[h=1]Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study[/h]
[h=3]Background/objectives[/h]Long-term testosterone therapy (TTh) in men with hypogonadism has been shown to improve all components of the metabolic syndrome. In this study, we investigated the effects of long-term TTh up to 8 years in hypogonadal men with a history of cardiovascular disease (CVD).
[h=3]Patients and methods[/h]In two urological clinics observational registries, we identified 77 hypogonadal men receiving TTh who also had a history of CVD. The effects of TTh on anthropometric and metabolic parameters were investigated for a maximum duration of 8 years. Any occurrence of major adverse cardiovascular events was reported. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals.
[h=3]Results[/h]In 77 hypogonadal men with a history of CVD who received TTh, we observed a significant weight loss and a decrease in waist circumference and body mass index. Mean weight decreased from 114±13 kg to 91±9 kg, change from baseline: −24±1 kg and −20.2%±0.5%. Waist circumference decreased from 112±8 cm to 99±6 cm, change from baseline: −13±0.3 cm. Body mass index decreased from 37±4 to 29±3, change from baseline: −8±0.2 kg/m2. Cardio-metabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time.
[h=3]Conclusion[/h]In men with hypogonadism, TTh appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.
Keywords: testosterone, long-term testosterone therapy, cardiovascular risk, hypogonadism, secondary prevention
[h=2]Introduction[/h]Testosterone (T) deficiency (TD; hypogonadism) is a well-established medical condition, which has been recognized for >70 years. T therapy (TTh) has been long reported as an effective and safe treatment in patients with TD, and several studies have reported beneficial effects of TTh in patients with peripheral vascular disease and angina pectoris.1 Over the past several decades, a wealth of knowledge has accumulated regarding the negative impact of hypogonadism on men’s overall health and quality of life.2Furthermore, the deleterious effects of androgen deprivation therapy (ADT) in men with prostate cancer on cardiometabolic risk seem to be well established.3
Despite the common belief that T may increase the incidence of coronary artery disease (CAD), the scientific evidence suggests that TD increases the likelihood and the degree of coronary atherosclerosis.4Hypogonadism is associated with increased cardiometabolic risk and increased risk of all-cause and cardiovascular (CV) mortality,1,4–7 while higher T levels were associated with lower incidence of sudden cardiac arrest.8
Despite the wealth of knowledge in the field of TTh and CV health,1 a few studies have recently reported controversial outcomes.9–12 However, in response to a petition to place a black box warning on T products, both the US Food and Drug Administration and the European Medicines Agency have evaluated the available evidence and concluded that there was no credible evidence that TTh contributes to increased cardiovascular disease (CVD) risk. More recent medium-term studies have refuted such claims.13–19 To date, no long-term studies have assessed the effects of TTh in men with a history of CVD. Here, we report on the effects of long-term TTh in 77 men with TD and a history of CVD.
[h=2]Patients and methods[/h][h=3]Patients[/h]From two prospective, cumulative observational registries of 622 unselected patients presenting to two urology clinics with hypogonadism (defined as T ≤12.1 nmol/L in the presence of symptoms), we identified 77 men (12.4% of all patients) with a history of CVD. In this subgroup, 77 men with a previous diagnosis of CAD (n=48) and/or a history of myocardial infarction (MI; n=40) and/or stroke (n=7) were analyzed. Mean age at baseline was 61±5 years and mean follow-up time 7.3±1.2 years (minimum: 4 years and maximum: 8 years). All 77 men were continuously treated with testosterone undecanoate (TU) injections (Nebido®; Bayer AG, Leverkusen, Germany) in 3-monthly intervals, following an initial interval of 6 weeks, for up to 8 years. Men were entered into the registry once they had received 1 year of treatment. Inclusion criteria were two separate morning measures of total testosterone ≤12.1 nmol/L and the presence of hypogonadal symptoms measured by the Aging Males’ Symptoms scale (AMS). Exclusion criteria for T administration included previous treatment with androgens, prostate cancer, or any suspicion thereof, such as prostate-specific antigen levels >4 ng/mL or abnormal findings upon digital rectal examination, International Prostate Symptom Score (IPSS) >19 points, breast cancer, recent angina, or severe untreated sleep apnea.
