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Age-Dependent Relationships Between Disease Risk and Testosterone Levels: Relevance to COVID-19 Disease.
Muehlenbein, M, Gassen, J, Nowak, T, Henderson, A, Morris, B, Weaver, S, Baker, E
American journal of men's health. 2023;17(2):15579883221130195
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A growing body of research finds that in men, testosterone levels may be prognostic of clinical outcomes related to coronavirus disease 2019 (COVID-19 disease). The presence of pre-existing chronic conditions in many patients with COVID-19 disease further complicates the relationship among testosterone and severe outcomes. The aim of this study was to examine whether pre-existing conditions for severe COVID-19 disease were related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This study obtained data from men (n = 142) who participated in the longitudinal study Waco COVID Survey. All data included in the study was collected as part of the initial intake survey and first laboratory appointment. Results show that serum-free testosterone levels decreased as a function of age. In fact, greater burden of pre-existing conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. Furthermore, in men older than 40 years of age the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Authors conclude that their findings add important insights into the complex role of androgens in chronic and infectious diseases and contribute to the growing body of literature on the relationship between chronic disease and men’s testosterone levels.
Abstract
Testosterone levels in men appear to be prognostic of a number of disease outcomes, including severe COVID-19 disease. Testosterone levels naturally decline with age and are lower in individuals with a number of comorbidities and chronic conditions. Low testosterone may therefore be both a cause and a consequence of illness, including COVID-19 disease. The present project examines whether preexisting conditions for severe COVID-19 disease were themselves related to serum-free testosterone levels in men who had not been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. A clinical risk score for severe COVID-19 disease was computed based on the results of previously published meta-analyses and cohort studies, and relationships between this score and testosterone levels were tested in 142 men ages 19 to 82 years. Greater burden of preexisting conditions for severe COVID-19 disease was related to lower testosterone levels among men younger than 40 years of age. In older men, the decrease in testosterone that accompanies aging attenuated the effect of the clinical risk score on free testosterone levels. Given that older age itself is a predictor of COVID-19 disease severity, these results together suggest that the presence of preexisting conditions may confound the relationship between testosterone levels and COVID-19 disease outcomes in men. Future research examining relationships among testosterone and outcomes related to infectious and chronic diseases should consider potential confounds, such as the role of preexisting conditions.
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Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.
O'Donoghue, ML, Rosenson, RS, Gencer, B, López, JAG, Lepor, NE, Baum, SJ, Stout, E, Gaudet, D, Knusel, B, Kuder, JF, et al
The New England journal of medicine. 2022;387(20):1855-1864
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Numerous epidemiologic studies over the past three decades have shown an association between higher circulating lipoprotein(a) concentrations and an increased risk of atherosclerotic cardiovascular disease. The aim of this study was to evaluate the efficacy and safety of repeated administration of a small interfering RNA designed to lower the body's production of apolipoprotein(a). This study is a multicentre, randomised, double-blind, placebo-controlled, dose-finding trial. Patients were randomly assigned in a 1:1:1:1:1 ratio to receive one of four doses of small interfering RNA (n= 281) (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. Results show that treatment with small interfering RNA markedly reduced the concentration of lipoprotein(a) in a dose-dependent manner and appeared to be safe. At higher doses, the treatment reduced the lipoprotein(a) concentration by more than 95%, as compared with placebo, with nearly all patients who received the treatment with small interfering RNA having a lipoprotein(a) concentration of less than 125 nmol per litre. Authors conclude that further large-scale interventions are needed to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease.
Abstract
BACKGROUND Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study.
Wang, JJ, Zhuang, ZH, Shao, CL, Yu, CQ, Wang, WY, Zhang, K, Meng, XB, Gao, J, Tian, J, Zheng, JL, et al
Chinese medical journal. 2021;134(9):1064-1069
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Obesity, dyslipidaemia, and metabolic syndrome are major risk factors for cardiovascular disease, however, effect of thyroid dysfunction on dyslipidaemia and cardiovascular disease is largely unknown. This study used mendelian randomisation (MR), where a genetic variant is used as an instrumental variable to detect the causal effects of exposure to disease. This study used two sample MR analyses to find out whether clinical thyroid function measures show a causal relationship with the changes in lipid levels. The results showed a significant association between the elevated thyrotropin (TSH) level and increased total cholesterol. Also, there was a significant correlation between the free triiodothyronine (FT3): free thyroxine (FT4) ratio and total cholesterol and low-density lipoprotein (LDL). Further robust studies are required to confirm the results and investigate the causal effect of thyroid hormone dysregulation and cardiometabolic diseases due to the limitations of this study. However, healthcare professionals can use the results of this study to understand the importance of the pituitary-thyroid-cardiac axis in lipid metabolism and its impact on cardiometabolic health.
Abstract
BACKGROUND Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.
