Pharma-Nutrition
Current state & Future direction
Laura Han
Jochem Jansen
Carlien ter Mors
University of Amsterdam:
Laura Han (laurakimmae@gmail.com)
Jochem Jansen (jochem.m.jansen@gmail.com)
Carlien ter Mors (carlientermors@gmail.com)
TNO:
Jasper Donker (Jasper.Donker@tno.nl)
Alain van Gool (Alain.vanGool@tno.nl) Peter Wielinga (Peter.Wielinga@tno.nl)
FNWI supervisors:
Joost Teixeira de Mattos (M.J.TeixeiradeMattos@uva.nl) Joris Buis (J.J.W.Buis@uva.nl)
Bertus Tulleners (B.A.W.Tulleners@uva.nl)
Date:
P
REFACE
Pharma-‐Nutrition approaches, combining pharmaceuticals and nutritional components in the context of prevention and treatment of diseases, could be a new way to innovate healthcare. The pharmaceutical and nutrition industry are not common collaborators in healthcare innovation, since they traditionally have distinct business models and markets. In the academic world, Pharma-‐ Nutrition remains largely understudied, with insurance companies not even having the topic on their agenda. Consequently, there is insufficient evidence of a benefit of Pharma-‐Nutrition approaches for patients. Furthermore, it has never been analyzed whether, and to what extent, producers of Pharma-‐Nutrition approaches could benefit from investing in this area. TNO noticed that it could be highly beneficial for both industries to work together in the production of new solutions for health problems. They experienced interest from different stakeholders, but also encountered pitfalls and hurdles towards such innovation. TNO would like to collaborate with both industries and facilitate a partnership. Therefore, the main objective of this Tesla minor project was to investigate the biological and commercial potential of Pharma-‐Nutrition approaches, with keeping in mind the added value for the different stakeholders. By combining literature research and expert interviews, evidence for the potential of combination approaches is collected and candidate combinations in the context of metabolic disease are defined. Finally, the knowledge derived lead to a strategy to approach potential stakeholders and to identify key partners in the development of innovative Pharma-‐Nutrition therapies.
E
XECUTIVE SUMMARY
There are indications that nutrition can be useful as a treatment method in combination with pharmaceuticals. This can be achieved by nutrition targeting the same pathway (having an additive effect) as the medication, by targeting different pathways (having a complementary effect), or by reducing side effects. Approaches combining pharma and nutrition have been coined by the term “Pharma-‐Nutrition”. Despite the biological rationale for Pharma-‐Nutrition, there are only a few studies that provide scientific evidence for the synergistic effect of certain Pharma-‐Nutrition combinations. Not to mention that pharmaceutical and nutritional companies still lack strong collaborations on this topic, as both industries generally have distinct markets and different business models. This study aimed to examine the potential of Pharma-‐Nutrition approaches in the current state of the field, by performing literature search, conducting expert interviews, extensive stakeholder mapping, and an in-‐depth case study for a candidate combination of Metformin and fish
oil.
The scope of the current study was metabolic disease, and more specifically Type 2 Diabetes (T2D). T2D is responsible for a huge global disease burden in terms of quantified mortality and disability. The prevalence of the disease continues to rise, suggesting that current medical treatments for the management of T2D are not successful in impeding the epidemic. T2D was chosen as a target disease because Pharma-‐Nutrition approaches may have high impact on disease
management.
There is a body of literature supporting the idea that nutrition can help in the treatment of T2D. Examples of this are polyphenols, vitamin D, dietary fiber, and unsaturated fatty acids. These compounds were compared and analyzed in the light of a potential Pharma-‐Nutrition approach for T2D. Moreover, we performed a variety of interviews with experts in the field of Pharma and Nutrition. Identified stakeholders in the development and use of possible Pharma-‐Nutrition approaches include T2D patients, healthcare professionals, diabetes associations, both the pharmaceutical and nutrition industry, government, health insurances and regulatory bodies. Additionally, the case study on the combination of Metformin and fish oil gave us insight in the
hurdles and opportunities for Pharma-‐Nutrition development.
We have to conclude that current state of affairs does not allow for the development of a Pharma-‐Nutrition approach (using Metformin and fish oil) in the treatment of T2D in adults, mainly because of low commercial potential. To date, there seem to be too great of a difference between business models of the nutrition and pharmaceutical industries. In addition, healthcare professionals prioritize prevention and the lifestyle of patients with chronic metabolic diseases over medical treatment enhancement. By means of this study, we developed a tool that can assess commercial feasibility of a Pharma-‐Nutrition approach beforehand. For instance, in applying the
tool to the case of depression and fish oil, the tool predicts higher commercial potential.
