Policosanol (sugarcane wax alcohols) 20 mg/day in Cuban Patients With Grade I Hypertension: A Randomized, Double‐Blind, Multicenter Study

Moura Revueltas Aguero; Amarilys Jimenez Chiquet; Yamile Valdes; Julio César Fernández Travieso; Yenney Reyes Nuñez; Yanay Fernández Dominguez; Evelyn González Pla; Sarahi Mendoza Castaño; Yohani Pérez Guerra; Manuel Delfin Pérez Caballero; Deisy Navarro; Yolanda Cruz Gomez; Meilis Mesa Angarica; Gladys Jiménez Rivero; Carlos Sánchez Texido; and the Family's Doctors of the Polyclinical Centres of Plaza Municipality

doi:10.1111/jch.70126

. 2025 Oct 1;27(10):e70126. doi: 10.1111/jch.70126

Policosanol (sugarcane wax alcohols) 20 mg/day in Cuban Patients With Grade I Hypertension: A Randomized, Double‐Blind, Multicenter Study

Moura Revueltas Aguero ¹, Amarilys Jimenez Chiquet ¹, Yamile Valdes ², Julio César Fernández Travieso ^3,^✉, Yenney Reyes Nuñez ³, Yanay Fernández Dominguez ³, Evelyn González Pla ³, Sarahi Mendoza Castaño ³, Yohani Pérez Guerra ³, Manuel Delfin Pérez Caballero ⁴, Deisy Navarro ⁵, Yolanda Cruz Gomez ⁶, Meilis Mesa Angarica ⁶, Gladys Jiménez Rivero ⁷, Carlos Sánchez Texido ⁷; and the Family's Doctors of the Polyclinical Centres of Plaza Municipality

PMCID: PMC12487964 PMID: 41032504

ABSTRACT

This study aimed to report the effects of policosanol (20 mg/day) on blood pressure values in Cuban patients with grade I hypertension. A double‐blind multicenter trial randomized 400 eligible patients divided into two strata of patients with either prehypertension or grade I hypertension (200 patients each) treated with either placebo or policosanol 20 mg/day (100 patients/group/stratum) for 12 weeks. Having published the results of pre‐hypertensive patients, here we report the grade I hypertension stratum (SBP 140–159 mmHg, DBP 90–99 mmHg) results. The primary outcome targeted whether policosanol could achieve significant systolic blood pressure (SBP) reductions ≥10 mmHg versus baseline and significantly different from placebo. Changes in diastolic blood pressure (DBP) and lipid profile variables were secondary outcomes. Safety indicators and adverse events were assessed. Statistical analyses were conducted by Intention to Treat. Both groups were similar at randomization. At study completion, policosanol significantly lowered (p < 0.001) SBP, the primary outcome, by more than 10 mmHg related to baseline and placebo, while also significantly decreasing (p < 0.001) DBP values versus baseline and placebo. Also, more (p < 0.001) policosanol patients reached SBP reductions ≥10 mmHg and DBP reductions ≥5 mmHg versus baseline (74% and 91%, respectively) than placebo patients (12% and 15%, respectively). Policosanol significantly lowered low‐density lipoprotein‐cholesterol (LDL‐C) and total cholesterol, while increasing high‐density lipoprotein‐cholesterol (HDL‐C). It is concluded that oral administration of policosanol 20 mg/day for twelve weeks significantly lowered SBP and DBP in Cuban patients with grade I hypertension, and improved lipid profile variables, being safe and well tolerated.

Trial registration: Cuban Public Registry of Clinical Trials identifier: RPCEC00000377; IRB approval number: IRB‐120721.

Keywords: diastolic blood pressure, grade I hypertension, lipid profile, policosanol, systolic blood pressure

1. Introduction

Cardiovascular diseases including coronary heart disease, cerebrovascular disease, and valvular heart disease are leading causes of death worldwide [1, 2].

Hypertension is the most significant controllable risk factor for cardiovascular diseases, accounting for about 57% of all cardiovascular‐related deaths [3, 4]. In addition, hypertension has been strongly associated with an increased risk of coronary heart disease, stroke, chronic kidney disease, and all‐cause mortality [4, 5]. There is enough evidence proving the impact of lowering blood pressure for improving cardiovascular outcomes and all‐cause mortality, being essential to spread the information related to the prevention, and treatment of high blood pressure levels to both primary care doctors and patients [6, 7, 8, 9].

Hence, the management of hypertension is crucial for reducing cardiovascular morbidity, cardiovascular mortality, and all‐cause mortality, incorporating non‐pharmacological and pharmacological approaches with lifestyle adjustments being a cornerstone part of treatment. But despite the integration of lifestyle and different classes of effective antihypertensive drugs, many hypertensive patients do not reach the recommended target according to their cardiovascular risk and need more than one medication for controlling their blood pressure. The current recommendation according to the Hypertension Task Force nowadays is to start the treatment with dual drug therapy, more important for those with high cardiovascular risk [6, 7, 8, 9].

According to Cuban [10] and international guidelines [6, 7, 8, 9], hypertension definition is based on SBP values ≥ 140 mmHg and/or DBP values ≥ 90 mmHg, supported by repeated office and/or home measurements, although they show some differences in the cut‐off values to define hypertension grades [6, 7, 8, 9, 10]. Cuban Hypertension guidelines [10] define grade (or stage) I hypertension as when SBP is consistently between 140 and 159 mmHg, and DBP between 90 and 99 mmHg. At such grade, doctors may choose to start managing hypertension with lifestyle changes only whilst considering early pharmacological intervention based on the patient's overall cardiovascular risk.

