A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus

Vinod Abichandani; Atul Kalhan

doi:10.4103/cdrp.cdrp_CDRP_20_22

REVIEW ARTICLE

Year : 2023 | Volume : 2 | Issue : 1 | Page : 26-45

A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus

Vinod Abichandani¹, Atul Kalhan²
¹ Department of Endocrinology, Raj Hospital, Ahmedabad, Gujarat, India
² Department of Endocrinology, Royal Glamorgan Hospital and University Hospital of Wales, Cardiff, Wales, UK

Date of Submission	28-Oct-2022
Date of Decision	13-Dec-2022
Date of Acceptance	16-Dec-2022
Date of Web Publication	18-Jan-2023

Correspondence Address:
Vinod Abichandani
Ramanand Clinic, 7, Vishwadeep Society, Ranip, Ahmedabad - 382 480 Gujarat
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_CDRP_20_22

Abstract

Background: There is a lack of consensus regarding efficacy and cardiovascular (CV) safety of testosterone-replacement therapy (TRT) in men with late-onset hypogonadism (LOH) secondary to obesity ±type 2 diabetes mellitus (T2DM). This is because of limited number of prospective randomized clinical trials (RCTs) in this cohort. Methods: A comprehensive retrospective review of medical literature was carried out using Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework to assess the CV outcomes and safety of TRT in men with LOH. The review included scientific publications from January 2000 to July 2021, which included men with obesity ± T2DM. Results: Out of the 723 publications, which were identified on preliminary screening, 154 conformed to broad inclusion criteria for this systematic review of literature. Out of these 154 publications, 34 studies with a total number of 4,365,684 patients were finally included for this systematic review (9 randomized controlled trials, 6 meta-analyses and 19 observational studies). Studies investigating whether TRT offers protection against CV disease (CVD) and stroke generally concluded that the use of Testosterone (T) in middle-aged to elderly men has no detrimental impact on their CV risk. Older men with T2DM, obesity and metabolic syndrome are likely to benefit from TRT, as several studies point to an improvement in insulin sensitivity, markers of inflammation, time to Angina, CV risk, CV mortality, and even all-cause mortality. Conclusions: This retrospective systematic review of the literature, suggests modest efficacy of TRT in reducing major adverse cardiovascular events (MACEs) and all-cause mortality in men with LOH secondary to obesity and/or T2DM. TRT was associated with an increased risk of overall CVDs and MACE only when T preparations were given at supratherapeutic dosage or when TRT was offered to frail men. The findings of the current review could not confirm TRT as a cause of adverse CV events.

Keywords: Cardiovascuar events, cardiovascular mortality, hypogonadism, late-onset hypogonadism, major adverse cardiovascular events, metabolic syndrome, obesity, testosterone, testosterone replacement therapy, type 2 diabetes mellitus

How to cite this article:
Abichandani V, Kalhan A. A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus. Chron Diabetes Res Pract 2023;2:26-45

How to cite this URL:
Abichandani V, Kalhan A. A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus. Chron Diabetes Res Pract [serial online] 2023 [cited 2023 Jun 2];2:26-45. Available from: https://cdrpj.org//text.asp?2023/2/1/26/368026

Introduction

Obesity is a chronic metabolic disorder and contributes to more than 80% of the overall risk of developing T2DM.^[1] Insulin resistance is at the core of both adiposity and T2DM. Around 33% of men with T2DM have hypogonadotropic hypogonadism (HH) and this augments their risk of cardiovascular (CV) and all-cause mortality. Another 33% of men with obesity or T2DM have subnormal free testosterone concentrations with inappropriately normal gonadotropin concentrations.^[2] Men with HH are more prone to developing T2DM. Men with general debility and poor health will experience accelerated age-related decline in their androgen levels.^[3] Motivational weight loss helps correct erectile dysfunction and low T levels in overweight or obese men.^[4],[5]

Aging in men is accompanied by a small but progressive decline in several sex hormones, in particular total and free testosterone (FT) and dehydroepiandrosterone (DHEA).^[6] Testosterone (T) is present in three different forms in the human blood circulation. About half of circulating testosterone is bound to SHBG, and another close to half to albumin. As a result only 0.5% to 3% of the testosterone is non-protein-bound, and is referred to as Free T.^[7] Bioavailable T (the sum of FT plus HSA-bound testosterone) ensures optimum bone mineral density and muscle strength, induces hematopoiesis, improves sexual performance along with libido, and provides a cardioprotective effect. There may be some relative increases in luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin levels.^[8]

In the landmark Baltimore Longitudinal Study of Aging, hypogonadism was observed in 20% of men over 60 years of age, in 30% of men over 70 years and in 50% of men over 80 years of age.^[6] Hypogonadism in aging men, referred to as late-onset hypogonadism (LOH),^[9] is defined as a clinical and biochemical set of symptoms that occur due to an age-related drop in testosterone levels.

