of the patients (50.9%) remained on the same statin monotherapy, irrespective of their treatment goal achievement [37]. The significance of this study is even bigger given that it is a real life situation, and not a randomized study with strictly predefined inclusion criteria, study population etc.
\nThe IMPROVE-IT study showed an on-trial average LDL-C level of 1.4 mmol/L in the simvastatin-ezetimibe group, as compared to 1.8 mmol/L in the simvastatin-monotherapy group (p < 0.001), leading to a total amount of LDL-C reduction of about 24% [38]. There are also a lot of small-scale studies that demonstrate superiority of ezetimibe ad-on statin therapy in terms of LDL-C lowering. For example, the Japanese study by Uemura, performed on 39 patients, compared two regimens: 10 mg atorvastatin + 10 mg ezetimibe vs. 20 mg atorvastatin in high risk patients with CAD and type 2 diabetes (T2DM). A significant improvement of the lipid profile was found in both groups in terms of total, LDL-C and high-density lipoprotein cholesterol (HDL-C), with a more pronounced improvement in the ezetimibe ad-on atorvastatin group (p = 0.005). A significant effect on the Apo B/Apo A-I ratio and remnant-like particle cholesterol was observed only in the atorvastatin ad-on ezetimibe treatment group. Probably the finding that gives as the most powerful information is the effect on oxidized LDL-C [malondialdehyde-modified LDL (MDA-LDL)], a form that is responsible for the proaterogenic effects of LDL-C, that was significantly more pronounced with the atorvastatin ad-on ezetimibe treatment (p = 0.0006) [39]. The existence of pleotropic effects, other than the hypo-lipemic effect that is widely recognized for statins, is evidentially true for ezetimibe as well. Evidence of anti-inflammatory and anti-oxidative effects is cumulating. Another Japanese study, by Tobaru, was performed on 35 CAD patients pre-treated with statins who remained above targeted LDL-C level. In terms of hypo-lipemic effect, significant additional decrease of total C, LDL-C, remnant lipoprotein C, LDL/HDL-C ratio was observed, and the percentage of patients who achieved target LDL-C level increased to 65.4% (p = 0.001) in the ezetimibe ad-on statin group. Although no significant effect was achieved on high-sensitive C-reactive protein (hsCRP) and oxidative stress markers, a significant reduction of tumor necrosis factor-α (TNF-α), 1.36 vs. 0.96 (p = 0.042) was observed [40]. On the other hand, given the IMPROVE-IT trial in which two laboratory targets were set: LDL-C (<1.8 mmol/L) and hsCRP (<2 mg/L), Bohula and colleagues summarized that ezetimibe ad-on statin treatment was far more successful in achieving both targets, or it was concluded: “Significantly more patients treated with ezetimibe/simvastatin met prespecified dual LDL-C and hsCRP targets, than patients treated with simvastatin alone (50% vs. 29%, p < 0.001)”. Reaching both LDL-C and hsCRP targets was associated with improved outcomes after multivariable adjustment (38.9% vs. 28.0%, adjusted hazard ratio, 0.73, 0.66–0.81; p < 0.001) [38].
\nThe potential benefits of adding an additional lipid lowering agent—ezetimibe on statin therapy for CVD prevention and risk reduction have been confirmed in several clinical trials.
\nThe impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: The Multicenter Randomized Controlled PRECISE-IVUS trial evaluated the effects of ezetimibe ad-on atorvastatin vs. atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). The combination therapy resulted in lower levels of LDL-C, compared to atorvastatin monotherapy (1.6 mmol/L vs. 1.9 mmol/L; p < 0.001), and in the same time coronary plaque regression was observed in significantly higher percentage of patients who received atorvastatin ad-on ezetimibe (78% vs. 58%; p = 0.004) [41].