The control of grade I hypertension is of paramount importance considering the trend to progress to grade II hypertension, and the associated increased cardiovascular disease risk over a decade. A prospective real‐world condition cohort study including 96 268 participants, found that 30.83% of these started with grade I hypertension, having a 10‐year cardiovascular disease risk of 2.80%, and a lifetime risk of 16.61%. Grade I hypertension was associated with a significant increase in 10‐year and lifetime cardiovascular disease risk since compared with the normal blood pressure group, it exhibited a 35% higher 10‐year risk (hazard ratio [HR], 1.35 [95% CI: 1.19–1.52]) and a 36% higher lifetime risk (HR, 1.36 [95% CI: 1.25–1.49]). Progression to grade II hypertension was associated with a marked increase in lifetime risk [11].

Looking at these facts, assessing the potential benefits of treatments that could lower blood pressure values in patients with grade I hypertension is encouraged.

Policosanol is a mixture of high molecular weight primary alcohols isolated from the sugarcane (Saccharum officinarum, L) wax, with cholesterol lowering effects supported by studies conducted in Cuba and other countries [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31], although some published studies have failed to find any lipid‐modifying effect of policosanol [32, 33, 34]. An early [35] and further meta‐analyses [36, 37], however, have supported the effects of policosanol on blood lipid variables, the last one emphasizing on the conflicting data reasons, including the diversity of study populations and products used in such studies [37]. Indeed, in addition to the variability due to different population settings, product differences, involving not only the active pharmaceutical ingredient (drug substance) used to produce the tablets, but their specific formulation, which can enhance, reduce or abolish the effects of the active ingredient depending of the proper selection of the excipients during the pharmaceutical development step.

The cholesterol‐lowering mechanism of policosanol has been associated with the inhibition of cholesterol synthesis through a modulatory action on the hydroxy‐methyl‐glutaryl Coenzyme A (HMGCoA)‐reductase activity triggered by the activation of the AMP kinase [38, 39, 40, 41, 42], and the increase in LDL receptor processing [42].

Beyond its effects on the blood lipid profile, policosanol has been shown to exhibit pleiotropic effects such as the inhibition of LDL oxidation [43], and of platelet aggregation and reactivity [44, 45, 46, 47, 48], all of which could be beneficial in preventing atherothrombotic complications associated with increased cardiovascular risk.

In such regard, early trials conducted in Cuban patients at high cardiovascular risk, including a large frequency of hypertensive subjects, found, while investigating policosanol effects on physical safety indicators, that it lowered their blood pressure values [15, 17, 18, 49, 50, 51, 52]. Later, clinical trials conducted in Korean and Japanese subjects have shown that policosanol significantly lowered both SBP and DBP in pre‐hypertensive subjects [53, 54, 55, 56]. Based on all this previous data, a meta‐analysis concluded that policosanol could lower SBP and DBP in adults but that further studies in different populations are required to confirm such results [57].

Since policosanol has been shown to have an excellent safety profile [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 45, 47, 48, 49, 50, 51, 52, 58, 59, 60], it could be an additional strategy for the long‐term control of blood pressure values in patients with low grades of hypertension, like prehypertension and grade I hypertension.

Considering such background, we conducted a randomized, double‐blind, placebo‐controlled, dual strata study aimed to investigate the effects of policosanol (20 mg/day) in Cuban patients with prehypertension or grade 1 hypertension. The results from the pre‐hypertensive stratum, published recently, demonstrated that policosanol 20 mg/day given for 12 weeks significantly lowered both SBP and DBP as compared to baseline and placebo [61].

By contrast, this report shows the effects on the blood pressure control found for the patients included in the grade I hypertension stratum of such study, being divided into two equal groups (100 patients each) receiving either policosanol or placebo for 12 weeks.

2. Participants and Methods

2.1. Study Design

This study was a randomized, double‐blind, placebo‐controlled multicenter clinical trial. The patients were enrolled in six different Polyclinic centers of the Plaza suburb in Havana, where visiting Drs. from the participating hospitals (National Institute of Hygiene, Epidemiology and Microbiology, Calixto Garcia and Ameijeiras Hospitals, Institute of Endocrinology) made the consultations, including physical examination, drug compliance assessment, and adverse events interviews as well as blood pressure measurements over the trial. Laboratory tests, however, were done in the Medical and Surgical Research Centre (CIMEQ), samples being transported within the next hour of extraction from each consulting site to the laboratory.

The study was carried out under the ethical principles established in the latest version of the Declaration of Helsinki [62]. The study protocol was approved by the Institutional Review Board (IRB‐120721) after receiving the inputs of the National Hypertension Group of the Cuban Ministry of Health and being registered in the Cuban Public Registry of Clinical Trials (RPCEC00000377). All participants provided written informed consent at enrolment.

Enrolled patients were eligible for randomization if they met inclusion criteria and had no exclusion criteria, being instructed to follow healthy lifestyle actions for hypertension management (healthy dietary advice with reduced salt and calorie intake, rich in vegetables and to be physically active by systematic walking and exercise).

Eligible patients were randomized to receive either policosanol 20 mg or placebo tablets (visit 2) for 12 weeks. Patients were seen at baseline (visit 2) and after 4, 8, and 12 weeks on therapy (visits 3–5). Patients were examined every 4 weeks for blood pressure measurements, while laboratory tests were conducted at baseline and at the end of the treatment period. At each visit, physical signs, compliance with study drugs and adverse events were assessed.

Clinic blood pressure values were measured at each visit by using manual aneroid sphygmomanometer (Gima, Italy) measurements, with a maximum error tolerance for static pressure of ±5 mmHg. Subjects were seated comfortably in a quiet environment for 5 min before blood pressure measurements. Values were determined by the average of two (2) recordings of SBP and DBP, obtained at 3 min intervals, after subjects had been seated on a chair with their feet on the floor and arms supported at heart level. If a ≥5 mmHg difference was recorded, a third measurement was taken, and its value was averaged with the nearest one. Blood pressure values were then recorded by ambulatory blood pressure monitoring (ABPM) to confirm if patients belong to the grade 1 hypertension or pre‐hypertension status before being randomized.