[h=3]Assessment and follow-up[/h]At each or each other visit, we measured the following parameters: total plasma T levels, weight, waist circumference (WC), body mass index (BMI), hemoglobin, hematocrit, fasting glucose levels, glycated hemoglobin (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DPB), heart rate, pulse pressure, lipid profile (total cholesterol [TC], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides [TGs]), C-reactive protein, and liver transaminases. We also assessed prostate volume, prostate-specific antigen, and questionnaires IPSS, AMS, and International Index of Erectile Function, Erectile Function domain (IIEF-EF). Measures were taken between two and four times per year, and annual average was calculated. Ethical guidelines as formulated by the German “Ärztekammer” (the German Medical Association) for observational studies in patients receiving standard treatment were followed. According to these guidelines, no formal ethical approval is required for the evaluation of results obtained during standard treatment. After receiving an explanation regarding the nature and the purpose of the study, all subjects provided written consent to be included in the registry and have their data analyzed. Measurements of the parameters measured in this study were carried out as previously described.20,21
Statistical analyses were described previously. Briefly, for continuous variables, mean, median, standard deviation, range, minimum, maximum, and sample size for the sample were reported at each time point. For categorical variables, the frequency distribution was reported. We tested the hypotheses regarding change in outcome scores across the study period by fitting a linear mixed-effects model to the data. Time (to indicate follow-up interviews) was included as a fixed effect in the model. A random effect was included in the model for the intercept. Estimation and test of change in scores were determined by computing the differences in least square means at baseline versus the score at each follow-up visit.20,21
[h=2]Results[/h][h=3]Baseline characteristics[/h]Baseline clinical characteristics of the 77 patients included in the long-term registry are described in Table 1: mean age was 61±5 years (minimum: 43 and maximum: 68). Approximately 52% of the subjects had a previous MI, and 9% had a previous stroke. A previous diagnosis of CAD had been made in 62% of the subjects. In all, 53% had type 2 diabetes mellitus. Furthermore, 94% of the subjects were on antihypertensives, 75% on statins, and 48% on antidiabetic medications.
Table 1
Baseline comorbidities and concomitant medication in 77 hypogonadal men with a history of cardiovascular diseases
[h=3]Effects of long-term TTh on weight loss, WC, and BMI[/h]A marked and significant weight loss (WL) was observed after 8 years of continuous TTh in the 77 hypogonadal men receiving TTh (Figure 1A). WL was progressive and significant from year to year and amounted to 24 kg after 8 years. The percentage of change in weight over the follow-up period is shown in Figure 1B. Gradual and significant fractional change in weight is noted. The percentage of change was progressive and increased with continuous treatment and appeared more marked after the initial period (model adjusted 2.6% after 1 year, 7.1% after 2 years, 10.4% after 3 years, 13.2% after 4 years, 15.4% after 5 years, 17.4% after 6 years, 19.0% after 7 years, and 20.2% after 8 years). The gradual WL was accompanied by a marked and significant gradual decrease in WC (Figure 1C). The reduction in WC in response to TTh was significant from year to year and amounted to 13 cm at the end of the follow-up period of 8 years (model adjusted 1.7% after 1 year, 4.4% after 2 years, 6.3% after 3 years, 7.7% after 4 years, 8.8% after 5 years, 9.6% after 6 years, 10.4% after 7 years, and 11.1% after 8 years). The anthropometric data were also analyzed to determine the changes in BMI. As shown in Figure 1D, considerable and significant reduction in BMI was observed over the entire follow-up period with a mean reduction of 8 kg/m2.
