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BACKGROUND: Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction. OBJECTIVE: To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism. METHODS: Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones. RESULTS: Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model-predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone. CONCLUSION: During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones.
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BACKGROUND: Recent observational and Mendelian randomization analyses have reported significant effects of very-low-density lipoprotein cholesterol (VLDL-C) on risk that is independent of ApoB. OBJECTIVES: To determine the independent association of VLDL-C and ApoB with the risk of new-onset cardiovascular events in the UK Biobank and the Framingham Heart Study Cohort. METHODS: We included 294â 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 52 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C. RESULTS: In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; P<0.001) but weakly negatively correlated with HDL-C (r=-0.11; P<0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.06, respectively; P<0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; P<0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; P=0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; P<0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; P=0.029). All results were consistent in the Framingham cohort. CONCLUSIONS: When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.
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BACKGROUND AND AIMS: Despite growing evidence that apolipoprotein B (apoB) is the most accurate marker of atherosclerotic cardiovascular disease (ASCVD) risk, its adoption in clinical practice has been low. This investigation sought to determine whether low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and triglycerides are sufficient for routine cardiovascular care. METHODS: A sample of 293 876 UK Biobank adults (age: 40-73 years, 42% men), free of cardiovascular disease, with a median follow-up for new-onset ASCVD of 11 years was included. Distribution of apoB at pre-specified levels of LDL-C, non-HDL-C, and triglycerides was examined graphically, and 10-year ASCVD event rates were compared for high vs. low apoB. Residuals of apoB were constructed after regressing apoB on LDL-C, non-HDL-C, and log-transformed triglycerides and used as predictors in a proportional hazards regression model for new-onset ASCVD adjusted for standard risk factors, including HDL-C. RESULTS: ApoB was highly correlated with LDL-C and non-HDL-C (Pearson's r = .96, P < .001 for both) but less so with log triglycerides (r = .42, P < .001). However, apoB ranges necessary to capture 95% of all observations at pre-specified levels of LDL-C, non-HDL-C, or triglycerides were wide, spanning 85.8-108.8â md/dL when LDL-C 130â mg/dL, 88.3-112.4â mg/dL when non-HDL-C 160â mg/dL, and 67.8-147.4â md/dL when triglycerides 115â mg/dL. At these levels (±10â mg/dL), 10-year ASCVD rates for apoB above mean + 1 SD vs. below mean - 1 SD were 7.3 vs. 4.0 for LDL-C, 6.4 vs. 4.6 for non-HDL-C, and 7.0 vs. 4.6 for triglycerides (all P < .001). With 19 982 new-onset ASCVD events on follow-up, in the adjusted model, residual apoB remained statistically significant after accounting for LDL-C and HDL-C (hazard ratio 1.06, 95% confidence interval 1.0-1.07), after accounting for non-HDL-C and HDL-C (hazard ratio 1.04, 95% confidence interval 1.03-1.06), and after accounting for triglycerides and HDL-C (hazard ratio 1.13, 95% confidence interval 1.12-1.15). None of the residuals of LDL-C, non-HDL-C, or of log triglycerides remained significant when apoB was included in the model. CONCLUSIONS: High variability of apoB at individual levels of LDL-C, non-HDL-C, and triglycerides coupled with meaningful differences in 10-year ASCVD rates and significant residual information contained in apoB for prediction of new-onset ASCVD events demonstrate that LDL-C, non-HDL-C, and triglycerides are not adequate proxies for apoB in clinical care.
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Apolipoproteínas B , Biomarcadores , LDL-Colesterol , Triglicéridos , Humanos , Triglicéridos/sangre , Persona de Mediana Edad , Femenino , Masculino , Anciano , Adulto , LDL-Colesterol/sangre , Biomarcadores/sangre , Apolipoproteínas B/sangre , HDL-Colesterol/sangre , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiologíaRESUMEN
Importance: The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. Objective: To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. Design, Setting, and Participants: This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Intervention: Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. Main Outcomes and Measures: The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Results: Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. Conclusions and Relevance: In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.