The ethical premise in obviating any adverse outcomes by adding a placebo group in this trial was supported as follows. First, participants should be grade I hypertensive patients with 0–2 concomitant cardiovascular risk factors, none at the secondary prevention stage. Second, all patients were advised to follow the Dietary Approaches to Stop Hypertension (DASH) during the study, which was closely monitored. Third, treatment duration (12 weeks) agreed with the time proposed by the guidelines, which recommend lifestyle interventions, subject to physician's opinion [63].

2.2. Study Participants

We enrolled women and men between 20 and 60 years of age (including the threshold values), diagnosed with grade I hypertension (SBP:140–159 mmHg and DBP:90–99 mmHg) with 0–2 cardiovascular risk factors, such as smoking, dyslipidemia, overweight, sedentarism, and males older than 55 years.

Exclusion criteria included having other grades of hypertension [Grade II Hypertension (SBP:160–179, DBP:100–109 mmHg) or Grade III Hypertension (SBP ≥ 180, DBP ≥ 110 mmHg)], isolated systolic hypertension (SBP ≥ 140, DBP < 90 mmHg), diagnosed vascular diseases (cardiovascular, cerebrovascular, peripheral); serious mental illness, malignant neoplastic diseases, pregnancy or planning a pregnancy, nursing mothers; suspected or definite allergy to any ingredient of the study medications, and any condition which could pose a risk for study patients.

Study withdrawals were pre‐defined as due to adverse events perceived by the patient and/or by medical judgment; unwillingness to continue in the trial; major protocol violations such as failure in consuming study medications for more than seven consecutive days; and/or the intake of antihypertensive or cholesterol‐lowering drugs other than study drugs.

2.3. Treatment and Randomization

Treatments were randomized by strata and then by using the permuted block technique, being assigned by computer generated balanced block randomization, with a 1:1 ratio for each treatment group. Treatments were given to the patients according to their consecutive inclusion in the trial.

To guarantee blinding, none of the researchers involved in the study knew the randomization code, which was independently managed by the National Clinical Trials Coordinating Centre (CENCEC, Spanish acronym) (Havana, Cuba). Sealed participant specific code break envelopes were made, being kept at the Quality Unit in a secure, accessible location, in case of a serious adverse event (SAE) occurring during the trial.

As stated, eligible patients in this stratum were randomized to receive either policosanol 20 mg or placebo for 12 weeks. Both policosanol 20 mg and placebo tablets were manufactured by Laboratorios MedSol (Havana, Cuba). The placebo tablets had similar composition to policosanol tablets, except for the content of the active ingredient, which was replaced by lactose, the inert filler of the formulation. Policosanol and placebo tablets were identical in outer packaging, color, shape, and flavor.

If the investigators considered an adverse event to be of such severity as to require specific knowledge of the identity and dose of the relevant product, the investigator was allowed to break the study code for that participant only.

Compliance with study drugs was assessed by tablet counts and patients’ self‐reporting in daily charts. It was defined as good if each patient consumed ≥85% of the scheduled tablets. Overall, compliance was good if >90% of patients adhered to such criterion.

2.4. Concomitant Medications

Consumption of antihypertensive and/or lipid‐lowering drugs was forbidden, including any drug that could affect such values, such as corticosteroids, except for emergency situations, if these happened.

2.5. Study Outcomes

The primary outcome was to determine whether policosanol could significantly lower SBP as assessed in conditions of routine clinical practice in Cuba. The study predefined that, to be effective, policosanol should achieve significant reductions of SBP ≥ 10 mmHg versus baseline. This assumption was based on the results of a network meta‐analysis of 42 clinical trials involving 144 220 patients with various risk comorbidities, age ranges, and mean blood pressure levels at baseline. A linear association was found between SBP reductions and the risk of cardiovascular events and all‐cause mortality, so that by lowering SBP by 10 mmHg to reach a target of 120 to 124 mmHg, the risk of a cardiovascular event was reduced by 29% [64].

Reductions in DBP and changes in lipid profile variables, such as decreases in low‐density lipoprotein cholesterol (LDL‐C) and total cholesterol and increases in high‐density lipoprotein cholesterol (HDL‐C) values, were considered as secondary study outcomes, compared with both baseline and placebo. To be considered effective, final DBP values in the policosanol group should be significantly lower than those of baseline and placebo, and the difference versus placebo should be ≥5 mmHg. In turn, to consider that the treatment was effective for cholesterol‐lowering in this population, policosanol should decrease LDL‐C values significantly versus baseline and placebo, with a difference ≥15% as compared to placebo.

2.6. Laboratory Variables and Analysis

Blood samples were drawn after a 12 h fast and aliquots were taken for laboratory determinations.

2.6.1. Lipid Profile

Serum total cholesterol and triglycerides were determined by enzymatic methods using reagent kits from Roche (Switzerland). Serum HDL‐C levels were determined according to the cholesterol content present in the supernatant obtained after β‐lipoproteins precipitation. LDL‐C values were calculated using the Friedewald formula in mmol/L [65].

2.6.2. Other Laboratory Tests

These included determinations of fasting glucose, alanine amino transferase (ALAT), aspartate amino transferase (ASAT), creatinine, and uric acid. All these were performed by routine laboratory tests based in enzymatic methods using reagent kits from Roche (Switzerland).

All tests were performed in Roche Cobas C311 autoanalyzer (Germany) located at the laboratory of the Center for Medical and Surgical Research (Havana City, Cuba). Systematic quality control of lab methods and results was performed throughout the study.