In order to progress the field of Pharma-‐Nutrition, we recommend to a) create more awareness and recognition among stakeholders, b) connect and stimulate collaboration between involved parties, and c) align health services for multidisciplinary treatment. Challenges that need to be considered are the current regulatory atmosphere and its enforcement and educational
systems in the healthcare sector.
T
ABLE OF
C
ONTENTS
Preface ... 3
Executive summary ... 4
1 Introduction ... 6
2 Opportunities for Pharma-‐Nutrition approaches ... 8
3 Methods ... 11
3.1
Literature research ... 11
3.2
Stakeholder analysis ... 11
3.3
Case study ... 12
3.4
Expert interviews ... 12
4 Metabolic diseases as a target for Pharma-‐Nutrition ... 13
4.1
Type 2 Diabetes ... 13
4.2
Global burden and growing problem ... 13
5 Results ... 15
5.1
Literature overview ... 15
5.2
Results stakeholder analysis ... 20
5.3
Results case study Metformin & Fish oil ... 21
5.4
Results expert interviews ... 25
6 Conclusions ... 32
7 Criteria and applications for Pharma-‐Nutrition ... 33
7.1
Assessment tool ... 33
7.2
Applications for Pharma-‐Nutrition ... 33
7.3
Using the tool on the proposed examples ... 37
8 Recommendations & Challenges ... 38
8.1
Recommendations for TNO ... 38
8.2
Challenges ... 40
9 Concluding remarks ... 41
References ... 42
Appendices ... 46
Appendix 1: Overview interviewees ... 46
Appendix 2: Example interview guide ... 49
Appendix 3: Biological mechanisms and treatment of Type 2 Diabetes ... 51
Appendix 4: Poster Universitas 21 conference Shanghai: The Digital Future ... 53
Appendix 5: Key points of interviews (in order of overview Appendix 1) ... 54
Acknowledgements ... 65
1 I
NTRODUCTION
Traditionally, nutrition is viewed as a way to maintain good health by providing the body with balanced nutrients, whereas pharmaceuticals are generally viewed as substances that can actually prevent, treat, and cure diseases (Eussen et al., 2011). In reality, a large part of the existing pharmaceuticals find their origin in components that occur in nature. For instance, aspirin (acetylsalicylic acid), a widely used painkiller, is originally derived from the bark of the white willow tree (Mahdi, 2010). Moreover, the link between food and both health and disease has been strongly suggested since ancient Greek times, with Hippocrates once stating: “Let food be thy medicine and medicine be thy food”. While many cultures and traditional medicine indeed use food to prevent and cure diseases, the rationalistic Western medicine views food merely as a source of nutrition, excluding other purposes beyond nutritional value (ATKearney, 2014). Whereas, the pharmaceutical industry mainly views nutrition as something that interacts with the pharmacological effect of their medicine. Consequently, the disciplines of pharma and nutrition have largely undergone separated developments and evolution. This results in differences in production, marketing, and cost profiles between the two industries. Furthermore, their regulatory frameworks are quite distinct.
Currently, the paradigm is starting to shift. Nutritional products are more often viewed as daily intake that is able to influence both health and disease in the human body in a positive, but also negative way. In fact, nutrition can be an important driver of disease, as it may play a large role in the etiology and progression of metabolic diseases (Cani et al., 2007). In addition, poor nutrition is currently accepted as a major risk factor for chronic diseases (ATKearney, 2014). At the same time, there is increased interest from both the consumer and industry, in specific foods that are suggested to have health-‐enhancing roles. These foods are so-‐called “functional foods” and can be defined as foods that have additional physiological benefit beyond their nutritional value, improving health, quality of life or well-‐being (Henry, 2010; Howlett, 2008 cited in (Eussen et al., 2011)). Examples of functional foods are fruit juices fortified with vitamin C, yoghurts enriched with pre-‐ and/or probiotica, margarine with plant sterol esters, or even enhanced eggs with increased omega-‐3 content achieved by altered chicken feed (Siró, Kápolna, Kápolna, & Lugasi, 2008). In this respect, functional foods are similar to dietary supplements, except for the fact that dietary supplements are usually marketed as pills or capsules, whereas functional foods are consumed as part of the usual diet (Eussen et al., 2011).
