Availability and Affordability of Medicines for Diabetes and Cardiovascular Disease across Countries: Information Learned from the Prospective Urban Rural Epidemiological Study

Abstract

The global burden of diabetes and cardiovascular disease (CVD) is increasing and, while cardiovascular event incidence is falling in some high-income countries (HICs), increasing rates are being observed in many middle-income countries (MICs) and low-income countries (LICs). There have been discrepancies in the availability and affordability of medicines for diabetes and cardiovascular disease among countries, of which LICs and MICs have seen low availability and affordability. The Prospective Urban Rural Epidemiological (PURE) study is a large prospective cohort study of over 200,000 people aged 35–70 years from 27 HICs, MICs, and LICs across six geographical regions (Asia, Africa, Europe, South America, North America, and the Middle East). Analyses from this study have contributed greatly to the understanding of the determinants of cardio–metabolic health in LICs and MICs especially. Here, we discuss information learned from the PURE study regarding the availability and affordability of key medicines for diabetes and cardiovascular disease.

1. Introduction

Cardiovascular disease (CVD) and diabetes are the leading causes of death globally [1,2]. The global burden of CVD and diabetes is increasing and, while cardiovascular event incidence is falling in some high-income countries (HICs), increasing rates are observed in many middle-income countries (MICs) and low-income countries (LICs). The determinants of this variation are important to understand.

In 2019, approximately 17.9 million people died from CVD globally, which accounted for 32% of all global deaths, and, of these deaths, 85% were due to heart attack and stroke. From 1990 to 2019, the prevalent cases of total CVD nearly doubled from 271 million to 523 million, and the number of CVD mortality steadily increased from 12.1 million to 18.6 million [1]. In 2017, it was estimated that there were 451 million adults living with diabetes globally, and this figure was predicted to increase to 693 million by the year 2045 [3]. The global disease burden of diabetes increased significantly from 1990 to 2017; the global incidence of diabetes increased from 11.3 million in 1990 to 22.9 million in 2017, and the global prevalence of diabetes increased from 211.2 million in 1990 to 476.0 million in 2017 [2]. From 1990 to 2017, there was an increase in the age-standardized mortality of type 2 diabetes, especially in lower-income regions compared to higher-income regions [2]. Diabetes increases the risk of cardiovascular diseases, blindness, chronic kidney disease, and lower limb amputation.

The World Health Organization’s Global Action Plan set a target of 80% availability of affordable essential medicines for non-communicable diseases worldwide and a target of at least 50% for people in need of these medicines by 2025 [4]. To reach this goal, these medicines need to be made widely available and affordable. The World Health Organization (WHO) defined essential medicines as those medications that satisfy the priority healthcare needs of a population [5]. Essential medicines should be available within functioning health systems at all times, in adequate amounts and appropriate dosage, with assured quality, and at affordable prices to individuals and communities [5].

Access to medicines is often described in terms of availability and affordability. Definitions for availability and affordability can vary. Availability might be defined as the presence of medications at any dose on the pharmacy shelf at the time of the visit. Affordability often refers to the cost of treatment in relation to people’s income. Several studies have reported discrepancies in availability and affordability of medicines for diabetes and cardiovascular disease among countries, in which LICs and MICs have seen a low availability and affordability of these medicines [6,7,8].