2.7. Safety and Tolerability

Data from the physical examination, laboratory tests, and interview for adverse events were included for the analysis of treatment safety and tolerability.

Adverse events were predefined as any undesired subjective experience or laboratory adverse data occurring during the study and which did not exist before or that was exacerbated over the trial, disregarding if they were or not treatment related. “Serious” adverse events (SAEs) were fatal or disabling experiences, leading to hospitalization; “moderate” were those events requiring discontinuation of therapy according to the physician and/or specific treatment of the adverse events. Finally, “mild” were those adverse events not requiring withdrawal of study drugs nor specific treatment for the events [66]. According to their estimated relationship with study medications, adverse events were also classified as unlikely, doubtfully, possibly, or probably drug‐related following WHO‐UMC system [67].

2.8. Statistical Analysis

Data are presented as mean ± standard deviations, and 95% CI are shown for the pivotal efficacy variables.

Statistical analysis was planned in the study protocol; all data being analyzed by Intention‐to‐treat (ITT) so that data of all randomized patients was included in the analyses. Missing data were managed by single imputation using the carry‐forward method, including the last observation carried forward.

ANOVA was used to compare continuous variables throughout the study. Within group comparisons of such data were conducted by the McNemar test once normal distribution of the data was confirmed. Categorical data were compared by chi‐squared test, with Yates correction (Tables 2×2). The 95% confidence intervals (CI) for the study outcomes were estimated.

Data management and statistical analysis were carried out in the Data Management and Processing Department of the CENCEC. For the analysis of the information, SPSS21.0 was used and EPIDAT3.1 was used as a specific auxiliary method.

2.9. Sample Size Estimation

The whole trial followed a typical ANOVA design in which the patients included in the pre‐hypertension and grade 1 hypertension strata, were assigned either to policosanol or placebo treatments, so that four groups were included in the whole analysis, here reporting the data of patients with grade I hypertension only.

The reduction of SBP was the primary outcome chosen to determine the number of patients to be included, and the magnitude of the decrease considered as clinically relevant (10 mmHg), was based on the previously mentioned meta‐analysis which reported that such a reduction in SBP was associated with a 29% decrease of the cardiovascular risk.

The planned sample size was based on 80% power at a two‐sided α‐level of 0.05 to detect a significant and clinically meaningful reduction of SBP of 10 mmHg in policosanol arms compared to placebo at week 12. According to GPower, version 3.1.19.2 (2014), it was calculated that a total of 360 patients were necessary for the complete study with 180 in each stratum allowing 90 patients to be included in each group. Assuming an approximate dropout rate of 10% over the trial period, the sample size was increased to 400 patients (200 patients per stratum, 100 patients per group). As explained above, this report includes the results of the grade I hypertensive patient stratum only (200 patients).

3. Results

3.1. Baseline Characteristics

Of 424 patients enrolled in the whole study, 400 were randomized to either the pre‐hypertensive stratum or the grade 1 hypertensive stratum. Each stratum was then divided equally into two groups of 100 subjects receiving either policosanol 20 mg/day or placebo. Twenty‐four (24) patients were not included in the whole study because 23 of these had failed to attend for lab testing and one more had missed the recruitment period deadline. Of the 212 grade I hypertensive patients enrolled in the whole study, 200 were randomized. Twelve (12) patients were not included because 11 did not attend for lab testing and another missed the recruitment period deadline (See Figure 1 for the Study Flow Diagram).

Flow diagram of study participants. In addition to statistical analysis by ITT, missing data managed by simple imputation, including the last observation carried forward.

Table 1 shows the baseline characteristics of the grade I hypertensive stratum, which were comparable in both groups. The average age of study patients was 48.0 ± 8.5 years, with the frequency of randomized women (74%) being higher than that of men (26%). Study patients had some additional cardiovascular risk factors. The most frequent (≥25%) cardiovascular risk factors were overweight, sedentary lifestyle, and smoking.

TABLE 1.

Baseline characteristics of study grade I hypertensive patients.

	Policosanol (n = 100)	Placebo (n = 100)	Total (n = 200)
Age (years) (X ± SD)	48.0 ± 8.5	47.9 ± 8.5	48.0 ± 8.5
Body mass index (BMI) (kg/m²) (X ± SD)	27.2 ± 4.7	26.5 ± 4.2	27.2 ± 4.7

	n	%	n	%	n	%
Women	73	73.0	75	75.0	148	74.0
Men	27	27.0	25	25.0	52	26.0
Overweight (BMI ≥ 25, < 30)	36	36.0	37	37.0	73	36.5
Smoking	29	29.0	35	35.0	64	32.0
Sedentary life	26	26.0	29	29.0	55	27.5
Salt rich diet	24	24.0	19	19.0	43	21.5
Postmenopausal women ^a	18	18.0	11	11.0	29	14.5
Obesity (BMI ≥ 30)	13	13.0	13	13.0	26	13.0
Dyslipidemia	12	12.0	8	8.0	20	10.0
Diabetes mellitus	4	4.0	4	4.0	8	4.0

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Note: All comparisons were not significant (ANOVA, χ ² test).

Abbreviations: n, number of cases; SD, standard deviation; X, mean.

^{^a}

Defined as those with ≥1 year of maintained amenorrhea.

The frequency of concomitant medications (not included in the table for simplicity) was statistically similar in both intervention groups in the whole population. The most frequent co‐medications, well matched in both groups, were antihistamines (6 patients) (3 placebo, 3 policosanol), bronchodilators (5 patients) (2 placebo, 3 policosanol), oral hypoglycemic drugs (5 patients) (2 placebo, 3 policosanol) and analgesics, paracetamol and/or non‐steroidal anti‐inflammatory drugs (NSAIDs) (4 patients) (2 in each group).