Functional foods can, amongst other mechanisms, exert their beneficial effects by interactions with the gastrointestinal (GI) tract that contains multiple complex receptors. Besides being a nutrient recognition and control system, the gut is also functional as a signal transducer, immunological recognition and presentation system, and neuroendocrine sensor (Guang-‐Chang, Jun-‐Bo, Qing-‐Sen, & Zhi-‐He, 2012). Functional foods are able to influence signal transduction networks through information exchange systems in the different cells of the GI tract, immobilized cells in organs, and mobile cells in the blood. Similarly, a large part of the pharmaceuticals are ingested orally and can therefore also modulate metabolic pathways and homeostatic regulation through analogous signal transduction pathways (Caskey, 2010; Pravenec and Kurtz, 2007 cited in Eussen et al., 2011). In other words, nutrition is able to exert influence on the same pathways as pharmaceuticals do, and when optimally balanced, can even boost the pharmaceuticals’ effects.
Important in this context is the fact that there is a global increase in the incidence of complex multifactorial diseases, including diabetes, cancer, metabolic disorder and many others. Their growing burden on society has narrowed the gap between separate pharmaceutical and nutritional approaches in prevention and disease management (Georgiou, Garssen, & Witkamp, 2011). Multi-‐targeting approaches are most likely needed to tackle these multifactorial diseases that require multi-‐pathway understanding (Georgiou et al., 2011). It seems reasonable to think that the combination of pharmaceuticals with supplementary nutritional therapy can potentially enhance efficacy of both components by means of targeting the same pathway (having an additive effect), by targeting different pathways (having a complementary effect), or by reducing side effects, thereby creating a synergistic effect. The common ground that is focused on the complementary values between pharma and nutrition has been coined by the term “Pharma-‐Nutrition” (Sagar, Folkerts, & Garssen, 2014).
Despite the biological rationale for Pharma-‐Nutrition, there are only a few studies that provide scientific evidence for the synergistic effect of certain Pharma-‐Nutrition combinations. Not to mention that pharmaceutical and nutritional companies still lack strong collaborations on this topic, as both industries generally have distinct markets and therefore different business models. For instance, the pharma industry encounters very high research and development costs; mainly due to the multiple obligatory phases of clinical testing such a product has to go through. If the product eventually reaches the market it often has to be prescribed by doctors and paid for by health insurance companies ensuring return on investment and a steady large revenue stream. In contrast, nutritional companies may have relatively low research costs because they investigate natural nutritional components that can be found in conventional food products. Regulations on testing of such a product are profoundly different. However, they have to convince the end user to use their product and thus revenue streams depend for a great deal on marketing and public image of their product. To date, it is unclear how far the field of Pharma-‐Nutrition has progressed in terms of clinical testing for candidate combinations, as well as in activating collaborations between stakeholders in developing such approaches. This study therefore aims to establish the current state of the field of Pharma-‐Nutrition, by performing literature search, conducting expert interviews, extensive stakeholder mapping, and an in-‐depth case study for a specific candidate combination. By doing so, an assessment tool has been developed to filter out cases with low market potential of Pharma-‐Nutrition approaches.
2 O
PPORTUNITIES FOR
P
HARMA
-‐N
UTRITION APPROACHES
Several opportunities can be identified as potential drivers for the emergence of Pharma-‐ Nutrition approaches and industry collaborations. For instance, joint effort and strategic alliances of multiple different companies/industries in the Pharma-‐Nutrition approach may be beneficial for commercial parties involved, but more importantly, may result in better treatment for patients. Enhanced treatment will benefit both patients and society by increasing workability and decreasing disability. Figure 1 shows several key drivers for the emergence of Pharma-‐Nutrition approaches.
In addition to benefits for society and the patient/end-‐user, strong collaboration between the nutrition and pharmaceutical industries could be beneficial to both parties for several reasons that are visualized on the next page.
Multidisciplinary approach
Both pharmacologists and nutritionists are noticing that multifactorial diseases probably require multi-‐pathway understanding and multi-‐targeting approaches, instead of the traditional one disease -‐ one target -‐ one drug (or nutritional component) concept (Sagar et al., 2014). In order to maintain long-‐term profitability, it is critical that strategic alliances will be formed that focus on multidisciplinary approaches (Bröring, Cloutier, & Leker, 2006)
Patent expiration
The pharmaceutical industry is facing both fewer product approvals on one hand, and blockbuster patent expirations on the other. This combination has created a growing necessity for new strategies such as collaboration with the nutrition industry (Brannback et al., 2002; Curran & Leker, 2011 cited in Sagar et al., 2014).
