INTRODUCTION:

Hypertension is one of the most universalchronic diseases. It is considered the most critical changeable risk factor for death around the world, and is linkedtoa greater risk of cardiovascular diseases (CVDs) and various other complications in the human body^1-4. Itis estimatedthat approximately one in four adults has hypertensionworldwide⁵. Hypertension is definedas systolic blood pressure of 140mm/Hg or higher and/or diastolic blood pressure of more than 90mm/Hg^6,7. It is shown that the anti-hypertensivedrug treatment is effective in preventing hypertension and riskof CVDs¹.

In addition, it has been reported that most patients with serious high blood pressure problems need a combination drug therapy rather than monotherapy⁸. One of the first-line medications for hypertension treatment are diuretics⁹. Thiazide diuretics are the most common useddiuretics and next come loop diuretics. However, despite their important role and considering them amongperfect tolerated antihypertensive drugs, they are linked tounfavorable effects such as electrolyte disorders. Both thiazide and loop diuretics promote urinary magnesium excretion. Several studies have suggested that diuretics are the most frequentreasonfor magnesium loss in hypertensive patients, as thiazide diuretics cause generally around 5-10% loss in serum magnesium levels¹⁰.

The importance of lipids and lipoproteins has increased in clinical practice. Dyslipidemia has arisen as a general threat to health around the world. It is also found to be a risk factor for hypertension¹¹, and when both disorders are present together, they further increase the risk of cardiovascular incidents and death¹². Moreover, dyslipidemia can lead to atherosclerosis, a well-recognized risk for CVD, stroke, and coronary heart disease (CHD)¹³; one of the most important cardiovascular diseases worldwide¹⁴. Thus, lipid profile is considered to be one of the major predictors of CVD¹⁵, and dyslipidemia should be determined early to manage CVD and prevent its complications¹⁶.

Due to the importance of magnesium role in regulating the efficiency of lipid metabolism enzymes^17,18, and in view of its increasing loss in patients on diuretics therapy, it has been focused to assess serum magnesium levels among cardiovascular high-risk patients.

Magnesium (Mg) is the fourth bountiful positive ion in the body and the second most bountiful inner-cellular positive ion. Magnesium behaves as a cofactor for over 300 enzymes that are required for many important and vital processes in the body like energy production and proteins synthesis. It plays a significant role in ATP synthesis. In addition, magnesium bound to ATP to compose Mg-ATP complex, which is necessary for the efficiency of ATP requiring enzymes like oxidative phosphorylation and lipase enzymes¹⁹. Magnesium also plays a pivotal role in controlling lipids and lipoproteins metabolism by regulating the activity of HMG-CoA Reductase, Also by activation of lecithin cholesterol acyl transferase (LCAT) and lipoprotein lipase (LPL)^17,
18,20. Magnesium levels in the serum range between 0.76 and 1.05 mmol/L²¹. The kidney regulates magnesium reabsorption and excretion²². The appraisal of magnesium status is essential to understand diseases associated with magnesium deficiency^23,24. Until now, there is no one easy, rapid, and precise analytical method to evaluate total magnesium levels in the body. However, serum magnesium concentration remains the most widely utilized analysis to assess magnesium status, as it is simple, inexpensive, and non-invasive analysis^25,26. Although magnesium balance is well controlled by the kidneys, hypomagnesaemia can occur in people with certain conditions like drug-induced renal magnesium loss²⁷. The terms magnesium deficiency and hypomagnesemia are commonly used alternately²³. However, clinical magnesium deficiency and the status of magnesium depletion in the body can occur with normal serum magnesium concentration²¹. Hypomagnesemia is characterized as serum magnesium levels below (1.7-1.8 mg/dl)²⁸. When serum magnesium concentration is lower than 2.0mg/dl with an excretion in the urine between 40-80mg/24hr and a dietary intake of magnesium<250mg/day, this strongly indicates a state of magnesium deficiency^21,29.

Due to the conflicted data on magnesium effect on lipid profile, and the absence of studies evaluating serum magnesium in hypertensive patients in Syria, we designed this study to evaluate serum magnesium levels in hypertensive group on diuretics and a matched healthy control group, and to determine the relationship between magnesium levels and lipid profile components among those subjects.