Various scientific societies maintain that an insufficient circulating T cannot alone define LOH and that such T deficiency should be accompanied by specific symptoms.^[10] Cluster of symptoms due to T deficiency include psychological (e.g., depression), physical (e.g., fatigue), and sexual dysfunction. Several clinical practice guidelines recommend testosterone-replacement therapy (TRT) for adult hypogonadal men with inadequate T levels, with an aim to ensure symptomatic relief and to raise the T levels close to the mid-normal range for young men.^{[11],[12],[13]}

Over the last decade, an exponential increase has been reported globally, in testosterone use, simply to address vague symptoms. In fact, many men, lured by some tall claims made by direct advertisers, have received T not for any confirmed, symptomatic T deficiency, but purely to boost up their body image and libido. Lack of evidence-based prescriptions of TRT was noticed when a large cohort of 63000 men from the Truven Health Marketscan® Commercial and Medicare Supplemental Insurance Database was analyzed, with 29% of the beneficiaries being offered TRT without any baseline T estimation. Only 12% had their gonadotropins measured before the initiation of TRT.^[14]

T levels start declining from fourth decade onwards in males. This decline has been implicated in the increased all-cause mortality and CV risk.^[15],[16] However, simply offering TRT to patients with low T does not necessarily guarantee reduction in the risk of CVD and/or overall mortality.^[17],[18] Whether low T and CV risk have a specific cause-and-effect relationship remains an enigma.^[19] Many observational studies have concluded that T deficiency is associated with an increased number of major adverse cardiovascular event (MACE) (such as myocardial infarction [MI] and stroke) and total or CV mortality [Table 1]. However, most of these studies were not designed to capture CV events as a primary outcome and hence had excluded persons with history of CVD.^[20]

Table 1: Population-based cohort studies showing association between low T and total or cardiovascular mortality

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Confoundingly, the impact of TRT on CV outcomes remains contested especially in subgroup of men with obesity ± T2DM and/or metabolic syndrome.^[21],[22] The dose of TRT and the mode of administration remain contentious.^[23] More effective routes of testosterone administration include intramuscular (IM) injection or skin application in the form of gel.^[24]

Epidemiological studies reveal an increased prevalence of sexual dysfunction in men with T2DM.^{[2],[25],[26]} Sexual dysfunction leads to poor quality of life and is the key symptom of functional hypogonadism in men with T2DM.

The 2016 guidelines of the Australian Endocrine Society had endorsed an earlier 2015 position statement by the Food and Drug Administration (FDA).^[27] that described the differences between true hypogonadism (which occurs due to some congenital or acquired organic damage to the brain or the testis and requires TRT) and LOH (due to age-related comorbidities, it may not require TRT).

Unlike the FDA, the American Urological Association, The American Association of Clinical Endocrinology (AACE) and the American College of Endocrinology (ACE) recommend the use of TRT in symptomatic confirmed hypogonadal men regardless of etiology, only after appropriately counseling the patients about the potential risks.^[27]

It is difficult to establish whether restoring T levels to normal values by adequate TRT protects against MACE or impedes the progression of atherosclerosis. This can be done only with the help of properly designed, large multi-center RCTs of long duration.

The Knowledge Gap

After careful examination and analysis of the literature, it is apparent that there are gaps in the medical community's understanding of the CV benefits and hazards of TRT in older males with symptomatic hypogonadism. Although exogenous TRT reduces fat mass and increase muscle mass, its effects on symptoms of sexual dysfunction^{[28],[29],[30]} and CV parameters^{[31],[32],[33]} are not uniform. Moreover, the long-term risks of TRT in men with T2DM and functional hypogonadism remain unclear.

Practicing HCPs have been confronted with conundrum regarding the safety of TRT, following red flags raised by the FDA in their 2015 position statement concerning TRT.

To address these gaps, the questions were articulated with a goal to answer them through high-quality Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based analysis of the literature [Table 2].

Table 2: List of questions articulated for the purpose of systematic review

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In an attempt to get the better of the limitations of the currently available evidence, an updated, in-depth systematic review of all placebo-controlled randomized clinical trials (RCTs) and relevant observational studies on the effect of TRT on CV-related outcomes was performed. Specifically, the focus was on older hypogonadal men, especially the ones with Type 2 diabetes, obesity, and/or metabolic syndrome.

Methods

This systematic review follows the PRISMA 2020 statement: An updated guideline for reporting systematic reviews.^[34] An extensive search of select trials and relevant reviews was conducted and the results are described below.

Data Sources and Searches

The PubMed and Google Scholar were searched for relevant literature in English language, published between January 2000 and July 2021. Terms such as “testosterone,” “TRT,” “androgen replacement therapy,” “type 2 diabetes” “obesity,” “metabolic syndrome,” “hypogonadism,” and “trial” were used for this screening purpose.

The initial research resulted in over 20,000 papers. After refining the search by using the keywords in conjunction with each other, a total of 723 papers were shortlisted. A thorough screening of the abstracts, key objectives, and conclusions of these 723 studies was carried out. Out of the 160 pertinent papers quoted, 34 studies formed the main corpus of this review.

RCTs, which captured CV events by both the study arms, were included for further analysis. Studies, which reported CV events only in the active TRT arm but failed to share similar data for the placebo arm, were excluded. The main text of this systematic review highlights the salient features of select studies, while the rest of the included research is summarized in the attached tables. [Figure 1] outlines the search and selection protocol.

Figure 1: Flow diagram depicting the literature search and selection protocol

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Data Extraction and Quality Assessment

A statistician was engaged to calculate the number of trial participants randomized to various study arms, and to record the CV events in each arm. For quality assessment of the trials included, the following parameters were considered: presence of tables enumerating individually, various CV-related events experienced during the trial duration, and information regarding whether such events preceded the allocation to either TRT or a placebo (non-TRT) arm.