Overlapping approaches
The nutritional industry and its associated research programs are gradually taking on the same approaches used in the pharmaceutical world. At the same time, the pharmaceutical industry is realizing the potential of nutrition in improving health, therapeutic outcome, and/or slowing down disease progression (Georgiou et al., 2011).
Consumer demand
Pharma-‐Nutrition meets the increasing public demand for a more ‘natural’ approach of treatment (Vranesic-‐Bender, 2010; Crowe & Francis, 2013 cited in Ameratunga, Crooks, Simmons, & Woon, 2014), offering an alternative for exclusively drug-‐based therapies.
First-‐mover advantage
The early stages of the Pharma-‐Nutrition interface offers powerful opportunities, including first-‐mover advantage, potentially setting the knowledge and technological industry standard in converging (Curran & Leker, 2011 cited in Sagar et al., 2014).
Overall, the field of Pharma-‐Nutrition seems to be demonstrating strong opportunities and qualities for biological and commercial aspects. However, biologically, it is still in dire need of demonstrators and scientific evidence confirming the clinical benefits and cost effectiveness of these candidate combinations. Commercially, it remains to be elucidated how different industries can overcome contrasting interests, before committing to Pharma-‐Nutrition collaborations.
3 M
ETHODS
Multiple approaches were used to get an overview of the current state of the Pharma-‐Nutrition field. First, both scientific and nonscientific literature searches were performed (for the results see Chapter 5.1). Second, stakeholders were identified and analyzed to get an overview of all parties involved, including their interests and roles (see Figure 6). A case study was carried out to structure the approach in search of a demonstrator (for the results, see Chapter 5.3). Finally, expert interviews were conducted to get explicit information from different stakeholder perspectives (see Appendix 1 for a complete overview of interviewees). These experts had hands-‐on experience with a variety of facets associated with Pharma-‐Nutrition approaches.
3.1 L
ITERATURE RESEARCHThe literature research performed was aimed at describing two matters: 1) to provide us with insights of the current state of the Pharma-‐Nutrition field 2) to build a showcase of a specific Pharma-‐ Nutrition approach. The field has been studied and described in dissertations such as the ones by Eussen (2011) and Weenen (2014). Together with further search in academic literature for examples of Pharma-‐ Nutrition, this provided a general overview of the current state, direction, and possibilities of Pharma-‐ Nutrition approaches. The scope of the current project was limited to metabolic diseases, and more specifically, Type 2 Diabetes (T2D). The biological mechanisms of T2D were investigated to find opportunities for Pharma-‐Nutrition approaches in the disease management (for an overview of the biological mechanisms of T2D, see Appendix 3). A literature review included an overview of the mechanisms of the disease and biological functioning of the most widely used pharmacological treatments (see Chapter 5.3.1.). With this information it was possible to assess the biological feasibility of using a nutritional component in combination with antidiabetic medication. Potential nutritional components were assessed as having a beneficial clinical effect on: a) T2D as a systemic disease in its whole, b) a specific dysregulated mechanism associated with T2D, or c) a specific drug given to a T2D patient. In addition, these components were also assessed based on the type, quality, and amount of literature supporting the alleged health claims (see Table 1).
3.2 S
TAKEHOLDER ANALYSISA stakeholder analysis was performed to identify and map the parties that could be involved in the development of Pharma-‐Nutrition approaches as complete as possible. Identifying stakeholders, their interests, and influence was determined by: a) reciprocity of insights of the researchers and supervisors literature on the Pharma-‐Nutrition field, and b) information from expert interviews. The insights of the researchers and supervisors, and literature on Pharma-‐Nutrition, determined the initial stakeholder mapping. Based on this, interviews were arranged and information was collected on, and from, these stakeholders. This process was continuous and has led to the overview of stakeholders and their interest and influence as described in the results chapter of this report (see Chapter 6).