\nThe majority of studies addressing the efficacy of ezetimibe ad-on statin treatment are with simvastatin, including the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, in patients with aortic stenosis, and the Study of Heart and Renal Protection (SHARP) (Simvastatin plus ezetimibe) trial, including 23% high risk patients with diabetes and chronic kidney disease (CKD) with or without requiring dialysis. The combination therapy demonstrated superiority over statin monotherapy in LDL-C reduction, translated in reduced primary endpoint of first major ASCVD event: nonfatal MI or CV death, non-hemorrhagic stroke, or any arterial revascularization procedure, over a median follow up of 4.9 years [3, 42].
\nThe landmark trial on ezetimibe-statin combination therapy, the largest and the longest one with ezetimibe, is the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). A total of 18,144 patients with acute coronary syndrome (ACS) were randomized to ezetimibe (10 mg) or placebo, all receiving 40 mg simvastatin, which was increased to 80 mg if LDL-C on treatment was >2.04 mmol/L. The event rates for the primary end point at 7 years were 32.7% in the simvastatin-ezetimibe group and 34.7% in the simvastatin-monotherapy group, with an absolute risk reduction of 2% (HR 0.936; 95% CI 0.89–0.99; p = 0.016). Ischemic stroke was reduced by 21% (p < 0.008). Nevertheless, no benefit in reducing all-cause mortality or deaths from CV causes was observed, which was not unexpected, as prior trials of intensive vs. standard-dose statin therapy did not demonstrate a benefit in terms of mortality as well. There was no evidence of harm caused by the further LDL-C reduction. In this group of patients, already treated with statins to reach the goal, the absolute benefit from the added ezetimibe was small, although significant. However, the study supports the proposition that LDL-C lowering by means other than statins is beneficial and can be performed without adverse effects [38].
\nThe diabetic sub-group analysis in the IMPROVE-IT trial provided the outcomes in 4933 (27%) patients with diabetes, one of the pre-specified trial subgroups. In this patient subset, ezetimibe ad-on statin decreased LDL-C at 1 year by 1.1 mmol/L, as compared to 0.6 mmol/L with statin monotherapy. Diabetic patients on ezetimibe ad-on statin therapy had a 14% relative risk reduction, or 5.5% absolute reduction, compared with a 2% absolute risk reduction for non-diabetics. The most notorious reductions were seen regarding ischemic stroke (39%), MI (24%), and the composite of death due to CV causes, MI or stroke (20%). These CV effects of ezetimibe ad-on statin therapy are considered to be a result of the more prominent reduction of LDL-C (mean 0.5 mmol/L), compared to simvastatin monotherapy, with an average value of 1.4 mmol/L. This sub-study analysis demonstrated superiority of the statin-ezetimibe combination therapy in CV prevention in diabetic subsets especially [26, 34, 35, 38].
\nAnother significant effect of ezetimibe ad-on statin therapy is cerebrovascular protection. The 2013 ACC/AHA cholesterol guideline recommends the use of ezetimibe as an ad-on statin, additional LDL-C lowering agent in stroke patients [35]. The advantage of ezetimibe ad-on statin therapy in this patient subgroup was observed in the IMPROVE-IT study. The highest risk benefit was observed in the subgroup of patients with ischemic CVD with a 21% relative reduction of ischemic stroke (p < 0.008). The addition of ezetimibe as a non-statin type drug, to statin treatment contributed to further reduction of LDL-C, which translated into additional decrease in reoccurrence and mortality of/from cerebrovascular events. Achieving target values with ezetimibe ad-on statin combination allows administration of low to moderate-dose statin, which decreases the risks of adverse effects related to high-dose statin therapy [43].
\nThe current trial results make it obvious that the higher the risk profile of the patient is, the bigger is the benefit, in terms of risk reduction, when ezetimibe is ad-on statin treatment. Taken together, all these studies support the decision to propose ezetimibe as a second-line therapy, in association with statins, when the therapeutic goal is not achieved with the maximal tolerated statin dose or in patients intolerant or with contraindications to these drugs [3, 35].
