2.1. High Blood Pressure
Hypertension is one of the major causes of morbidity and mortality worldwide, involving one in four men and one in five women, totalling 1.13 billion adults, who had raised blood pressure in 2015
[22]. A recent comparative assessment of the risk of health loss related to systolic blood pressure (SBP), based on 844 studies in 154 countries (published between 1980 and 2015) and 8.69 million participants, has estimated approximately 874 million of people in the world with SBP above 140 mmHg
[23]. In 2025, it is estimated that there will be approximately 1.56 billion hypertensive adults
[24].
CoQ
10 seems to exert a direct effect on the endothelium, provoking vasodilation and lowering blood pressure
[25][26]. This effect is linked to its ability to improve nitric oxides bioavailability and to induce vasodilatation especially in patients with hypertension. In addition, CoQ
10 adjusts the angiotensin effect in sodium retention and decreases the level of aldosterone
[27][28]. Despite exciting blood pressure results observed in preliminary trials (systolic and diastolic blood pressure reduced respectively by 6 and 5 mmHg vs. placebo)
[29] and the positive results confirmed by old meta-analyses of RCTs
[30][31], a recent meta-analysis of 17 randomized controlled trials including 684 subjects showed that CoQ
10 supplementation significantly decreased systolic blood pressure (Standardized Mean Difference (SMD) −0.30; 95%CI −0.52, −0.08), but not diastolic blood pressure (SMD −0.08; 95%CI −0.46, 0.29)
[32]. However, in patients with type 2 diabetes mellitus and ischemic left ventricular systolic dysfunction, when the blood pressure is on target, the supplementation of CoQ
10 did not modify the blood pressure
[33][34][35]. In conclusion, despite some promising evidence, the antihypertensive effect of CoQ
10 is still unclear in patients with primary hypertension
[36][37].
2.2. Insulin-Resistance and Type 2 Diabetes
Mitochondria seem to play a key role in the development of insulin resistance. They are well known to convert nutrients from diet such as fats and sugars into ATP; however, ATP production can generate harmful intermediates such as ROS and the increase in the amount of oxidant agents produced in mitochondria has been linked to the increase of insulin resistance
[38][39]. Several studies in vitro and in vivo as well
[40] found that the concentrations of CoQ
10 were lower in mitochondria from insulin-resistant fat and muscle tissue, probably for a change in expression of mevalonate/CoQ
10 pathway proteins and thus altered CoQ
10 metabolism, suggesting a direct correlation between the low levels of CoQ
10 and the high levels of oxidants in the mitochondria. In addition, the administration of CoQ
10 in deficient and insulin resistant mice has been shown to improve the insulin sensitivity by reducing ROS levels
[40].
In patients with metabolic syndrome (MetS), a condition typically caused by insulin-resistance and strongly associated with the risk to developing cardiovascular disease, the intake of 100 mg/day of CoQ
10 for 8 weeks significantly improved Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic Model Assessment of β-cell Function (HOMA-B), serum insulin levels, and plasma total antioxidant capacity
[41]. The effect of CoQ
10 on insulin-resistance seems to not be related to its effect on body fat. In fact, a recent meta-analysis of RCTs showed that CoQ
10 had no significant impact on body weight (
p = 0.64) and body mass index (BMI) (
p = 0.86), independent from the CoQ
10 tested dosage and trial duration
[42].
Another highly prevalent cardiovascular risk factor related to insulin-resistance is nonalcoholic fatty liver disease (NAFLD)
[43]. Despite the numerous mechanisms investigated, the exact biological one related to increased hepatic inflammation and fat accumulation in NAFLD remains largely unknown
[44][45]. However, recent studies have focused attention on the role of mitochondrial protein mitofusin 2 (Mfn2) that protects against liver disease. In fact, reduced Mfn2 expression was detected in liver biopsies from patients with nonalcoholic steatohepatitis
[46]. The loss of Mfn2 seems to impair mitochondrial respiration and to reduce ATP production, and this defective oxidative phosphorylation process seems to unexpectedly originate from a depletion of the mitochondrial CoQ
10 pool
[47].