3.3 C
ASE STUDYTo get detailed insight into opportunities and hurdles for the development of Pharma-‐Nutrition approaches, we created a case study. The information collected to structure this case study was gained by literature search and expert interviews. The case study is a Pharma-‐Nutrition approach with a specific combination of a pharmaceutical drug and a nutritional component for the treatment of T2D. Using a concrete example allowed us to form a strategy to approach potential stakeholders and to identify key partners (for the results see Chapter 6).
3.4 E
XPERT INTERVIEWSThe expert interviews have been an important source of information. For a complete overview of the interviewees and their contribution to the research, see Appendix 1. The assembled information in these interviews has been useful for three reasons: a) contact details of other stakeholders, b) insight into their attitude and influence towards a Pharma-‐Nutrition approach, and c) information about the different perspectives of other stakeholders. Finally, the interviews were useful to test whether the case study we constructed would be feasible (biologically, commercially) based on the opinions of the stakeholders. The interviews were semi-‐structured as can be seen in the example interview guide (Appendix 2). Topics addressed in all interviews dealt with their vision and possible criteria for Pharma-‐ Nutrition approaches. The remaining part of the interview was mainly focused on the unique knowledge of the interviewee. The interviewee was allowed to contribute to the agenda and free to discuss other topics they deemed relevant. Key points of the interviews were checked and approved by the interviewee and can be found in Appendix 5. The interviews were performed either face-‐to-‐face, over the phone or by skype.
Interviewees were recruited in three ways: ● Personal networks.
● Referrals from people we interviewed, personal network, or contact made through TNO. ● Cold acquisition through LinkedIn and company websites.
4 M
ETABOLIC DISEASES AS A TARGET FOR
P
HARMA
-‐N
UTRITION
4.1 T
YPE2
D
IABETESType 2 diabetes (T2D) is a complex metabolic disorder associated with many long-‐term pathogenic conditions including cardiovascular complications, neuropathy, retinopathy, nephropathy, resulting in a consistent decrease in quality of life and increased risk of mortality (Bahadoran, Mirmiran, & Azizi, 2013). One of the main reasons to believe that a Pharma-‐Nutrition approach could be effective in T2D is because it is a metabolic disease. Metabolic diseases are a result of hyperglycemia with disturbances of carbohydrate, fat and protein metabolism (WHO, 1999) (for a complete overview of the biological mechanisms associated with T2D, see Appendix 3). All these aspects concern the way in which the body processes substances that are a direct result of food intake. Hence, there is biological rationale for using food intake to target the mechanism of the disease. Due to the metabolic nature of diabetes, a large body of literature is dedicated to the link between nutrition and diabetes. In addition to identifying a strong association between obesity and diabetes (Donath & Shoelson, 2011; Georgiou et al., 2011; Rhodes, 2011) there is a plethora of literature identifying the effects of different foodstuffs (whole food items) or nutritional components on diabetes or the biological systems associated with diabetes (Bahadoran et al., 2013). This increases the chance of finding a nutritional component that could be effective in combination with a pharmaceutical and thus can be used in a showcase for Pharma-‐ Nutrition.
Another aspect of metabolic diseases that is useful for the process of creating a showcase for Pharma-‐Nutrition is the ease and speed in which the effects of the treatment on the disease can be measured using biomarkers. The easiest way to diagnose a metabolic disease is to measure blood glucose levels, which is a very quick, low cost, and reliable method. Even though one measurement of blood glucose levels should never be taken as a valid result, multiple sober measurements over the course of 8-‐12 weeks (HbA1c levels) is considered a reliable measurement of the metabolic state of a person (Chen, Magliano, & Zimmet, 2011; Grauw, Bakx, & Gerwen, 2007; WHO, 1999). In addition, cholesterol levels can also be measured from a blood sample. Both blood sugar levels and blood cholesterol have a quick response rate to intervention methods. This means that testing whether a possible Pharma-‐Nutrition approach for diabetes works can be tested for quickly, cheaply, and reliable.
4.2 G
LOBAL BURDEN AND GROWING PROBLEMTo date, T2D is responsible for a huge global disease burden in terms of quantified mortality and disability (Aguiree, Brown, Cho, & Dahlquist, 2013). The number of people with T2D in the Netherlands was estimated at 886.800 by the end of 2011 (Tamayo et al., 2014), resulting in an estimated economic burden of 6.4 billion euro on Dutch society (Booz&co, 2011). The prevalence of the disease continues to rise, suggesting that current medical treatments for the management of T2D are not successful in impeding the epidemic (Chen et al., 2011). The most effective and at the same time cheapest way of the prevention and treatment of diabetes, is a change in lifestyle and diet. However, this method of treatment is very often ineffective due to low compliance rates despite it being well known and widely implemented. As a result of this, it seems necessary to focus on the improvement of the pharmaceutical treatment since this is almost always required (for an overview of the current pharmaceutical treatment, see Appendix 3).