Figure 1
Anthropometric parameters in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=3]Effects of long-term TTh on metabolic parameters[/h][h=4]Effects on HbA1c[/h]Over the course of treatment, a significant and sustained change in the levels of HbA1coccurred: 7.6% at baseline, 7.2% after 1 year, 6.8% after 2 years, 6.6% after 3 years, 6.4% after 4 years, 6.2% after 5 years, 6.0% after 6 years, 5.9% after 7 years, and 5.7% after 8 years (Figure 2). By the end of follow-up period, a reduction in HbA1c of 2.0% was recorded (P<0.0001).
Figure 2
HbA1c (%) in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
Long-term TTh resulted in decreased fasting glucose from 6.0±1.2 mmol/L to 5.2±0.4 mmol/L. The change from baseline was −0.9±0.1 mmol/L (P<0.0001).
The TGs:HDL ratio, a surrogate marker of insulin resistance, decreased from 5.4±2 to 2.5±0.6 (P<0.0001).
[h=4]Effects on lipid profiles[/h]TTh resulted in gradual and consistent decrease in TC levels. The decrease was statistically significant as early as 12 months (P<0.0001) and reached a plateau at 48 months (P<0.01 vs 36 months, thereafter nonsignificant). TC decreased from 7.8±0.9 mmol/L to 4.8±0.2 mmol/L, LDL from 4.7±0.9 mmol/L to 3.0±0.7 mmol/L, and TGs from 3.4±0.7 mmol/L to 2.1±0.1 mmol/L. HDL increased from 1.6±0.5 mmol/L to 2±0.5 mmol/L. The TC:HDL ratio declined from 5.5±2.0 to 2.6±0.7. Non-HDL cholesterol decreased from 241±30 mg/dL to 108±21 mg/dL (P<0.0001 for all).
[h=4]Effects on SBP and DBP[/h]TTh produced marked and sustained gradual decrease in SBP from 164±14 mmHg to 133±9 mmHg representing a reduction of 33±1 mmHg (P<0.0001; Figure 3A). The decrease was significant and gradual over the first 6 years and remained low over the entire course of the 8 years of treatment. Similar results were recorded with the DBP, which decreased from 99±11 mmHg to 77±5 mmHg representing a reduction of 24±1 mmHg (P<0.0001; Figure 3B). Again, a marked decrease was noted over the first 6 years of treatment and then remained low over the entire 8 years of treatment.
Figure 3
Blood pressure (mmHg) in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=4]Effects on pulse pressure[/h]As shown in Figure 4, long-term TTh in hypogonadal patients with a history of CVD resulted in marked and significant reduction in pulse pressure from 65±6 to 57±8. The reduction in pulse pressure was gradual and significant over the course of treatment versus baseline as well as compared to the previous year for the first 2 years, with a mean change in pulse pressure of 9±1 at the end of the follow-up period.
Figure 4
Pulse pressure in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=4]Effects on heart rate and inflammation[/h]Heart rate (bpm) decreased from 79±4 to 73±2. C-reactive protein (mg/dL) declined from 3.7±4.5 to 0.2±0.3 (P<0.0001).
[h=4]Effects on liver enzymes[/h]Both aspartate aminotransferase and alanine aminotransferase decreased significantly.
[h=4]Effects on quality of life[/h]Questionnaires for general quality of life (AMS), voiding function (IPSS), and erectile function (IIEF-EF) improved significantly. Table 2 summarizes the findings of this study with regard to the changes in metabolic parameters and quality of life in men with history of CVD.
Table 2
Changes following testosterone therapy in anthropometric, metabolic, and quality of life parameters in hypogonadal men with a history of cardiovascular diseases
[h=3]Safety and compliance[/h]No patient had a major adverse CV event. No patient had a urological event (prostate cancer or voiding dysfunction). No patient missed a single injection. No patient dropped out.