Sensitivity Analysis

The key sensitivity analyses looked at the baseline T levels and the type of TRT used while studying their individual impact on occurrence of CV events. CV mortality was included as an outcome of interest. The risk of bias was studied using the Cochrane Risk of Bias Tool. The overall quality of the 34 studies included in the current manuscript, ranged from low to medium in terms of their methodology. The average duration of these studies varied from 3 months to 3 years.

Discussion

The discussion will focus on studies addressing the research questions mentioned in [Table 2].

The Link between Obesity, Type 2 Diabetes Mellitus, and Metabolic Syndrome with Hypogonadism

According to Quang and Kalhan,^[35] T2DM and/or metabolic syndrome are associated with HH. An alarming number (40%) of men with T2DM were found to have hypogonadism by some studies.^[36],[37] Up to 75% of such individuals may present with symptoms such as altered libido and erectile issues including lack of morning erections.

Lowered circulating total testosterone level in obese males is partly explained by diminished SHBG levels documented in such individuals. Three peptides, kisspeptin, NKB, and dynorphin (DYN), are found in a single subpopulation of neurons in the hypothalamic arcuate nucleus (ARC). The inputs from these neurons regulate pulsatile GnRH secretion.^[38] The GPR54-kisspeptin pathway is downregulated in morbid obesity and T2DM. This leads to suppression of the hypothalamic–pituitary–testicular axis and low serum T levels. A vicious cycle of excess visceral fat and a flare-up of pro-inflammatory cytokines ensues, augmenting the CV risk in such individuals. PWD have lower circulating T compared to normal individuals.^[39] Interestingly, higher T levels have been reported to mitigate the risk of developing T2DM.^[40]

Various studies looking at the aging male have found both low T and low SHBG to be vital risk factors for metabolic syndrome and T2DM, in both obese and nonobese men.^{[41],[42],[43]} Holmboe et al.^[44] in a study that included 5250 Danish men followed for almost three decades, observed that participants with low T and low SHBG had greater chance of developing T2DM. Low T has been identified as a marker for obesity^[45],[46] and vice versa, obesity is implicated as a driving factor in T deficiency.^[47] An increased incidence of diabetes is noticed in men with Klinefelter's syndrome. Abrupt withdrawal of TRT in men with hypogonadism can lower their insulin sensitivity.^[48] Androgen deprivation therapy for prostate cancer can precipitate hyperglycemia and some features of the metabolic syndrome.^[49] Such observations endorse the medical opinion that T deficiency may cause diabetes in some men.

In spite of availability of such indicative findings, strategies to prevent T2DM do not focus on low T. This is explained by the unavailability of proven causal relationship of low T with T2DM and by the tendency to pursue weight reduction to correct low T. A large number of males with metabolic disorders exhibit functional interruption of their gonadal axis, accompanied by moderate reductions in T levels. Such low T concentrations respond well to appropriate weight reduction and management of comorbidities. Majority of older PWD with symptomatic hypogonadism may require simultaneous lifestyle modification, TRT and therapies to address erectile dysfunction.^[50]

Effects of Testosterone-Replacement Therapy in Persons with Type 2 Diabetes Mellitus or Metabolic Syndrome

In a study by Daka et al.,^[51] PWD were found more prone to develop acute MI if their T levels were low. TRT, offered for adequate duration to hypogonadal PWD or MetS appears to favorably impact many of the associated risk factors for CVD in these subjects. Reduction of central adiposity and a subsequent decrease in insulin resistance, point to a possibility of CV benefits with TRT of longer duration.

Parameters such as waist circumference (irrespective of BMI), insulin resistance, fasting blood sugar, HbA1c, and serum leptin levels came down from baseline in the TRT arm compared to placebo users.^{[31],[36],[52]} Overall impact on lipids was neutral.^[53] T-induced decreases in various harmful lipid fractions can alleviate CV risk. However, T may marginally decrease the levels of the 'good' HDL cholesterol.

In the TIMES2 (Testosterone replacement In hypogonadal men with either MEtabolic Syndrome or type 2 diabetes) study by Jones et al.^[54] transdermal TRT continued for at least 6 months resulted in improvement of insulin resistance, lipid levels and health-related quality of life in the study subjects [Table 3].

Table 3: Trial studying the effects of testosterone-replacement therapy in persons with type 2 diabetes mellitus or metabolic syndrome

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A meta-analysis by Corona et al.,^[55] while attempting to examine the relationship between TRT and T2DM, revealed that TRT facilitates glycemic control and optimizes HbA1C, triglycerides, and body fat mass in PWD.

Corona et al.^[56] tried to decipher the link between testosterone and MetS by carrying out a meta-analysis that included 21 studies exploring the role of TRT in MetS. The findings of this meta-analysis indicated that TRT led to improvement of fasting plasma glucose, fasting triglycerides, HDL, insulin sensitivity and waist circumference, without any impact on total cholesterol or the BMI.

TRT was shown to improve exercise tolerance and delay appearance of effort induced ST segment changes during a treadmill test.^[57] T could increase the myocardial perfusion supplied by unobstructed coronary arteries. TRT has been shown to alter inflammatory markers favorably, levels of tumor necrosis factor alpha go down and those of interleukin-10, which is anti-inflammatory in nature, increase.^[58],[59]

Optimum treatment with physiological replacement doses of T in the elderly males has no documented adverse impact on the serum levels of the inflammatory marker high-sensitivity C-reactive protein (CRP).^[60] TRT does not alter the levels of prothrombotic factors such as tissue plasminogen activator, plasminogen activator inhibitor-1, and fibrinogen.^[61] Li et al.,^[62] while sharing the results of a meta-analysis, observed that TRT improved the metabolic milieu and facilitated weight loss.

