madman
Super Moderator
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 (2023)
Vinod Abichandani, Atul Kalhan
Background: There is a lack of consensus regarding the 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 the limited number of prospective randomized clinical trials(RCTs) in this cohort.
Methods: A comprehensive retrospective review of medical literature was carried out using the 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 the literature. Out of these 154 publications, 34 studies with a total number of 4,365,684 patients were finally included in 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 the 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.
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 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] The cluster of symptoms due to T deficiency includes 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.[11-13]
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. A 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 were 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 the fourth decade onwards in males. This decline has been implicated in increased all‑cause mortality and CV risk.[15,16] However, simply offering TRT to patients with low T does not necessarily guarantee a 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 events (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 a history of CVD.[20]
Confoundingly, the impact of TRT on CV outcomes remains contested especially in subgroups 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 a 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 increases muscle mass, its effects on symptoms of sexual dysfunction[28‑30] and CV parameters[31-33] 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 a 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 the goal to answer them through high‑quality Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA)‑based analysis of the literature [Table 2].
*In an attempt to get a 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.
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
*Effects of Testosterone‑Replacement Therapy in Persons with Type 2 Diabetes Mellitus or Metabolic Syndrome
*Adverse Cardiovascular Effects of Testosterone‑Replacement Therapy in Men with Low Testosterone
*Effects of Testosterone and Its Metabolites on the Cardiovascular System
*Levels of Endogenous T Affecting the Occurrence of Cardiovascular Disease in Older Men
*Risk of Thromboembolism with Testosterone‑Replacement Therapy
*Level of Evidence Currently Available Regarding Testosterone‑Replacement Therapy
*Current Guidance for Testosterone‑Replacement Therapy and the Future Strategy
*Reasons for the Contradictory Cardiovascular Results Reported by Various Testosterone‑Replacement Therapy Trials and Ways to Address Them?
*Learning from Meta‑Analyses Exploring the Impact of T on Cardiovascular Health in Hypogonadal Men?
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 that have been carried out in this cohort. The 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].
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 the 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 the 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 the impact of TRT in this cohort.
Vinod Abichandani, Atul Kalhan
Background: There is a lack of consensus regarding the 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 the limited number of prospective randomized clinical trials(RCTs) in this cohort.
Methods: A comprehensive retrospective review of medical literature was carried out using the 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 the literature. Out of these 154 publications, 34 studies with a total number of 4,365,684 patients were finally included in 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 the 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.
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 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] The cluster of symptoms due to T deficiency includes 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.[11-13]
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. A 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 were 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 the fourth decade onwards in males. This decline has been implicated in increased all‑cause mortality and CV risk.[15,16] However, simply offering TRT to patients with low T does not necessarily guarantee a 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 events (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 a history of CVD.[20]
Confoundingly, the impact of TRT on CV outcomes remains contested especially in subgroups 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 a 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 increases muscle mass, its effects on symptoms of sexual dysfunction[28‑30] and CV parameters[31-33] 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 a 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 the goal to answer them through high‑quality Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA)‑based analysis of the literature [Table 2].
*In an attempt to get a 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.
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
*Effects of Testosterone‑Replacement Therapy in Persons with Type 2 Diabetes Mellitus or Metabolic Syndrome
*Adverse Cardiovascular Effects of Testosterone‑Replacement Therapy in Men with Low Testosterone
*Effects of Testosterone and Its Metabolites on the Cardiovascular System
*Levels of Endogenous T Affecting the Occurrence of Cardiovascular Disease in Older Men
*Risk of Thromboembolism with Testosterone‑Replacement Therapy
*Level of Evidence Currently Available Regarding Testosterone‑Replacement Therapy
*Current Guidance for Testosterone‑Replacement Therapy and the Future Strategy
*Reasons for the Contradictory Cardiovascular Results Reported by Various Testosterone‑Replacement Therapy Trials and Ways to Address Them?
*Learning from Meta‑Analyses Exploring the Impact of T on Cardiovascular Health in Hypogonadal Men?
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 that have been carried out in this cohort. The 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].
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 the 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 the 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 the impact of TRT in this cohort.