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Hipogonadismo , Estado Prediabético , Masculino , Humanos , Persona de Mediana Edad , Testosterona/uso terapéutico , Estado Prediabético/tratamiento farmacológico , Hemoglobina Glucada , Hipogonadismo/complicaciones , Hipogonadismo/tratamiento farmacológico , Terapia de Reemplazo de Hormonas , GlucosaRESUMEN
CONTEXT: The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood. OBJECTIVE: We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial. METHODS: A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously "dysthymia"); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with significant depressive symptoms; and changes in depressive symptoms, energy, sleep quality, and cognition in testosterone-treated vs placebo-treated men in the 3 subgroups. RESULTS: Of 5204 randomly assigned participants, 2643 (50.8%) had significant depressive symptoms, but only 49 (1.5%) met rigorous criteria for LG-PDD. Among those with LG-PDD, there was no significant difference in any outcome measure between the TRT and placebo groups, possibly reflecting low statistical power. In men with significant depressive symptoms (n = 2643) and in all randomly assigned participants (n = 5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality. CONCLUSION: Depressive symptoms are common in middle-aged and older men with hypogonadism but LG-PDD is uncommon. TRT is associated with small improvements in mood and energy in hypogonadal men with and without significant depressive symptoms.
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Depresión , Terapia de Reemplazo de Hormonas , Hipogonadismo , Testosterona , Humanos , Masculino , Testosterona/administración & dosificación , Testosterona/uso terapéutico , Persona de Mediana Edad , Terapia de Reemplazo de Hormonas/métodos , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/psicología , Método Doble Ciego , Anciano , Depresión/tratamiento farmacológico , Anciano de 80 o más Años , Trastorno Depresivo/tratamiento farmacológico , Resultado del TratamientoRESUMEN
CONTEXT: Few long-term randomized trials have evaluated the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism and whether effects are sustained beyond 12 months. OBJECTIVE: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. The Sexual Function Study, nested within the parent trial, determined testosterone's efficacy in improving sexual activity, hypogonadal symptoms, libido, and erectile function among men reporting low libido. METHODS: Among 5204 men, 45-80 years, with 2 testosterone concentrations <300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in the TRAVERSE trial, 1161 with low libido were enrolled in the Sexual Function Study (587 randomized to receive 1.62% testosterone gel and 574 to placebo gel for the duration of their participation in the study). Primary outcome was change from baseline in sexual activity score. Secondary outcomes included hypogonadal symptoms, erectile function, and sexual desire. RESULTS: TRT was associated with significantly greater improvement in sexual activity than placebo (estimated mean [95% CI] between-group difference 0.49 [0.19,0.79] and 0.47 [0.11, 0.83] acts per day at 6 and 12 months, respectively; omnibus test P = .011); treatment effect was maintained at 24 months. TRT improved hypogonadal symptoms and sexual desire, but not erectile function, compared with placebo. CONCLUSION: In middle-aged and older men with hypogonadism and low libido, TRT for 2 years improved sexual activity, hypogonadal symptoms, and sexual desire, but not erectile function.
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Enfermedades Cardiovasculares , Disfunción Eréctil , Hipogonadismo , Masculino , Persona de Mediana Edad , Humanos , Anciano , Conducta Sexual , Testosterona/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Hipogonadismo/complicaciones , Hipogonadismo/tratamiento farmacológicoRESUMEN
Importance: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown. Objective: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism. Design, Setting, and Participants: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023. Intervention: Participants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo. Main Outcomes and Measures: The primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model. Results: A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14â¯304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men. Conclusions and Relevance: In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.