The Prospective Urban Rural Epidemiological (PURE) study is a large prospective cohort study of 202,072 people aged 35–70 years from 27 HICs, MICs, LICs across six geographical regions (Asia, Africa, Europe, South America, North America, and the Middle East) [9,10]. These countries include Canada, Saudi Arabia, Sweden, United Arab Emirates (HICs), Argentina, Brazil, Chile, China, Colombia, Ecuador, Iran, Kazakhstan, Kyrgyzstan, Malaysia, Palestine, Philippines, Poland, Russia, South Africa, Turkey, Uruguay (MICs), and India, Bangladesh, Pakistan, Peru, Tanzania, and Zimbabwe (LICs). More details of the PURE design, sampling, and recruitment have been previously published [9,10]. In brief, participants have been recruited in three phases since 2003. In phase one, participants were recruited from 17 countries (Argentina, Bangladesh, Brazil, Canada, Chile, China, Colombia, India, Iran, Malaysia, Pakistan, Poland, South Africa, Sweden, Turkey, the United Arab Emirates, and Zimbabwe). In phase two, participants were recruited from an additional four countries (Palestine, Philippines, Saudi Arabia, and Tanzania), and, in phase three, participants were recruited from four more countries (Ecuador, Kazakhstan, Kyrgyzstan, and Russia) [9]. The PURE study aimed to recruit adults from communities in low-, middle-, and high-income regions of the world representing various levels of development and encompassing great sociocultural diversity [10]. The choice and number of countries selected in the PURE study reflects a balance between involving a large number of communities in countries at different economic levels with the substantial diversity in social and economic circumstances and policies and the feasibility of study centers to successfully accomplish follow-ups in the long term [10]. Analyses from this study have contributed greatly to the understanding of the determinants of cardio–metabolic health, in LICs and MICs especially. Data were collected at the national, community, household, and individual levels using standardized questionnaires. Recruitment began in 2003, and follow-ups have occurred since 2008. Information about specific events was obtained from participants or their families. Major cardiovascular events included death from cardiovascular causes and nonfatal strokes, myocardial infarction, and heart failure. Non-major cardiovascular events included all other CVD events that led to hospitalization [11]. Data for availability and costs of medicines were collected from one community pharmacy in each community with the Environmental Profile of a Community’s Health (EPOCH) instrument. The EPOCH contained information about environmental and societal factors that can have an influence on cardiovascular disease [12]. In the PURE study, the affordability of medicines was assessed using the total monthly costs at standard doses and recommended frequencies [13]. The combined costs of medicines were defined as affordable if they constituted less than 20% of a household’s capacity to pay, which was the household income remaining after basic subsistence needs, which were defined as the household monthly income spent on food [14,15,16,17]. In this paper, we discuss information learned from the PURE study regarding the availability and affordability of key medicines for diabetes and cardiovascular disease.

2. Availability and Affordability of Essential Medicines for Diabetes

In the PURE study, the prevalence of diabetes varied among country income groups. The age- and sex-adjusted prevalence of diabetes was highest in LICs (12.3%, 95%CI 10.9–13.9%), followed by upper-middle-income countries (11.1%, 95%CI 9.7–12.6%), lower-middle-income countries (8.7%, 95%CI 7.9–9.6%), and the lowest in HICs (6.6%, 95%CI 5.7–7.7%) [18]. The availability and affordability of essential medicines for diabetes (metformin, sulfonylureas, and insulin) and their effect on use was presented in a PURE publication in 2018 [14]. There were disparities in the availabilities and affordabilities of essential medicines for diabetes among LICs, MICs, and HICs. For example, the availability of metformin was 100% in HICs, 88.2% in upper-middle-income countries, 86.1% in lower-middle-income countries, and 64.7% in LICs. In terms of affordability, 26.9% of households in LICs could not afford metformin, compared to 0.7% in HICs. The availability and affordability of insulin were particularly poor in LICs. The availability of insulin was 93.8% in HICs, 40.2% in upper-middle-income countries, 29.3% in lower-middle-income countries, and only 10.3% in LICs. For insulin affordability, the divide between HICs and LICs was greater; 63.0% of households in LICs were not able to afford insulin compared to 2.8% in HICs. In multilevel models, availability and affordability were significantly associated with the use of diabetes medicines; for the availability of oral hypoglycemic agents (OHA), the odds ratio for use was 1.97, 95%CI 1.51–2.59, and for affordability of OHA, odds ratio for use was 1.24, 95%CI 1.05–1.46 (adjusted for age, gender, country income and location, and medication availability). A variety of factors may explain the pronounced lack of availability of insulin in this study. The additional resources required to store insulin, in terms of refrigeration and lack of adequate support to train individuals in the safe use of insulin, are likely to contribute to the observation of a lack of availability. It could be that use of newer oral agents to manage type 2 diabetes, such as sodium–glucose transport protein 2 (SGLT2) inhibitors or longer-acting injections, e.g., glucagon-like peptide-1 (GLP-1) receptor agonists, may help address such barriers. This study did not examine the availability and affordability of the newer agents, nor examples of newer diabetes medication combinations, e.g., SGLT2 inhibitors with metformin.