Adverse Cardiovascular Effects of Testosterone-Replacement Therapy in Men with Low Testosterone

Responding to a spurt of T prescriptions, certain investigators conducted trials that suggested that TRT caused adverse CV events.^[63],[64] One of these trials called the Testosterone in Older Men With Mobility Limitations (TOM)^[65] had to be prematurely stopped because of excessive CV events in the TRT arm. This instigated the FDA to investigate the suspected detrimental role of TRT in causing adverse CV event rate.

The TOM trial results were released in 2010. Interestingly, the trial had aimed primarily to study improvement in leg muscle strength with TRT, but had to be halted in view of a larger number of CV events in the TRT arm, compared to the placebo arm (23 versus 5 events). Another peculiar finding of this study was that, while on TRT, persons with T levels in excess of 500 ng/dL suffered from more adverse CV events compared to those whose T levels remained below 500 ng/dL. The elder population with multiple comorbidities were perhaps exposed to stringent exercise protocol enforced during the trial.

This trial received criticism because of the short duration of TRT (6 months) and very wide confidence intervals arrived at, possibly due to erroneous statistical analysis. The TOM^[65] investigators later on agreed that their results could be a chance occurrence.

Subsequently, the FDA analysis took cognizance of two observational and retrospective trials.

The first trial results reported by Vigen et al.^[22] shared outcomes of 8709 hypogonadal men (T levels <300 ng/dL), who underwent coronary angiography earlier. Men who were offered TRT postcardiac catheterization had higher number of cardio-cerebrovascular events compared to the group never initiated on TRT, irrespective of presence or absence of CAD. Both the groups had similar control of their risk factors such as blood pressure and lipids and comparable use of secondary prevention medicines as indicated.

A year later, a statistical correction was announced by Vigen et al.,^[66] stating that the rate of CV events in the active TRT arm was actually lower by 50% compared to the no-TRT arm. This meant a major deviation from the groups' data published in 2013. Other shortcomings, such as offering low-dose topical TRT, not achieving adequate concentrations of T, lack of clarity regarding the duration of prescription, failure to repeat T tests periodically during follow-up, and statistical errors, were chastised by several critics.^{[15],[67],[68],[69],[70],[71]}

A retrospective cohort study reported in 2014 by Finkle et al.^[72] observed that after the first prescription of a topical T preparation in elderly persons over 65 year old, or in persons <65 years of age with prior history of heart disease, the risk of developing an acute nonfatal MI was significantly elevated. This risk remained substantially higher when compared to the use of phosphodiesterase 5 inhibitors in similar age group people in either category.

Despite the flaws identified later on, both of the abovementioned trials garnered undue publicity after managing some unfounded spread of misinformation claiming enhanced cardio-cerebrovascular events due to TRT. In fact, this instigated the New York Times to come out with an editorial captioned “Overselling Testosterone, Dangerously.”

Xu et al,^[73] conducted an important systematic review and meta-analysis of TRT that included only those trials where TRT was offered for at least 3months or longer. The authors concluded that more acute adverse CV events occurred mainly in T users with high background CV risk (any T preparation). There were differences observed in the results of various placebo-controlled trials included in this meta-analysis, and pharma sponsors could, according to the authors, due to influence, wield these. It was felt by various critics that the selection of trials for this research was biased in favor of studies that had captured CV event(s).

Budoff et al.^[74] studied the impact of daily topical TRT on noncalcified coronary artery plaque volume. The calibrations were done using computer-aided coronary angiography. TRT was found to increase this parameter compared to a placebo, despite the fact that the elderly citizens who received TRT harbored more CV risk factors such as dyslipidemia, hyperglycemia, and high blood pressure, compared to placebo users [Table 4].

Table 4: Trials studying adverse cardiovascular effects of testosterone-replacement therapy in men with low testosterone

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Soisson et al.^[75] observed that in senior male citizens, a level of CRP ≥2 mg/L suggestive of subclinical inflammation may accompany reduced plasma T levels and higher carotid intima-media thickness

According to some researchers, TRT can lead to worsening of OSA-obstructive sleep apnea^[76] and an overexpression of vascular cell adhesion molecule 1 (VCAM1),^[77] and together these deleterious effects can accelerate the process of atherosclerosis and partially explain the higher incidence of CV events reported by some TRT studies. In general, short-term worsening of parameters such as oxygen desaturation index and nighttime hypoxemia are noticed in obese men with preexisting severe OSA, once they are initiated on TRT. Long-acting testosterone undecanoate preparations have been shown to improve insulin sensitivity and diminish hepatic fat deposition.^[76]

Low serum T level has been implicated as an independent risk factor in the development of Non-Alcoholic Fatty Liver Disease (NAFLD).^[78] Seo et al.^[79] could document low T levels in NAFLD candidates compared to normal individuals. A recent study has witnessed improvement in liver function in hypogonadal males, when they were put on long-term TRT.^[80] Every improvement in the features of NAFLD can translate into lower incidence of CVD.^[81]

Testosterone and its metabolites can exert varied impact on the CV system, making the pathophysiological connect between low T, TRT, and CVD, difficult to understand [Table 5].^{[82],[83],[84]} Reduced T levels can compromise endothelial health and coronary microcirculation.^[35]

Table 5: Effects of testosterone and its metabolites on the cardiovascular system

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In summary, the aforementioned studies that have tried to highlight the CV hazards of TRT have been unable to put forth any unequivocal or convincing proof of their claims. This lack of clarity stems from analytical bias/errors and questionable study protocols.