3.2. Study Withdrawals

Seven (7) of 200 randomized patients in the stratum of patients with grade I hypertension (3.5%) (2 policosanol, 5 placebo) prematurely discontinued the trial (Table 2). The withdrawal rate was similar in both groups. No patient discontinued the trial due to adverse events.

TABLE 2.

Study withdrawals among the grade I hypertensive patients included in the whole study.

	Policosanol (n = 100)		Placebo (n = 100)
Withdrawal reasons	n	%	n	%
Protocol violation	2	2.0	1	1.0
Travels abroad	0	0.0	4	4.0
Total	2	2.0	5	5.0

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Note: n indicates number of cases. All comparisons were not significant (χ ² test). Protocol violations were due to intake of antihypertensive drugs.

3.3. Efficacy Analysis

Compliance with treatment was very good over the study since, apart from the premature dropouts, all other patients consumed the scheduled tablets. This fact was controlled by counts of the scheduled remaining tablets and personal interviews based in auxiliary record charts for medication intake.

3.3.1. Effects on Systolic and Diastolic Blood Pressure (SBP and DBP)

Table 3 summarizes the effects of policosanol on blood pressure values. At study completion, policosanol significantly reduced (p < 0.001) both SBP (primary outcome) and DBP values, compared to baseline and placebo group. SBP and DBP reductions were significant versus placebo after 4 and 8 weeks of treatment. At week 12, differences were significant as compared to both baseline and placebo. It should be noted that the final mean values of SBP and DBP were within the normal range or within the prehypertensive to normal range.

TABLE 3.

Effects on blood pressure values (X ± SD) in study with grade I hypertensive patients.

Treatment	Baseline	4 weeks	8 weeks	12 weeks
Systolic blood pressure (mm Hg)
Policosanol	142 ± 5	134 ± 10 ⁺⁺	132 ± 14 ⁺⁺	128 ± 10 ^*** ^, ⁺⁺⁺
95% CI	141–143	132–136	129–134	126–130
Placebo	143 ± 4	139 ± 9	138 ± 9	141 ± 6
95% CI	142–144	137–141	136–140	140–142
Diastolic blood pressure (mm Hg)
Policosanol	92 ± 2	85 ± 7 ⁺⁺	86 ± 8 ⁺⁺	81 ± 6 ^*** ^, ⁺⁺⁺
95% CI	92–92	84–86	84–88	80–82
Placebo	91 ± 2	88 ± 6	88 ± 6	90 ± 3
95% CI	91–91	87–89	87–89	89–91

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Abbreviations: CI, confidence interval; SD, standard deviation; X, mean.

^***

p < 0.001 comparison with baseline (McNemar test).

^⁺⁺

p < 0.01.

^⁺⁺⁺

p < 0.001 comparison with placebo group (ANOVA).

The frequency of policosanol‐treated patients with SBP reductions (≥10 mmHg vs. baseline) (74/100, 74%) was significantly higher (p < 0.0001) than in the placebo matched group (12/100, 12%) (Table 4). In turn, the rate of policosanol responders according to DBP reductions (≥5 mmHg vs. baseline) (91/100, 91%) was significantly higher (p < 0.001), than in the placebo group (15/100, 15%). Likewise, significantly (p < 0.0001) more policosanol patients (72/100) than placebo patients (7/100) achieved pre‐scheduled reductions of both SBP and DBP.

TABLE 4.

Responders to treatment based on SBP and DBP reductions.

	Policosanol (n = 100)		Placebo (n = 100)
Patients with	n	%	n	%
SBP reductions ≥ 10 mmHg	74 ⁺⁺	74.0	12	12.0
DBP reductions ≥ 5 mmHg	91 ⁺⁺	91.0	15	15.0
SBP and DBP reductions ≥ 10 and 5 mmHg, respectively	72 ⁺⁺	72.0	7	7.0
SBP and DBP values < 140 and 90 mmHg, respectively	93 ⁺⁺	93.0	14	14.0
SBP and DBP values < 120 and 80 mmHg, respectively	11 ⁺	11.0	0	0.0

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Abbreviations: DBP diastolic blood pressure; n, number of cases; SBP, systolic blood pressure.

^⁺

p < 0.001.

^⁺⁺

p < 0.0001 Comparisons with placebo group (χ ² test).

3.4. Effects on the Lipid Profile

Table 5 lists the effects on the lipid profile. In grade I hypertensive patients, policosanol significantly lowered LDL‐C (p < 0.05 vs. baseline, p < 0.001 vs. placebo) and total cholesterol (p < 0.05 vs. baseline, p < 0.01 vs. placebo), and significantly increased HDL‐C (p < 0.05 vs. baseline and placebo), these changes accounting for net differences versus placebo of 26.0%, 20.1%, 9.7% for LDL‐C, total cholesterol, and HDL‐C, respectively. Triglycerides significantly (p < 0.05) increased in placebo group.

TABLE 5.

Effects on the lipid profile (X ± SD) in study grade I hypertensive patients.