MATERIALS AND METHODS:

The study was carried out from March 2021 to July 2022at Tishreen University Hospital (TUH) of Lattakia City in Syria. It was confirmed by Institutional ethics committee of Tishreen University. Informed agreement was obtained from all members in this study.

Participants:

Fifty patients (27 males and 23 females) with hypertension and under diuretic therapy for at least 6 months (thiazide-type diuretics (hydrochlorothiazide) and loop diuretics (furosemide)) were included in this study, along with a control group of 25 healthy subjects. Patients were divided into three groups in accord with total cholesterol (TC) and low density lipoprotein cholesterol (LDLc) levels and into two groups in accord with high density lipoprotein cholesterol (HDLc) and triglycerides (TG). All cases were interviewed using a questionnaire about age, sex, smoking, alcoholism, medical history, and medications. Hypomagnesemia was identified by serum magnesium levelsbelow1.7mg/dl.

Exclusion criteria:

Type 1 and type 2 Diabetes Mellitus, pancreatitis, renal failure, Crohn's disease, chronic liver disease, patients on lipid-lowering drugs, patients supplemented with oral magnesium, patients taking medications such as insulin and insulin mimetic drugs, chemotherapeutic agents (cisplatin), digoxin, amino glycoside antibiotics, proton pump inhibitors (PPIs), and immunosuppressants (cyclosporine).

Analytical methods and instrumentation:

Fasting blood samples were collected after 12h fasting. Lipid profile components were measured using standard enzymatic method. The biochemical assays for TC and TG have been performed by kits from Biosystems (Spain), whereas LDL cholesterol and HDL cholesterol assays have been performed using kits from QUIMICA CLINICA APLICADA (Spain). Magnesium concentrations were measured by a kit from Bio Systems^® using Xylidyl blue method. All assays were performed by a Mindray BS-380 analyzer (China).

Statistical analysis:

The study used the Statistical Package for Social Sciences (SPSS) 20.0 and Excel 2010 for data analyzing. Data was presented as mean±SD. All variables were normally distributed. Student's t-test was used to compare means between two independent samples. Analysis of variance (ANOVA) was used to compare variances between different groups. Pearson's correlation was applied to determine the association between different variables. In all applied tests, P values less than 0.05 were related to statistical importance.

RESULTS:

Table 1 shows the characteristics of included subjects. This study includedSeventy five subjects. There was no significant differences between the patients and controls according to age (P=0.063). Both groups had no significant sex differences (P=0.534). The males in patients groups were 54% (n=27) and the females were 46% (n=23), while the males in the control group were 56% (n=14) and the females were 44% (n=11).

Table 1: General Characteristics of Subjects in the Study.

Demographic characteristics	Patients	Controls
Number of subjects	50	25
Males	27	14
Females	23	11
Age (mean±SD)	61.42±9.18	56.92±10.72

Table 2 shows a comparison of the examined parameters between the studied groups. Serum magnesium levels were lower in the patients contrasted to the controlswith a significant difference (P<0.05). Triglycerides,total cholesterol, and LDL cholesterol were higher in the patients group in comparison to the controls and statistically differences between the two groups were detected (P<0.05). Whereas HDL cholesterol levels were higher in the controls in comparison to the patients with also a significant difference between the two groups (P<0.05).

Table 3 shows the association of serum magnesium levels with age, sex, and lipid profile in patients with HTN. According to age, patients were divided into three categories. Statistically significant association was observed between serum magnesium and age (P<0.001). Lower serum magnesium concentrations were found in older patients in comparison to first and second category (1.75+0.12 versus 2.16+0.11 and 1.93+0.14 respectively), And when Pearson’s correlation test was applied, we found a negative correlation between Mg and age (Fig.1). Conversely, males had higher serum magnesium levels than females but there was no statistically significant differences (P=0.373). The relationship between serum magnesium levels and lipid profile was also identified. Statistically significant association between magnesium and triglycerides was observed. According to this, higher TG levels were related to lower magnesium levels. Likewise, patients with higher total cholesterol and LDL cholesterol had lower serum magnesium levels, and the difference in serum magnesium categories by TC and LDL-c was significant. Another significant association with HDL cholesterol levels was noticed. It was shown that lower HDL-c levels were related tolower magnesium levels, and the difference was significant. When Pearson's correlation test was applied, the results demonstrated a significant negative correlation between serum magnesium and TG, TC, LDL-c; (Fig.2, Fig.3, Fig.4 respectively). However, a significant positive correlation between magnesium and HDL-c was found (Fig.5), (Table 3).