\n\n
The FDA approved the first PCSK9 inhibitor in 2015
There are currently two PCSK9 inhibitors on the market, alirocumab and evolocumab
There was a third PCSK9 inhibitor—bococizumab, but its’ development was discontinued by Pfizer in late 2016. The key reasons for this were a high level of immunogenicity and wide variability in the LDL-C lowering response. Immunogenicity: in statin-treated patients, PCSK9 inhibition with bococizumab led to a short-term LDL-C reduction of 55–60%. However, this effect was attenuated over time in 10–15% of patients due to the development of antidrug antibodies. This effect was specific to bococizumab, which is a partially humanized monoclonal antibody, characterized by substitution of rodent deoxyribonucleic acid (DNA) sequences for <5% of human DNA sequences. It is thought that this substitution may have directly affected the immunogenicity of the antibody. This effect has not been reported for either evolocumab or alirocumab, which are fully human monoclonal antibodies. This immunogenicity may also explain the higher rate of injection site reactions (~10%) observed with bococizumab, compared with either alirocumab or evolocumab (<5%). Variability in LDL-C lowering response: Irrespective of the presence or absence of antidrug antibodies, there was wide individual variability in the LDL-C lowering response with bococizumab; about 1 in 10 showed no reduction in LDL-C levels
Patients with familial hyperlipidemia and those with clinical ASCVD, not reaching lipid-reducing goals, including those with statin intolerance, are at greatest need of PCSK9 inhibitors, because no adequate alternative treatment exists
Multiple guidelines with different approaches to lipid treatment have created confusion among clinicians; thus, defining the patients with ASCVD, or at high CV risk, who have not met LDL-C treatment goals is complicated
Although PCSK9 inhibitors seem to support the LDL-C hypothesis (the lower the LDL-C level, the lower the CV risk), results of ongoing long-term outcome studies are yet to be presented
Prescribing PCSK9 inhibitors will likely be limited by economics rather than by clinicians’ judgment about the best interest of their patients [44].
Many believe that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the pharmacotherapeutic innovation of the past 2 decades in terms of CV events prevention.
\nThe 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolemia defined:
\nPatients with clinical ASCVD and substantially elevated LDL-C levels (patients already on maximally tolerated statin therapy (ideally with concomitant ezetimibe), or unable to tolerate three or more statins), and,
\nFamilial hypercholesterolemia (FH) patients without clinical ASCVD but with substantially elevated LDL-C levels (patients on maximally tolerated statin therapy plus ezetimibe), as priority patient groups for PCSK9 inhibitors (Figure 1) [45].
\nAppropriate use of PCSK9 inhibitor, as recommended in 2017 update of ESC/ESC task force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolemia. ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein-cholesterol; 1Including: familial hypercholesterolemia; diabetes mellitus with target organ damage, or a major risk factor; severe and/or extensive ASCVD; rapid progression of ASCVD (i.e. repeated ACS, unplanned coronary revascularizations). 2Including: diabetes mellitus with target organ damage, or a major risk factor; Lipoprotein(a) > 50 mg/dL; major risk factors: smoking, marked hypertension; >40 years of age without treatment; premature ASCVD (<55 years in males and <60 years in females) in first-degree relatives; imaging indicators.
The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, aimed to evaluate the efficacy of evolocumab, compared to placebo, in patients with clinically evident CVD. 69% of the patients were on a high-intensity statin, while 30% were on a moderate-intensity statin therapy, randomized to evolocumab 140 mg subcutaneous every 2 weeks or 420 mg monthly (n = 13,784) vs. placebo every 2 weeks (n = 13,780). Evolocumab led to a 59% LDL-C level reduction (from 2.4 mmol/L to 0.78 mmol/ L), with an absolute LDL-C reduction of 1.4 mmol/L [46].
\nThe Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3) trial aimed to evaluate the effect of 24 weeks of evolocumab administered subcutaneously (SC) every month, compared with ezetimibe, on LDL-C levels in adults with high cholesterol, who are unable to tolerate an effective dose of a statin due to muscle-related side effects (MRSE). Evolocumab produced significantly larger reductions in LDL-C levels, compared to ezetimibe (16.7% reduction with ezetimibe and a more than 50% reduction with evolocumab). Despite very high baseline values, the LDL-C goal of less than 1.8 mmol/L was achieved in nearly 30% of evolocumab-treated patients and 1.4% of ezetimibe-treated patients. The LDL-C reduction for both drugs was stable for 4 weeks and sustained during the course of the 24 weeks of treatment [47].