Effects of Testosterone and Its Metabolites on the Cardiovascular System

Several elegant papers have alluded to the CV protective benefits of TRT in hypogonadal men. Two of the studies reviewed by the FDA had demonstrated an increase in mortality when hypogonadal men were not offered TRT. Shores et al.^[85] could show a statistically significant 50% drop in mortality in the older veterans put on adequate TRT, compared to those who were not initiated on TRT. The mortality benefit of TRT persisted even after taking into account all confounders such as age, BMI, baseline T levels, and other comorbidities. The Shores study was criticized for its faulty methodology. Another important study involving persons with T2DM and confirmed hypogonadism was done by Muraleedharan et al.^[86] The researchers retrospectively looked at the all-cause mortality rates of participants with T levels of ≤300 ng/dl and found them to be twice as high, compared to those PWD with T levels >300 ng/dl. Those study participants who were offered long-term TRT had much lower mortality rates (8.4%) compared to those who did not receive TRT (19.2%).

Sharma et al.^[87] retrospectively studied a large cohort of veterans with low T. The authors conceptually divided this large cohort into three clinical groups: Group 1 were the complete responders to TRT, Group 2 participants had inadequate rise of their T in response to the given doses of TRT and Group 3 did not receive TRT. Group 1 people, whose T had risen into the desired range, had the lowest incidence of all-cause mortality and Cardio-Cerebrovascular events. This study underlined the importance of optimizing T levels nearer to upper values of normal range with the help of appropriate doses of testosterone.

Data provided by Anderson et al.^[88] suggested that TRT for low testosterone (<212 ng/l) in men (mean age 62.2 years), managed by appropriately trained and qualified physicians is relatively safe at the end of 1 and 3 years of adequate TRT, when TRT to high levels is avoided. A total number of 4,736 hypogonadal men were studied to capture composite of all-cause death or nonfatal MI or stroke as a primary endpoint. TRT could normalize the T to desired levels and resulted in lower mortality and CV morbidity.

Wallis et al.^[89] retrospectively analyzed a large cohort of elderly hypogonadal men. Approximately 27% of them were offered TRT and the rest of the study population served as controls. They were followed up for over 5 years. TRT users had statistically significantly lower mortality and fewer adverse CV events, compared to controls.

Baillargeon et al.^[90] carried out an in-depth retrospective analysis of 6355 men suffering from hypogonadism and concluded that TRT not only is CV safe but may even confer some CV protection to the hypogonadal males having multiple CV risk factors.

Hackett et al.^[91] made an incisive analysis of the impact of TRT initiation either alone, or along with PDE5i and HMG-CoA inhibitors on all-cause mortality in T2DM men with hypogonadism. The authors concluded that PWD with low T who were not offered TRT had the highest all-cause mortality when compared either to those PWD whose low T was adequately corrected with TRT, or to the members of the study cohort who already had normal T levels since their inclusion in the study. According to the authors, combination of TRT, PDE5i and statins proved to be synergistic and helped bring down mortality rates in the aging elderly males.

Cheetham et al.^[92] carried out a retrospective cohort study to examine the effects of dispensed TRT on incidence of Cardio-Cerebrovascular events and sudden cardiac death (SCD) in men aged 40 years and above having documented low T levels. The authors opined that dispensed TRT provided to men with hypogonadism, helped in bringing down occurrence of MACE, SCD, Strokes and the need for coronary stenting or bypass grafting, by an impressive 33%.

Traish et al.^[93] furnished interesting and reassuring results of an observational study carried out by them to ascertain the safety and efficacy of long term T Undecanoate (TU) therapy in men with hypogonadism. The authors stated that prolonged TU therapy was uniquely safe and ensured excellent patient adherence to the treatment. Moreover, this treatment protocol was associated with negligible mortality or occurrence of no-fatal cardio or cerebrovascular events.

Gagliano-Jucá et al.^[94] selected two RCTs (the testosterone and pain and the testosterone effects on atherosclerosis in aging men [TEAAM] trials) to assess the changes, if any, induced by TRT on electrocardiographic parameters such as corrected QT (QTc) interval. The authors surmised that TRT helps in preventing the age related QTc interval prolongation. Muensterman et al.^[95] could replicate these results in their series of hypogonadal men aged ≥65. Topical application of T in these men could prevent drug-induced QTc prolongation.

Snyder et al.,^[30] while reporting results of their RCT, shared that TRT was as CV safe as a placebo at the end of 1 year of its regular topical use.

Basaria et al.^[96] tried to ascertain in a RCT TEAAM whether TRT for older males with hypogonadism could arrest the progression of subclinical atherosclerosis and improve their sexual health and HRQoL. The authors could document statistically insignificant, yet numerically visible decreases in intima-media-thickness in the aortic arteries and the coronary artery calcium scores, in individuals regularly using topical T daily for 36 months.