[h=3]Background/objectives[/h]Long-term testosterone therapy (TTh) in men with hypogonadism has been shown to improve all components of the metabolic syndrome. In this study, we investigated the effects of long-term TTh up to 8 years in hypogonadal men with a history of cardiovascular disease (CVD).
[h=3]Patients and methods[/h]In two urological clinics observational registries, we identified 77 hypogonadal men receiving TTh who also had a history of CVD. The effects of TTh on anthropometric and metabolic parameters were investigated for a maximum duration of 8 years. Any occurrence of major adverse cardiovascular events was reported. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals.
[h=3]Results[/h]In 77 hypogonadal men with a history of CVD who received TTh, we observed a significant weight loss and a decrease in waist circumference and body mass index. Mean weight decreased from 114±13 kg to 91±9 kg, change from baseline: −24±1 kg and −20.2%±0.5%. Waist circumference decreased from 112±8 cm to 99±6 cm, change from baseline: −13±0.3 cm. Body mass index decreased from 37±4 to 29±3, change from baseline: −8±0.2 kg/m2. Cardio-metabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time.
[h=3]Conclusion[/h]In men with hypogonadism, TTh appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.
Keywords: testosterone, long-term testosterone therapy, cardiovascular risk, hypogonadism, secondary prevention
[h=2]Introduction[/h]Testosterone (T) deficiency (TD; hypogonadism) is a well-established medical condition, which has been recognized for >70 years. T therapy (TTh) has been long reported as an effective and safe treatment in patients with TD, and several studies have reported beneficial effects of TTh in patients with peripheral vascular disease and angina pectoris.1 Over the past several decades, a wealth of knowledge has accumulated regarding the negative impact of hypogonadism on men’s overall health and quality of life.2Furthermore, the deleterious effects of androgen deprivation therapy (ADT) in men with prostate cancer on cardiometabolic risk seem to be well established.3
Despite the common belief that T may increase the incidence of coronary artery disease (CAD), the scientific evidence suggests that TD increases the likelihood and the degree of coronary atherosclerosis.4Hypogonadism is associated with increased cardiometabolic risk and increased risk of all-cause and cardiovascular (CV) mortality,1,4–7 while higher T levels were associated with lower incidence of sudden cardiac arrest.8
Despite the wealth of knowledge in the field of TTh and CV health,1 a few studies have recently reported controversial outcomes.9–12 However, in response to a petition to place a black box warning on T products, both the US Food and Drug Administration and the European Medicines Agency have evaluated the available evidence and concluded that there was no credible evidence that TTh contributes to increased cardiovascular disease (CVD) risk. More recent medium-term studies have refuted such claims.13–19 To date, no long-term studies have assessed the effects of TTh in men with a history of CVD. Here, we report on the effects of long-term TTh in 77 men with TD and a history of CVD.
[h=2]Patients and methods[/h][h=3]Patients[/h]From two prospective, cumulative observational registries of 622 unselected patients presenting to two urology clinics with hypogonadism (defined as T ≤12.1 nmol/L in the presence of symptoms), we identified 77 men (12.4% of all patients) with a history of CVD. In this subgroup, 77 men with a previous diagnosis of CAD (n=48) and/or a history of myocardial infarction (MI; n=40) and/or stroke (n=7) were analyzed. Mean age at baseline was 61±5 years and mean follow-up time 7.3±1.2 years (minimum: 4 years and maximum: 8 years). All 77 men were continuously treated with testosterone undecanoate (TU) injections (Nebido®; Bayer AG, Leverkusen, Germany) in 3-monthly intervals, following an initial interval of 6 weeks, for up to 8 years. Men were entered into the registry once they had received 1 year of treatment. Inclusion criteria were two separate morning measures of total testosterone ≤12.1 nmol/L and the presence of hypogonadal symptoms measured by the Aging Males’ Symptoms scale (AMS). Exclusion criteria for T administration included previous treatment with androgens, prostate cancer, or any suspicion thereof, such as prostate-specific antigen levels >4 ng/mL or abnormal findings upon digital rectal examination, International Prostate Symptom Score (IPSS) >19 points, breast cancer, recent angina, or severe untreated sleep apnea.