\nThe effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia—the LAPLACE-2 randomized clinical trial evaluated the efficacy and tolerability of evolocumab when used in combination with a moderate- vs. high-intensity statin. 2067 patients with primary hypercholesterolemia and mixed dyslipidemia were randomized to 24 treatment groups. Patients were initially randomized to a daily, moderate-intensity (atorvastatin 10 mg, simvastatin 40 mg, or rosuvastatin 5 mg) or high-intensity (atorvastatin 80 mg, or rosuvastatin 40 mg) statin. After a 4-week lipid-stabilization period, patients were randomized to compare evolocumab (140 mg every 2 weeks) vs. placebo (every 2 weeks) or ezetimibe (10 mg daily; atorvastatin patients only) when added to statin therapies. In patients treated with atorvastatin (10 mg or 80 mg), the addition of ezetimibe resulted in LDL-C reductions by 17–24% from baseline, compared with the addition of evolocumab, administered every 2 weeks, which reduced LDL-C values by 61–62% (treatment differences vs. placebo and ezetimibe both significant [p < 0 .001]. For patients receiving a moderate-intensity statin, evolocumab reduced LDL-C values from a baseline mean of 3.1 mmol/L to an on-treatment mean of 1.2 mmol/L, and 88–94% of the patients achieved target LDL-C levels, less than 1.8 mmol/L. For patients receiving a high-intensity statin, evolocumab reduced LDL-C values from a baseline mean of 2.4 mmol/L to an on-treatment mean of 0.9 mmol/L, and 94% achieved the target LDL-C value. In the atorvastatin-treated patients, addition of ezetimibe resulted in achievement of an LDL-C level less than 1.8 mmol/L in 17–20% of patients receiving moderate-intensity statins and 51–62% of those receiving high-intensity statins, vs. 86–94% of patients achieving target LDL-C values in the evolocumab-atorvastatin group [31].
\nThe efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial aimed to compare efficacy, in terms of LDL-C lowering, and safety of alirocumab vs. ezetimibe as ad-on therapy to maximally tolerated statin treatment in high CV risk patients with inadequately controlled hypercholesterolemia. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At week 24, mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe (p < 0.0001). 77.0% of alirocumab and 45.6% of ezetimibe patients achieved target LDL-C values of <1.8 mmol/L (p < 0.0001). Mean achieved LDL-C levels, by week 24, were 1.3 mmol/L with alirocumab and 2.1 mmol/L with ezetimibe [32].
\nThe FOURIER trial, evaluating the effect of evolocumab on the risk of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, in 27,564 patients with clinically evident CVD, is the first randomized study to be completed, regarding PCSK9 inhibitors long-term efficacy and safety. The primary outcome, incidence of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group vs. 14.6% of the placebo group (p < 0.0001). There was a 9.8% absolute MACE rate reduction, compared to 11.3% with placebo, over 2.2 years, with a relative risk reduction of 15%. This finding was consistent among all tested subgroups. Benefit was enhanced among higher-risk subgroups (those with recent MI, multiple prior MIs, and residual multivessel coronary artery disease), compared to those without such characteristics. There was a linear relationship between LDL-C and adverse CV events, such that adverse events continued to decline to the lowest levels of LDL-C (p = 0.0012). Among those with baseline LDL-C < 1.8 mmol/L, evolocumab reduced the primary endpoint (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.60–1.07) to a similar degree as those with baseline LDL-C ≥ 1.8 mmol/L (HR 0.86, 95% CI 0.79–0.92; p = 0.65 for interaction).
\nThere was a greater absolute reduction in major adverse events for evolocumab vs. placebo among those with the highest baseline inflammatory risk (among those with high-sensitivity C-reactive protein <1 mg/dl, 1–3 mg/dl, and >3 mg/dl, there was an absolute reduction in the primary outcome of 1.6, 1.8, and 2.7%, respectively). PCSK9 inhibition represents a novel approach to lower LDL-C levels and improves cardiovascular outcomes. However, for the duration of follow-up, there was no benefit on cardiovascular or all-cause mortality, and cost remains an issue [46].