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Ferulic Acid Supplementation Improves Lipid Profiles, Oxidative Stress, and Inflammatory Status in Hyperlipidemic Subjects: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Bumrungpert, A, Lilitchan, S, Tuntipopipat, S, Tirawanchai, N, Komindr, S
Nutrients. 2018;10(6)
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Cardiovascular disease (CVD) is a leading cause of death. Smoking cessation, regular physical exercise and dietary modification can decrease the risk of developing CVD. Ferulic acid is a compound found in many plant foods with anti-inflammatory and antioxidant properties. The aim of this double-blind, placebo-controlled study was to evaluate the effect of ferulic acid supplementation, 500mg twice daily for six weeks, on CVD risk markers in patients with hyperlipidaemia (elevated blood lipids). Ferulic acid significantly improved lipid profile, decreased oxidative stress and reduced inflammation compared to placebo. No adverse effects were reported. The authors conclude that ferulic acid supplementation improves lipid profiles, oxidative stress, and inflammatory status in hyperlipidaemic subjects and may lower risk of CVD.
Abstract
Ferulic acid is the most abundant phenolic compound found in vegetables and cereal grains. In vitro and animal studies have shown ferulic acid has anti-hyperlipidemic, anti-oxidative, and anti-inflammatory effects. The objective of this study is to investigate the effects of ferulic acid supplementation on lipid profiles, oxidative stress, and inflammatory status in hyperlipidemia. The study design is a randomized, double-blind, placebo-controlled trial. Subjects with hyperlipidemia were randomly divided into two groups. The treatment group (n = 24) was given ferulic acid (1000 mg daily) and the control group (n = 24) was provided with a placebo for six weeks. Lipid profiles, biomarkers of oxidative stress and inflammation were assessed before and after the intervention. Ferulic acid supplementation demonstrated a statistically significant decrease in total cholesterol (8.1%; p = 0.001), LDL-C (9.3%; p < 0.001), triglyceride (12.1%; p = 0.049), and increased HDL-C (4.3%; p = 0.045) compared with the placebo. Ferulic acid also significantly decreased the oxidative stress biomarker, MDA (24.5%; p < 0.001). Moreover, oxidized LDL-C was significantly decreased in the ferulic acid group (7.1%; p = 0.002) compared with the placebo group. In addition, ferulic acid supplementation demonstrated a statistically significant reduction in the inflammatory markers hs-CRP (32.66%; p < 0.001) and TNF-α (13.06%; p < 0.001). These data indicate ferulic acid supplementation can improve lipid profiles and oxidative stress, oxidized LDL-C, and inflammation in hyperlipidemic subjects. Therefore, ferulic acid has the potential to reduce cardiovascular disease risk factors.
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Testosterone Deficiency, Weakness, and Multimorbidity in Men.
Peterson, MD, Belakovskiy, A, McGrath, R, Yarrow, JF
Scientific reports. 2018;8(1):5897
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With age, the occurrence of total testosterone (TT) deficiency in men also increases. Such deficiency can have a detrimental impact on the musculoskeletal system leading to bone and muscle loss, increasing the risk of cardiovascular disease and all-cause mortality. Hence muscle weakness is a known a predicitve factor for chronic disease. Whereby reference ranges have been set for testosterone levels in young healthy men, uncertainty exists about optimal levels throughout different age ranges, ethnicities and in concurrence with diseases. This observational study evaluated how TT deficiency and muscle weakness assessed via grip strength, relates to chronic health conditions in men. The study included 2399 young, middle-aged, and older men in the US, with a diverse ethnic backgrounds, who presented with and without testosterone deficiency. The findings indicated that TT levels were highest amongst young men, yet no particular difference was seen in levels between middle-aged and older men. Grip strength decreased in the higher age categories. Chronic health conditions were more common in young and older men who displayed testosterone deficiencies, whilst low testosterone and reduced grip strength were linked to the presence of chronic disease in all age groups. Overall the study confirmed previous research, that in men with testosterone deficiency chronic disease was much more prevalent, even after accounting for other variables. The study also observed a much lower average of TT levels in young men compared to previous research, in mostly white males. Thus testosterone deficiency appears much more common in men of all ages when including a variety of ethnic groups. As low testosterone may play an early, causal role in the chronic disease process, continuous monitoring of testosterone levels through the life span may aid the early identification of chronic disease development or disease progression. Further research is needed on the independent and joint effects of low TT and muscular weakness. From a clinical perspective, this study affirms that low testosterone in men is a presenting risk factor for chronic disease and that chronic disease is commonly accompanied by low testosterone. It also highlights some unsettled aspects around reference ranges of testosterone
Abstract
The purposes of this study were to evaluate the association between total testosterone (TT) deficiency and weakness on multimorbidity in men. Analyses were performed to examine the prevalence of multimobidity among young, middle-aged, and older men, with and without testosterone deficiency. Multivariate logistic models were also used to determine the association between age-specific TT tertiles and multimorbidity, adjusting for key sociodemographic variables, as well as a secondary analysis adjusted for grip strength. Multimorbidity was more prevalent among men with testosterone deficiency, compared to normal TT in the entire group (36.6% vs 55.2%; p < 0.001); however, differences were only seen within young (testosterone deficiency: 36.4%; normal TT: 13.5%; p < 0.001) and older men (testosterone deficiency: 75.0%; normal TT: 61.5%; p < 0.001). Robust associations were found between the age-specific low-TT (OR: 2.87; 95%CI: 2.14-3.83) and moderate-TT (OR: 1.67; 95%CI: 1.27-2.20) tertiles (reference high-TT) and multimorbidity. Secondary analysis demonstrated that both low TT (OR: 1.82; 95%CI: 1.29-2.55) and moderate-TT (OR: 1.31; 95%CI: 1.01-1.69) were associated with multimorbidity, even after adjusting for obesity (OR: 1.75; 95%CI: 1.07-2.87) and NGS (OR: 1.21 per 0.05 unit lower NGS). Low TT and weakness in men were independently associated with multimorbidity at all ages; however, multimorbidity was more prevalent among young and older men with testosterone deficiency.