To date, the treatment of NAFLD is essentially based on lifestyle optimization because there are currently no specific drugs approved on the market for this condition. At the same time, few nutraceuticals have been adequately studied for their effects on NAFLD
[48]. Among these, CoQ
10 is a well-known anti-adipogenic molecule and thus could have a positive impact on NAFLD, even if its exact mechanism is still unclear. It is possible that CoQ
10 downregulates the expression of fatty acid synthase (FAS), sterol regulatory element-binding protein-1c (SREBP-1c), and acetyl-CoA carboxylase (ACC), which are related to lipid synthesis, and increases in the expression of carnitine palmitoyltransferase-1 (CPT-1) and peroxisome proliferator-activated receptors α (PPARα) associated with fatty acid oxidation
[49]. In addition, CoQ
10 could change the response to inflammation through nuclear factor kappa B (NF-kB)-dependent gene expression
[50]; thus, its deficiency might have a role in increasing levels of inflammatory molecules like NF-kB
[51].
CoQ
10 could serve as an adenosine monophosphate-activated protein kinase (AMPK) activator and could regulate the hepatic lipid metabolism to inhibit the abnormal accumulation of hepatic lipids as well as to prevent NAFLD progression
[49]. Finally, CoQ
10 was also found to bind and activate both PPARs alpha and gamma, suggesting a key role in relaying the states of mitochondria and peroxisomes
[52]. At the same time, the experiments performed with peroxisomal inducers indicate that nuclear receptors are involved in the regulation of CoQ
10 biosynthesis
[13].
In an RCT, 41 subjects with NAFLD were randomly divided into 2 groups to receive CoQ
10 (100 mg/day) or placebo for 12 weeks. At the end of the study, the active group benefited from a significant decrease in aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), tumor necrosis factor α, high-sensitivity C-reactive protein (hs-CRP), and NAFLD grade compared to placebo (
p < 0.05 for all). In addition, patients who received the CoQ
10 supplement had higher serum levels of adiponectin (
p = 0.016) even if serum leptin levels reduced marginally (
p = 0.053)
[53]. However, CoQ
10 administration (300 mg/day for 12 weeks) in patients with coronary artery disease did not find any significant effect on serum adiponectin levels
[54], confirming previous data obtained by Gokbel et al. with the supplementation of CoQ
10 100 mg/day in healthy volunteers
[55]. In another RCT, the same dose of CoQ
10 in 44 NAFLD patients for 4 weeks was associated with significantly decreased waist circumference (WC), serum AST, and total antioxidant capacity (TAC) concentration (
p < 0.05 for all)
[56].
CoQ
10 could also improve the atherogenic dyslipidemia typically associated with NAFLD (reducing triglycerides (TG) and increasing high-density lipoprotein cholesterol (HDL-C) as well as reduce oxidized low-density lipoprotein (LDL) levels and arterial pressure with a very high safety profile and without any risk of drug interactions
[15]. In conclusion, the studies conducted to date emphasize a potential for CoQ
10 therapy in improving several anthropometric and biochemical variables in NAFLD.
A further disease typically characterized by insulin resistance is polycystic ovary syndrome (PCOS). In these women, as showed by the study of Samimi et al., the supplementation with CoQ
10 (100 mg/day) for 12 weeks could have beneficial effects on glucose metabolism and on serum total- and LDL-cholesterol levels
[57]. Afterwards, the same research group carried out another RCT on 40 women with a diagnosis of PCOS, observing that a supplementation for 12 weeks with CoQ
10 (100 mg/day), beside the positive effects on lipid and glucose levels, was responsible for a downregulation of gene expression of oxidized low-density lipoprotein (LDL) receptor 1 (
p < 0.001) and an upregulated gene expression of PPAR-γ (
p = 0.01) in peripheral blood mononuclear cells. In addition, compared to the placebo group, CoQ
10 supplementation downregulated gene expression of interleukin-1 (IL-1) (
p = 0.03), IL-8 (
p = 0.001), and tumor necrosis factor-alpha (TNF-α) (
p < 0.001) in peripheral blood mononuclear cells of subjects with PCOS
[58]. Similar results were obtained by Izadi et al. in a RCT of 85 PCO women treated with CoQ
10 and/or vitamin E or placebo. In particular, CoQ
10 alone improved the sex homone profile, specially either reduced testosterone and luteinizing hormone (LH) levels, and improved insulin resistence. Moreover, it is noteworthy that CoQ
10 in coadministration with alfa-tocopherol presented a more pronunced effect and stimulated the release of sex hormone-binding globulin (SHBG), justifing the enhancement of insulin tolerance, since an insulin resistance condition is associated with a reduced synthesis of SHBG at the hepatic level. Then, CoQ
10 might promote steroid hormone biosynthesis and normal reproductive function (among which are oocyte maturation, fertilization, and embryonic development) through the improvement of mitochondrial functionality
[59]. However, new, larger RCTs are needed to confirm the results obatined by Izadi et al.