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Terapia de Reemplazo de Hormonas , Hipogonadismo , Neoplasias de la Próstata , Testosterona , Retención Urinaria , Anciano , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares , Hipogonadismo/tratamiento farmacológico , Próstata , Antígeno Prostático Específico , Neoplasias de la Próstata/epidemiología , Testosterona/efectos adversos , Testosterona/uso terapéutico , Terapia de Reemplazo de Hormonas/efectos adversosRESUMEN
Importance: Testosterone deficiency causes mild anemia. Whether testosterone replacement therapy (TRT) can correct anemia or prevent the development of anemia in men with hypogonadism remains incompletely understood. Objective: To assess the efficacy of TRT in correcting anemia in men with hypogonadism and anemia, and reducing the risk of developing anemia in those without anemia. Design, Setting, and Participants: This randomized, placebo-controlled trial included men with hypogonadism at 316 US sites enrolled between May 2018 and February 2022. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study, which evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. Eligible participants were aged 45 to 80 years, with 2 testosterone concentration results below 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. The last study visit took place in January 2023. Data were analyzed between March and August 2023. Intervention: Participants were randomized with stratification for preexisting CVD to 1.62% testosterone gel or placebo gel daily for the study duration. Main Outcomes and Measures: Proportion of participants with anemia (hemoglobin below 12.7 g/dL) whose anemia remitted (hemoglobin 12.7 g/dL or above) over the study duration. Secondary end points included incidence of anemia among men who were not anemic. Binary end points were analyzed using repeated-measures log-binomial regression. Results: A total of 5204 men were included, 815 with anemia (mean [SD] age, 64.8 [7.7] years; 247 Black [30.3%], 544 White [66.7%], 24 other [2.9%]) and 4379 without anemia (mean [SD] age, 63.0 [7.9] years; 629 Black [14.4%], 3603 White [82.3%], 147 other [3.4%]). Anemia corrected in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (143 of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24 months (124 of 290 [42.8%] vs 95 of 307 [30.9%]), 36 months (94 of 216 [43.5%] vs 76 of 229 [33.2%]), and 48 months (41 of 92 [44.6%] vs 38 of 97 [39.2%]) (P = .002). Among participants without anemia, a significantly smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Changes in hemoglobin were associated with changes in energy level. Conclusions and Relevance: In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. Among men who were not anemic, a smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.
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Anemia , Enfermedades Cardiovasculares , Hipogonadismo , Masculino , Persona de Mediana Edad , Humanos , Anciano , Hipogonadismo/complicaciones , Hipogonadismo/tratamiento farmacológico , Testosterona/uso terapéutico , Anemia/tratamiento farmacológico , Anemia/etiología , Hemoglobinas , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
BACKGROUND: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. RESULTS: The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. CONCLUSIONS: In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).
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Enfermedades Cardiovasculares , Terapia de Reemplazo de Hormonas , Hipogonadismo , Testosterona , Anciano , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2 , Método Doble Ciego , Hipogonadismo/sangre , Hipogonadismo/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/epidemiología , Testosterona/efectos adversos , Testosterona/sangre , Testosterona/uso terapéutico , Terapia de Reemplazo de Hormonas/efectos adversos , Terapia de Reemplazo de Hormonas/métodos , Anciano de 80 o más Años , Geles , Parche TransdérmicoRESUMEN
BACKGROUND: Nicotinamide adenine dinucleotide (NAD) precursors, nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) extend healthspan and ameliorate some age-related conditions in model organisms. However, early-phase trials of NAD precursors have yielded varying results and their pharmacokinetics remain incompletely understood. Here, we report the pharmacokinetics and pharmacodynamics of MIB-626, a microcrystalline unique polymorph ßNMN formulation. METHODS: In this double-blind, placebo-controlled study, 32 overweight or obese adults, 55-80 years, were block-randomized, stratified by sex, to 1 000-mg MIB-626 once daily, twice daily, or placebo for 14 days. NMN, NAD, and NAD metabolome were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Participant characteristics were similar across groups. MIB-626 was well tolerated and frequency of adverse events was similar across groups. Blood NMN concentrations on Day 14 in MIB-626-treated groups were significantly higher compared to placebo (1.7-times and 3.7-times increase above baseline in 1 000 mg once-daily and twice-daily groups in mean AUClast, respectively). MIB-626 treatment was associated with substantial dose-related increases in blood NAD levels. Blood levels of NAD metabolites were higher in NMN-treated participants on Days 8 and 14 than at baseline. Changes in NMN or NAD levels were not related to sex, body mass index, or age. Very little unmodified NMN was excreted in the urine. CONCLUSION: MIB-626 1 000 mg once-daily or twice-daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome. These foundational data that were obtained using a pharmaceutical-grade ßNMN, standardized sample collection, and validated liquid chromatography-tandem mass spectrometry assays, should facilitate design of efficacy trials in disease conditions.