\nRegarding alirocumab, cardiovascular outcomes and safety will be assessed in an ongoing study, the ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trial. 18,600 patients, who have experienced an acute coronary syndrome (ACS), are allocated to alirocumab or placebo, for a maximum duration of 64 months. The primary objective of the trial is to compare the effect of alirocumab with placebo on the occurrence of cardiovascular events (composite endpoint of coronary heart disease (CHD) death, non-fatal MI, fatal and non-fatal IS, unstable angina requiring hospitalization). No results are reported yet [32].
\nThe only excesses of adverse events that have been reliably demonstrated to be caused by statin therapy are myopathy and diabetes mellitus, along with a probable excess of hemorrhagic stroke. However, the absolute risks of these adverse effects remain small, by comparison with the absolute benefits [25].
\nApproved statin regimens have been associated, both in observational studies and in randomized trials, with large relative risks for myopathy, but typically with small absolute excesses (about 1 case per 10,000 people treated per year), and even smaller excesses in the incidence of rhabdomyolysis (about 2–3 cases per 100,000 treated per year). It usually resolves rapidly when statin therapy is . [48]. The risk of myopathy is dose related and it appears to depend on the statin circulation levels. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) randomized trial, simvastatin 80 mg daily produced a more than ten-fold higher rate (at least 1 case of myopathy per 1000 patients treated yearly), compared to 20 mg daily (about 1 case per 10,000 yearly), so the high-dose regimen is no longer recommended routinely [49].
\nIn the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) randomized trial, among 17,802 patients without a history of vascular disease, concentrations of glycated hemoglobin, after 2 years, were slightly higher among the patients allocated to rosuvastatin 20 mg daily compared to those allocated to placebo (5.9 vs. 5.8%; p = 0.001). There was also a small excess of newly diagnosed diabetes (3.0 vs. 2.4%; p = 0.01), which corresponds to a 25% proportional increase. In subsequent meta-analyses, standard statin dose regimens were associated with a proportional increase of about 10% in reported diabetes, and more intensive statin regimens (as used in JUPITER) with about a 10% further increase. This excess of diabetes diagnoses appeared soon after the start of statin therapy, mainly among patients who had previous risk factors for diabetes [50].
\nIn The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial, among 4731 patients with prior cerebrovascular disease, allocation to atorvastatin 80 mg daily produced a definite reduction in ischemic stroke (218 [9.2%] vs. 274 [11.6%]; p = 0.008), but there was also a possible increase in hemorrhagic stroke (55 [2.3%] vs. 33 [1.4%]; p = 0.02). When these results were combined with those from the other trials included in the CTT meta-analysis, there was a 21% (95% CI 5–41; p = 0.01) proportional increase in the incidence of hemorrhagic stroke per mmol/L reduction in LDL-C [51].
\nThe relationship between lipid-lowering medications, glycemic control, insulin resistance and new-onset diabetes has been studied since the introduction of hipo-lipemic medications. We know that glycemic control is impaired not only by statin treatment but also with niacin. At the opposite, bile-acid sequestrates demonstrate moderate lipid and glucose lowering effects, and fibrates (particularly bezafibrate) may produce beneficial effects on glucose metabolism and insulin sensitivity. Considering statins, as the most widely used hypo-lipemic drugs, this is an important issue. Statins lead to a mild elevation of hemoglobin A1c (HgbA1c) and fasting plasma glycose (FPG), and increase the incidence of new-onset diabetes, an effect known to be dose and agent dependent (Pravastatin and Pitavastatin have less diabetogenic effect and positive impact on insulin sensitivity). The aforementioned is most pronounced in patients with baseline impaired fasting blood glucose (FBG), at older age and with metabolic syndrome. However, it has been demonstrated that the risk of new-onset diabetes is overweight by the benefit of CV risk reduction [3].