	Baseline	12 weeks	Changes (%)
Low‐density lipoprotein cholesterol (LDL‐C) (mmol/L)
Policosanol	3.06 ± 0.68	2.57 ± 0.80 ^* ^, ⁺⁺⁺	−16.0 ⁺⁺⁺
95% CI	2.93–3.83	3.11–4.14
Placebo	3.10 ± 0.82	3.41 ± 0.80	+10.0
95% CI	2.94–4.01	3.44–4.53
Total cholesterol (mmol/L)
Policosanol	4.47 ± 0.75	4.06 ± 0.87 ^* ^, ⁺⁺	−9.2 ⁺⁺
95% CI	4.32–5.16	4.48–5.45
Placebo	4.55 ± 0.92	5.05 ± 0.97	+10.9
95% CI	4.37–5.40	4.86–5.90
High‐density lipoprotein cholesterol (HDL‐C) (mmol/L)
Policosanol	1.22 ± 0.39	1.29 ± 0.28 ^* ^, ⁺	+5.7 ⁺
95% CI	1.14–1.91	1.13–1.69
Placebo	1.24 ± 0.39	1.19 ± 0.29	−4.0
95% CI	1.17–1.92	1.13–1.73
Triglycerides (mmol/L)
Policosanol	0.93 ± 0.47	1.02 ± 0.54	+9.7
95% CI	0.84–1.88	0.92–2.07
Placebo	1.02 ± 0.44	1.24 ± 0.65 ^* ^, ⁺	+21.6
95% CI	0.93–1.88	1.11–2.38

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Abbreviations: SD, standard deviation; X, mean.

p < 0.05 Comparison with baseline (McNemar test).

^⁺

p < 0.05.

^⁺⁺

p < 0.01.

^⁺⁺⁺

p < 0.001 Comparisons versus placebo (ANOVA).

3.5. Safety and Tolerability

3.5.1. Effects on Physical and Blood Safety Indicators

No significant within or between group differences were found regarding to bodyweight, body mass index, and pulse rate values. Also, no significant changes versus placebo were found for any laboratory variable, although significant reductions of blood glucose and significant increases of uric acid were found in both groups (table not included for simplicity). Since these changes occurred in both groups and individual values were within normal ranges, we exclude any clinically relevant meaning of this finding.

3.5.2. Adverse Events (AE)

Only eight patients reported some AE (5 from the policosanol group, 3 from the placebo group) (Table 6). Of these, three were classified as moderate because they required paracetamol for headache or sciatic pain. All other AE were mild. All AE were classified, according to the potential causal relation with the treatment, as “doubtfully related.”

TABLE 6.

Adverse events (AE) reported by grade I hypertensive patients during the study.

	Policosanol (n = 100)		Placebo (n = 100)
AE	n	%	n	%
Headache	4	4.0	0	0.0
Sciatic pain	1	1.0	0	0.0
Amenorrhea	0	0.0	1	1.0
Somnolence	0	0.0	1	1.0
Vomits	0	0.0	1	1.0
Total of AE	5	5.0	3	3.0
Total of patients referring AE	5	5.0	3	3.0

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Note: All comparisons were no significant (χ ² test).

Abbreviation: n, number of patients.

No discontinuation of the study was due to an AE.

4. Discussion

This study report is the first to investigate the effects of policosanol (20 mg/day) on blood pressure levels in patients with grade I hypertension. Our results demonstrate that policosanol 20 mg/day given for twelve weeks to Cuban patients with grade I hypertension was effective in significantly lowering SBP as compared to baseline and placebo, achieving mean SBP reductions of ≥10 mmHg. Likewise, the treatment also achieved significant reductions of DBP ≥ 5 mmHg versus baseline and placebo.

Indeed, previous studies in pre‐hypertensive patients conducted in Korea and Japan were the first to report a blood pressure lowering effect of policosanol, but in pre‐hypertensive patients [53, 54, 55, 56]. Considering that these Asian populations tend to be ethnically homogeneous, their results cannot be simply extrapolated to other populations. This was one reason to conduct this study in Cuban patients, who exhibit a high ethnic diversity, far enough of Asian populations, with high contribution of persons with black, white, and mixed skin colors. Said that, once we confirmed the effect of policosanol 20 mg/day in our population, markedly different from the Korean and Japanese populations, it will be interesting to investigate these effects on other populations.

It is interesting, however, that in contrast to the results on Cuban pre‐hypertensive patients [53], where significant decreases were seen only at study completion (12 weeks), the grade I hypertension stratum showed significant reductions of SBP and DBP from as early as week 4.

Baseline characteristics were well matched in both groups, evidencing their homogeneity and thus supporting that the outcomes found here were not attributable to initial disparities in the comparison groups. The study patients were, on average, within the middle age range (mean age 48 years), lower than that found in our early trials in populations at high vascular risk [14, 15, 16, 19, 41, 42, 43, 44].

The higher frequency of women as compared with men amongst the study patients reflects a common scenario in Cuban patients enrolling in research projects, women being more motivated to participate in clinical studies than men. Gender distribution, however, was well matched in both groups.

The personal history of patients reflects the coexistence of other cardiovascular risk factors, with sedentary lifestyle, smoking and overweight being the most common risk factors. None of the patients included had been treated with antihypertensive medications before, having ignored their high blood pressure values until the enrolment campaign for this study began.

The discontinuation rate was low (3.5%). Seven patients (5 placebo, 2 policosanol) withdrew prematurely from the study, but this number of withdrawals did not affect the efficacy analysis since we used the ITT approach for conducting it. Reasons for withdrawals were not associated with AE, in line with the good safety profile of policosanol. This factor, together with the sample size of the study and that statistical analyses were in an independent center (CENCEC), support the validity of the present results.

The efficacy of policosanol was supported through the mean changes of SBP and DBP values as compared with baseline and placebo. Also, the efficacy of policosanol is supported by the rate of responders who reached the SBP and DBP reductions established in the study protocol, since there were significantly more policosanol patients with SBP reductions ≥10 mmHg versus baseline (74/100, 74%) than in the placebo group (12/100, 12%). Moreover, the rate of policosanol patients with DBP reductions ≥5 mmHg versus baseline (91/100, 91%) was also significantly greater than those found in the placebo group (15%).