3. Availability and Affordability of Antihypertensives

In the PURE study, 40.8% of participants had hypertension, and 46.5% of participants with hypertension were aware of the diagnosis, with a blood pressure control rate of 32.5% among those being treated [19].

Data from cross-sectional surveys at the baseline of the PURE study revealed that only 13% of communities in LICs had access to all four classes of antihypertensive drugs (angiotensin-converting-enzyme inhibitors, beta-blockers, and calcium-channel blockers, diuretics), while the proportion was 47% in lower-middle-income countries, 71% in upper-middle-income countries, and 94% in HICs. There was also a lower availability of ≥2 drug classes in lower income countries compared with HICs. Notably, 10% of PURE communities had no available blood pressure-lowering medicines, mainly in low-income and lower-middle-income countries. Participants with known hypertension in communities with availability of all four antihypertensive drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio 2.23, 95%CI 1.59–3.12) or combination therapy (adjusted odds ratio 1.53, 95%CI 1.13–2.07) and to have their blood pressure controlled (adjusted odds ratio 2.06, 95%CI 1.69–2.50) compared with participants living in communities where blood pressure-lowering medicines were not available. In terms of affordability, participants with known hypertension from households that were able to afford all four classes of antihypertensive drugs were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio 1.42, 95%CI 1.25–1.62) or combination therapy (adjusted odds ratio 1.26, 95%CI 1.08–1.47) and were more likely to have their blood pressure controlled (adjusted odds ratio 1.13, 95%CI 1.00–1.28) compared with participants who could not afford the medicines [15]. This study highlights the relationship of access, in terms of availability, with the use of blood pressure lowering medicines and control. This study did not provide data on the availability of combination medicines in pharmacy, nor what the comparability was in terms of the costs of monotherapy versus single drug combination therapy. Increasing the availability of combination therapy as well as the early use of combination therapy is likely to be important to blood pressure control [20].

4. The Availability and Affordability of Essential Cardiovascular Medicines (for CVD Secondary Prevention)

Data from the PURE study showed that the incidence of major cardiovascular events was highest in low-income countries; the overall rates of major cardiovascular events over a mean duration of follow-up of 4.1 years were 6.43 events per 1000 person-years in LICs, 5.38 events per 1000 person-years in MICs, and 3.99 events per 1000 person-years in HICs. All-cause mortality and deaths after major cardiovascular events were also highest in LICs compared to higher income countries [11]. Only 25.3% of participants with established cardiovascular disease took antiplatelet drugs, and the rates were 17.4% for beta-blockers, 19.5% for angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and 14.6% for statins. Use was lowest in LICs (antiplatelet drugs 8.8%, beta-blockers 9.7%, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 5.2%, and statins 3.3%) and highest in high-income countries (antiplatelet drugs 62.0%, β blockers 40.0%, angiotensin-converting enzyme inhibitors/ angiotensin II receptor blockers 49.8%, and statins 66.5%) [13].