It is important to note that effective treatment of T2D can potentially lower the economic burden not only by reducing direct care costs, but also by reducing work disability caused by disease progression and/or negative side effects of antidiabetic medication. As a result of this, there is a very large market for T2D treatment and chances of obtaining a share in this market for a possible Pharma-‐ Nutrition approach are high. In addition to having higher economic incentives due to this large and growing market, when a Pharma-‐Nutrition approach successfully makes it to this market, it would function as an example of how such a product can be exposed to a wide-‐scale roll out. By targeting this large portion of the (world) population (approximately 1 in 16.5 in the Netherlands and approximately 1 in 18.5 worldwide (Aguiree et al., 2013), having a proven working Pharma-‐Nutrition product on the market would result in both high visibility and awareness. As a result of this visibility and awareness, the demand for Pharma-‐Nutrition approaches for other diseases is expected to increase accordingly. When the demand for such approaches starts growing, it is likely that the industries will gradually start investing more in it. Investments from industries, which are being spurred on by consumer demand, will in turn lead to a larger market for Pharma-‐Nutrition products. The combination of these factors makes T2D a good focus for showcasing the potential of Pharma-‐Nutrition approaches.
5 R
ESULTS
5.1 L
ITERATURE OVERVIEW5.1.1 Current nutrition guidelines for T2D
In general, a healthy diet including fruits and vegetables, essential fatty acids, and whole grain food products is recommended to T2D patients. The use of sweetened products, alcohol, and high salt concentrations is principally discouraged. This dietary advice, together with weight loss and regular exercise, is recommended by the Nederlandse Diabetes Federatie to prevent and help treatment of T2D (Jullens, 2015; Rutten et al., 2013)
5.1.2 Nutritional components and their health effects
Functional foods are claimed to have additional physiological benefit beyond their nutritional value by improving health, quality of life or well being (Henry, 2010; Howlett, 2008 cited in (Eussen et al., 2011)). There is evidence that there are functional foods that can help in the treatment of T2D; the nutritional components that are responsible for these health effects include polyphenols, vitamins, dietary fiber, and fatty acids (Al-‐Sofiani et al., 2015; Bahadoran et al., 2013; Chandalia et al., 2000; Gillingham, Harris-‐Janz, & Jones, 2011). More specifically, it is shown that these components can have positive effects on conditions like dyslipidemia, oxidative stress, and mitochondrial dysfunction (Prabhakar, Kumar, & Doble, 2014). Here we will go more into detail about these four promising candidate compounds. We will compare these compounds (see Table 1) and analyze them in the light of a potential Pharma-‐Nutrition approach for T2D.
Polyphenols
One group of functional foods that we looked into for their antidiabetic properties is polyphenols. Polyphenols are natural phytochemical compounds in plant-‐based foods, such as fruits, vegetables, whole grains, cereal, legumes, tea, coffee, wine, and cocoa. Polyphenols may be classified into several categories based on the number of phenol rings and structural elements that bind these rings to one another, see Figure 2 (Bahadoran et al., 2013). The positive effects of polyphenols on T2D include anti-‐hyperglycemic, cardiovascular protective, anti-‐oxidative properties, and effects on adipose tissue metabolism, as well as favorable effects in preventing long-‐term diabetes complications (Bahadoran et al., 2013). These results were found in vivo, animal studies, and a few human studies. However, in many cases the in vitro data conflict with results obtained in human subjects which can potentially be explained by the limited bioavailability and extensive metabolism in humans (Han, Shen,
& Lou, 2007). The relevant action mechanisms must be studied extensively before these compounds can
Vitamin D
Vitamin D was also found to aid in the treatment of T2D (Al-‐Sofiani et al., 2015; Khan, Kunutsor, Franco, & Chowdhury, 2012; Mitri, Dawson-‐hughes, Hu, & Pittas, 2011). Vitamin D is a group of fat-‐ soluble secosteroids that helps the absorption of calcium, iron, magnesium, phosphate, and zinc in the body. Vitamin D2 (ergocalciferol, plant based) and D3 (cholecalciferol, animal based) can be ingested from food or from supplements (see Figure 3). A study by Al-‐Sofiani et al. (2015) showed that T2D patients with a vitamin D deficiency may benefit from vitamin D supplementation, because it seems to positively influence β-‐cell function in these patients. The results of a review by Khan et al. (2012), examining long-‐term prospective studies involving healthy adults, indicated an inverse association of baseline vitamin D status and the incidence of T2D. In addition, a randomized controlled trial in adults at risk for T2D by Mitri et al. (2011) showed that short term supplementation of vitamin D was associated with improved pancreatic b cell function. Another study showed that diabetic subjects who took a daily vitamin D–fortified yogurt drink, either with or without added calcium have improved glycemic status (Nikooyeh et al., 2011). In summary, vitamin D has repeatedly been associated with T2D, showing beneficial effects when supplemented in people at risk for T2D or T2D patients with vitamin D deficiency. However, this does not make a strong case for full-‐blown diabetic patients. Also, most studies are not specific about which type of D they study. For example, Seida et al. (2014) performed a meta-‐analysis on most of this literature on vitamin D supplementation and concluded that all available trials show no effect of vitamin D3 supplementation on glucose homeostasis or diabetes prevention (Seida et al., 2014).