Carson and Rosano^[97] selected for a review article, several meta-analysis and RCTs published between years 2004-2012. Their elegant effort endorsed the CV safety of TRT, when offered to older men (>45 years of age) with proved hypogonadism [Table 6].

Table 6: Trials studying protective value of testosterone-replacement therapy against cardiovascular disease and strokes

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Almost 20% of men with heart failure (HF) have symptoms due to established low T and the physical incapacities conferred by HF correlate well with the severity of hypogonadism, TRT offered to such HF patients can improve their exercise capacity and overall QOL and prognosis, especially when T2DM or obesity coexist.^[98]

Several trials have shown that overweight men with hypogonadism display favorable body composition changes when initiated on TRT (an increase in lean body mass at the cost of body fat).^[99],[100] This could translate into a lower incidence of adverse CV events. Such metabolic benefits are not enjoyed by eugonadal men who were treated with T supplements.^[101]

Levels of Endogenous T Affecting the Occurrence of Cardiovascular Disease in Older Men

Ohlsson et al.^[102] tried to answer two questions when they chose to study 2416 elderly men, recruited in the MrOS (Osteoporotic Fractures in Men) trial. The first question was “Does endogenous T protect men against CV events?” And the second was “Can SHBG predict CV events?”, 485 CV events were recorded during the follow-up period. It was observed that T levels in the higher normal range (680 ± 127 ng/dL) in this study, correlated with a statistically vital 23% risk reduction of CV events during a 5-year follow-up, when compared to lower serum levels of T. High serum T but not SHBG offered such a benefit [Table 7].

Table 7: Trials studying effects of higher or lower levels of endogenous testosterone on the occurrence of cardiovascular disease in older men

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Some of the participants in the Copenhagen City Heart study (4615 men) were followed up for 29 years. It was observed that those with significantly reduced levels of T had excessive occurrence of neuroischemic cerebral injuries,^[103] The European Prospective Investigation into Cancer in Norfolk study^[104] came up with some interesting data. The authors found that every 173 ng/dl rise in endogenous T levels was associated with approximately 14% lesser risk of all-cause mortality. Furthermore, it was observed that men with the highest levels of endogenous T enjoyed significantly lower possibility of all-cause mortality, compared to men whose T levels fell under the lowest segment. This study received flak because the investigators had managed only one measurement of total T and free T was never measured.^[105] Yet another famous study came out with similar findings, wherein men whose T levels remained below 241 ng/dl ran a 38% higher risk of experiencing adverse CV events.^[106]

Yeap et al.^[107] studied 3690 community dwelling males, 70-89 years old who were residents of Perth city. They concluded that older men whose T and DHT (Dihydrotestosterone) levels remained above the desired mid-range experienced least all-cause mortality rates. Higher levels of the metabolite DHT were shown to mitigate the risk of mortality due to ischemic heart disease.

According to Goodale et al.,^[108] high normal endogenous T concentration confers a reduced CV risk; TRT improves known CV risk factors and brings down mortality, when offered to T-deficient men compared to those T-deficient men who remain untreated.

An association has been repeatedly found between low T and other CVD risk factors such as high blood pressure, persistent hyperglycemia, dyslipidemia, and elevated fibrinogen values. English et al., in 2000,^[109] could identify low levels of bio-available T in elderly males having preexisting CAD [Table 8].

Table 8: Randomized placebo-controlled testosterone trials done between year 2000 and 2009 with cardiovascular events as a primary endpoint

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Aging males with established hypogonadism are vulnerable to development of CVD and strokes. Tivesten et al.^[110] could highlight the relationship between low T and low serum free T with presence of PAD (peripheral arterial disease) in seventy-plus men. Akishita et al.,^[111] in their study of 171 middle-aged men age, could reiterate the independent relationship between low endogenous T and the higher associated risk of CV events.

Araujo et al.^[112] did a systematic review and meta-analysis, trying to decipher the relationship between low endogenous T and mortality in older men. They could establish relationship between low titers of endogenous T and enhanced all-cause and CV mortality in the study subjects. However, statistically significant heterogeneity between the studies included in the meta-analysis, prevented the authors from issuing any firm conclusions. Militaru et al.^[113] gathered from their small prospective study of older men with acute MI, that the lowest T levels were independently associated with maximum mortality rates. Thompson et al. in their study of 32 elderly men with stable CAD, concluded that acute T supplementation does not improve or deteriorate the onset and gravity of stress-induced myocardial ischemia in such individuals.^[114] On similar lines, Li et al.^[115] suggested in their study of 800 plus men that study participants whose T levels fell under the highest bracket, experienced statistically much less severe CV events.

Various epidemiological studies have observed that elderly men, whose T levels remain below normal, often succumb to a MACE.^[116] Similar findings have been echoed in men with T2DM.^[86] Hu et al.^[117] studied a small number of 87 men in their early fifties who were suffering from various grades of CAD. These researchers could implicate both low endogenous T and higher BMI in the occurrence of CV events.

Farias et al.^[118] tried to scrutinize the effects of low T on markers of atherosclerosis progression, in 79 PWD aged around 50 years. The authors could infer that low total T appeared to be an independent risk factor (after discounting various confounders such as age, body mass, dyslipidemia, and degree of hyperglycemia) for progression of IMT (Intima-Media-Thickness) and worsening of endothelial dysfunction.