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NAD , Mononucleótido de Nicotinamida , Humanos , Persona de Mediana Edad , Anciano , NAD/metabolismo , Mononucleótido de Nicotinamida/metabolismo , Mononucleótido de Nicotinamida/farmacología , Metaboloma , Espectrometría de Masas , Índice de Masa CorporalRESUMEN
BACKGROUND: We examined the interplay of apolipoprotein B (apoB) and LDL particle size, approximated by the LDL-cholesterol (LDL-C)/apoB ratio, on the risk of new-onset coronary heart disease (CHD). METHODS: Participants without cardiovascular disease from the UK Biobank (UKB; n = 308 182), the Women's Health Study (WHS; n = 26 204), and the Framingham Heart Study (FHS; n = 2839) were included. Multivariable Cox models were used to assess the relationship between apoB and LDL-C/apoB ratio and incidence of CHD (14 994 events). Our analyses were adjusted for age, sex (except WHS), HDL-cholesterol (HDL-C), systolic blood pressure, antihypertensive treatment, diabetes, and smoking. RESULTS: In all 3 studies, there was a strong positive correlation between apoB and LDL-C (correlation coefficients r = 0.80 or higher) and a weak inverse correlation of apoB with LDL-C/apoB ratio (-0.28 ≤ r ≤ -0.14). For all 3 cohorts, CHD risk was higher for higher levels of apoB. Upon multivariable adjustment, the association between apoB and new-onset CHD remained robust and statistically significant in all 3 cohorts with hazard ratios per 1 SD (95% CI): 1.24 (1.22-1.27), 1.33 (1.20-1.47), and 1.24 (1.09-1.42) for UKB, WHS, and FHS, respectively. However, the association between LDL-C/apoB and CHD was statistically significant only in the FHS cohort: 0.78 (0.64-0.94). CONCLUSIONS: Our analysis confirms that apoB is a strong risk factor for CHD. However, given the null association in 2 of the 3 studies, we cannot confirm that cholesterol-depleted LDL particles are substantially more atherogenic than cholesterol-replete particles. These results lend further support to routine measurement of apoB in clinical care.
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Enfermedad Coronaria , Humanos , Femenino , LDL-Colesterol , Tamaño de la Partícula , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/etiología , Apolipoproteínas B , Colesterol , Factores de Riesgo , HDL-ColesterolRESUMEN
BACKGROUND: Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories. OBJECTIVE: To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma. FT in dialysate was measured using a CDC-certified liquid chromatography tandem mass spectrometry assay. RESULTS: In healthy nonobese men, the 2.5th, 10th, 50th, 90th, and 97.5th percentile values for FT were 66, 91, 141, 240, and 309 pg/ml, respectively; corresponding values for men, 19-39 years, were 120, 128, 190, 274, and 368 pg/ml, respectively. FT levels by age groups exhibit the expected age-related decline. FT levels were negatively associated with body mass index, age, and sex hormone-binding globulin (SHBG) levels. Percent FT was lower in middle-aged and older men than young men adjusting for SHBG level. DISCUSSION: Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions. CONCLUSION: Reference intervals for free FT levels (normative range 66-309 pg/ml [229-1072 pmol/L] in all men and 120-368 pg/ml [415-1274 pmol/L] in men, 19-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials.
