Introduction

The progress in pharmacotherapy that has been made in recent years — the introduction of very effective and safe lipid-lowering and antihypertensive drugs — has not yet translated into the expected universal control of blood pressure and lipid disorders [1]. We have much to do in terms of non-pharmacological and pharmacological methods to control these risk factors, detect them early and implement effective therapy [2–4]. We still do not deal well with such basic risk factors as obesity and smoking [5]. On the other hand, an increasing number of patients worldwide suffer nowadays from diabetes, and a growing number are being diagnosed with chronic kidney disease [6]. All these factors lead to increased prevalence of atherosclerotic cardiovascular diseases (ASCVD) such as coronary artery disease (CAD), peripheral artery disease, cerebrovascular disease, heart failure and chronic kidney disease [7].

Experts from five countries as varied as Italy, Poland, Spain, Uzbekistan and Vietnam, located on one Eurasian continent, decided to recall in several points the selected paradigms of cardiological and cardiometabolic care from the perspective of the year 2023 and highlight those aspects that might be, in our opinion, successfully implemented in clinical practice. A comparison of the epidemiological, population wealth, social-economic and medical care characteristics in our countries are presented in Table 1 [8, 9].

According to the classification made by the European Society of Cardiology, four of the countries represented by experts fell into completely separate categories of the population for cardiovascular risk (Fig. 1) [10]:

Figure 1. Classification of cardiovascular risk in individual countries according to the 2021 European Society of Cardiology Guidelines on cardiovascular disease prevention in clinical practice.

This classification does not include Vietnam, but based on the recently published data, it might be considered as a country of at least highest cardiovascular risk, like Poland [11].

The gathered experts from five countries with fundamentally different populations for cardiovascular risk: Italy, Poland, Spain, Uzbekistan and Vietnam believe that common guidelines for optimizing pharmacotherapy can be formulated for all these countries based on the strategy: STRUGGLE FOR.

STRUGGLE FOR

Struggle for better control of the cardiovascular risk factors remains the cornerstone of medical activity. Daily therapeutic efforts should be aimed at combating cardiovascular risk factors, implementing healthy lifestyle, appropriate diet — optimally in the DASH (Dietary Approaches to Stop Hypertension) model or the Mediterranean diet, maintaining optimal body weight, increasing physical activity and combating smoking [12].

TIMES TO ACT — the first Expert Position Paper of the present group, published in the year 2022, mainly focused on combating hypertension and hypercholesterolemia, which are still important epidemiological problems, since the percentage of patients with hypertension ranges from 25% to 40% and patients with hypercholesterolemia ranges from 15% to 53% in all these five countries [13–16]. We should not forget, however, that in total, in these five countries, it is estimated that over 34 million patients are obese, over 53 million smoke cigarettes, over 21 million suffer from diabetes, more than 28 million have chronic kidney disease, and at least 5 million suffer from heart failure with reduced left ventricular ejection fraction (HFrEF). Millions of these patients suffer from ASCVD and should be chronically treated with three basic drugs: acetylsalicylic acid (ASA), statins, angiotensin-converting enzyme (ACE) inhibitors in many cases; often also beta-blockers, cardioprotective and metabolic drugs [17]. Cardiovascular risk factors closely coexist, but arterial hypertension and hypercholesterolemia are undoubtedly among the most feasible to control with the use of adequately selected, modern drugs, well-tolerated by patients [18, 19]. The most important reasons for poor control of these two factors on a population scale remain unchanged and can be mainly considered as:

Roughly speaking, 80–90% of cardiovascular risk reduction could be obtained by controlling only four major cardiovascular modifiable factors [25, 26]:

Since our first document TIMES TO ACT was mainly dedicated to arterial hypertension and hypercholesterolemia, in the document STRUGGLE FOR we will focus more on diabetes and smoking, among other risk factors [27, 28].

Urgent actions in many of our countries are required to implement easier, more convenient forms of drugs essential for the optimal control of the above risk factors and diseases, mainly: arterial hypertension, hypercholesterolemia, diabetes. Many different forms of single pill combinations (SPCs) were introduced to the pharmaceutical market, and it is our duty to promote this form of therapy in the guidelines of national scientific societies and in the reimbursement regulations of individual countries [29, 30]. For example, in an Italian Awareness-raising Campaign on Hypertension, among 13,196 treated hypertensive elderly patients, only 25% were on a fixed combination therapy of two and only 1.3% of three drugs. What is crucial, patients on a fixed combination therapy were more adherent to treatment than their counterparts (p < 0.001) and full adherence increased with the decreasing number of pills used [14].