Dietary fiber
Another component that may help in the treatment of T2D is dietary fiber. Fruit, vegetables, and whole grain foods are examples of food products that contain high amounts of fiber (Figure 4). A study with T2D patients showed that a high intake of dietary fiber improved glycemic control, decreased hyperinsulinemia, and lowered plasma lipid concentrations (Chandalia et al., 2000). This study showed the effect of a whole diet change in patients with T2D. It was also emphasized that the fibers should be coming from a natural source and not from enriched products (Chandalia et al., 2000). Therefore, dietary fiber seems less suitable to use as a single nutrient source in our Pharma-‐Nutrition approach.
Figure 3. The molecular structure of plant-‐based Vitamin D2 (left) and animal-‐based Vitamin D3 (right).
Figure 4. Examples of food products containing high fiber concentrations.
Unsaturated fatty acids
Lastly, we investigated the use of mono-‐ and polyunsaturated fatty acids in T2D treatment. Monounsaturated fatty acids (MUFAs) are classified as fatty acid chains containing one double bond (see Figure 5). Polyunsaturated fatty (PUFAs) acids have two or more double bonds (also see Figure 5). Clinical trials replacing dietary saturated fatty acids (SFAs) with MUFAs have noted improvements in insulin sensitivity and glycemic response in both individuals predisposed to insulin resistance, as well as healthy people (Gillingham et al., 2011). Also, the KANWU (Kuopio, Aarhus, Naples, Wollongong and Uppsala) study showed a reduction in insulin sensitivity after 3 months of SFA rich diet, and improved insulin resistance when replacing a SFA rich diet with a MUFA rich diet (Vessby et al., 2001). Furthermore, polyunsaturated fatty acids have shown to have beneficial effect on T2D patients, specifically on lipid metabolism. A study by Hartweg et al. (2008) looked at 23 randomized trials in which a total number of 1075 people took part to compare the use of omega-‐3 PUFA to a vegetable oil or placebo. This review of the field concluded that omega-‐3 PUFAs helped hypertriglyceridemic patients to lower their triglycerides with dietary supplementation (Hartweg et al., 2008). This could mean that omega-‐3 PUFAs can be a very good candidate to serve as a therapeutic component in the T2D management strategy.
Table 1. Criteria and nutritional components explored for selecting a Pharma-‐Nutrition combination approach for Type 2 Diabetes
Polyphenols Vitamin D Dietary Fiber Unsaturated fatty acids
Specific nutrient -‐ + + -‐
Consensus in literature + ± ± +
Biological availability -‐ + + +
Use for glucose regulation ± ± + ±
Use for lipid regulation ± ± -‐ +
Nutrient availability + + + +
Side effects -‐ -‐ -‐ -‐
Safe + + + +
Tested in healthy subjects + + + +
Tested in T2D patients + -‐ + +
Tested in combination with T2D
medication + -‐ -‐ -‐
Criteria explored: Specificity of the component (individual nutrient or a group of different compounds), general consensus about the effect of the nutrient in literature, biological availability in the human body, purpose for which it could be used (glucose or lipid metabolism regulation), availability from raw materials, side effects, safety and phase of testing (clinical and in combination with standard T2D medication). Assumptions were based on literature review of scientific articles. (+ = yes, -‐= no, ± = unclear).
