Editorial comments: Focus on pharmacological management 

This special issue is dedicated to several topics related to the pharmacological management of cardiovascular (CV) risk factors in both primary and secondary prevention. In particular, the role in controlling high blood pressure and lipid has been investigated in different settings.

Medications and cardiovascular disease and death in obese adults

An elevated body mass index (BMI) is a significant cause of illness and mortality, and its worldwide significance is projected to expand as obesity rates rise in low- and middle-income nations. A high BMI is associated with higher blood pressure, dysglycaemia, and dyslipidaemia, which are major risk factors for atherosclerotic CV disease (ASCVD).¹ In clinical studies of highly selected adults, blood pressure-lowering, lipid-lowering, anti-thrombotic, and several oral hypoglycaemic medications have been shown to reduce CV morbidity and mortality. However, it is unknown if these benefits translate into reduced CVD and death among persons with an increased BMI.

Here, Leong et al.² investigated whether the use of pharmaceuticals to treat high blood pressure, diabetes, and dyslipidaemia, as well as anti-thrombotic agents, is related to better clinical outcomes in people with a high BMI. The Prospective Urban and Rural Epidemiology study included 145 986 participants (mean age 50 years, 58% women) from 21 high-, middle-, and low-income countries who had no history of cancer, ischaemic heart disease, heart failure (HF), or stroke. A positive association between an elevated BMI and the risk of CVD and death was found among those not taking a CV medication. Instead in those taking a CV medication, this association is attenuated, such that compared with individuals with a BMI of 20–25 kg/m², the risk of CVD and death was only elevated for those with a BMI >35 kg/m², mostly driven by the use of blood pressure-lowering medications.

Histamine H2 receptor antagonist and all-cause mortality in critically ill heart failure patients

By inhibiting histamine H2 receptors, histamine H2 receptor antagonists (H2RAs) are widely utilized in the treatment and prevention of peptic ulcer disease. This histamine receptor subtype, on the other hand, is ubiquitous in the CV system and mediates histamine-induced positive chronotropic and inotropic effects in cardiomyocytes as well as vasodilatory effects in vascular endothelial cells. On the basis of this action, it has been hypothesized that H2RAs may have therapeutic effects similar to β-blockers, reducing the heart rate and lowering blood pressure in individuals with HF.

In this issue of the journal, using the open-source Medical Information Mart for Intensive Care III database, the connections between H2RA exposure and all-cause mortality in critically ill HF patients were investigated.³ The data of 10 387 patients, including 4440 H2RAs users and 5947 non-users, who were hospitalized to the critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012 were retrospectively examined. One thousand five hundred and forty-eight of these individuals had an acute decompensated HF diagnosis. Both univariate and multivariate analyses showed that H2RA exposure was significantly associated with lower 30-, 90-day, and 1-year mortality rates, implying that prophylactic H2RA administration in the critical care unit may improve HF prognosis. However, information on the underlying HF aetiology, NYHA class, and baseline medication was missing.

Effect of mineralocorticoid receptor antagonist at baseline on the efficacy of sodium–glucose cotransporter-2 inhibitors in heart failure

Mineralocorticoid receptor antagonists (MRAs) as well as sodium–glucose cotransporter-2 inhibitors (SGLT2i) are considered part of the cornerstone of treatment in patients with HF with reduced ejection fraction. Here, a meta-analysis of four randomized controlled trials (RCTs) demonstrates that SGLT2i reduced the composite of HF hospitalization (HHF)/CV death and HHF in both MRA users and non-users similarly, but differing benefits were only observed in MRA users for CV death (and all-cause mortality).⁴ The lack of significant subgroup differences between MRA users and non-users suggests that the MRA usage does not modify the treatment effect of SGLT2is on clinical outcomes in patients with HF. A marked 15% reduction noted in the risk of CV death in MRA users relative to non-users, however, may have important clinical implications. Although subgroup interactions failed to attain significance, this potential mortality benefit with concomitant usage of SGLT2is and MRAs should not be ignored and warrants further investigation. Supporting the administration of MRAs and SGLT2i together and taking advantage of different cardioprotective mechanisms of each drug may help to achieve cumulative benefit.