\nFor a long period of time there was a lack of clinical trials addressing the same question in ezetimibe treatment, but data was gathered from experimental animal studies that described how ezetimibe ameliorates metabolic markers, such as hepatic steatosis and insulin resistance. The process is via inhibition of the intestinal cholesterol absorption, and inhibition of the hepatic NPC1L1, leading to decreased hepatic insulin resistance, improved glycemic control and insulin sensitivity, especially in patients with metabolic disorders (obesity and hepatic steatosis). This was harder to prove in humans, as ezetimibe is usually used as statin co-therapy and individual impact of ezetimibe cannot be evaluated. In a recently published systematic review of randomized clinical trials, performed by Wu and co-authors on 2440 patients, experimental data was confirmed. Ezetimibe did not cause any adverse effects in terms of increased levels of FBG and HbA1c. Compared with high-dose statin therapy, ezetimibe ad-on low-dose statin for more than 3 months may even have beneficial effects on glycemic control [52].
\nStatin associated muscle symptoms are a very common side effect, also known to be dose-dependent. It seems that ezetimibe ad-on low dose statin therapy is one of the possibilities to achieve good LDL-C control and CV risk reduction with lesser side effects, as demonstrated with myalgia [53]. The 2016 ESC/EAS Guidelines for the management of dyslipidemias recommend ezetimibe to be considered in combination with a low-dose statin or second- or third-line statin in order to manage statin-attributed muscle symptoms [3].
\nDespite this new evidence from the FOURIER trial, gaps remain in our knowledge regarding the use of PCSK9 inhibition in clinical practice. The ODYSSEY Outcomes trial will provide additional information in patients treated with a PCSK9 inhibitor within 1–12 months [45].
\nAs with all novel treatments, long-term safety remains to be established. To date there are exposure data for up to 4 years’ treatment with a PCSK9 inhibitor, involving a background of concomitant statin therapy. Potential injection site reactions occurred in <5% of patients, and were mainly of very mild intensity with no evidence of a cumulative effect. When the PCSK9 inhibitor was compared to the previous standard of care (statin with or without ezetimibe), annualized event rates for muscle symptoms (4.7% vs. 8.5% with standard of care), and new-onset diabetes (2.8% vs. 4.0%, respectively) appeared similar [45].
\nThe safety of very low LDL-C levels merits special consideration, given that one in four patients treated with evolocumab in FOURIER attained LDL-C levels less than 0.5 mmol/L. Evidence to date suggests no detrimental impact on steroid hormone production, enterohepatic circulation of bile acids, or neuronal cell function. Indeed, these LDL-C levels are also consistent with the very low levels observed in newborns which, despite the physiological and developmental demands of infancy, are compatible with normal development [54].
\nAdditionally, data from the ODYSSEY program, the FOURIER and 6-year follow-up from the IMPROVE-IT trial showed no increase in adverse events including severe muscle symptoms, liver enzyme elevation, cognitive adverse events, or hemorrhagic stroke with very low LDL-C levels [45].
\nWe now know the battle is going to be very hard. The “old ones” are not ready to go to history, while the “young ones” are still to be proven. What does the newest published data say? In January 2018 Khan and co-authors published a meta-analysis of statins, PCSK9 inhibitors and ezetimibe, the later two with or without statins, regarding ASCVD reduction benefit. The most comprehensive meta-analysis included 189,116 patients from 39 randomized control trials. PCSK9 inhibitors were ranked as the best treatment for prevention of major adverse cardiovascular events: myocardial infarction and stroke. Statins were ranked as the most effective therapy for reducing all-cause and CV mortality. In terms of reduction of CV mortality PCSK9 inhibitors were ranked as the second best treatment followed by ezetimibe ad-on statin [55].