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Diálisis Renal , Globulina de Unión a Hormona Sexual , Persona de Mediana Edad , Masculino , Adulto , Humanos , Anciano , Adulto Joven , Globulina de Unión a Hormona Sexual/análisis , Testosterona , Cromatografía Liquida , Índice de Masa CorporalRESUMEN
BACKGROUND: This study examines the risk of new-onset diabetes in patients with hypertriglyceridaemic hyperapolipoprotein B (high triglycerides, high apolipoprotein B [apoB], low LDL cholesterol to apoB ratio, and low HDL cholesterol). The aim was to establish whether this lipoprotein phenotype identified a substantial group at high risk of developing diabetes over the next 20 years. METHODS: In this prospective, longitudinal, observational cohort study, we used data from the Framingham Offspring cohort (recruited in Framingham, MA, USA). Participants were aged 40-69 years and free of diabetes and cardiovascular disease at a baseline examination done between April, 1987, and November, 1991, and were followed up until March, 2014. Cox proportional hazards regression with hierarchical adjustment for age and sex, waist circumference, and fasting blood glucose were used to model the relationship between each lipid marker and incident diabetes, as well as the relationship between hypertriglyceridaemic hyperapoB (defined as values greater than sample medians of triglycerides and apoB, and less than medians of HDL cholesterol and LDL cholesterol to apoB ratio) and incident diabetes. FINDINGS: Of 3446 individuals aged 40-69 years who completed baseline examination, 2515 participants were eligible and included in all analyses. During median 21·1 years (IQR 11·1-23·1) of follow-up, 402 (16·0%) individuals developed diabetes. Age (p=0·032), waist circumference (p<0·0001), fasting blood glucose (p<0·0001), and natural logarithm-transformed triglycerides (p<0·0001) were associated with new-onset diabetes, as were apoB (p=0·0016), LDL cholesterol to apoB ratio (p=0·0018), and HDL cholesterol (p=0·0016) when added to this model. The age and sex-adjusted incidence of diabetes in the hypertriglyceridaemic hyperapoB group was 32·4% (95% CI 27·8-37·7) versus 5·5% (3·5-8·6) in the optimal lipid phenotype group and 15·5% (13·5-17·7) in the mixed lipid phenotype group. The fully adjusted hazard ratio, including glucose and waist circumference, for individuals with hypertriglyceridaemic hyperapoB was 3·30 (95% CI 2·06-5·30; p=0·0008) and for mixed lipid phenotype was 2·17 (1·38-3·40; p<0·0001) compared with those with the optimal lipid phenotype. INTERPRETATION: Our findings suggest that individuals with hypertriglyceridaemic hyperapoB are at high risk of new-onset diabetes and might benefit from intensive measures to prevent diabetes. The association between this phenotype and incident diabetes is consistent with a pro-diabetic effect due to increased clearance of apoB particles from plasma, which could injure pancreatic islet cells. This mechanism might explain the increased risk of diabetes with statin therapy. FUNDING: Doggone Foundation.
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Diabetes Mellitus Tipo 2 , Apolipoproteínas B , Glucemia , HDL-Colesterol , LDL-Colesterol , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Lipoproteínas , Fenotipo , Estudios Prospectivos , TriglicéridosRESUMEN
Context: Selective androgen receptor modulators (SARMs), because of their preferential muscle vs prostate selectivity, are being developed for muscle-wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown. Objective: To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies. Methods: We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5, or 15 mg of an oral SARM (OPK-88004). Results: SARM significantly suppressed HDL-C (Pâ <â .001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (changeâ +â 0.016, -0.036, +0.070, and -0.048%/µmol-HDL/L-1 at 0, 1, 5, and 15 mg SARM, Pâ =â .045). SARM treatment suppressed APOAI (Pâ <â .001) but not APOB (Pâ =â .077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement C3, or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) (Pâ <â .001). Conclusion: SARM treatment suppressed HDL-C but had minimal effect on its size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events.
RESUMEN
Diagnosing testosterone deficiency requires accurate and precise measurement of total testosterone levels by an accurate method, such as liquid chromatography-tandem mass spectrometry in a laboratory certified by an accuracy-based program (eg, Centers for Disease Control and Prevention's Hormone Standardization (HoST) Program), and, if needed, free testosterone level. Free testosterone level should ideally be measured by equilibrium dialysis method. Testosterone levels should be measured in 2 or more fasting samples obtained in the morning. Harmonized reference ranges for total testosterone can be applied to laboratories that certified by the HoST Program.
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Espectrometría de Masas en Tándem , Testosterona , Cromatografía Liquida/métodos , Humanos , Estándares de Referencia , Valores de Referencia , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared with their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared with uninfected people remain understudied. SETTING: The study site was Brigham and Women's Hospital, Harvard Medical School, Boston, MA. METHODS: We evaluated skeletal muscle tissue for levels of total nicotinamide adenine dinucleotide (NAD), NAD+, and nicotinamide adenine dinucleotide (NADH) in middle-aged asymptomatic PLWH, coinfected with hepatitis C virus and/or cytomegalovirus and compared them with uninfected control participants. RESULTS: Of the 54 persons with muscle biopsy data, the mean age was 57 years with 33% women. Total NAD levels declined in skeletal muscle in association with HIV infection and was exacerbated by hepatitis C virus and cytomegalovirus coinfection, with lowest levels of total NAD, NAD+, and NADH among persons who were coinfected with all 3 viruses (P = 0.015, P = 0.014, and P = 0.076, respectively). Levels of total NAD, NAD+, and NADH in skeletal muscle were inversely associated with inflammation (P = 0.014, P = 0.013, and P = 0.055, respectively). Coinfections were also associated with measures of inflammation (CD4/CD8 ratio: P < 0.001 and sCD163: P < 0.001) and immune activation (CD38 and human leukocyte antigen-DR expression on CD8 T cells: P < 0.001). In addition, coinfection was associated with increased physiologic frailty based on the Veteran Aging Cohort Study 1.0 index assessment (P = 0.001). CONCLUSIONS: Further research is warranted to determine the clinical relevance of preclinical deficits in NAD metabolites in skeletal muscle in association with viral coinfection and inflammation, as well as the observed association between viral coinfection and physiologic frailty.