[h=3]Assessment and follow-up[/h]At each or each other visit, we measured the following parameters: total plasma T levels, weight, waist circumference (WC), body mass index (BMI), hemoglobin, hematocrit, fasting glucose levels, glycated hemoglobin (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DPB), heart rate, pulse pressure, lipid profile (total cholesterol [TC], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides [TGs]), C-reactive protein, and liver transaminases. We also assessed prostate volume, prostate-specific antigen, and questionnaires IPSS, AMS, and International Index of Erectile Function, Erectile Function domain (IIEF-EF). Measures were taken between two and four times per year, and annual average was calculated. Ethical guidelines as formulated by the German “Ärztekammer” (the German Medical Association) for observational studies in patients receiving standard treatment were followed. According to these guidelines, no formal ethical approval is required for the evaluation of results obtained during standard treatment. After receiving an explanation regarding the nature and the purpose of the study, all subjects provided written consent to be included in the registry and have their data analyzed. Measurements of the parameters measured in this study were carried out as previously described.20,21
Statistical analyses were described previously. Briefly, for continuous variables, mean, median, standard deviation, range, minimum, maximum, and sample size for the sample were reported at each time point. For categorical variables, the frequency distribution was reported. We tested the hypotheses regarding change in outcome scores across the study period by fitting a linear mixed-effects model to the data. Time (to indicate follow-up interviews) was included as a fixed effect in the model. A random effect was included in the model for the intercept. Estimation and test of change in scores were determined by computing the differences in least square means at baseline versus the score at each follow-up visit.20,21
[h=2]Results[/h][h=3]Baseline characteristics[/h]Baseline clinical characteristics of the 77 patients included in the long-term registry are described in Table 1: mean age was 61±5 years (minimum: 43 and maximum: 68). Approximately 52% of the subjects had a previous MI, and 9% had a previous stroke. A previous diagnosis of CAD had been made in 62% of the subjects. In all, 53% had type 2 diabetes mellitus. Furthermore, 94% of the subjects were on antihypertensives, 75% on statins, and 48% on antidiabetic medications.
Table 1
Baseline comorbidities and concomitant medication in 77 hypogonadal men with a history of cardiovascular diseases
[h=3]Effects of long-term TTh on weight loss, WC, and BMI[/h]A marked and significant weight loss (WL) was observed after 8 years of continuous TTh in the 77 hypogonadal men receiving TTh (Figure 1A). WL was progressive and significant from year to year and amounted to 24 kg after 8 years. The percentage of change in weight over the follow-up period is shown in Figure 1B. Gradual and significant fractional change in weight is noted. The percentage of change was progressive and increased with continuous treatment and appeared more marked after the initial period (model adjusted 2.6% after 1 year, 7.1% after 2 years, 10.4% after 3 years, 13.2% after 4 years, 15.4% after 5 years, 17.4% after 6 years, 19.0% after 7 years, and 20.2% after 8 years). The gradual WL was accompanied by a marked and significant gradual decrease in WC (Figure 1C). The reduction in WC in response to TTh was significant from year to year and amounted to 13 cm at the end of the follow-up period of 8 years (model adjusted 1.7% after 1 year, 4.4% after 2 years, 6.3% after 3 years, 7.7% after 4 years, 8.8% after 5 years, 9.6% after 6 years, 10.4% after 7 years, and 11.1% after 8 years). The anthropometric data were also analyzed to determine the changes in BMI. As shown in Figure 1D, considerable and significant reduction in BMI was observed over the entire follow-up period with a mean reduction of 8 kg/m2.