\nStatins remain the cornerstone anti-lipemic treatment, proven to be very effective in reducing ASCVD risk. Ezetimibe ad-on statin combination therapy is an effective treatment that leads to additional LDL-C lowering, recommended in situations where with maximal or maximally tolerated statin monotherapy treatment LDL-C target goals cannot be achieved. It leads to an additional CVD risk reduction, and in the same time is safe, with a possible beneficial effect over the statin adverse influence on glycemic metabolism. Having in mind the evidence from the first of the cardiovascular outcomes studies with PCSK9 inhibitors, the addition of a PCSK9 inhibitor should be considered in patients with ASCVD, and in FH patients without a prior clinical event, who have substantially elevated LDL-C levels despite maximally tolerated statin with or without ezetimibe therapy, or inability to tolerate appropriate doses of at least three statins. Prioritizing the use of combination therapy in these specific patient groups may help reduce cardiovascular outcomes and the impact of the associated physical and/or psychological disability.
\nBoth authors equally contributed to this chapter.
\nWe declare no conflict of interest. This chapter was written independently. No company or institution supported it financially.
AACE | American Association of Clinical Endocrinologists |
ABC | ATP-binding cassette |
ACC/AHA | American College of Cardiology/American Heart Association |
ACE | American College of Endocrinology |
ACS | acute coronary syndrome |
ApoB | apolipoprotein B |
ARIC study | the Atherosclerosis Risk in Communities study |
ASCVD | atherosclerotic cardiovascular disease |
CAD | coronary artery disease |
CHD | coronary heart disease |
CKD | chronic kidney disease |
CTT | Cholesterol Treatment Trialists’ Collaboration |
CV | cardiovascular |
CV | coefficient of variation |
CVD | cardiovascular disease |
CYP450 | cytochrome P450 |
DNA | deoxyribonucleic acid |
ESC/EAS | European Society of Cardiology/European Atherosclerosis Society |
FBG | fasting blood glucose |
FDA | Food and Drug Administration |
FH | familial hypercholesterolemia |
FOURIER trial | Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial |
FPG | fasting plasma glycose |
GAUSS-3 trial | the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 trial |
HDL-C | high-density lipoprotein cholesterol |
HgBA1C | hemoglobin A1c |
HMG-CoA | 3-hydroxy-3-methylglutaryl coenzyme A |
HoFH | homozygote familiar hyperlipidemia |
hsCRP | high-sensitive C-reactive protein |
IDEAL trial | the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering trial |
IDL | intermediate density lipoproteins |
IgG1 | immunoglobulin G1 |
IMPROVE-IT study | Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs. Simvastatin |
IS | ischemic stroke |
JUPITER trial | in the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin randomized trial |
LAPLACE-2 trial | the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy 2 trial |
LDL | low-density lipoprotein |
LDL-C | low-density lipoprotein cholesterol |
LDL-R | LDL receptor |
Lp(a) | lipoprotein(a) |
MDA-LDL | malondialdehyde-modified LDL |
MI | myocardial infarction |
MoAbs | monoclonal antibodies |
MRSE | muscle-related side effects |
MVE | major vascular events |
NPC1L1 | Niemann Pick C1 like 1 protein |
ODDYSSEY trial | the Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control |
PCI | percutaneous coronary intervention |
PCSK9 | Proprotein Convertase Subtilisin/Kexin Type 9 |
PRECISE-IVUS trial | the Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled trial |
PROVE-IT trial | Pravastatin or Atorvastatin Evaluation and Infection Therapy trial |
RCTs | randomized clinical trials |
RMSE | root mean squared error |
SC | subcutaneously |
SD | standard deviation |
SEARCH trial | in the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine randomized trial |
SEASE study | Simvastatin and Ezetimibe in Aortic Stenosis study |
SHARP trial | the Study of Heart and Renal Protection (Simvastatin plus ezetimibe) trial |
SLC | solute carrier |
SPARCL trial | in The Stroke Prevention by Aggressive Reduction of Cholesterol Levels trial |
T2DM | type 2 diabetes mellitus |
TNF-α | tumor necrosis factor-α |
TNT trial | treating to New Targets trial |
UGT | UDP-glucuronosyltransferase |
VLDL | very low-density lipoproteins |
IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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\\n\\nIn order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\\n\\nIf you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\\n\\nPlease note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\\n\\nPlease be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
\\n\\nOpen Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\nIn order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\nIf you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\n\nPlease note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at oapf@intechopen.com
\n\nPlease be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
\n\n