Haring et al.^[118] carried out a population based study of 1954 men, with average age 63 years and a low baseline T value of ≤250 ng/dl. Low baseline T levels were found to be directly associated with an excess of CV mortality after removing other possible risk factors such as lack of exercise, obesity, kidney impairment, and bad lifestyle habits.

Corona et al.^[56] carried out a meta-analysis of more than 12,500 individuals, all with low T. 41% of these persons had pre-existing CAD and they displayed much lower total T levels when compared to participants without pre-existing CAD. The authors postulated that lower total T levels, but not DHEA or elevated estradiol (E2) were independently contributed to the presence of prior CAD.

In yet another study of 3637 men aged around 77 years, Hyde et al.^[119] found that lower free T levels were consistently and in a statistically vital manner, associated with higher CV mortality rates.

Soisson et al.,^[120] while comparing the impact of both lower and higher endogenous levels of total T on incidence of ischemic arterial disease (IAD), found that both these extreme end levels of endogenous total T as well as the sum of albumin-bound and free T are significantly associated with greater number of IAD events. These observations underscore the importance of optimizing T levels in older men.

An independent association was documented between lowest T and free T levels and all-cause mortality in older men, during a retrospective analysis of their data captured over a 4-year follow-up period. This analysis was conducted by Pye et al.,^[121] who had arrived at this conclusion after removing various confounders such as general debility, unhealthy lifestyle choices, dysglycemia, and obesity.

As can be seen from these studies, in elderly men, low T has a distinct association with higher CVD morbidity and mortality. Whether the low T is directly detrimental to the CV health of these individuals or just serves as predictor of impending CV events, remains contentious.

Risk of Thromboembolism with Testosterone-Replacement Therapy

Warnings issued by the FDA regarding possibilities of thromboembolism precipitated by TRT should be examined closely. All available modes of TRT induce very high concentrations of red blood cells and amplify platelet activation. These effects are thought to make the blood more viscous and result in thromboembolic events.^[122] However, it is yet not clear whether this is per se due to TRT or due to an age related elevations of serum estrogens in hypogonadal elderly males.^[123]

Recently, two different meta-analyses failed to pinpoint any increment of venous thromboembolism in patients on TRT, the first with odds ratio (OR) 1.9 (95% confidence interval [CI] 0.75–5.17)^[123] and the second with OR 1.41 (95% CI 0.96-2.07).^[124] The route of T usage did not make any difference to these findings.

Discerning views were expressed by Martinez et al.^[125] and Walker et al.^[126] These two groups of investigators arrived at a common conclusion that venous thromboembolic events were frequently seen within 6 months of initiation of TRT in hypogonadal men, irrespective of the route of exposure.

Level of Evidence Currently Available Regarding Testosterone-Replacement Therapy

The FDA issued an advisory in 2015 that raised concerns regarding possible adverse CV effects of TRT. This was based on findings of few observational trials and a meta-analysis, that suggested greater risk of adverse CV events in the TRT arm^{[22],[65],[72],[73]} However, the observations made by Vigen et al.^[22] were criticized for their flawed statistical analyses.

In contrast, Haddad et al.^[127] and Corona et al.^[128] found no increased CV risk in their research. In fact, several other observational studies^{[85],[86],[87],[90]} could demonstrate decreased CV risk or occurrence of MACEs^[88] with TRT. A systematic review by Huo et al.^[129] suggested that TRT might improve cardiac pump function and exercise tolerance.

Current Guidance for Testosterone-Replacement Therapy and the Future Strategy

Certain evidence-based recommendations were made in 2017 regarding offering TRT, guided by levels of low total T [Table 9]: ^[130] Symptomatic males with total T <230.8 ng/dL ought to be offered appropriate TRT. Initiating a therapeutic challenge with TRT for a minimum duration of 6 months would be justified when offered to men whose total T levels hover between 230 and 346 ng/dL.

Table 9: Testosterone-replacement therapy in men: Main indications and contraindications

Click here to view

The American Urology Association guidelines stress upon raising awareness regarding perils of untreated hypogonadism in men including elevated CV risk.^[131] According to the AACE/ACE,^[13] it is advisable to confirm low total T or free T in two separate early morning blood samples. Once done, such low T levels should be accompanied by relevant symptoms to stamp a diagnosis of hypogonadism.

Most RCTs of TRT have not been specific CV outcome trials, rather they have occasionally reported CV outcomes, while pursuing other primary endpoints like Muscle mass and power, and impact on glycemia. Hence, most of these trials have refrained from including candidates with history of significant cardiac pump dysfunction, acute coronary syndrome or acute cerebrovascular accidents.^[132]

In future, we need large and long-term RCTs of TRT in hypogonadal men with uniformly pre-specified and defined primary endpoints of MACE and mortality. Such RCTs should include a large number of older males with obesity, persistent hyperglycemia and classified metabolic syndrome. The TRAVERSE trial (ClinicalTrials.govIdentifier: NCT03518034),^[133] is the first ongoing RCT that is empowered enough to issue a reliable guidance in future, regarding the influence of prolonged TRT on the CV system in men with hypogonadism and multiple metabolic disorders.

Reasons for the Contradictory Cardiovascular Results Reported by Various Testosterone-Replacement Therapy Trials and Ways to Address Them?