Burden and predictors of statin use in primary and secondary prevention in the USA

Despite evidence for statin use in primary and secondary prevention of CVD, data published to date show suboptimal statin use among eligible individuals. Based on representative data from the 2017 to 2020 National Health and Nutrition Examination Survey, statin use was assessed in primary prevention groups [high CVD risk ≥ 20%, LDL-cholesterol (LDL-C) ≥ 190 mg/dL, diabetes aged 40–75 years, intermediate CVD risk (7.5 to <20%) with ≥1 CVD risk enhancer] and secondary prevention group (established ASCVD). Among 70 million eligible individuals (2.3 million with LDL-C ≥ 190 mg/dL; 9.4 million with CVD ≥ 20%; 15 million with diabetes and age 40–75years; 20 million with intermediate ASCVD risk and ≥1 risk enhancers; and 24.6 million with established CVD), only 30 million were on statin therapy. The proportion of individuals not on statin therapy was highest in the isolated LDL-C ≥ 190 mg/dL group (92.8%) and those with intermediate CVD risk plus enhancers (74.6%) followed by 59.4% with high CVD risk, 54.8% with diabetes, and 41.5% of those with established CVD groups. Increasing age and those with health insurance were more likely to be on statin therapy in both the primary and secondary prevention categories. Individuals without a routine place of care were less likely to be on statin therapy.⁵ This study confirms the importance of social determinants of health such as access to care and healthcare coverage in CVD prevention.^6,7

Achievement of European treatment goals after an acute coronary syndrome with statin and alirocumab

European guidelines set LDL-C treatment goals <1.4 mmol/L after acute coronary syndrome (ACS), and <1.0 mmol/L for patients with recurrent CV events ≤2 years.⁸ Many ACS patients do not achieve these goals on statin alone.⁹ Using the ODYSSEY OUTCOMES trial data,¹⁰ it was examined actual goal achievement with alirocumab and projected achievement with ezetimibe, either added to optimized statin therapy. Among patients with recent ACS on optimized statin therapy, the LDL-C ≥ 1.4 mmol/L was achieved by few patients (17.3%). In contrast, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal <1.4 mmol/L, and 85.2% of those with recurrent CV events to achieve <1.0 mmol/L. In contrast, the addition of ezetimibe to optimized statin therapy was projected to achieve LDL-C < 1.4 mmol/L in only 10.6% of patients at baseline, and in 0% of those with recurrent CV events to achieve <1.0 mmol/L.

Timing of statin dose: morning vs. evening dose

The best timing of statin administration is still a controversial issue. The objective of this study¹¹ was to compare the efficacy and safety of statin morning vs. evening dose by a meta-analysis of 13 RCTs, which enrolled a total of 1129 patients (621 were randomized to evening dosing and 631 to morning dosing group). A significant reduction in LDL-C and TC was found in patients randomized to evening compared with morning dosing despite identical statin dose strength. However, there was no significant difference in triglycerides and HDL-C. The results were consistent regardless of statin half-life or statin type used, although there was a greater magnitude of benefit with short half-life statins. Adverse events were similar between evening and morning dosing. Possible explanations of these findings include the possibility of a better compliance with evening dose; the higher expression and hence biosynthesis at night of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol biosynthesis); the fact that evening dose statins reach plasma level peak simultaneously with HMG-CoA reductase peak expression, potentially explaining greater statin efficacy in LDL-C reduction when administered in the evening compared with morning dose. Limitations of this meta-analysis are the inclusion of only small RCTs in specific geographical areas which limits generalizability; the short duration of follow-up of included trials; lack of information on statin adherence and on whether night-time dosing was based on post-prandial status; and the fact that not all commercially available statins were represented in this meta-analysis. Nevertheless, the finding in this study that evening dosing of statins significantly reduces LDL-C when compared with morning dosing, regardless of statin half-life, suggests that their evening administration should be considered in the management of patients with hypercholesterolaemia.