Simultaneous reductions of SBP ≥ 10 mmHg and DBP ≥ 5 mmHg occurred in more policosanol patients (72, 72%) than in matched placebo cases (7, 7%); and the rate of policosanol patients (93/100, 93%) who reached SBP and DBP values < 140 and 90 mmHg, respectively, was greater than in those receiving placebo (14, 14%).

As noted, at baseline we used not only office blood pressure measurements but also ABPM to confirm the hypertension grade of the patients. But thereafter, blood pressure was monitored by office measurements only OBP and thus compared with baseline values. It is well known, however, that for routine blood pressure control, ABPM is preferred over office readings since it provides a more accurate assessment of blood pressure values over 24 h, including night ones. ABPM helps identify both white‐coat hypertension and masked hypertension, which can be missed by office readings. ABPM, however, is a more expensive method and requires the patient to wear a device for 24 h, and that proper calibrated devices are available for all patients, which is not always possible in all clinical settings.

Although less accurate than ABPM, doesn't follow blood pressure values over a day, is prone to the “white coat effect” and may obviate masked hypertension, office measurements are simple, quick, reliable, and cost‐effective for long‐term periodical screening, this being the method used in routine clinical practice in our country.

Interestingly, the effects of policosanol 20 mg/day on blood pressure values of the grade 1 stratum seem to be higher than those reported for the pre‐hypertensive patients included in the whole study, in which, although significantly higher than in the placebo group, just 36% of policosanol patients reached SBP and DBP reductions ≥10 and ≥5 mmHg at study completion. Also, the reductions in the blood pressure values seen in this report became significant earlier, just after 4 weeks of treatment, as compared with those found in the pre‐hypertension stratum [61], and were further enhanced over the remaining study.

The root cause of the apparently enhanced effects of policosanol in this stratum cannot be demonstrated from this study design. Study patients were advised to follow lifestyle modifications, the core of hypertension management, including a healthy dietary pattern with low sodium intake, systematic physical activity, smoking cessation, and reduced alcohol consumption, all of which should enhance the efficacy of pharmacological antihypertensive therapy. Nevertheless, the fact that bodyweight values did not decrease in any group suggests that dietary advice was not well followed by study participants since a bodyweight reduction should be expected after 12 weeks on such a dietary regime. This suspicion is reinforced by the fact that triglycerides significantly increased. Future studies should confirm if this difference in policosanol efficacy in pre‐hypertensive and grade I hypertensive patients is reproduced, or if such a distinction was just a random result.

The magnitude of the SBP reduction achieved by the policosanol‐treated patients, and the rate of policosanol responders achieving the predefined goals, support the efficacy of policosanol 20 mg/day, given for 12 weeks, for lowering blood pressure in Cuban grade I hypertensive patients.

Adding even more evidence on the magnitude of SBP decreases and cardiovascular risk, a large‐scale analysis of randomized trials proved that just a simple SBP reduction of 5 mmHg lowered the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease and even at normal or high‐normal blood pressure values [64]. Hence, obtaining a SBP reduction ≥ 10 mmHg in our study population would be expected to attract clinical interest.

Regarding the secondary outcomes, policosanol 20 mg/day significantly lowered LDL‐C and total cholesterol versus placebo by 26.0% and 20.1% respectively, and significantly increased HDL‐C by 9.7% versus placebo, all these changes being favorable for the control of cardiovascular risk. Triglycerides significantly increased versus baseline in the placebo group, while an apparent upward drift is noted in the policosanol group, without difference between both groups. These trends suggest, as discussed previously, that the healthy dietary recommendations were not strictly followed by the subjects during the trial.

The mechanism of action was not a study target. The rationale behind the study was to confirm that policosanol 20 mg/day could make a significant and clinically important impact on elevated blood pressure readings in grade 1 hypertension patients. How this effect is achieved by policosanol does remain unclear, although there are some potential pathways which may contribute to such a result.

Small sample size trials conducted in Korea and Japan support that policosanol lowers blood pressure due to the enhancement of HDL cholesterol functionality, like the increase of cholesterol efflux, antioxidant properties, and inhibition of cholesteryl ester transfer protein (CETP), which may help to reduce the risk of atherosclerosis. Also, these studies found a policosanol effect on aldosterone levels, not on the angiotensin converting enzyme, suggesting a potential effect on the Renin Angiotensin Aldosterone System (RAAS) [55, 56].

Looking for the potential contribution of the effects on lipid profile as causative of the blood pressure lowering effect of policosanol, our study examined the correlation between the values of blood pressure and lipid variables, but no correlation was found, thus not adding new data for supporting such a hypothesis.

However, some beneficial pleiotropic and antithrombotic effects of policosanol could be related, at least in part, with such results. The ability of policosanol for inhibiting LDL oxidation [43], and reducing plasma thromboxane 2 levels [45, 46], could contribute to reduce the sequential events leading to high blood pressure.

Early unpublished experimental studies discarded a diuretic effect of policosanol but did not follow sodium urinary excretion in the animals, and to the best of our knowledge, no clinical trial has followed urinary sodium excretion after policosanol dosing. Further studies could examine the evolution of such a variable during policosanol treatment on a similar study hypertensive population.

This study also corroborates the very good safety of policosanol. No treatment‐related impairment of any safety indicator was observed. As expected, treatments were well tolerated by study patients. The frequency of patients referring adverse events during the trial (8/200, 4.0%) was low and statistically similar in both policosanol (5 patients) and placebo (3 patients) groups. AE reported were transient and, apart from three declared as moderate because paracetamol was requested for pain management, the others were classified as mild.