The availability and affordability of essential cardiovascular medicines (defined as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and statins) and their effect on use across HICs, MICs, and LICs were presented in a PURE paper in the Lancet 2016 [16]. That study found that all four medicines were available in 90% of rural and 95% of urban communities in HICs, 73% (rural) to 80% (urban) in upper-middle-income countries, 37% (rural) to 62% (urban) in lower-middle-income countries, and 3% (rural) to 25% (urban) in LICs. The four cardiovascular medicines were potentially unaffordable for 0.14% of households in HICs, 25% of upper-middle-income countries, 33% of lower-middle-income countries, 60% of LICs. While these medicines were all off-patent with generic formulations available and were also, thus, lower in cost, the differences in absolute cost of these medicines across regions were not as marked as the differences in income across the regions. The income differences, therefore, drove the unaffordability in LICs. Participants living in communities with low availability of all four medicines were less likely to use them (adjusted odds ratio 0.16, 95%CI 0.04–0.57) compared to participants living in communities that had all four medicines available. In communities where all four medicines were available, patients were far less likely to use the medicines if the household potentially could not afford them (adjusted odds ratio 0.16, 95%CI 0.04–0.55). The stark differences in the availabilities of these basic cardiovascular medicines across regions were surprising, as were the enormous differences in affordability. While it seems reasonable to focus on reaching all suitable patients with existing CVD on medications for secondary prevention, this study demonstrated that cost and availability were huge barriers to CVD secondary prevention.

5. Availability and Affordability of Essential Cardiovascular Medicines and Cardiovascular Outcomes

Following from the paper above, the recent paper published in BMJ Global Health was the first study to include an analysis of follow-up data across HICs, MICs, and LICs to enable the analysis of the impact of the availability and affordability of cardiovascular medicines on the hazard of CVD outcomes over time [21].

In this analysis, standardized methods were used to assess availability and affordability, as in previous PURE publications, and standard definitions were used to define cardiovascular adverse event rates in adults with high risk of CVD in 592 urban and rural communities. There were 93,200 participants with high CVD risk; they were classified as such if they had any of the following conditions: hypertension, coronary artery disease, stroke, smoker, diabetes, or age >55 years. Figure 1 presents the percentages of PURE participants with high cardiovascular risk from communities where three types of essential cardiovascular medicines were available and affordable. The essential cardiovascular medicines that were examined included blood pressure-lowering drugs, antiplatelets, and statins. Participants with high CVD risk were classified into three groups: Group 1 (all three drug types were available and affordable), Group 2 (all three types were available but not affordable), and Group 3 (all three types were not available). The availability of these three drug types was consistently lower in LICs compared with countries with higher income (except for India, where medicines were relatively widely available) (Figure 2). Multilevel models showed that lower availabilities and affordabilities of essential CVD medicines were significantly associated with a higher risk of major adverse cardiac events (MACEs) and mortality. Compared to the adults from Group 1, the risk of MACEs and all-cause mortality was higher among participants in Group 2 (the hazard ratios were 1.19, 95%CI 1.07–1.31 for MACEs and 1.20, 95%CI 1.08–1.33 for mortality), and among participants from Group 3 (the HRs were 1.25, 95%CI 1.08–1.50 for MACEs and 1.25, 95%CI 1.04–1.50 for mortality). The analyses were adjusted for comorbidities, as well as sociodemographic and economic factors. The study findings indicate that affordability is particularly crucial across HICs, MICs and LICs, and, hence, it is likely that, without affordable access to essential cardiovascular medicines, there will continue to be a barrier to good medication compliance and cardiovascular outcomes.

These findings from the PURE study highlight the importance of ensuring the availability and affordability of essential cardiovascular medicines globally, especially in LICs and MICs. This is in accordance with the Global Action Plan for the Prevention and Control of NCDs 2013–2020 proposed by the World Health Organization, in which a target of 80% availability of affordable essential medicines for non-communicable diseases was set, with least 50% of the eligible people receiving such treatment.