These SPCs may include:

Goals of treatment are more easily achievable when the means leading to their accomplishment are more straightforward, easier to apply and more accepted by patients. Common cardiovascular risk factors (especially hypertension, dyslipidemia, diabetes, smoking) accelerate atherosclerosis, thus leading to ASCVD. In many patients, the first manifestation of CAD is an acute coronary syndrome, the latter resulting sometimes in left ventricular damage and the pandemic of HFrEF. Heart failure is also a consequence of hypertension and diabetes, where it manifests mainly as heart failure with preserved left ventricular ejection fraction (HFpEF) and less commonly as HFrEF.

Patients from these three large epidemiological groups:

can also be offered, among the basic drugs used in these diseases, various forms of SPC, the use of which is still too rare. The chart below illustrates well how some patient groups can be treated according to the current guidelines with the use of only a few tablets, for example patients with heart failure — with only three tablets, CAD — only two tablets, and arterial hypertension — with only one two- or three-compound tablet (Central illustration).

Central illustration. Coexistence of diseases and available single pill combinations; A. Coexistence of three cardiovascular diseases: arterial hypertension, heart failure and coronary artery disease with indication for pharmacotherapy recommended by the current guidelines in these diseases, as well as a list of available drug combinations (rectangular frames) that can be used to reduce the number of tablets taken and improve compliance. To simplify the chart, the widely available single pill combinations of angiotensin-converting enzyme (ACE) inhibitors with diuretics and ACE inhibitors with calcium antagonists were omitted, which was extensively discussed in the first document of our group — TIMES TO ACT [13]; B. Coexistence of three diseases: diabetes, heart failure and coronary artery disease with indications for pharmacotherapy recommended by the current guidelines in these diseases, as well as a list of available drug combinations (rectangular frames) that can be used to reduce the number of tablets taken and improve compliance; ASA — acetylsalicylic acid; DDP-4 — dipeptidil peptidase-4; GLP-1 — glucagon-like peptide-1; SGLT-2 — sodium-glucose cotransporter-2.

Great progress has been made recently in the pharmacotherapy of diabetes. Oral antidiabetic drugs that prolong life, reduce the risk of cardiovascular death, decrease the risk of heart failure or kidney damage have emerged in front of our eyes [34]. Today, we attribute the above-mentioned features to flozins (SGLT-2 inhibitors) [35, 36]. The second extremely important group of drugs — glucagon-like peptide-1 (GLP-1) receptor agonists — seem to be even more beneficial than SGLT-2 inhibitors in two aspects: weight loss and stroke prevention [37]. Unfortunately, in some of our countries, the economic availability of SGLT-2 inhibitors and GLP-1 receptor agonists is low, as these drugs are not reimbursed at all or not in the first line of treatment, which means that antidiabetic therapy is still initiated with other oral drugs. While metformin is still the first-line drug in this situation, including its more favourable and more convenient forms of extended release for the patient (metformin XR), which have much improved gastrointestinal tolerance [38] and are recommended in the current NICE (UK) guidelines for type 2 diabetes as first-line treatment when conventional (immediate release) metformin is not well tolerated [39]. In addition, the wide use of sulfonylureas in many countries (including Poland and Uzbekistan) raises serious concerns. Therefore, it seems necessary to introduce more modern oral drugs, which are not associated with weight gain and risk of hypoglycemia, and have proven cardiovascular and renal safety such as DPP-4 inhibitors [40] instead of sulfonylureas, as well as SPCs combining DPP-4 inhibitors with modern forms of metformin (for example sitagliptin/metformin XR). The early use of metformin and DPP-4 inhibitors as first-line therapy is recommended in the present American Diabetes Association type 2 diabetes guidelines [41] when there are no compelling indications for SGLT-2 inhibitor or GLP-1 receptor agonists, and is associated with greater and more long-term benefits than the conventional first-line monotherapy with metformin [42].

In some countries, there is plenty of action to be taken to switch the therapy from drugs with no cardiovascular benefit and safety concerns (sulfonylureas) to newer classes of drugs with well-established safety profile in terms of hypoglycaemia and cardiovascular risk such as DPP-4 inhibitor/metformin XR combinations, SGLT-2 inhibitors and GLP-1 receptor agonists. The latter two also have well-established cardioprotective effects. The difference in the use of particular groups of drugs in some of our countries is striking, for example in Spain approximately 50% of oral antidiabetics prescribed are DPP-4 inhibitors and only 10% are sulfonylureas. In contrast, in Poland and Uzbekistan over 50% are sulfonylureas and only below 10% are DPP-4 inhibitors, according to pharmaceutical data reports from the beginning of 2023.