A limitation of this study is the low upper limit of age to be included in the trial (60 years) thus excluding older patients who exhibit a higher risk of suffering cardiovascular events, needing good control of their blood pressure values. A meta‐analysis and systematic reviews have evaluated the impact of antihypertensive medications on blood pressure and cardiovascular outcomes in the elderly demonstrating its effectiveness not only for reducing SBP and DBP, but for reducing the risk of cardiovascular events in this population [68, 69] and have proposed the usefulness of aggressive control of blood pressure in such population [70]. Therefore, further studies of the effects of policosanol on older patients (60–80 years) with high blood pressure values should be investigated to establish the potential benefits of policosanol for the control of blood pressure in such a vulnerable population.

Another limitation was that the randomized patients included some with diabetes. Having concomitant diabetes and hypertension supports that these patients are at higher coronary risk. These subjects were incorrectly included, representing protocol deviations, but since we applied ITT for data analysis, their data were included in this report, which represents a slight impact in the proposed risk categorization for study participants. Since this factor was homogeneously distributed among the comparison groups, it did not affect the validity of the present results.

Indeed, this trial was the first to confirm a potential blood pressure lowering effect of policosanol in this grade 1 hypertension, for which is typically measured against a placebo in this assessment stage, at least. Later trials should expand to possible comparisons with standard medical therapy.

Finally, it is important to remark that this study alone does not support policosanol as a new antihypertensive monotherapy. Indeed, looking at the final values, only a few patients (11/200), all treated with policosanol, none with placebo, achieved normal blood pressure values at study completion, which means that, although policosanol at 20 mg/day was effective to lower SBP and DBP significantly in a clinically important magnitude, it alone was not enough for optimal control of blood pressure in grade I hypertension. Further studies, therefore, including dose‐effect trials and effects on different populations such as the elderly, should explore the potential benefits of policosanol for managing high blood pressure in lower grades of hypertension (pre‐hypertension and grade I hypertension), added to lifestyle recommendations, as a potential alternative therapy.

Despite these limitations, the study achieved the objective to demonstrate the effects of policosanol 20 mg/day on the blood pressure values of Cuban patients with grade I hypertension, being part of the first trial focused on blood pressure lowering effects in our population, and the first study in such hypertension grade stratum.

5. Conclusions

This report demonstrates, for the first time, the efficacy of policosanol given at 20 mg/day for 12 weeks for lowering SBP and DBP in Cuban patients with grade I hypertension, achieving the predefined reductions considered as clinically meaningful, being also the first clinical study of the effects of policosanol in patients at such grade (or stage) of hypertension. The treatment also produced beneficial changes on the lipid profile, being safe, and well tolerated. Further studies including different doses, study designs and older populations, however, are required to extrapolate the present results to other populations of patients with grade I hypertension.

Author Contributions

Revueltas Moura: conceptualization, investigation, review. Jiménez Amarilys: conceptualization, investigation, review. Valdes Yamile: investigation, methodology. Fernández Julio César: conceptualization, investigation, project administration, writing – original draft. Reyes Yenney: investigation, methodology. Fernández Yanay: investigation, methodology. González Evelyn Anie: investigation, methodology. Mendoza Sarahi: review, editing. Pérez Yohani: methodology, resources. Pérez Manuel Delfin: methodology, resources. Navarro Daisy: methodology, resources. Cruz Yolanda: methodology, resources. Mesa Meilis: methodology, resources. Jiménez Gladys: software, data analysis. Sánchez Carlos: software, statistical analysis. All authors have read and agreed to the published version of the manuscript.

Ethics Statement

The study followed the ethical principles established in the latest version of the Declaration of Helsinki and Tokyo.

Consent

All participants provided written informed consent at enrolment.

Conflicts of Interest

The authors declare no conflicts of interest.

Revueltas Aguero M., Jimenez Chiquet A., Valdes Y., et al. “Policosanol (sugarcane wax alcohols) 20 mg/day in Cuban Patients With Grade I Hypertension: A Randomized, Double‐Blind, Multicenter Study.” The Journal of Clinical Hypertension 27, no. 10 (2025): e70126. 10.1111/jch.70126

Funding: This study was supported by the National Centre for Scientific Research, as part of its research‐development projects.

Data Availability Statement

The authors have nothing to report.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The authors have nothing to report.

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PERMALINK

Policosanol (sugarcane wax alcohols) 20 mg/day in Cuban Patients With Grade I Hypertension: A Randomized, Double‐Blind, Multicenter Study

Moura Revueltas Aguero

Amarilys Jimenez Chiquet

Yamile Valdes

Julio César Fernández Travieso

Yenney Reyes Nuñez

Yanay Fernández Dominguez

Evelyn González Pla

Sarahi Mendoza Castaño

Yohani Pérez Guerra

Manuel Delfin Pérez Caballero

Deisy Navarro

Yolanda Cruz Gomez

Meilis Mesa Angarica

Gladys Jiménez Rivero

Carlos Sánchez Texido

ABSTRACT

1. Introduction

2. Participants and Methods

2.1. Study Design

2.2. Study Participants

2.3. Treatment and Randomization

2.4. Concomitant Medications

2.5. Study Outcomes

2.6. Laboratory Variables and Analysis

2.6.1. Lipid Profile

2.6.2. Other Laboratory Tests

2.7. Safety and Tolerability

2.8. Statistical Analysis

2.9. Sample Size Estimation

3. Results

3.1. Baseline Characteristics

FIGURE 1.

TABLE 1.

3.2. Study Withdrawals

TABLE 2.

3.3. Efficacy Analysis

3.3.1. Effects on Systolic and Diastolic Blood Pressure (SBP and DBP)

TABLE 3.

TABLE 4.

3.4. Effects on the Lipid Profile

TABLE 5.

3.5. Safety and Tolerability

3.5.1. Effects on Physical and Blood Safety Indicators

3.5.2. Adverse Events (AE)

TABLE 6.

4. Discussion

5. Conclusions

Author Contributions

Ethics Statement

Consent

Conflicts of Interest

Data Availability Statement

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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