The extreme consequence of insulin-resistance is Type 2 diabetes (T2DM). A deficiency of CoQ
10 plasma levels in patients with T2DM can be observed compared to healthy people
[60][61]. In particular, the ubiquinone–ubiquinol ratio, a validated marker of oxidative stress
[62], is much higher in a patient with T2DM after breakfast and throughout the day, which suggests heightened oxidative stress in the background of postprandial hyperglycemia
[63]. In a recent pooled analysis of 14 trials including 693 overweight diabetic patients, CoQ
10 interventions significantly reduced fasting plasma glucose (FPG) (−0.59 mmol/L; 95%CI −1.05 to −0.12;
p = 0.01), HbA1c (−0.28%; 95%CI −0.53 to −0.03;
p = 0.03), and TG levels (0.17 mmol/L; 95%CI −0.32 to −0.03;
p = 0.02). Even in the subgroup analysis, the low-dose consumption of CoQ
10 (<200 mg/d) effectively reduced the values of FBG, HbA1c, fasting blood insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and TG with high tolerability profile
[64]. In a rat model, the administration of metformin combined with CoQ
10 showed a better renoprotective effect than CoQ
10 or metformin alone
[65]. This is also confirmed for other oral antidiabetic drugs like sitagliptin
[66]. This brings up an important point that CoQ
10 may potentiate the protective effects of some conventional treatments, but it is yet to be demonstrated in humans.
2.3. Dyslipidemias
Several mechanisms have been proposed by which CoQ
10 supplements could improve metabolic profiles which probably might be through the induction of gene expression of PPAR-γ
[67], a nuclear receptor protein that regulates gene expression involved in insulin and lipid metabolism, differentiation, proliferation, survival, and inflammation
[68]. In human endothelial cells, the exposure to CoQ
10 is associated with downregulation of the lectin-like oxidized LDL receptors, stimulation of the AMPK, and reduction of the ROS-induced endothelial damage
[69]. In fact, the main effect of CoQ
10 on plasma lipids seems to be the increased LDL resistance to oxidative stress
[70], as also demonstrated in healthy adults after acute strenous physical exercise
[71].
In an RCT, 101 dyslipidemic subjects without taking any lipid-lowering drugs were administrated 120 mg CoQ
10 or placebo daily for 24 weeks. At the end of the study, CoQ
10 supplementation mildly reduced TG (
p = 0.020) and LDL-C (
p = 0.016), increased apolipoprotein (Apo)A-I (
p < 0.001) and serum total antioxidant capacity (TAC;
p = 0.003), while decreased homeostasis model assessment of insulin resistance index (
p = 0.009) compared to placebo
[24]. In the meta-analysis conducted by Sharifi et al.
[72], CoQ
10 administration to patients with metabolic diseases mildly but significantly reduced TG concentrations (SMD −0.28 mmol/L; 95% CI, −0.56 to −0.005,
p = 0.001). A recent meta-analysis including six clinical trials suggests that CoQ
10 could mildly reduce the lipoprotein (a) plasma level
[73]. Overall, the effect of CoQ
10 supplementation on plasma lipid levels is, however, quantitatively small and its clinical relevance has yet to be demonstrated.