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Coinfección , Infecciones por Citomegalovirus , Fragilidad , Infecciones por VIH , Hepatitis C , Estudios de Cohortes , Coinfección/complicaciones , Coinfección/virología , Infecciones por Citomegalovirus/complicaciones , Femenino , Fragilidad/complicaciones , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético , NADRESUMEN
BACKGROUND: Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an antiaging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy. METHODS: We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous measurement of circulating GDF-8 and GDF-11 that employs denaturation, reduction, and alkylation; cation-exchange solid-phase extraction; tryptic digestion; followed by separation and quantification using 2 signature peptides for multiple reaction monitoring and C-terminal [13C615N4]-Arg peptides as internal standards. We evaluated age trends in serum GDF-11 and GDF-8 concentrations in community-dwelling healthy men, 19 years or older, and determined the effects of graded testosterone doses on GDF-8 and GDF-11 concentrations in healthy men in a randomized trial. RESULTS: The assay demonstrated linearity over a wide range, lower limit of quantitation 0.5 ng/mL for both proteins, and excellent precision, accuracy, and specificity (no detectable cross-reactivity of GDF-8 in GDF-11 assay or of GDF-11 in GDF-8 assay). Mean ± SD (median ± 1QR) GDF-8 and GDF-11 levels in healthy community-dwelling men, 19 years and older, were 7.2â ±â 1.9 (6.8â ±â 1.4) ng/mL. Neither GDF-8 nor GDF-11 levels were related to age or body composition. Testosterone treatment significantly increased serum GDF-8 but not GDF-11 levels. CONCLUSIONS: The LC-MS/MS method for the simultaneous measurement of circulating total GDF-8 and GDF-11 demonstrates the characteristics of a valid assay. Testosterone treatment increased GDF-8 levels, but not GDF-11. Increase in GDF-8 levels by testosterone treatment, which increased muscle mass, suggests that GDF-8 acts as a chalone to restrain muscle growth.
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Miostatina , Testosterona , Adulto , Cromatografía Liquida/métodos , Factores de Diferenciación de Crecimiento/sangre , Humanos , Masculino , Miostatina/sangre , Espectrometría de Masas en Tándem/métodos , Testosterona/administración & dosificaciónRESUMEN
BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Hipogonadismo , Anciano , Enfermedades Cardiovasculares/etiología , Método Doble Ciego , Humanos , Hipogonadismo/inducido químicamente , Hipogonadismo/complicaciones , Hipogonadismo/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Testosterona/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion. METHODS: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants. CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
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Sarcopenia , Velocidad al Caminar , Anciano , Femenino , Marcha , Humanos , Vida Independiente , Masculino , Limitación de la Movilidad , CaminataRESUMEN
BACKGROUND: Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low-grade, organ-confined prostate cancer. METHODS: In this placebo-controlled, randomized, double-blind trial, 114 men, ≥19 years of age, who had undergone radical prostatectomy for low-grade, organ-localized prostate cancer, undetectable PSA (<0.1 ng/mL) for ≥2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5, or 15 mg OPK-88004 daily for 12 weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue, and bone markers. RESULTS: Participants were on average 67.5 years of age and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3 and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole-body (P < 0.001) and appendicular (P < 0.001) lean mass and a significantly greater decrease in percent body fat (P < 0.001) and serum alkaline phosphatase (P < 0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (P = 0.73). CONCLUSIONS: Administration of OPK-88004 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass but did not improve sexual symptoms or physical performance.