Table 2: Comparison of the Examined Parameters between Patients and Controls.

Parameter	Patients	Controls	P-value
Parameter	Mean±SD	Mean±SD	P-value
Magnesium (mg/dl)	1.87±0.16	2.40±0.41	P<0.05
Triglycerides (mg/dl)	138.02±25.62	97.80±22.52	P<0.05
Total cholesterol (mg/dl)	201.14±34.24	169.28±31.38	P<0.05
LDL cholesterol (mg/dl)	133.42±31.67	103.50±32.66	P<0.05
HDL cholesterol (mg/dl)	39.86±2.21	45.59±5.99	P<0.05

* T-test to independent samples, Values are mean ± SD.

Table 3: Correlation of Magnesium and the Studied Parameters in the Patients Group.

Parameters	Values	N	Serum magnesium levels (mg/dl)
			Mean±SD	P-value	Correlation Coefficient	P-value***
Triglycerides (mg/dl)	<150	30	0.17±1.93	0.002*	- 0.486	≤0.001
	150≤	20	0.08±1.78
Total cholesterol (mg/dl)	<200	22	0.15±1.96	0.001**	- 0.63	≤0.001
	200-239	21	0.14±1.83
	≥240	7	0.11±1.72
LDL cholesterol (mg/dl)	<100	7	0.07±2.05	0.019**	- 0.627	≤0.001
	100-159	32	1.89±0.14
	160-189	11	1.71±0.09
HDL cholesterol (mg/dl)	<40	21	0.15±1.79	0.003*	+0.375	0.007
	40≤	29	0.15±1.93
Age	<40	3	2.16±0.11	≤0.001**	-0.606	≤0.001
	40-60	21	1.93±0.14
	>60	26	1.79±0.12
Sex	male	27	0.16±1.89	0.373	-	-
	female	23	0.16±1.85

*T-test to independent samples, **ANOVA of a factor, ***Pearson’s Correlation

Fig 1: Correlation of Magnesium Levels and Age in HTN Patients.

Fig 2: Correlation of Magnesium Levels and Triglycerides in HTN Patients.

Fig 3: Correlation of Magnesium Levels and Total Cholesterol in HTN Patients.

Fig 4: Correlation of Magnesium Levels and LDLcin HTN Patients.

Fig 5: Correlation of Magnesium Levels and HDLcin HTN Patients.

Depending on the kit used for measuring Mg concentrations (BioSystems^®), the reference values for magnesium in serum range from 1.7mg/dl to 2.4mg/dl. Thus, in our study, the value of 1.7mg/dl was used as the cut-off point for hypomagnesemia. The prevalence of hypomagnesemia was 8% (n=4) in the hypertension group and 0% (n=0) in the control group.

DISCUSSION:

Magnesium has been studied for its important role in many physiological processes and biochemical pathways associated with body health and illness^28,30. Many studies have shown that abnormalities in magnesium status can cause undesirable consequences such as neuromuscular, cardiac, and nervous disorders³¹. Serum magnesium concentrations were evaluated in all study subjects; hypertensive patients on diuretics seemed to have significantly lower serum magnesium concentrations when compared to the controls. Similar observations were found by a previous study³². This magnesium loss can be explained by the possible hydrochlorothiazide-induced TRPM6 channel downregulation observed in mice. TRPM6 is responsible for magnesium reabsorption in the kidney. This suggests that the thiazides inhibition of Na⁺Cl^- channel can also inhibit indirectly TRPM6 channel³³. In addition, increased potassium (k+) excretion in the urine related to the use of thiazides depolarizes the membrane and impairs the passive reabsorption of Mg³⁴.