6. Availability, Affordability, and Consumption of Fruits and Vegetables

In addition to essential medicines, adequate consumption of fruits and vegetables is beneficial for cardiometabolic health. According to most nutritional guidelines, consumption of at least two servings of fruits and three servings of vegetables per day was recommended [22]. However, a large proportion of individuals do not meet these targets due to the low affordability of fruits and vegetables, and it is important to determine the affordability of essential foods such as fruits and vegetables in countries with different income levels. The PURE publication in the Lancet Global Health in 2016 was the first to describe the availability and affordability of fruits and vegetables across economic regions globally and to examine the association between affordability and consumption [23]. A checklist of 48 types of fruit and 59 types of vegetable was used to evaluate the variety of fruits and vegetables available in the studied communities. The affordability of two servings of fruits and three servings of vegetables per day was examined using the least expensive fruit and vegetable available for sale within each community. The study results showed that the consumption of fruit and vegetables was low worldwide, particularly in LICs, and this was associated with low affordability. Most participants consumed fewer than the recommended five daily servings of fruits and vegetables: mean fruit and vegetable intake was 3.8 servings (95%CI 3.7–3.9) per day overall, 2.1 servings (1.9–2.4) in LICs, 3.2 servings (3.0–3.4) in lower-middle-income countries, 4.3 servings (4.1–4.5) in upper-middle-income countries, and 5.4 servings (5.1–5.7) in HICs. Purchasing the recommended amount of fruits and vegetables required a substantial proportion of household income, making fruits and vegetables unaffordable in many low-income and middle-income countries; the cost of two servings of fruits and three servings of vegetables per day per individual accounted for 52.0% (95%CI 46.1–57.9) of household income in LICs, 18.1% (14.5–21.7) in lower-middle-income countries, and 15.9% (11.5–20.2) in upper-middle-income countries, while this proportion was only 1.9% (–3.9 to 7.6) in HICs. In some countries, such as Bangladesh, Pakistan, and Zimbabwe, households spent about two-thirds of their income on food. These results suggested the need for policies that enhance the affordability of fruits and vegetables to meet these recommendations.

Besides the PURE study, several other studies have also provided evidence on the issue of availability and affordability of essential cardiovascular medicine in low- and middle-income countries [6,24,25,26,27,28]. A recent state-wide survey in India on the availability, price, and affordability of 23 essential medicines for diabetes and CVD revealed that the availability of these essential medicines failed to reach WHO’s 80% target in both the public and private sectors, and, although availability in the private retail pharmacies was near-optimal, medicine prices were unaffordable compared to the public sector [29]. In a study published in 2020 based on data from 84 surveys of 59 countries from the WHO’s Health Action International Project to provide a cross-country assessment of availability and affordability of cardiovascular medicine and antihypertensive medicine [8], there was an insufficient availability of cardiovascular and hypertension medicines in low-resource countries with a high prevalence of hypertension. The average availability of the select medications was 54% in low- and lower-middle-income countries and 60% in high- and upper-middle-income countries. Patients in low- and lower-middle-income countries experienced higher prices and a lower affordability compared with higher income countries for both branded and generic medicines [8].

7. Discussion

Access to cardiovascular medicines is crucial for the long-term care of people with cardio–metabolic disease. The analyses arising from the multi-country PURE study have demonstrated that the WHO’s target of 80% is far from being met in many countries; they also demonstrate the importance of the target as a global key performance indicator in health. Most people with chronic health conditions need multiple medications, so affordability with respect to only one medicine is not sufficient. Several of the studies described here demonstrate how the problem of access is compounded if multiple medicines are examined, as was indicated for people with coronary heart disease, diabetes, and hypertension. These suggest that simple availability and affordability measures for separate medicines underestimate the concept of access to medicines for chronic conditions. Moreover, under-estimates are likely, as costs do not include additional costs such as travel or money lost due to time spent obtaining treatments, missing work, or waiting in long queues competing for limited supplies.