Acetaminophen (Paracetamol) and blood pressure

Acetaminophen is one of the most widely used over-the-counter medications, used for its analgesic and antipyretic properties. It has been widely utilized in part because of its favourable safety profile. It is often weighed against non-steroidal anti-inflammatory drugs, and although it lacks the anti-inflammatory effects, it has been thought to be a safer medication for long-term use. Here, the first meta-analysis¹² of the RCT looking into the effects of acetaminophen on blood pressure suggests a direct association between acetaminophen use and elevated systolic blood pressure. Subgroup analysis demonstrated that this increase in blood pressure was also significant in patients with pre-existing hypertension. Interestingly, there was no significant difference in the effect on diastolic blood pressure. This adds to concern regarding the safety of regular acetaminophen use, particularly in patients with pre-existing hypertension or CV risk factors.

Lipid cut-offs in non-diabetic young people

Guidelines on CVD prevention recommend assessing traditional atherosclerotic CV risk factors or estimating 10-year CVD risk in apparently healthy young adults, and many researchers now focus on trials of younger individuals with less advanced disease that is more amenable to reversal. However, we currently do not have suitable lipid cut-offs to estimate the CVD risk of people below 40 years of age. By analysing the data of a large non-diabetic young population, it was found that the risk of CVD was significantly increased in people with a total cholesterol (TC) level of ≥200 mg/dL, triglyceride level of ≥60 mg/dL, LDL-C level of ≥130 mg/dL, and non-HDL-C level of ≥140 mg/dL. It also showed that the optimal lipid levels differed by CV risk status in this population: the cut-off levels that were statistically significant for increased risk of CVD were 240, 220, and 200 mg/dL for TC and 150, 130, and 120 mg/dL for LDL-C in subjects with 0, 1, or 2–3 CVD risk factors, respectively.¹³

Cardioprotective effects of influenza vaccination in patients with cardiovascular disease or at high risk

It is still a matter of debate whether influenza vaccination might have a clinical impact on CV outcomes in people with established CVD. Nasir and colleagues¹⁴ in their meta-analysis have investigated this issue with a meta-analysis of 18 articles derived from a total of 22 532 165 patients, among whom 217 072 (mean age 68 years) were included in the high CV risk or established CVD population (vaccinated n = 111 073 and unvaccinated n = 105 999). At a mean follow-up of 1.5 years, the vaccinated group was associated with a lower risk of all-cause mortality, major adverse clinical events (MACEs), CV mortality, and myocardial infarction (MI) (hazard ratio of 0.71, 0.83, 0.78, and 0.82, respectively, P < 0.001) when compared with the unvaccinated group, with no differences in the incidence of stroke and HF. This study provides evidence that influenza vaccination has a protective effect in established CVD or high CV risk patients, reducing MACEs, all-cause mortality, CV mortality, and MI.

Vegetarianism, microbiota, and cardiovascular health

Unhealthy diet is an often-overlooked important modifiable risk factor, accounting for nearly 26% of all deaths, of which 84% were attributed to CVD. Plant-based diets (PBDs), which include different types of vegetarian dietary patterns based on products derived from plants, have been suggested to decrease the incidence of various cardiometabolic diseases. This review article¹⁵ has examined the different PBDs in-depth, comparing them with standard non-vegetarian diets, and exploring possible plausible mechanisms underlying the benefits of PBDs. In particular, in this paper, the dietary manipulation of gut microbiota–host interaction and its effect on energy metabolism, and local and systemic inflammation, are addressed. Also, the evidence on the impact of PBDs on CVD is critically examined, highlighting the challenges and limitations associated with studies on dietary intervention and proposing strategies for drawing valid conclusions out of them. The conclusions of this paper are that PBDs are to be considered among the most powerful, affordable, and cost-effective tools for health and environmental protection at the population level.

References

Author notes