In patients with established cardiovascular disease, current guidelines recommend the use of aspirin, a statin, and BP-lowering agents with little constraints. This reflects the enormous body of evidence that such treatments reduce the risk of cardiovascular events and mortality, regardless of the initial levels of risk factors and independent of other treatments [6–9]. Among people without established cardiovascular disease, there has been a transition in recent decades from treatment recommendations for statin and BP treatment being based on single risk factors, e.g., BP thresholds, to treatment based on predicted absolute risk of cardiovascular disease [10]. Also in high-risk patients, such as those with dyslipidemia and high BP, statin and BP-lowering agents are recommended to be used unless clear contraindications exist. The reduction of risk factors is proportional to the clinical benefits [7, 8]. The use of aspirin in primary prevention is still under debate, although recent evidence, demonstrating a potential reduction in cancer deaths with long-term use, might be expected to further change the risk/benefit equation [6, 11].

Given the evidence that reductions in any level of cholesterol and BP reduce cardiovascular risk, pharmacological treatment should be prescribed to the vast majority of high-risk patients. However, a substantial gap exists between recommended treatment and clinical practice. Several reports indicate inadequate prescription rates of antiplatelet lipid- and BP-lowering agents and nonachievement of treatment goals. The EUROASPIRE III survey has shown that in patients with established coronary artery disease (CAD) cholesterol was on target in 54 % and BP in 39 % of the patients. Antiplatelet agents were used in 91 %, statins in 78 %, beta-blockers in 80 %, and angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) in 71 % of the patients [12]. A survey performed in LMICs showed that patients with CAD and ischemic cerebrovascular disease received aspirin in 80 and 71 %, statins in 30 and 14 %, beta-blockers in 48 and 23 %, and ACEis in 40 and 38 % of the cases respectively [13]. These data indicate that even larger prescription gaps exist in LMICs compared to suboptimal prescription rates in high-income countries. It should also be emphasized that prescription rates exceed consumption or individual dosing rates. Various barriers may underlie suboptimal prescribing rates and low treatment continuation rates in high-risk patients, which include the complexity of preventive treatment regimens for both doctors and patients, inequities in health care delivery, and medication costs.

Furthermore, nonadherence to therapy is one of the main obstacles for the unsatisfactory reduction of risk factors. Nonadherence is characterized by premature cessation of treatment together with suboptimal use of medication and is correlated with an increased risk of mortality [14]. Patients usually do not understand the importance of taking long-term preventive medication. Long-term adherence is low, with only 70 % adherence to aspirin therapy and 45 % to lipid- and BP-lowering therapy after 12 months [15]. The problem gets worse as the number of prescribed drugs per day increases. Increasing age, established cardiovascular disease, and/or type 2 diabetes mellitus usually indicate the use of more than five drugs per day, called polypharmacy [16]. Treating high-risk patients often requires prescription of multiple medications even though this is known to be associated with diminishing adherence, inadequate prescription, and drug interactions.

High drug costs largely affect treatment gaps in LMICs where most healthcare services are paid for out of pocket with little or no subsidy through health insurances or the government. In this setting, the economic burden of secondary prevention of cardiovascular diseases is enormous [17]. Consequently, preventive drugs are unaffordable for the majority of individuals in developing countries. Although the efficacy concerns of preventive strategies may be recognized at a high scientific level, access and supply for the target population remains the major challenge.

Combining multiple well-established cardiovascular drugs into a single polypill may be likely to result in a significant reduction of cardiovascular events when implemented in a low-risk population. However, the use of the polypill in high-risk populations could be seen as the “low-hanging fruit” for research and implementation of FDC pills for several reasons. Patients with established cardiovascular disease are at the highest absolute risk. In these patients, there is no doubt that the multiple components are indicated and the margin of benefit is high. By avoiding complex decision algorithms and enhancing the simplicity of prescribing medication, the polypill may well help in closing current substantial treatment gaps in this group. The polypill could be considered as baseline therapy providing the minimum standard therapy for high-risk individuals. The principal goal of the polypill strategy is reducing the risk of cardiovascular events and mortality and not normalizing risk factors. It should be noted that this strategy does not rule out tailored care as every individual can be treated with additional cholesterol- and/or BP-lowering agents if the treatment goals are not achieved.

Improvement of adherence in patients at high cardiovascular risk is an important principle of the polypill. The World Health Organization (WHO) suggested that increasing the effectiveness of adherence to therapy may have greater impact on the health of the population than any new interventions [18].

One further issue is cost-effectiveness. The use of aspirin, a statin, a beta-blocker, and an ACEi in the secondary prevention of cardiovascular disease is well accepted and part of standard care in most LMICs. Current standards qualify these treatments as highly cost effective [19]. A major advantage of the polypill, with tremendous consequences on health care in developing countries, relates to the low costs and improved affordability. By dispensing a single generic pill instead of the individual drugs, packaging, dispensing, and pharmacy expenditure can be reduced enormously. The intended pricing, motivated by public health considerations, would increase equitable access in LMICs and has the potential to bring an effective preventive strategy within the financial reach of poorer individuals and governments in LMICs.

Even though the polypill strategy is conceptually simple, there are certain drawbacks to a combination pill meaning that a polypill strategy will not be applicable in every individual. Due to fixed combinations in the polypill, there is no flexibility in being able to change the class of BP-lowering drugs due to unacceptable side effects or contraindications. This may be addressed in the future by the marketing of several polypills with various components, thereby giving the clinician greater choice of drug class while retaining the convenience of the polypill.