The findings here also demonstrate why the drivers of availability and affordability are not just individual-wealth related. The very low rates of insulin availability in some countries and regions likely speaks to the lack of infrastructure for the safe management of medicines. It may be that, in some regions, the lack of continuous power and the lack of trained staff are key factors that need addressing to improve the availability and affordability of essential medicines. Such factors may also be common to the availability of fresh food and indeed other items that provide people with the opportunity to improve their health. Many of the rural regions examined in the PURE study are or are close to farming and fresh food producers, and the lack of fresh fruit and vegetable consumption may seem an irony. It is likely that this lack of fruit and vegetable consumption is not only a product of wealth, but also the result of a lack of infrastructure to conduct local distribution efficiently. In addition, competing market and socio-cultural forces that may reduce availability or drive up the costs of medicines are strongly present in some countries. The presence and reliance on alternative medicines can be supported by both strong social-cultural beliefs as well as an existent health workforce dominated by alternative treatment providers, as is the case in India.

Improving access to medicines for cardio–metabolic diseases should be a key part of the strategy to lower the burden of CVD globally. There is an urgent need for more efforts and innovative approaches to improve access to medicines for cardio–metabolic diseases. Findings from the multi-country PURE study, while suggesting similarities regarding the issue of poor access across lower and lower middle-income countries, also suggest that ways to address this at the local level are likely to be different. Some initiatives could be commonly applicable, such as simpler medical regimens, for example, treatment with a combination therapy should be considered to address barriers to access to cardiovascular medicines [30], in addition to increasing generic prescribing, improving price transparency, and addressing common reasons for medicines shortages (such as market-related factors, supply chain management, manufacturing processes, and reduced public health funding) [31]. However, the pathways to actually addressing some of these issues require local knowledge. For clinicians working in these countries, some initial solutions could be in sharing the workload with non-physician health workers, encouraging self-management, and involving and building capacity in family members. An example of an innovative approach is the Heart Outcomes Prevention and Evaluation 4 (HOPE-4) study conducted in 30 communities in Columbia and Malaysia. The HOPE 4 was an open, community-based, cluster-randomized, controlled trial conducted on 1,371 participants with new or poorly controlled hypertension, with 16 communities randomly assigned to the control group (usual care, 727 participants) and 14 communities (644 participants) to the intervention group. The intervention included the treatment of cardiovascular disease risk factors by non-physician health workers using tablet-computer-based simplified management algorithms and counselling programs, free antihypertensive and statin medications recommended by non-physician health workers but supervised by physicians, and support from a family member or friend to improve adherence to medications and healthy behaviors. The HOPE-4 study showed that the provision of free drugs (antihypertensives and statins), along with the use of non-physician health workers, resulted in a large improvement of blood pressure control and reduction of CVD risk by 50% [32].

The limitations of the PURE study have been discussed in previous publications [9,10,14,15,16,21]. The relationship between contextual variables, such as access to medicines and access to health care, and health outcomes is complex. PURE has captured some data with respect to the availability and affordability of medications and some data on available health services and types, but the data collection was limited by resources. As such, a detailed examination of the health system, e.g., a systematic examination of all healthcare providers and hospitals and all sites that dispense medications was not able to be completed. During the study, several countries transitioned to other income categories, for example, India: LIC—LMIC (2009), China: LMIC—UMIC (2013), Colombia: LMIC—UMIC (2008), and Iran: LMIC—UMIC (2010). Along with these transitions, their health systems may have changed as well. There are several more recent global surveillance studies, but they will all not be as comprehensive as PURE with respect to contextual determinants, individual determinants, and cardiovascular outcomes.

8. Conclusions

The multi-country PURE study has contributed greatly to the knowledge and realities of access to essential cardiovascular medicines and their importance as a factor in limiting the improvement of cardiovascular outcomes in many regions. More work is indeed needed to understand how these can be addressed and also in innovating in partnership with local community stakeholders on how to address these. The work also underwrites the importance of monitoring access to treatments and health-supporting commodities and the need to do this for rural and urban communities and not just at a country level.