Figure 1
Anthropometric parameters in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=3]Effects of long-term TTh on metabolic parameters[/h][h=4]Effects on HbA1c[/h]Over the course of treatment, a significant and sustained change in the levels of HbA1coccurred: 7.6% at baseline, 7.2% after 1 year, 6.8% after 2 years, 6.6% after 3 years, 6.4% after 4 years, 6.2% after 5 years, 6.0% after 6 years, 5.9% after 7 years, and 5.7% after 8 years (Figure 2). By the end of follow-up period, a reduction in HbA1c of 2.0% was recorded (P<0.0001).
Figure 2
HbA1c (%) in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
Long-term TTh resulted in decreased fasting glucose from 6.0±1.2 mmol/L to 5.2±0.4 mmol/L. The change from baseline was −0.9±0.1 mmol/L (P<0.0001).
The TGs:HDL ratio, a surrogate marker of insulin resistance, decreased from 5.4±2 to 2.5±0.6 (P<0.0001).
[h=4]Effects on lipid profiles[/h]TTh resulted in gradual and consistent decrease in TC levels. The decrease was statistically significant as early as 12 months (P<0.0001) and reached a plateau at 48 months (P<0.01 vs 36 months, thereafter nonsignificant). TC decreased from 7.8±0.9 mmol/L to 4.8±0.2 mmol/L, LDL from 4.7±0.9 mmol/L to 3.0±0.7 mmol/L, and TGs from 3.4±0.7 mmol/L to 2.1±0.1 mmol/L. HDL increased from 1.6±0.5 mmol/L to 2±0.5 mmol/L. The TC:HDL ratio declined from 5.5±2.0 to 2.6±0.7. Non-HDL cholesterol decreased from 241±30 mg/dL to 108±21 mg/dL (P<0.0001 for all).
[h=4]Effects on SBP and DBP[/h]TTh produced marked and sustained gradual decrease in SBP from 164±14 mmHg to 133±9 mmHg representing a reduction of 33±1 mmHg (P<0.0001; Figure 3A). The decrease was significant and gradual over the first 6 years and remained low over the entire course of the 8 years of treatment. Similar results were recorded with the DBP, which decreased from 99±11 mmHg to 77±5 mmHg representing a reduction of 24±1 mmHg (P<0.0001; Figure 3B). Again, a marked decrease was noted over the first 6 years of treatment and then remained low over the entire 8 years of treatment.
Figure 3
Blood pressure (mmHg) in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=4]Effects on pulse pressure[/h]As shown in Figure 4, long-term TTh in hypogonadal patients with a history of CVD resulted in marked and significant reduction in pulse pressure from 65±6 to 57±8. The reduction in pulse pressure was gradual and significant over the course of treatment versus baseline as well as compared to the previous year for the first 2 years, with a mean change in pulse pressure of 9±1 at the end of the follow-up period.
Figure 4
Pulse pressure in hypogonadal men with a history of cardiovascular disease receiving long-term testosterone therapy.
[h=4]Effects on heart rate and inflammation[/h]Heart rate (bpm) decreased from 79±4 to 73±2. C-reactive protein (mg/dL) declined from 3.7±4.5 to 0.2±0.3 (P<0.0001).
[h=4]Effects on liver enzymes[/h]Both aspartate aminotransferase and alanine aminotransferase decreased significantly.
[h=4]Effects on quality of life[/h]Questionnaires for general quality of life (AMS), voiding function (IPSS), and erectile function (IIEF-EF) improved significantly. Table 2 summarizes the findings of this study with regard to the changes in metabolic parameters and quality of life in men with history of CVD.
Table 2
Changes following testosterone therapy in anthropometric, metabolic, and quality of life parameters in hypogonadal men with a history of cardiovascular diseases
[h=3]Safety and compliance[/h]No patient had a major adverse CV event. No patient had a urological event (prostate cancer or voiding dysfunction). No patient missed a single injection. No patient dropped out.