The availability of metformin XR varies per country as well. For example, in Italy and Poland it is present and reimbursed, in Uzbekistan it is present, but not reimbursed, while in Spain it was not available until last year.

Surprisingly, the current targets for blood pressure, LDL-cholesterol, HbA1c and the use of flozins/GLP-1 receptor agonists are met in only a small minority of our patients with type 2 diabetes. New drugs and SPCs might help our patients in many aspects. The introduction of an SPC consisting of metformin XR and sitagliptin to the Spanish market, where extended-release metformin was never available before, in spite of its greatly improved tolerability, has created the opportunity to rechallenge patients previously labelled as metformin-intolerant [43]. The recent observational trial has been highly successful, with 86% of patients tolerating half the target dose and 72% tolerating the full target dose; while the metabolic control of the patients was significantly improved, both for fasting glucose and HbA1c [43]. Many of those patients with diabetes also have CAD or heart failure. Here, too, substantial use of the newer SPCs can be made, as we have proposed in the Central illustration.

Last but not least, some CAD patients still need better control of ischemic syndromes irrespectively of cardiac invasive procedures, statins, beta-blockers, ACE-inhibitors, anti-platelets. In those patients, European Guidelines for the diagnosis and management of CAD offer optimization of treatment based on metabolic drugs [44], among which they mention four substances in the following order:

The current place of these drugs as an adjunctive to the classical therapy of CAD is shown in Table 2. While nicorandil is not available in many countries, the use of ranolazine, ivabradine, trimetazidine differs between our countries.

Ranolazine mechanism of action is summarized in Figure 2. Ranolazine is becoming more and more popular in some countries, as a unique inhibitor of the fast Na+ current (INaF) and the late Na+ current (INaL), which is responsible for depolarization of the myocardial cell. The effects of ranolazine are mainly related to the influence on the late INaL current. INaL current activation is induced by “acquired” pathological conditions such as ischemia and myocardial infarction, where its benefits are supported by large-scale clinical data. Moreover, some benefits in terms of left ventricular hypertrophy, HFpEF and HFrEF, as well as atrial fibrillation and genetically determined diseases: long QT syndrome (types 3, 9, 10) and Brugada syndrome have been suggested. However, these data are mostly experimental and currently do not support the clinical use of ranolazine in these conditions [45].

Figure 2. The mechanism of action of ranolazine. The effect of INaL activation is the accumulation of Na+ ions inside the cell, which leads to increased activity of the sodium-calcium exchanger (NCX) and Ca2+ overload. Intracellular excess of Ca2+ leads to contractile dysfunction of the heart muscle and its electrical instability. Ranolazine therefore counteracts this phenomenon. Reducing the concentration of Na+ ions decreases the intracellular concentration of Ca2+ ions, which improves the intracellular ion balance (adapted from [33], modified); ATP — adenosine triphosphate.

Ranolazine was first used as an antianginal drug. Information regarding its antiarrhythmic properties emerged from the MERLIN-TIMI 36 study. In a group of 6,560 patients with acute coronary syndrome without ST segment elevation in whom ranolazine was started and the ambulatory electrocardiogram was monitored to assess ischemic changes, a significant reduction in arrhythmias including atrial fibrillation and ventricular tachycardia was observed. Thus, ranolazine has a satisfactory safety profile and seems to have additional anti-arrhythmic activity.

Eventually, our attention goes back to nonpharmacological optimalization and control of traditional risk factors. Smoking is such a risk factor. Among the nicotine addiction treatment, short-term administration of nicotine is considered to be an adjunctive to behavioural therapy for patients planning to quit smoking. Various forms of nicotine replacement therapy are available in the world in the form of gums (may cause: dry mouth, dyspepsia, hiccups, heartburn, nausea), patches (may cause: local skin reactions in a very large percentage of people, the need to stick them on depilated skin or in anatomical areas with little hair, sleep disorders, heart rhythm disturbances, strong morning craving for nicotine when using the patches at night), oral inhalers, pulmonary inhalers, nasal sprays, nicotine tablets (may cause: local reactions in the administration routes). Due to the above-mentioned heart rhythm disorders, relative contraindications to such therapy include tachycardia, arrhythmias, CAD, acute coronary syndromes or other conditions corresponding to high cardiovascular risk. The use of the described forms of nicotine replacement therapy is assessed as burdensome, potentially harmful for patients with a cardiovascular history and not very effective. Therefore, it is difficult to qualify nicotine replacement therapy as a form of the real treatment of nicotine addiction.