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Randomized placebo control study of insulin sensitizers (Metformin and Pioglitazone) in psoriasis patients with metabolic syndrome (Topical Treatment Cohort).
Singh, S, Bhansali, A
BMC dermatology. 2016;16(1):12
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As an immune-mediated chronic inflammatory skin condition, psoriasis is associated with obesity, metabolic syndrome, diabetes, and cardiovascular disease. Medications capable of sensitising insulin, such as Metformin and Pioglitazone, have also shown benefits in improving factors associated with metabolic syndrome and psoriasis. This single-centre, parallel-group, randomised, open-label with blinded endpoint evaluated the effects of Metformin with Pioglitazone and placebo in psoriatic patients. Patients with mild-to-moderate psoriasis were randomised to a topical treatment cohort to take 1000 mg metformin daily or 30 mg pioglitazone or placebo groups for 12 weeks. Each participant received a topical ointment containing 5% coal tar during the treatment period. The Metformin and Pioglitazone groups showed significant improvements in psoriasis and metabolic syndrome parameters, such as fasting plasma glucose, total cholesterol, and triglyceride levels, after 12 weeks of treatment. The treatment with metformin resulted in significant improvements in weight, BMI, waist circumference, FPG, triglycerides, and total cholesterol, while the treatment with pioglitazone resulted in significant improvements in FPG, triglycerides, systolic and diastolic blood pressure, cholesterol levels, and LDL cholesterol levels. There was no significant improvement in inflammatory cytokine levels in any group. For further evaluation of the beneficial effects of insulin-sensitising drugs in patients suffering from psoriasis and metabolic syndrome, more robust studies are needed. The study results can be used by healthcare professionals to better understand how insulin-sensitising drugs may decrease the risk of diabetes, cardiovascular disease, and psoriasis in psoriasis patients with metabolic syndrome.
Abstract
BACKGROUND Increased prevalence of metabolic syndrome (MS) is observed in psoriasis. Metformin has shown improvement in cardiovascular risk factors while pioglitazone demonstrated anti proliferative, anti-inflammatory and anti angiogenic effects. Study objective is to evaluate the efficacy and safety of Insulin sensitizers (metformin and pioglitazone) in psoriasis patients with metabolic syndrome (MS). METHODS Single centre, parallel group, randomized, study of metformin, pioglitazone and placebo in psoriasis patients with MS. RESULTS Statistically significant improvement was observed in Psoriasis Area and Severity Index (PASI), Erythema, Scaling and Induration (ESI) and Physician global assessment (PGA) scores in pioglitazone (p values - PASI = 0.001, ESI = 0.002, PGA = 0.008) and metformin groups (p values - PASI = 0.001, ESI = 0.016, PGA = 0.012) as compared to placebo. There was statistically significant difference in percentage of patients achieving 75 % reduction in PASI and ESI scores in metformin (p value - PASI = 0.001, ESI = 0.001) and pioglitazone groups (p vaue - PASI = 0.001, ESI = 0.001). Significant improvement was observed in fasting plasma glucose (FPG) and triglycerides levels in metformin and pioglitazone arms. Significant improvement was noted in weight, BMI, waist circumference, FPG, triglycerides and total cholesterol after 12 weeks of treatment with metformin while pioglitazone showed improvement in FPG, triglyceride levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and LDL cholesterol levels. There was no difference in pattern of adverse drug reaction in three groups. CONCLUSION Insulin sensitizers have shown improvement in the parameters of MS as well as disease severity in psoriasis patients. TRIAL REGISTRATION CTRI Registration Number: CTRI/2011/12/002252 . Registered on 19/12/2011.