5.2 R
ESULTS STAKEHOLDER ANALYSISWe identified the main stakeholders in the development and use of potential Pharma-‐Nutrition approaches for the treatment of T2D. Here, we visualized these stakeholders and mention their function and stake in possible Pharma-‐Nutrition approaches for T2D (see Figure 6).
Abbreviations: PN, Pharma-‐Nutrition; IP, Intellectual Property. Healthcare professionals include general practitioner, professor diabetology, psychologist, dietitian. Diabetes associations include the Diabetes Vereniging Nederland and Diabetesfonds. Government is represented by The Ministry of Health and Sports (in Dutch: Volksgezondheid, Welzijn en Sport), as well as the Ministry of Education, Culture and Science (in Dutch: Onderwijs, Cultuur en Wetenschap). The nutrition industry is represented by companies like Danone. Regulatory bodies include the Dutch Food and Goods Authority (NVWA), the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), and the College ter Beoordeling van Geneesmiddelen (CGB). Health insurance companies are represented by companies such as CZ. The pharmaceutical industry is represented by companies such as MSD (Organon), PharmaPlexus, OctoPlus.
5.3 R
ESULTS CASE STUDYM
ETFORMIN&
F
ISH OIL5.3.1 Case introduction
In order to fully investigate the biological and market potential of Pharma-‐Nutrition for the treatment of T2D, we created a case study. A successful Pharma-‐Nutrition case is one that makes the treatment more (cost)-‐effective, by making the drug function better, reduce side effects or make the treatment cheaper. The case study is constructed based on the knowledge we gained from literature and expert interviews. We investigated the standard of care to see whether there were possibilities to combine current medicinal treatment with nutritional components.
The current standard treatment for T2D is Metformin for regulation of glucose metabolism and statins for regulation of lipid metabolism. Metformin is a glucophage in the class of biguanide drugs. It has been on the market in the UK since 1957 and is used ever since. The long-‐term effects are known, which makes it a well-‐trusted drug that is prescribed by healthcare professionals. The drug is effective in regulating blood sugar, and can be used in high doses without many side effects. The most common side effect is gastrointestinal problems (5-‐10% of users), but this is mostly at the beginning of treatment. A very small percentage (<5%) of the users is intolerant for the drug (Zorginstituut Nederland, 2015).
It is debated whether the focus of treatment should even be on glucose management, since cardiovascular risk seems so much more urgent (Yudkin, Richter, & Gale, 2011). The most widely used drug for this is statins, which are HMG-‐CoA reductase inhibitors that are used to lower cholesterol levels. This type of drug is very effective in lowering cardiovascular risk and is therefore used on a large scale. Currently, 95% of all T2D patients are prescribed statins to prevent the cardiovascular complications associated with T2D (Grauw et al., 2007). However, the safety of statins is debated lately, since there are some studies that claim serious side effects of statins; increased concentrations of liver enzymes, muscle damage, and even increased risk of diabetes (Sattar & Taskinen, 2012; Tomlinson & Mangione, 2005). Furthermore, 1-‐7% of statin users experience side effects like muscle pain which might indicate myopathy which can have kidney and organ damage as a result which can end in death (Zorginstituut Nederland, 2015).
Due to these serious potential drawbacks of statins, this group of medication could be a good target for Pharma-‐Nutrition. We can match this finding to the most potent nutritional component out of the literature analysis; unsaturated fatty acids. We found that omega-‐3 fatty acids derived from fish oil, can help in the treatment of cardiovascular complications in T2D (Hartweg et al., 2008).
For these reasons we designed the showcase ‘Metformin and Fish oil’ for treatment of T2D instead of the standard of care (Metformin and statins). This chapter will outline the literature support for this case and the feedback from experts on this particular combination. Finally, we will conclude and explain whether or not this case is a successful demonstrator for Pharma-‐Nutrition approaches.
5.3.2 Fish oil
Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-‐3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Many investigators claim that these omega-‐3 fatty acids have health effects, by for example treating dyslipidemia in diabetes (Lorente-‐ Cebrián et al., 2013). The ability of fish oil to reduce the plasma triglyceride concentration was already shown in the 80’s (Nestel et al., 1984). Since then, many investigators have looked at the effects of fish