Varenicline, bupropion or cytisine may be administered as an aid in the treatment of nicotine addiction. Varenicline, invented as anti-depressant, may be associated with the risk of suicidal thoughts, aggravation of depression, and sleep disorders. Bupropion, a dopamine and norepinephrine reuptake inhibitor, may be effective, but it lowers the seizure threshold and is contraindicated in patients with risk factors for seizures. The drug can also cause headaches, dry mouth, agitation, and insomnia. It has been used traditionally for anxiety-related depression in the United States since 1985 (withdrawn from use in 1986–1989 due to the aforementioned risk of seizures), but since 1997 it also has registration in helping to quit smoking. Caution is also required when using bupropion in patients with hypertension and/or tachycardia. Cases of smoking cessation in people using a combined preparation of bupropion and naltrexone are described, but this form is registered only in the treatment of obesity in some countries and in some cases of overweight associated with chronic diseases. Altogether, the clinical use of varenicline and bupropion in our countries is scarce.

Cytisine has been used for years in Eastern European countries in the treatment of nicotine addiction, available as an over-the-counter drug (Italy, Poland), and recently as a prescribed drug in other countries (Spain, Vietnam) [46]. Cytisine is a natural alkaloid that occurs naturally in several plant genera, such as Laburnum and Cytisus of the family Fabaceae and is generally obtained from the seeds of golden rain Acacia (Laburnum anagyroides). The drug has a growing scientific literature on its use [47]. Cytisine is a partial agonist of nicotinic receptors, and its mechanism of action is not fundamentally different from varenicline, which is, after all, its derivative. The above drug approaches can be used sequentially, but subsequent therapeutic failures do not predict success in terms of undertaking the next attempt of pharmacological treatment. Some experts are also inclined to postulate earlier inclusion of heat-not-burn products or electronic cigarettes in schemes facilitating quitting cigarettes in a shared-decision making process with a patient [48].

STRUGGLE FOR better control of the cardiovascular risk factors remains the cornerstone of our medical activity and “STRUGGLE for” is 2023-year title of our Position Paper. We believe that the need to intensify treatment, actively search for patients with cardiovascular risk factors, especially with arterial hypertension, hypercholesterolemia and diabetes, should go hand in hand with the implementation of the latest therapy, based on SPCs including proven, effective antihypertensive, lipid-lowering and antidiabetic molecules, many of which we have listed in our document and in the recent European Society of Hypertension Guidelines for the management of arterial hypertension and 2023 European Society of Cardiology Guidelines for the management of cardiovascular disease in patients with diabetes [49, 50]. We need to use new technological concepts (SPC preparations), completely new drugs and treatment concepts (metabolic treatment in CAD), try to intensify the fight against smoking in every way, including the available range of drugs and procedures in reducing harm. Given that over 55% of cases of incident cardiovascular may be attributable to five modifiable risk factors [51], this approach will give us substantially better control of the underlying cardiovascular risk factors in Italy, Poland, Spain, Uzbekistan and Vietnam. Since many of the risk factors might be attributed to impaired microcirculation function in different vascular beds, therapies to improve microcirculatory function might also prevent cardiovascular complications and subsequently improve prognosis [52].

Acknowledgments

The material was prepared by the International Council of Experts in cooperation with Adamed Pharma S.A.

Conflict of interest: Krzysztof J. Filipiak — Adamed, Alfasigma, AstraZeneca, Bausch Health, Boehringer Ingelheim, Krka, Mundipharma, Mylan, Novartis, Pro.Med.Pl, Servier; Vivencio Barrios — Adamed, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Ferrer International, Menarini, MSD, Novartis, Novo Nordisk, Organon, Pfizer, Recordati, Sanofi-Aventis, Servier, Viatris; Claudio Ferri — Adamed; Khurshid Fozilov — Adamed; Santiago Jesus Freire Castro — Adamed; Ravshanbek Kurbanov — Adamed; Agnieszka Kuzior — Novo Nordisk (scientific and teaching activities); Francisco Javier Martinez-Martin — Adamed, Amgen, Boehringer Ingelheim, Eli Lilly, Menarini, Novo Nordisk (honoraria for advisories, scientific and teaching activities); Guzal Mullabaeva — Novo Nordisk, Pfizer, Servier; Lan Hieu Nguyen — Adamed; Ulugbek Nizamov — Adamed; Anna Tomaszuk-Kazberuk — Adamed, Boehringer Ingelheim, Krka, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Takeda; Raisa Trigulova — Adamed; Aleksandra Gąsecka — Abiomed, Adamed, AstraZeneca, Krka, Philips.