The CV effects of TRT have been intensely studied and widely contested, with mixed results in the literature.^{[22],[16],[65],[69],[72],[73],[128],[134],[135],[136],[137]}

Factors responsible for the divergent results of TRT studies include dissimilar database,^[138] some devoid of accurate description of various medical comorbidities^{[72],[139],[140]} and health of the testes.^[89],[141] Methodological discrepancies,^[142] such as immortal time bias^[143] and having missed to regulate the time-oriented changes in various covariates, may also contribute to the conundrum.^[90]

Nonuniform trial protocols, differing definitions of CV events, short duration of trial, lack of adequate statistical power to draw any firm conclusion, and questionable therapeutic strategies, all may additionally contribute to the contradictory CV outcomes of research focusing on TRT.

Prolonged T use in elderly men has been shown to confer CV benefits in several studies.^{[87],[92],[128]} Sharma et al.^[87] stated that TRT use could reduce all-cause mortality by an impressive 56% and the incidence of MI by 24%. Contrary to such reassuring reports, few studies involving short-term T use have shown evidence of harm. However, these studies had a number of shortcomings.^[144]

Shores et al.^[145] have attempted to overcome such methodological lacunae, while studying the association between TRT and CVD. The investigators recruited a cohort of military veterans, having high background CV risk. The investigators divided T exposure as current use, former use, and no use, which helped them to capture intermittent treatment, too. They deftly bracketed T exposure into transdermal and IM formulations, thus considering the vast differences in Pharmacokinetics/Pharmacodynamics (PK/PD) of these two types of T preparations.^[146]

Shores et al.^[145] also tried to compare current T users to previous T users in the large cohort of T-treated men (82,555) and CV events, to remove bias arising out of comparing “any T use-no T use” categories of men or comparing T treated to untreated men.^[147]

Learning from Meta-Analyses Exploring the Impact of T on Cardiovascular Health in Hypogonadal Men?

The results of an earlier meta-analysis by Calof et al.^[148] showed that the CV event rates remained unaffected by TRT. Similar findings have been shared by many other trials. A rise in hematocrit of more than 50% from baseline value was the most common side effect noted. This may prove detrimental in acute coronary syndrome, on the other hand, may be helpful in correcting anemia of old age. A small drop of HDL cholesterol, clinically of doubtful significance, was also noticed [Table 10].^[149]

Table 10: Comparison of the included meta-analysis

Click here to view

Haddad et al.^[127] carried out a systematic review of RCTs that examined the effects of T on CV health of men with proven hypogonadism. This group found many methodological lacunae in the RCTs included for the review. Only few of the selected trials reported allocation concealment, thus lending bias to the methodology. The authors alluded to the CV safety of TRT, albeit, supported by insufficient evidence.

RCTs included in a systematic review by Isidori et al.^[150] were analyzed primarily for the effects of T on lipid fractions, body fat composition and bone health. The lipid effects were inexplicable, however the authors felt that there was some decrease in visceral fat that could translate into CV benefits.

Significant risk of bias, lack of precision, and inconsistency among trials included for their research, prevented Alexander et al.^[137] from drawing any definite conclusion regarding CV safety or superiority of TRT, when compared to a placebo [Table 11].

Table 11: Comparison of the meta-analyses included in the manuscript

Click here to view

Corona et al.^[151] importantly could highlight that the low quality, short duration, and inadequate power of trials included in their meta-analysis were the major drawbacks that prevented the researchers from drawing any major conclusions.

Conclusions

This research was carried out to evaluate CV safety and benefits (if any) related to TRT use in men with hypogonadism secondary to nongonadal illness (visceral obesity ± T2DM). The evidence related to TRT use in men with obesity ± T2DM has been derived mainly from observational studies with only a limited number of RCTs which have been carried out in this cohort. Majority of the studies confirm that TRT is CVD safe in older men. TRT aggravated overall CVDs and MACE only when T was administered in supratherapeutic dosage or when TRT was offered to older and frail men. Excess T and pharmacological (experimental) T dosages can worsen sleep disordered breathing and gynecomastia and cause an increase in hematocrit. To avoid excessive dosing, serum T levels and hematocrit levels need to be monitored (more closely after initiation of TRT and annually once on stable TRT dose) [Table 12].

Table 12: Benefits versus potential risks of testosterone-replacement therapy

Click here to view

In conclusion, the signs and symptoms of hypogonadism in men with visceral adiposity ± T2DM should never escape a clinician's attention. Biochemical confirmation of diagnosis by checking early morning testosterone and luteinizing hormone levels and excluding treatable causes of central hypogonadism (e.g., prolactinoma, opioids, anabolic steroid abuse, pituitary macroadenoma, and rarely hemochromatosis) remain crucial steps in management. Lifestyle modification and weight loss remain the key steps in improving overall metabolic profile of such men. TRT use in such men with biochemically confirmed secondary hypogonadism is deemed safe and associated with modest CVD benefits. Prescribing TRT should be a well-informed and careful decision with pros and cons of therapy being explained to the patient.

There is a need for well-structured RCTs enrolling a large number of “at higher CV risk” elderly persons with central obesity ± T2DM to develop a better understanding of impact of TRT in this cohort.

Acknowledgement

The authors would like to thank Mr. Mitul Patel, CEO, Bhumi Medicines for the help in the data search and preparation of the tables.

Ethical statement

The institutional Ethics Committee of University of South Wales on Thu approved this research, 12 Aug 2021, under the LOW RISK projects with a green light approval pathway.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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