In addition, because of the combination of agents at a fixed dose in a polypill, it may not be suitable for all the patients, as, for example, it may cause adverse events like orthostatic hypotension or dizziness in those requiring lower doses of BP-lowering agents. Alternatively, if the doses of some agents in a polypill are insufficient for some patients and treatment goals are not reached, then additional doses of those agents may be prescribed in addition to the polypill.

Although the effectiveness and efficacy of the individual agents of polypills have been demonstrated widely, the effectiveness of this strategy of providing treatment needs to be assessed. Currently, several academic collaborations have been launched for performing randomized clinical trials, assessing the efficacy of the polypill in various patient populations, from pharmacodynamic and pharmacokinetic studies to clinical end-point trials.

One of the first clinical studies compared the effect of an FDC formulation to the components of the polypill on risk factor levels and safety parameters [20, 21]. In “The Indian Polycap Study” (TIPS), 2053 individuals aged 45–80 years with one cardiovascular risk factor were randomized to a 12 week treatment with the polycap (aspirin 100 mg, simvastatin 20 mg, atenolol 50 mg, hydrochlorothiazide 12.5 mg, and ramipril 5 mg) or to one of the eight other treatment groups (aspirin, simvastatin, hydrochlorothiazide, three combinations of the two BP-lowering drugs, three BP-lowering drugs, or three BP-lowering drugs plus aspirin). After 12 weeks of treatment, a mean LDL-cholesterol reduction of 0.70 mmol/L and 7.4 mmHg systolic BP reduction was observed when using the polycap compared to placebo. The trial demonstrated that the risk factor reductions and number of adverse events from each treatment modality were similar in the presence and absence of other treatments. Only simvastatin in the polypill reduced the LDL-cholesterol slightly less compared to the single drug (0.70 mmol/L versus 0.83 mmol/L; p = 0.04), although this could be the play of chance [22].

The bioavailability of the ingredients of the polycap was compared with that of identical capsules with each of the ingredients separately in a five-arm clinical trial in 195 healthy individuals. Plasma concentrations of each drug and, where applicable, its active metabolite were measured. The plasma concentration of simvastatin was significantly lower (3–4 %) than the allowed 80 % bound. However, the concentration of the active metabolite, simvastatin acid, was significantly higher, which appeared to compensate for the loss of bioavailability of simvastatin. Comparative bioavailability was computed for all other components, and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient [23].

The effect of the polypill in the morning or the evening (aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and hydrochlorothiazide 12.5 mg) on LDL-cholesterol and 24-h systolic ambulatory BP was compared to the administration of individual, identical dosed components of the polypill. “The Evening versus Morning Polypill Utilization Study” (TEMPUS) was a randomized cross-over trial in which 78 participants were included. When the polypill was administered in the evening, the reduction of LDL-cholesterol (mean difference:−0.1 mmol/L; 95 %-CI: −0.1 to 0.0) and mean 24-h systolic BP (mean difference: 1.0 mmHg; 95 %-CI:−0.8 to 2.8) was not different than when using the individual agents. However, compared to the individual agents, the mean LDL-cholesterol was 0.2 mmol/L (95 %-CI: 0.1 to 0.3) higher when using the polypill in the morning, while the mean 24-h systolic BP was similar (mean difference: 0.4 mmHg; 95 %-CI: −1.5 to 2.3). Importantly, therapy with a polypill was highly preferred over treatment with the individual, identical dosed agents of the polypill supporting the role for the polypill in the prevention of cardiovascular disease [24].

An FDC formulation corresponds closely to combinations that are already in widespread use. Remarkably, the generic drugs used as components of the polypill have been marketed for many years in the prevention of cardiovascular disease. It may very well be that many patients use the identical components as polypill administered at the same time, although not in one pill or capsule. However, substantially different from when using the polypill, each of the individual components was prescribed at the discretion of the treating physician for a specific indication and taking into account contraindications. The concept of the polypill includes promoting widespread use of cardiovascular risk-lowering treatments regardless of risk factor levels leaving limited potential for flexibility.

In a double-blind, randomized, placebo-controlled trial in Iran, 475 low-risk participants, aged 50–79 years, were randomized to a polypill (aspirin 81 mg, atorvastatin 20 mg, enalapril 2.5 mg, and hydrochlorothiazide 12.5 mg) or placebo for a period of 12 months. The trial showed that the polypill achieved modest reductions of LDL-cholesterol (mean difference: 0.46 mmol/L) and BP levels (mean difference systolic: 4.5 and diastolic: 1.6 mmHg) [25].

In the randomized, double-blind, placebo-controlled “Programme to Improve Life and Longevity” (PILLpilot) trial, 378 individuals at intermediate risk of cardiovascular disease were randomized to using a polypill (aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg, and hydrochlorothiazide 12.5 mg) or placebo during 12 weeks. Using the polypill resulted in a 0.9 mmol/L (95 %- CI: 0.8–1.0) lower mean LDL-cholesterol and 10 mmHg (95 %-CI: 8–12) lower mean systolic BP compared to using placebo [26]. The effect of the polypill on risk factor levels was modified by the baseline levels of these risk factors. Yet, the achieved cardiovascular relative risk reduction was only modestly modified by the baseline levels of these risk factors. Although mild adverse events such as cough and hypotension were reported more often in the polypill group, these were not related to baseline risk factor levels, suggesting that patients with mildly increased risk factor levels, but an overall raised cardiovascular risk, would also benefit from being treated with a polypill (unpublished data).