We have also identified the association of serum magnesium levels with lipid profile. According to Pearson's correlation test, this study showed a significant negative correlation between magnesium and each of TG, TC, LDLc. Whereas a significant positive correlation between magnesium and HDLc was found. Magnesium acts as the cofactor of LPL and it is essential for its activation. LPL induces triglycerides catabolysis and chylomicron clearance and delays triglycerides levels elevation^35,36. In addition, Mg-ATP complex is the controlling element in cholesterol biosynthesis by the phosphorylation of HMG-CoA Reductase, which results in the inhibition of the enzyme. Mg is also essential for the activation of LCAT, which elevates HDL-c and lowers LDL-c levels. Magnesium also activates desaturase (DS), which is involved in lipid metabolism and is necessary for converting linoleic acid and linolenic acid into prostaglandins²⁰. Our data are partially in line with previous studies that reported magnesium concentration can be associated with lipid profile disorders^37-39. Mahalle et al.³⁷ reported a negative correlationbetweem serum Mg levels and TG, TC, LDL-c in hypertensive patients, but a positive association with HDL-c. Liu et al.³⁸ also reported increased levels of TG, TC, and LDL-c and decreased levels of Mg in dyslipidemic patients in comparison to controls. Jin et al.³⁹found a negative correlation between high Mg dietary intake and TG in both genders, while a positive association with HDL-c in females. Moreover, the outcome of Mg supplements on lipid profile has been tested in previous studies^40,41. Kim et al.⁴⁰showed a positive correlation between dietary magnesium intake and HDL-c levels. Rodríguez -Moran et al.⁴¹reported a significant increase in serum Mg levels and HDL-c levels with a decrease in TG levels when MgCl₂was applied orally in the hypomagnesemia group. Conversely, Randell et al.⁴² showed a positive correlation of serum magnesium with TC, LDL-c, HDL-c, and TG. In addition, Barragán et al.⁴³ reported that no significant association between serum magnesium levels and TG or HDL-c was found, but there was a positive significant association with both TC and LDL-c in their study.

The prevalence of hypomagnesemia (Mg less than 1.7 mg/dl) in our study was calculated to be 8% in the HTN group and 0% in the control group. Kieboom, et al. ³² reported that the prevalence of hypomagnesemia in thiazide-treated patients was 2.5%. While Sarikayaet al.⁴⁴ showed that hypomagnesemia was found in 7.1% of hypertensive patients on diuretics. Many studies suggested that magnesium deficiency mayoccur even with normal serum Mg levels^21,29 because only less than 1% of Mg is found in serum, whereas the rest is positioned in bone, muscles and soft tissues²³. In addition, it was mentioned that thiazide diuretics can induce intracellular magnesium depletion, which cannot be detected by serum Mg concentrations²¹. Hence, this can explain the low prevalence in our study despite the long-term diuretic therapy applied. Furthermore, Razzaque⁴⁵ suggests that individuals with serum magnesium levels between 1.8-2.07mg/dlhave tobe investigated with additional tests to check their body magnesium content.

CONCLUSION:

This study suggests that hypertensive patients using diuretics for at least a 6 months duration have lower serum magnesium concentrations and elevated risk of hypomagnesemia compared to healthy people. In addition, hypertensive patients with lower serum Mg levels have higher levels of total cholesterol, LDL cholesterol, triglycerides and lower levels of HDL cholesterol. In order to minimize the potential lipid profile derangement and its complications, we recommend more attention to be paid in medical practice to the magnesium status. This could be achieved by routine magnesium investigation, particularly in people with serious risk including patients with hypertension and individuals under long-term therapy with diuretics. We are aware that this present study is limited by the small sample size related to the numerous exclusion criteria we had. Further large-scale studies are necessary to affirm our results and explore the effect of Mg on lipid profile in hypertensive patients.

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Received on 02.08.2023 Modified on 15.09.2023

Research J. Pharm. and Tech 2024; 17(4):1461-1466.

DOI: 10.52711/0974-360X.2024.00231